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WO2020181386A1 - Fluorinated benzo[f]benzimidazol-4-9-dione ium derivatives and pharmaceutical compositions thereof and their use as survivin suppressants - Google Patents

Fluorinated benzo[f]benzimidazol-4-9-dione ium derivatives and pharmaceutical compositions thereof and their use as survivin suppressants Download PDF

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Publication number
WO2020181386A1
WO2020181386A1 PCT/CA2020/050336 CA2020050336W WO2020181386A1 WO 2020181386 A1 WO2020181386 A1 WO 2020181386A1 CA 2020050336 W CA2020050336 W CA 2020050336W WO 2020181386 A1 WO2020181386 A1 WO 2020181386A1
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Prior art keywords
substituted
unsubstituted
compound
cancer
compounds
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PCT/CA2020/050336
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French (fr)
Inventor
Abdelmalik Slassi
Peter Dove
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Trillium Therapeutics Inc.
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Publication of WO2020181386A1 publication Critical patent/WO2020181386A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present application relates to novel fluorinated derivatives, to processes for their preparation, to compositions comprising them, and to their use in therapy. More particularly, it relates to compounds useful in the treatment of diseases, disorders or conditions mediated by survivin suppression.
  • Cancer is a leading cause of death worldwide. Despite significant efforts to find new approaches for treating cancer, the primary treatment options remain surgery, chemotherapy and radiation therapy, either alone or in combination. Surgery and radiation therapy, however, are generally useful only for fairly well- defined types of cancer, and are of limited use for treating patients with disseminated disease. Chemotherapy is a method that is useful in treating patients with metastatic cancers or diffuse cancers such as leukemias. However, although chemotherapy can provide a therapeutic benefit, it often fails to result in cure of the disease due to the patient’s cancer cells becoming resistant to the chemotherapeutic agent. Therefore, a need exists for additional chemotherapeutics to treat cancers.
  • Survivin is a 142-amino acid, 16.5 kDa protein encoded by a single gene located on the human 17q25 chromosome, consisting of three introns, and four exons [Nature 1998, 396: 580-584; Nat Med 1997, 3: 917-921; Cancer Res 1999, 59: 3143-3151] and exists physiologically as a functional homodimer [Nat Struct Biol 2000, 7: 602-608; Mol Cell 2000, 6: 183-189]
  • Alternative splicing of survivin pre-mRNA produces five different mRNAs with the potential to encode up to five distinct proteins, survivin, survivin 2B, survivin AEx3, survivin 3B and survivin 2a [Cancer Res 1999,
  • NF-kB nuclear factor-kappa b
  • PI3K phosphatidylinositol 3-kinase
  • TCF- 4/b-catenin pathway TCF- 4/b-catenin pathway
  • Survivin degradation occurs via the ubiquitin- proteasome pathway in the G1 phase of the cell cycle and is stabilized when bound to heat shock protein 90 (Hsp90) [Proc Natl Acad Sci USA 2003, 100: 13791-13796]
  • Hsp90 heat shock protein 90
  • the survivin protein is closely associated with Cdc2/Cdkl and it is phosphorylated at the threonine-34 (T34) residue. This phosphorylation stabilizes the protein and allows it to interact with the mitotic spindle and inhibit caspase-9 [Proc Natl Acad Sci USA 2000, 97: 13103-13107]
  • Survivin also plays a central role in cell division, where its expression is coordinated within the cell cycle [Nature 1998, 396: 580-584; Clin Cancer Res 2008, 14: 5000-5005] Survivin levels increase in G1 and peak in the G2/M phase. During mitosis, survivin functions as a regulator of microtubule dynamics and as part of the chromosomal passenger complex (CPC).
  • CPC chromosomal passenger complex
  • Survivin functions both at the centrosomes and the microtubules of the metaphase and anaphase spindle providing stabilization and ensuring accurate separation of sister chromatids [Nature 1998, 396: 580-584; Cancer Cell 2002, 2: 43-54; Curr Opin Cell Biol 2006, 18: 609-615] Survivin also localizes to the kinetochores, the mid-region or centromeric portion of the metaphase chromosomes where it is associated with regulators of cytokinesis, such as Aurora B kinase, the inner centromere protein antigens (INCENP), and Borealin/ Dasra [Mol Biol Cell 2002, 13: 3064-3077; J Cell Biol 2004, 166: 179-191] This supports the hypothesis that survivin acts as a subunit of the CPC which is required for proper chromosome segregation and cytokinesis [Curr Opin Cell Biol 2006, 18: 616-622] Hence, if survivin
  • microtubule-bound survivin becomes phosphorylated on Thr34. This leads to stabilization of the protein and efficient counter-activation of apoptosis in dividing cells. Elimination of survivin leads to apoptosis of dividing cells.
  • CDK1 cyclin-dependent kinase 1
  • survivin might constitute a unique Achilles’ heel for cancer cells, as a non-redundant network of tumour maintenance that is unable to be circumvented.
  • putative survivin antagonists might function not as single protein suppressants but, in fact, as pathway inhibitors that are suitable for disabling multiple signalling circuits in tumours, regardless of their heterogeneity or genetic make-up.
  • pathway inhibitors that are suitable for disabling multiple signalling circuits in tumours, regardless of their heterogeneity or genetic make-up.
  • therapeutic disabling of survivin may have global effects on tumour cells, conceptually similar to the therapeutic targeting of other nodal proteins in tumorigenesis.
  • YM-155 a transcriptional repressor of survivin expression
  • Fluorine has found interest in bioorganic and structural chemistry over the past decade and incorporation of it has become a useful feature in drug design.
  • the small and highly electronegative fluorine atom can play a useful role in medicinal chemistry.
  • Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can result in an improvement of a number of useful pharmacokinetic and/or physicochemical properties such as improved metabolic stability and enhanced membrane permeation.
  • Increased binding affinity of fluorinated drug candidates to a target protein has also been documented in a number of cases.
  • a further emerging application of the fluorine atom is the use of 18 F as a radiolabel tracer atom in the sensitive technique of Positron Emission Tomography (PET) imaging.
  • PET Positron Emission Tomography
  • Factors to be considered when synthesising fluorine-containing compounds include (a) the relatively small size of the fluorine atom (van der Waals radius of 1.47 A), comparable to hydrogen (van der Waals radius of 1.20 A), (b) the highly electron-withdrawing nature of fluorine, (c) the greater stability of the C-F bond compared to the C-H bond and (d) the greater lipophilicity of fluorine compared to hydrogen.
  • Formula I and Formula II have been prepared and found to be useful in the treatment of cancers and other survivin mediated disorders.
  • the present application includes a compound of Formula I or a compound of Formula II or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • R 1 is H or Ci- 6 alkyl
  • R 2 is selected from H, CN, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-iohaloalkyl, Ci- l ocyanoalkyl, O-Ci-ioalkyl, 0-C 2 -ioalkenyl, 0-C 2 -ioalkynyl, C3-iocycloalkyl, heterocycloalkyl, C 6 -ioaryl, heteroaryl, Ci- 6 alkylene-0-Ci- 6 alkyl, Ci- 6 alkylene-0-Ci- 6 haloalkyl, C 2-6 alkenylene-0-Ci- 6 haloalkyl, C 2-6 alkynylene-0-Ci- 6 haloalkyl, Ci- 6alkylene-C3-8Cycloalkyl, Ci-ealkylene-heterocycloalkyl.
  • Ci-ealkylene-aryl Ci- ealkylene-heteroaryl, wherein any cyclic moiety is optionally substituted with Ci- 4alkyl or is optionally fused to a further 5- to 7-membered heterocycloalkyl;
  • X- is a counter anion
  • A is Co-ealkylene, O, S, SO, SO2 or NR 3 ;
  • R 3 is H or Ci- 6 alkyl
  • n 0, 1, 2 or 3;
  • Xi, X2, X3 are the same or different and are selected from H, halogen and Ci- 6 alkyl, provided that at least one of X 1 , X 2 and X 3 is F.
  • the present application also includes a composition comprising one or more compounds of the application and a carrier.
  • the composition is a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.
  • the compounds of the application have been shown to inhibit survivin activity. Therefore the compounds of the application are useful for treating diseases, disorders or conditions mediated by survivin inhibition. Accordingly, the present application also includes a method of treating a disease, disorder or condition mediated by survivin inhibition, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the compounds of the application are used as medicaments. Accordingly, the application also includes a compound of the application for use as a medicament.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition mediated by survivin inhibition as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition mediated by survivin inhibition.
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition mediated by survivin inhibition.
  • the disease, disorder or condition mediated by survivin inhibition is a neoplastic disorder.
  • the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass in a subject in need of such treatment.
  • the disease, disorder or condition mediated by survivin inhibition is cancer.
  • the disease, disorder or condition mediated by survivin inhibition is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by survivin inhibition.
  • the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by survivin inhibition is proliferative activity in a cell.
  • the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the disease, disorder or condition mediated by survivin inhibition is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments.
  • the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
  • compound of the application or“compound of the present application” and the like as used herein refers to a compound of Formula I and/or a compound of Formula II, and/or pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
  • composition of the application or“composition of the present application” and the like as used herein refers to a composition, such as a pharmaceutical composition, comprising one or more compounds of Formula I, and/or one or more compounds of Formula II, or pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
  • the term “and/or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that“at least one of’ or“one or more” of the listed items is used or present.
  • the term “and/or” with respect to pharmaceutically acceptable salts, solvates and/or prodrugs thereof means that the compounds of the application exist as individual salts, hydrates or prodrugs, as well as a combination of, for example, a salt of a solvate of a compound of the application or a salt of a prodrug of a compound of the application.
  • suitable means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed and/or specific use for the compound, but the selection would be well within the skill of a person trained in the art.
  • the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.
  • the compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.
  • the compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.
  • the expression“proceed to a sufficient extent” as used herein with reference to the reactions or process steps disclosed herein means that the reactions or process steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.
  • alkyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups.
  • the number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix“Cni-n2”
  • Ci- 6 alkyl means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkylene whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends.
  • the number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2”
  • Ci- 6 alkylene means an alkyl ene group having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • alkenyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond.
  • the number of carbon atoms that are possible in the referenced alkenyl group are indicated by the prefix “C n i-n2”.
  • C2-ealkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.
  • alkynyl as used herein, whether it is used alone or as part of another group, means straight or branched chain unsaturated alkyl groups containing at least one triple bond.
  • the number of carbon atoms that are possible in the referenced alkynyl group are indicated by the prefix “C n i-n2”
  • C2-ealkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one triple bond.
  • haloalkyl refers to an alkyl group wherein one or more, including all of the hydrogen atoms are replaced by a halogen atom.
  • the halogen is fluorine, in which case the haloalkyl is referred to herein as a“fluoroalkyl” group.
  • the haloalkyl comprises at least one -CHF2 group.
  • cyanoalkyl refers to an alkyl group wherein one or more, including all of the hydrogen atoms are replaced by a cyano group.
  • Ci-iocyanoalkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one cyano group attached thereto.
  • alkoxy refers to the group“alkyl-O-” or“-O-alkyl”.
  • Ci-ioalkoxy means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms bonded to an oxygen atom.
  • Exemplary alkoxy groups include without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and isobutoxy.
  • cycloalkyl as used herein, whether it is used alone or as part of another group, means a saturated carbocylic group containing a number of carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the prefix“C n i-n2”
  • C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • aryl refers to cyclic groups that contain from 6 to 20 carbon atoms and at least one aromatic ring. In an embodiment of the application, the aryl group contains from 6, 9, 10 or 14 atoms, such as phenyl, naphthyl, indanyl or anthracenyl.
  • heterocycloalkyl refers to cyclic groups containing 3 to 20 atoms, suitably 3 to 10 atoms, and at least one non-aromatic ring in which one or more of the atoms are a heteromoiety selected from O, S, N, NH and NCi- 6 alkyl.
  • Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds) and contain one or more than one ring (i.e. are polycyclic).
  • heterocycloalkyl group contains more than one ring
  • the rings may be fused, bridged, spirofued or linked by a bond.
  • a heterocycloalkyl group contain the prefix“C ni-n 2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as defined above.
  • a first ring group being“fused” with a second ring group means the first ring and the second ring share at least two atoms there between.
  • Heterocycloalkyl includes monocyclic heterocycloalkyls such as but not limited to aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1 ,4-dihydropyridinyl
  • heterocycloalkyl includes polycyclic heterocycloalkyls such as but not limited to pyrolizidinyl, and quinolizidinyl.
  • heterocycloalkyl includes polycyclic heterocycloalkyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include but are not limited to quinuclidinyl, diazabicyclo[2.2.1]heptyl and 7-oxabicyclo[2.2.1]heptyl.
  • heteroaryl refers to cyclic groups containing from 5 to 20 atoms, suitably 5 to 10 atoms, at least one aromatic ring and at least one heteromoiety selected from O, S, N, NH and Ci- 6 alkyl.
  • Heteroaryl groups contain one or more than one ring (i.e. are polycyclic). When a heteroaryl group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond.
  • heteroaryl group contains the prefix “C n i-n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as defined above.
  • a five-membered heteroaryl is a heteroaryl with a ring having five ring atoms, where 1, 2 or 3 ring atoms are a heteromoiety selected from O, S, NH and NCi- 6 alkyl.
  • a six-membered heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are a heteromoiety selected from O, S, NH and NCi-ealkyl.
  • the term“substituted” as used herein refers to a structure, molecule or group in which one or more available hydrogen atoms are replaced with one or more other chemical groups.
  • the chemical group is a Ci- 4alkyl.
  • the chemical group is a Ci-i2alkyl or a chemical group that contains one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P.
  • substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.
  • the term“substituted” as used herein in relation to a first structure, molecule or group, followed by one or more variables or names of chemical groups refers to a second structure, molecule or group that results from replacing one or more hydrogens of the first structure, molecule or group with the one or more variables or named chemical groups.
  • a“phenyl substituted by nitro” refers to nitrophenyl.
  • amine or“amino,” as used herein, whether it is used alone or as part of another group, refers to radicals of the general formula -NRR', wherein R and R' are each independently selected from hydrogen or a alkyl group, such as Ci- 6 alkyl.
  • halo or“halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.
  • acac as used herein refers to acetylacetonate.
  • DCM as used herein refers to dichloromethane.
  • DIPEA as used herein refers to N,N-diisopropylethylamine
  • DMF as used herein refers to dimethylformamide.
  • DMSO as used herein refers to dimethylsulfoxide.
  • EDCI.HC1 refers to N-[3-(dimethylamino)propyl]-N'- ethylcarbodiimide hydrochloride.
  • EDC as used herein refers to l-ethyl-3-(3- dimethylaminopropyl)carbodiimide.
  • Et20 refers to diethylether.
  • EtOAc refers to ethyl acetate.
  • Et as used herein refers to the group ethyl.
  • Fmoc refers to the group 9-fluorenylmethyloxycarbonyl.
  • min(s) refers to minute(s).
  • HOBt as used herein refers to N-hydroxybenzotriazole.
  • HBTU as used herein refers to 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate.
  • MeOH as used herein refers to methanol.
  • Me as used herein refers to the group methyl.
  • t-BuLi refers to tert-butyllithium.
  • RT refers to room temperature
  • TEA as used herein refers to triethylamine.
  • TFA as used herein refers to trifluoroacetic acid.
  • THF as used herein refers to tetrahydrofuran.
  • t-Bu as used herein refers to the group tertiary butyl.
  • SPE as used herein refers to solid phase extraction, for example using columns containing silica gel for mini-chromatography.
  • protecting group refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule.
  • the selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in“Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W.
  • cell refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.
  • subject includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods of the present application are applicable to both human therapy and veterinary applications.
  • the subject is a mammal. In another embodiment, the subject is human.
  • pharmaceutically acceptable means compatible with the treatment of subjects, for example humans.
  • pharmaceutically acceptable carrier means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject.
  • a pharmaceutical composition i.e., a dosage form capable of administration to a subject.
  • a pharmaceutically acceptable oil typically used for parenteral administration.
  • pharmaceutically acceptable salt means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.
  • An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.
  • Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids.
  • organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p- toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid.
  • Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.
  • acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • a base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.
  • Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like.
  • organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicycl
  • Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • the selection of the appropriate salt may be useful so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed.
  • the selection criteria for the appropriate salt will be known to one skilled in the art.
  • prodrugs will be functional derivatives of the compounds of the application which are readily convertible in vivo into the compound from which it is notionally derived.
  • Prodrugs of the compounds of the application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups.
  • available OH or N3 ⁇ 4 groups in the compounds of the application may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine).
  • Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C8-C24) esters, acyloxymethyl esters, carbamates and amino acid esters.
  • the prodrugs of the compounds of the application are those in which the hydroxyl and/or amino groups in the compounds is masked as groups which can be converted to hydroxyl and/or amino groups in vivo.
  • Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in“Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
  • solvate means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a“hydrate”.
  • solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
  • beneficial or desired clinical results means an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e.
  • “Treating” and“treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.“Treating” and“treatment” as used herein also include prophylactic treatment.
  • a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition described herein to prevent recurrence.
  • Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations.
  • the compounds of the application may be administered at least once a week.
  • the compounds may be administered to the subject from about one time per three weeks, or about one time per week to about once daily for a given treatment.
  • the compounds are administered 2, 3, 4, 5 or 6 times daily.
  • the length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and/or the activity of the compounds of the application, and/or a combination thereof.
  • the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • the compounds are administered to the subject in an amount and for a duration sufficient to treat the patient.
  • “Palliating” a disease or disorder means that the extent and/or undesirable clinical manifestations of a disease, disorder or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
  • prevention or“prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition mediated by survivin inhibition or manifesting a symptom associated with a disease, disorder or condition mediated by survivin inhibition.
  • disease, disorder or condition refers to a disease, disorder or condition treatable by inhibition of survivin activity and particularly using a survivin inhibitor, such as a compound of the application herein described.
  • the term“mediated by survivin” as used herein means that the disease, disorder or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes aberrant survivin activity, in particular, increased survivin activity and the like. These diseases respond favorably when survivin activity associated with the diseases is blocked by one or more of the present compounds.
  • an effective amount means an amount of one or more compounds of the application that is effective, at dosages and for periods of time necessary to achieve the desired result.
  • an effective amount is an amount that, for example, increases survivin inhibition compared to the survivin inhibition without administration of one or more compounds of the application.
  • effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject.
  • the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon various factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art.
  • the effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom.
  • amounts that are effective can cause a reduction in the number, growth rate, size and/or distribution of tumours.
  • administered means administration of a therapeutically effective amount of one or more compounds or compositions of the application to a cell either in cell culture or in a subject.
  • Neoplasm refers to a mass of tissue resulting from the abnormal growth and/or division of cells in a subject having a neoplastic disorder. Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ ) or malignant (i.e. cancer).
  • neoplastic disorders include but are not limited to carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplastic disorders, (e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders), metastatic tumors and other cancers.
  • metastatic disorders e.g., tumors arising from the prostate
  • hematopoietic neoplastic disorders e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders
  • metastatic tumors e.g., metastatic tumors and other cancers.
  • Prevalent cancers include breast, prostate, colon, lung, liver, brain, ovarian and pancreatic cancers.
  • cancer refers to cellular-proliferative disease states.
  • the present application includes a compound of Formula I or a compound of Formula II or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
  • Ri is - H or Ci- 6 alkyl
  • R2 is selected from the group consisting of H, CN, Ci-ioalkyl, C2-ioalkenyl, C2- l oalkynyl, Ci-iohaloalkyl, Ci-iocyanoalkyl, O-Ci-ioalkyl, 0-C 2 -ioalkenyl, O-C2- l oalkynyl, C3-iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci-ealkylene-O-Ci- 6 alkyl, Ci- 6 alkylene-0-Ci- 6 haloalkyl, C 2-6 alkenylene-0-Ci- 6 haloalkyl, C2-ealkynylene- 0-Ci- 6 haloalkyl, Ci-6alkylene-C3-8cycloalkyl, Ci- 6 alkylene-heterocycloalkyl, Ci- 6 alkylene-aryl, Ci- 6 al
  • X- is a counter anion
  • A is Co-ealkylene, O, S, SO, SO2 or NR 3 ;
  • R 3 is H or Ci-ealkyl; n is 0, 1, 2 or 3; and
  • Xi, X2, X3 are the same or different and is selected from H, halogen andCi- 6 alkyl, provided that at least one of X 1 , X 2 and X 3 is F.
  • R 1 is Ci- 6 alkyl.
  • R 1 is selected from methyl, ethyl, propyl, isopropyl, vec-butyl and /-butyl.
  • R 1 is selected from methyl, ethyl and propyl.
  • R 1 is methyl.
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is selected from:
  • R 2 is selected from Ci- 6 alkyl. In another embodiment, R 2 is /-butyl. In a further embodiment, R 2 is methyl.
  • R 2 is selected from an unsubstituted 5- or 6- membered heteroaryl, a 5- or 6-membered heteroaryl substituted with a Ci-4alkyl and C3-8heterocycloalkyl.
  • R 2 is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl,
  • R 2 is selected from indolyl, indobnyl, isoindobnyl, quinobnyl, tetrahydroquinobnyl, isoquinobnyl, tetrahydroisoquinobnyl, 1,4- benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indobzinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazobnyl, cinnobnyl, pteridinyl, phenanthridinyl, phenanthrid
  • R 2 is selected from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,
  • R 2 is selected from pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • R 2 is an unsubstituted 5- or 6-membered heteroaryl, a 5-membered heteroaryl substituted with a Ci-4alkyl or a 6-membered heterocycloalkyl.
  • R 2 is an unsubstituted 5- or 6-membered heteroaryl or a 5- or 6-membered heteroaryl substituted with a Ci-4alkyl. In another embodiment, R 2 is an unsubstituted 5-membered heteroaryl. In a further embodiment, R 2 is an unsubstituted 6-membered heteroaryl. In an embodiment, R 2 is a 5-membered heteroaryl, substituted with a Ci-4alkyl. In another embodiment, R 2 is a 5-membered heteroaryl, substituted with a methyl.
  • R 2 is a substituted or unsubstituted Ci- 4 alkylene-C 6 - l oaryl, wherein the substituent is Ci-4alkyl.
  • R 2 is substituted or unsubstituted Ci-2alkylene-C6-ioaryl, wherein the substituent is Ci-4alkyl.
  • R 2 is substituted Ci-2alkylene-C6-ioaryl, wherein the substituent is methyl.
  • R 2 is selected from:
  • R 2 is selected from:
  • substituents for isoxazolyl, isothiazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl and imidazolyl are independently selected from a Ci-4alkyl such as a methyl.
  • R 2 is selected from:
  • substituents for isooxazolyl, furanyl and thiazolyl are independently selected from a Ci-4alkyl such as a methyl.
  • R 2 is selected from:
  • R 2 is selected from: wherein ' represents the point of attachment with the remainer of the compound.
  • X 1 , X 2 and X 3 are the same or different and are selected from H, F, and Ci-4alkyl, provided that at least one of X 1 , X 2 and X 3 is F.
  • X 1 , X 2 and X 3 are the same or different and are selected from H and F, provided that at least one of X 1 , X 2 and X 3 is F.
  • one or two of X 1 , X 2 and X 3 are F and the other of X 1 , X 2 and X 3 is H.
  • two of X 1 , X 2 and X 3 are F and the other one of X 1 , X 2 and X 3 is H. In yet a further embodiment, X 1 , X 2 and X 3 are F.
  • X- is any suitable counter anion.
  • X- is a halide.
  • X- is iodide, chloride or bromide.
  • X- is chloride or bromide.
  • X- is carbonate, bicarbonate, sulfate, nitrate, phosphate, acetate, trifluoroacetate, propionate, glycolate, lactate, lactobionate, pyruvate, malonate, succinate, glutamate, gluconate, gluceptate, fumarate, malate, maleate, mandelate, mucate, napsylate, tartrate, teoclate, bitartrate, citrate, ascorbate, maleic, hydroxymaleic, benzoate, besylate, camsylate, hexanoate, hydroxynaphthoate, octanoate, oleate, decanoate, edetate, esylate, isethionate, hydroxybenzoate, pamoate, pantothenate, polygalacturonate, phenylacetate, cinnamate, mandelate, salicylate, stearate, 2-phenoxybenz
  • A is Co-4alkylene or O. In an embodiment, A is CH 2 or O.
  • R 3 is H or Ci-4alkyl. In an embodiment R 3 is H or
  • n is 1 or 2. In an embodiment, n is 2.
  • the compound of the present application is selected from the compounds of Examples 2(a)-(j) as illustrated below or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: 3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(pyrazin-2- ylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
  • Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and/or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I or Formula II is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. [00138] The compounds of Formula I and II generally can be prepared according to the process illustrated in Scheme I and Scheme II. Variables in the following schemes are as defined above for Formula I and II unless otherwise specified.
  • the compounds of the present application can be prepared, for example, by coupling an amine with 2,3-dichloronaphthalene-l,4- dione to give intermediate A. Subsequent acylation of intermediate A with acylating agents such as anhydrides provide the intermediate B. Coupling of B with amines affords intermediate C which is subsequently cyclized into the compounds of Formula I upon treatment with an acid HX, in a methanolic solution.
  • the symmetrical compounds of Formula II are prepared in a similar fashion as outlined in Scheme II.
  • a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation.
  • Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified.
  • the compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.
  • the compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art.
  • a compound of the application is administered by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly.
  • administration is by means of a pump for periodic or continuous delivery.
  • Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration.
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet.
  • the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like.
  • carriers that are used include lactose, com starch, sodium citrate and salts of phosphoric acid.
  • Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fdlers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
  • the tablets are coated by methods well known in the art.
  • Oral dosage forms also include modified release, for example immediate release and timed-release, formulations.
  • modified-release formulations include, for example, sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet.
  • timed-release compositions are formulated, e.g.
  • liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc.
  • Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
  • useful carriers or diluents include lactose and dried com starch.
  • liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use.
  • aqueous suspensions and/or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents.
  • certain sweetening and/or flavoring and/or coloring agents may be added.
  • Such liquid preparations for oral administration are, for example, prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
  • a compound of the application is administered parenterally.
  • solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations.
  • sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered.
  • ointments or droppable liquids are, for example, delivered by ocular delivery systems known to the art such as applicators or eye droppers.
  • such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers.
  • diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
  • the compounds of the application are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and optioanlly contain formulating agents such as suspending, stabilizing and/or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
  • compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders.
  • the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use.
  • the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon.
  • Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas.
  • the dosage unit is suitably determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer contains a solution or suspension of the active compound.
  • Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch.
  • the aerosol dosage forms take the form of a pump-atomizer.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein ingredient compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine.
  • Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
  • Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations.
  • Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature.
  • the substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences , 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.
  • a compound of the application is coupled with soluble polymers as targetable drug carriers.
  • soluble polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
  • a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, poly cyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a drug for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, poly cyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
  • a compound of the application including pharmaceutically acceptable salts, solvates and/or prodrugs thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier.
  • the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.
  • a compound of the application is either used alone or in combination with other known agents useful for treating diseases, disorders or conditions mediated by survivin inhibition.
  • a compound of the application is administered contemporaneously with those agents.
  • “contemporaneous administration” of two substances to a subject means providing each of the two substances so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable.
  • two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances.
  • a combination of agents is administered to a subject in a non- contemporaneous fashion.
  • a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form.
  • the present application provides a single unit dosage form comprising one or more compounds of Formula I and/or one or more compounds of Formula II, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
  • the dosage of a compound of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • a compound of the application is administered initially in a suitable dosage that is optionally adjusted as required, depending on the clinical response.
  • Dosages will generally be selected to maintain a serum level of a compound of the application from about 0.01 pg/cc to about 1000 pg/cc, or about 0.1 pg/cc to about 100 pg/cc.
  • oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day.
  • a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg will be administered.
  • a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg.
  • a representative amount is from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1 mg/kg.
  • compositions are formulated for oral administration and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet.
  • the one or more compounds of the application are administered in a single daily, weekly or monthly dose or the total daily dose is divided into two, three, four, five or daily doses.
  • a compound also includes embodiments wherein one or more compounds are referenced.
  • the present application includes a method for suppressing survivin in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the application also includes a use of one or more compounds of the application for inhibition of survivin activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of survivin in a cell.
  • the application further includes one or more compounds of the application for use in suppressing survivin in a cell.
  • the compounds of the application have been shown to inhibit survivin activity, the compounds of the application are useful for treating diseases, disorders or conditions mediated by survivin inhibition. Therefore the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.
  • the present application also includes a method of treating a disease, disorder or condition that is mediated by survivin suppression comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition mediated survivin inhibition as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition mediated by survivin inhibition.
  • the application further includes one or more compounds of the application for use in treating a disease, disorder or condition mediated by survivin inhibition.
  • the disease, disorder or condition mediated by survivin suppression is a neoplastic disorder.
  • the present application also includes a method of treating a neoplastic disorder comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of a neoplastic disorder as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a neoplastic disorder.
  • the application further includes one or more compounds of the application for use in treating a neoplastic disorder.
  • the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass, among others, in a subject in need of such treatment.
  • the disease, disorder or condition mediated by suppressing survivin expression is cancer.
  • the present application also includes a method of treating cancer comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application for treatment of cancer as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of cancer.
  • the application further includes one or more compounds of the application for use in treating cancer.
  • the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer.
  • the cancer is selected from, but to limited to: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor,
  • the cancer is selected from a cancer of the skin, blood, prostate, colorectum, pancreas, kidney, ovary, breast, for example mammary, liver, tongue and lung.
  • the cancer is selected from leukaemia, lymphoma, non-Hodgkin’s lymphoma and multiple myeloma.
  • the cancer is selected from leukemia, melanoma, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer and kidney cancer.
  • the disease, disorder or condition mediated by survivin inhibition is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by survivin inhibition.
  • the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by survivin inhibition is proliferative activity in a cell.
  • the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the present application also includes a use of one or more compounds of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of proliferative activity in a cell.
  • the application further includes one or more compounds of the application for use in inhibiting proliferative activity in a cell.
  • the present application also includes a method of inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application to the cell.
  • the application also includes a use of one or more compounds of the application for inhibition of uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell.
  • the application further includes one or more compounds of the application for use in inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell.
  • the present application also includes a method of treating a disease, disorder or condition that is mediated by survivin inhibition comprising administering a therapeutically effective amount of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition to a subject in need thereof.
  • the present application also includes a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition for treatment of a disease, disorder or condition mediated by survivin inhibition as well as a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition for the preparation of a medicament for treatment of a disease, disorder or condition mediated by survivin inhibition.
  • the application further includes one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition for use in treating a disease, disorder or condition mediated by survivin inhibition.
  • the disease, disorder or condition mediated by survivin inhibition is cancer such as multiple myeloma, lymphoma, leukemia, ovarian cancer, brain cancer, lung cancer, pancreatic cancer and brain cancers.
  • the disease, disorder or condition mediated survivin inhibition is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments.
  • the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
  • the introduction of the fluorine atom into molecules may bring about changes in the physical and/or chemical properties of the parent molecules, for example it may result in the enhancement of desirable pharmacokinetic properties and/or biological activities.
  • Replacement of hydrogen atoms may also result in improved thermal and metabolic stability. Improved metabolic stability is generally a desirable feature since the possibility exist that in vivo decomposition may produce toxic effects.
  • the properties of the fluorine atom include its small size, low polarizability, high electronegativity and its ability to form strong bonds with carbon. Accordingly, bioactive compounds containing fluorinated groups such as -OCHF2 are useful.
  • Example 2 Representative synthesis of compounds of Formula 1 and compounds of Formula II
  • the fdtrate was washed with a small amount of saturated Na 2 CC> 3 , dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to near dryness.
  • the obtained material was used directly in the subsequent reaction (product was visualized on TLC plate with h stain, elutes with EtOAc).
  • NCI screening panel :
  • NCI National Cancer Institute
  • NCI National Cancer Institute
  • a panel of 60 different human tumor cell lines representing leukemia [CCRF-CEM, HL-60 (TB), K-562, MOLT-4, SR], melanoma [LOX IMVI, MALME-3M, M14, SMDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257 and UACC-62] and cancers of the lung [A549/ATCC, EKVX, HOP-62, HOP-93, NCI-H226, NCI-H23, NCI-H322M, NCI-H460], colon [COLO 205, HCT-116, HCT-15, HT29, KM12, SW-620], brain [SF-268, SF-295, SF-539, SNB-19, SNB-75, U251], ovary [IGROV1, OVCAR-3, OVC
  • the plates are incubated for an additional 48 h at 37°C, 5% CO2, 95 % air, and 100% relative humidity.
  • the assay is terminated by the addition of cold TCA (trichloroacetic acid).
  • Cells are fixed in situ by the gentle addition of 50 m ⁇ of cold 50% (w/v) TCA (final concentration, 10% TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried.
  • Sulforhodamine B (SRB) solution (100 m ⁇ ) at 0.4 % (w/v) in 1% acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature.
  • mice were irradiated (200 rads) using a Co60 irradiator source. After 24 hrs, each mouse was inoculated subcutaneously with 5 x 10 6 MM. IS tumor cells in 0.1 ml PBS for tumor development. Treatments were started when the tumor volume reached 100 mm 3 . Each treatment group consisted of 10 mice.
  • the test articles of compounds of Formula I were administrated to the tumor-bearing mice according to a specific predetermined regimen.
  • Compound of example 2(a) at dose levels of 50 mg/kg (p.o, qd x 28 days) and 100 mg/kg (p.o, days 1, 3, 5/wk x 4 wks) produced statically significant antitumor activity vs. control with no observed gross adverse effects including reductions in body weight or alterations in behaviour.

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Abstract

The present application relates to novel fluorinated derivatives, to processes for their preparation, to compositions comprising them, and to their use in therapy. More specifically, it relates to compounds useful in the treatment of diseases, disorders or conditions mediated by survivin inhibition. In particular, the present application includes compounds of Formula (I) or (II), and compositions and uses thereof: (Formulae (I) (II)).

Description

FLUORINATED BENZO[f]BENZIMIDAZOL-4-9-DIONE IUM DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF AND THEIR USE AS SURVIVIN SUPPRESSANTS
RELATED APPLICATIONS
[0001] The present application claims benefit of priority co-pending United
States provisional patent application no. 62/817,696 filed on March 13, 2019, the contents of which are incorporated herein by reference in their entirety.
FIELD
[0002] The present application relates to novel fluorinated derivatives, to processes for their preparation, to compositions comprising them, and to their use in therapy. More particularly, it relates to compounds useful in the treatment of diseases, disorders or conditions mediated by survivin suppression.
BACKGROUND
[0003] Cancer is a leading cause of death worldwide. Despite significant efforts to find new approaches for treating cancer, the primary treatment options remain surgery, chemotherapy and radiation therapy, either alone or in combination. Surgery and radiation therapy, however, are generally useful only for fairly well- defined types of cancer, and are of limited use for treating patients with disseminated disease. Chemotherapy is a method that is useful in treating patients with metastatic cancers or diffuse cancers such as leukemias. However, although chemotherapy can provide a therapeutic benefit, it often fails to result in cure of the disease due to the patient’s cancer cells becoming resistant to the chemotherapeutic agent. Therefore, a need exists for additional chemotherapeutics to treat cancers.
[0004] Survivin (BIRC5), a member of the inhibitor-of-apoptosis proteins
(IAPs) family, is highly expressed in most cancers. It is associated with chemotherapy resistance, increased tumor recurrence, and reduced patient survival rates [Nat Rev Cancer 2008, 8: 61-70; Nature 1998, 396: 580-584] Survivin is a 142-amino acid, 16.5 kDa protein encoded by a single gene located on the human 17q25 chromosome, consisting of three introns, and four exons [Nature 1998, 396: 580-584; Nat Med 1997, 3: 917-921; Cancer Res 1999, 59: 3143-3151] and exists physiologically as a functional homodimer [Nat Struct Biol 2000, 7: 602-608; Mol Cell 2000, 6: 183-189] Alternative splicing of survivin pre-mRNA produces five different mRNAs with the potential to encode up to five distinct proteins, survivin, survivin 2B, survivin AEx3, survivin 3B and survivin 2a [Cancer Res 1999, 59: 6097-6102; Mol Cancer 2005, 4: Biochem Biophys Res Commun 2004, 314: 902-907] Survivin has been implicated in both control of cell survival and regulation of mitosis in cancer [Carcinogenesis 2007, 28: 1133-1139] Survivin is preferentially and highly expressed in cancer cells, with little expression in most normal non-dividing adult tissues [Nat Med 1997, 3: 917- 921] The integral role of survivin in cancer cell division and survival makes it an attractive therapeutic target to inhibit cancer cell growth. It was originally suggested that survivin inhibits cell death via the extrinsic and intrinsic apoptotic pathways and confers resistance to apoptosis by directly inhibiting caspase activity [Cancer Res 1998, 58: 5315-5320]
[0005] Survivin expression also is up-regulated at a transcriptional level by both nuclear factor-kappa b (NF-kB) which in turn, can be activated indirectly by growth factors via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and by TCF- 4/b-catenin pathway [Trends Cell Biol 1998, 8: 107-111; Blood 2009, 113: 4016- 4026] The insulin like growth factor- 1/mTOR/RAS and Wnt-2 signaling pathways have also been reported to up-regulate survivin via rapid changes in mRNA translation [Oncogene 2007, 26:2678-2684; Oncogene 2003, 22: 4266-4280; Oncogene 2004, 23: 6170-6174 ]. Survivin degradation occurs via the ubiquitin- proteasome pathway in the G1 phase of the cell cycle and is stabilized when bound to heat shock protein 90 (Hsp90) [Proc Natl Acad Sci USA 2003, 100: 13791-13796] The survivin protein is closely associated with Cdc2/Cdkl and it is phosphorylated at the threonine-34 (T34) residue. This phosphorylation stabilizes the protein and allows it to interact with the mitotic spindle and inhibit caspase-9 [Proc Natl Acad Sci USA 2000, 97: 13103-13107]
[0006] Survivin also plays a central role in cell division, where its expression is coordinated within the cell cycle [Nature 1998, 396: 580-584; Clin Cancer Res 2008, 14: 5000-5005] Survivin levels increase in G1 and peak in the G2/M phase. During mitosis, survivin functions as a regulator of microtubule dynamics and as part of the chromosomal passenger complex (CPC). Survivin functions both at the centrosomes and the microtubules of the metaphase and anaphase spindle providing stabilization and ensuring accurate separation of sister chromatids [Nature 1998, 396: 580-584; Cancer Cell 2002, 2: 43-54; Curr Opin Cell Biol 2006, 18: 609-615] Survivin also localizes to the kinetochores, the mid-region or centromeric portion of the metaphase chromosomes where it is associated with regulators of cytokinesis, such as Aurora B kinase, the inner centromere protein antigens (INCENP), and Borealin/ Dasra [Mol Biol Cell 2002, 13: 3064-3077; J Cell Biol 2004, 166: 179-191] This supports the hypothesis that survivin acts as a subunit of the CPC which is required for proper chromosome segregation and cytokinesis [Curr Opin Cell Biol 2006, 18: 616-622] Hence, if survivin function is disrupted, the kinetochore- microtubule system does not form properly and cell division is either halted or improperly completed, and ultimately cell death occurs. Through its association with cyclin-dependent kinase 1 (CDK1), microtubule-bound survivin becomes phosphorylated on Thr34. This leads to stabilization of the protein and efficient counter-activation of apoptosis in dividing cells. Elimination of survivin leads to apoptosis of dividing cells.
[0007] Molecular profiling studies and retrospective analyses of patient cohorts have consistently identified the increased expression of survivin as a risk factor for cancer progression and poor prognosis [ Nature 2002, 415 530-536] In breast cancer, survivin expression might also have a role in predicting recurrence [/V. Engl. J. Med. 2004 351, 2817-2826] Although it is possible that distinct subcellular pools of survivin might differentially influence prognosis [Cancer Res. 2007 67, 5999-6002], the survivin networks seem to confer on tumour cells a greater adaptability, proliferative capacity and resistance to cell death, which translates into a clinically worsened disease state. However, the nodal functions of survivin might constitute a unique Achilles’ heel for cancer cells, as a non-redundant network of tumour maintenance that is unable to be circumvented. Following this logic, putative survivin antagonists might function not as single protein suppressants but, in fact, as pathway inhibitors that are suitable for disabling multiple signalling circuits in tumours, regardless of their heterogeneity or genetic make-up. Although it is likely that some of the survivin networks become operative in a specific spatial-temporal context, for instance, as cells approach mitosis, or during the cellular stress response, therapeutic disabling of survivin may have global effects on tumour cells, conceptually similar to the therapeutic targeting of other nodal proteins in tumorigenesis.
[0008] Survivin is significantly overexpressed in human glioblastoma tissues
[Br J Cancer 2006; 94: 108] Studies have shown that the 3-year survival rate of glioblastoma tissues with positive nuclear survivin expression is zero; thus, survivin may be a useful biomarker for predicting clinical prognosis in patients with glioblastoma [J Neurooncol 2009; 91 :353] Brain tumors are one of the most common solid neoplastic disorders that present in children. The death of a pediatric patient with a brain tumor, especially a high-grade glioma, usually results from cancer. Glioblastoma demonstrates the worst therapeutic response among high-grade gliomas, with a very low 5-year survival rate despite aggressive chemotherapy and/or radiation therapy. Thus novel treatments aimed at inhibiting survivin expression could be a new strategy for the treatment of glioblastomas.
[0009] Despite previous challenges of disrupting survivin function, YM-155, a transcriptional repressor of survivin expression, has succeeded in reaching the clinic. YM-155 produced impressive clinical responses in phase I trials of heavily pretreated cancer patients [J. Clin. Oncol. 2006 24, 3014]
[0010] The search for novel suppressors of survivin function is predominantly conducted by high-throughput screening for inhibitors of the activity at the survivin gene promoter [Cancer Res. 2007 67, 8014-21] YM155, {l-(2-Methoxyethyl)-2- methyl- 4,9-dioxo-3- (pyrazin-2-ylmethyl)-4,9-dihydro-lH-naphtho [2, 3-d] imidazolium bromide}, is a survivin suppressant and has been shown to inhibit the progression of some neoplasms in vitro and/or in vivo [Cancer Lett 2011;302:29-36, Anticancer Drugs 2011;22:454- 62, Clin Cancer Res 2008;14:6496-504, Pediatr Neonatol. 2012 ;53(3): 199-204]
[0011] Fluorine has found interest in bioorganic and structural chemistry over the past decade and incorporation of it has become a useful feature in drug design. The small and highly electronegative fluorine atom can play a useful role in medicinal chemistry. Selective installation of fluorine into a therapeutic or diagnostic small molecule candidate can result in an improvement of a number of useful pharmacokinetic and/or physicochemical properties such as improved metabolic stability and enhanced membrane permeation. Increased binding affinity of fluorinated drug candidates to a target protein has also been documented in a number of cases. A further emerging application of the fluorine atom is the use of 18F as a radiolabel tracer atom in the sensitive technique of Positron Emission Tomography (PET) imaging. [0012] Factors to be considered when synthesising fluorine-containing compounds include (a) the relatively small size of the fluorine atom (van der Waals radius of 1.47 A), comparable to hydrogen (van der Waals radius of 1.20 A), (b) the highly electron-withdrawing nature of fluorine, (c) the greater stability of the C-F bond compared to the C-H bond and (d) the greater lipophilicity of fluorine compared to hydrogen.
[0013] Despite the fact that fluorine is slightly larger than hydrogen, studies have demonstrated that it is a reasonable hydrogen mimic with minimal steric perturbations with respect to the compound’s mode of binding to a receptor or enzyme [Annu. Rev. Pharmacol. Toxicol. 2001, 41, 443-470] However, the introduction of a fluorine atom can significantly alter the physicochemical properties of the compound due to its high electronegativity. Therefore this type of modification can induce altered biological responses of the molecule. The effect of fluorine functionality in imidazolium derived survivin inhibitors is uncharted.
SUMMARY
[0014] A novel class of fluorinated imidazolium bromide derivatives of
Formula I and Formula II have been prepared and found to be useful in the treatment of cancers and other survivin mediated disorders.
[0015] Accordingly, the present application includes a compound of Formula I or a compound of Formula II or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
Figure imgf000006_0001
wherein:
R1 is H or Ci-6alkyl, R2 is selected from H, CN, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-iohaloalkyl, Ci- locyanoalkyl, O-Ci-ioalkyl, 0-C2-ioalkenyl, 0-C2-ioalkynyl, C3-iocycloalkyl, heterocycloalkyl, C6-ioaryl, heteroaryl, Ci-6alkylene-0-Ci-6alkyl, Ci-6alkylene-0-Ci- 6haloalkyl, C2-6alkenylene-0-Ci-6haloalkyl, C2-6alkynylene-0-Ci-6haloalkyl, Ci- 6alkylene-C3-8Cycloalkyl, Ci-ealkylene-heterocycloalkyl. Ci-ealkylene-aryl, Ci- ealkylene-heteroaryl, wherein any cyclic moiety is optionally substituted with Ci- 4alkyl or is optionally fused to a further 5- to 7-membered heterocycloalkyl;
X- is a counter anion;
A is Co-ealkylene, O, S, SO, SO2 or NR3;
R3 is H or Ci-6alkyl;
n is 0, 1, 2 or 3; and
Xi, X2, X3 are the same or different and are selected from H, halogen and Ci-6alkyl, provided that at least one of X1, X2 and X3 is F.
[0016] The present application also includes a composition comprising one or more compounds of the application and a carrier. In an embodiment, the composition is a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier.
[0017] The compounds of the application have been shown to inhibit survivin activity. Therefore the compounds of the application are useful for treating diseases, disorders or conditions mediated by survivin inhibition. Accordingly, the present application also includes a method of treating a disease, disorder or condition mediated by survivin inhibition, comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
[0018] In a further embodiment, the compounds of the application are used as medicaments. Accordingly, the application also includes a compound of the application for use as a medicament.
[0019] The present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition mediated by survivin inhibition as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition mediated by survivin inhibition. The application further includes one or more compounds of the application for use in treating a disease, disorder or condition mediated by survivin inhibition. [0020] In an embodiment, the disease, disorder or condition mediated by survivin inhibition is a neoplastic disorder. In an embodiment, the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass in a subject in need of such treatment.
[0021] In an embodiment, the disease, disorder or condition mediated by survivin inhibition is cancer.
[0022] In an embodiment, the disease, disorder or condition mediated by survivin inhibition is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by survivin inhibition. In another embodiment, the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by survivin inhibition is proliferative activity in a cell.
[0023] The application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell.
[0024] In a further embodiment the disease, disorder or condition mediated by survivin inhibition is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments. In another embodiment, the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
[0025] The application additionally provides a process for the preparation of compounds of Formula I and II. General and specific processes are discussed in more detail and set forth in the Examples below.
[0026] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating embodiments of the application are given by way of illustration only, since various changes and modifications within the spirit and scope of the application will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION
[0027] I. Definitions
[0028] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the application herein described for which they are suitable as would be understood by a person skilled in the art. Unless otherwise specified within this application or unless a person skilled in the art would understand otherwise, the nomenclature used in this application generally follows the examples and rules stated in“Nomenclature of Organic Chemistry” (Pergamon Press, 1979), Sections A, B, C, D, E, F, and H. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001, Advanced Chemistry Development, Inc., Toronto, Canada.
[0029] The term“compound of the application” or“compound of the present application” and the like as used herein refers to a compound of Formula I and/or a compound of Formula II, and/or pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
[0030] The term“composition of the application” or“composition of the present application” and the like as used herein refers to a composition, such as a pharmaceutical composition, comprising one or more compounds of Formula I, and/or one or more compounds of Formula II, or pharmaceutically acceptable salts, solvates and/or prodrugs thereof.
[0031] The term “and/or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that“at least one of’ or“one or more” of the listed items is used or present. The term “and/or” with respect to pharmaceutically acceptable salts, solvates and/or prodrugs thereof means that the compounds of the application exist as individual salts, hydrates or prodrugs, as well as a combination of, for example, a salt of a solvate of a compound of the application or a salt of a prodrug of a compound of the application.
[0032] As used in the present application, the singular forms“a”,“an” and
“the” include plural references unless the content clearly dictates otherwise. For example, an embodiment including“a compound” should be understood to present certain aspects with one compound, or two or more additional compounds. [0033] In embodiments comprising an“additional” or“second” component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A“third” component is different from the other, first, and second components, and further enumerated or“additional” components are similarly different.
[0034] In understanding the scope of the present application, the term
“comprising” (and any form of comprising, such as“comprise” and“comprises”), “having” (and any form of having, such as“have” and“has”),“including” (and any form of including, such as“include” and“includes”) or“containing” (and any form of containing, such as“contain” and“contains”), are inclusive or openended terms and do not exclude additional, unrecited elements or process steps.
[0035] The term“consisting” and its derivatives as used herein are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and/or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and/or steps.
[0036] The term“consisting essentially of’ as used herein is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and/or steps.
[0037] The term“suitable” as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed and/or specific use for the compound, but the selection would be well within the skill of a person trained in the art.
[0038] In embodiments of the present application, the compounds described herein may have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present application. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (for example, less than 20%, suitably less than 10%, more suitably less than 5%) of compounds of the present application having alternate stereochemistry. It is intended that any optical isomers, as separated, pure or partially purified optical isomers or racemic mixtures thereof are included within the scope of the present application.
[0039] The compounds of the present application may also exist in different tautomeric forms and it is intended that any tautomeric forms which the compounds form, as well as mixtures thereof, are included within the scope of the present application.
[0040] The compounds of the present application may further exist in varying polymorphic forms and it is contemplated that any polymorphs, or mixtures thereof, which form are included within the scope of the present application.
[0041] Terms of degree such as“substantially”,“about” and“approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies or unless the context suggests otherwise to a person skilled in the art.
[0042] The expression“proceed to a sufficient extent” as used herein with reference to the reactions or process steps disclosed herein means that the reactions or process steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.
[0043] The term“alkyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the prefix“Cni-n2” For example, the term Ci-6alkyl means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.
[0044] The term“alkylene”, whether it is used alone or as part of another group, means straight or branched chain, saturated alkylene group, that is, a saturated carbon chain that contains substituents on two of its ends. The number of carbon atoms that are possible in the referenced alkylene group are indicated by the prefix “Cni-n2” For example, the term Ci-6alkylene means an alkyl ene group having 1, 2, 3, 4, 5 or 6 carbon atoms.
[0045] The term“alkenyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain, unsaturated alkyl groups containing at least one double bond. The number of carbon atoms that are possible in the referenced alkenyl group are indicated by the prefix “Cni-n2”. For example, the term C2-ealkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.
[0046] The term“alkynyl” as used herein, whether it is used alone or as part of another group, means straight or branched chain unsaturated alkyl groups containing at least one triple bond. The number of carbon atoms that are possible in the referenced alkynyl group are indicated by the prefix “Cni-n2” For example, the term C2-ealkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one triple bond.
[0047] The term“haloalkyl” as used herein refers to an alkyl group wherein one or more, including all of the hydrogen atoms are replaced by a halogen atom. In an embodiment, the halogen is fluorine, in which case the haloalkyl is referred to herein as a“fluoroalkyl” group. In another embodiment, the haloalkyl comprises at least one -CHF2 group.
[0048] The term“cyanoalkyl” as used herein refers to an alkyl group wherein one or more, including all of the hydrogen atoms are replaced by a cyano group. For example, the term Ci-iocyanoalkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one cyano group attached thereto.
[0049] The term“alkoxy” as used herein, whether it is used alone or as part of another group, refers to the group“alkyl-O-” or“-O-alkyl”. The term Ci-ioalkoxy means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms bonded to an oxygen atom. Exemplary alkoxy groups include without limitation methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and isobutoxy.
[0050] The term“cycloalkyl,” as used herein, whether it is used alone or as part of another group, means a saturated carbocylic group containing a number of carbon atoms and one or more rings. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the prefix“Cni-n2” For example, the term C3-iocycloalkyl means a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
[0051] The term“aryl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups that contain from 6 to 20 carbon atoms and at least one aromatic ring. In an embodiment of the application, the aryl group contains from 6, 9, 10 or 14 atoms, such as phenyl, naphthyl, indanyl or anthracenyl.
[0052] The term“heterocycloalkyl” as used herein, whether it is used alone or as part of another group, refers to cyclic groups containing 3 to 20 atoms, suitably 3 to 10 atoms, and at least one non-aromatic ring in which one or more of the atoms are a heteromoiety selected from O, S, N, NH and NCi-6alkyl. Heterocycloalkyl groups are either saturated or unsaturated (i.e. contain one or more double bonds) and contain one or more than one ring (i.e. are polycyclic). When a heterocycloalkyl group contains more than one ring, the rings may be fused, bridged, spirofued or linked by a bond. When a heterocycloalkyl group contain the prefix“Cni-n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as defined above.
[0053] A first ring group being“fused” with a second ring group means the first ring and the second ring share at least two atoms there between.
[0054] Heterocycloalkyl includes monocyclic heterocycloalkyls such as but not limited to aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, dioxolanyl, sulfolanyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, tetrahydrofuranyl, thiophanyl, piperidinyl, 1,2,3,6-tetrahydropyridinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, 2,3-dihydropyranyl, tetrahydropyranyl, 1 ,4-dihydropyridinyl, 1,4-dioxanyl, 1,3-dioxanyl, dioxanyl, homopiperidinyl, 2.3.4.7-tetrahydro- 1 H- azepinyl, homopiperazinyl, 1,3-dioxepanyl, 4,7-dihydro-l,3-dioxepinyl, and hexamethylene oxidyl. Additionally, heterocycloalkyl includes polycyclic heterocycloalkyls such as but not limited to pyrolizidinyl, and quinolizidinyl. In addition to the polycyclic heterocycloalkyls described above, heterocycloalkyl includes polycyclic heterocycloalkyls wherein the ring fusion between two or more rings includes more than one bond common to both rings and more than two atoms common to both rings. Examples of such bridged heterocycles include but are not limited to quinuclidinyl, diazabicyclo[2.2.1]heptyl and 7-oxabicyclo[2.2.1]heptyl.
[0055] The term“heteroaryl” as used herein refers to cyclic groups containing from 5 to 20 atoms, suitably 5 to 10 atoms, at least one aromatic ring and at least one heteromoiety selected from O, S, N, NH and Ci-6alkyl. Heteroaryl groups contain one or more than one ring (i.e. are polycyclic). When a heteroaryl group contains more than one ring, the rings may be fused, bridged, spirofused or linked by a bond. When a heteroaryl group contains the prefix “Cni-n2” this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, in which one or more, suitably 1 to 5, of the ring atoms is replaced with a heteromoiety as defined above.
[0056] A five-membered heteroaryl is a heteroaryl with a ring having five ring atoms, where 1, 2 or 3 ring atoms are a heteromoiety selected from O, S, NH and NCi-6alkyl.
[0057] A six-membered heteroaryl is a heteroaryl with a ring having six ring atoms wherein 1, 2 or 3 ring atoms are a heteromoiety selected from O, S, NH and NCi-ealkyl.
[0058] As a prefix, the term“substituted” as used herein refers to a structure, molecule or group in which one or more available hydrogen atoms are replaced with one or more other chemical groups. In an embodiment, the chemical group is a Ci- 4alkyl. In another embodiment, the chemical group is a Ci-i2alkyl or a chemical group that contains one or more heteroatoms selected from N, O, S, F, Cl, Br, I, and P. Exemplary chemical groups containing one or more heteroatoms include heterocyclyl, -N02, -OR, -R'OR, -Cl, -Br, -I, -F, -CF3, -C(=0)R, -NR2, -SR, -S02R, -S(=0)R, -CN, -C(=0)OR, -C(=0)NR¾ -NRC(=0)R, -NRC(=0)OR, -R'NR2, oxo (=0), imino (=NR), thio (=S), and oximino (=N-OR), wherein each “R” is hydrogen or a Ci-i2alkyl and“R1” is a Ci-i2alkylene. For example, substituted phenyl may refer to nitrophenyl, pyridylphenyl, methoxyphenyl, chlorophenyl, aminophenyl, etc., wherein the nitro, pyridyl, methoxy, chloro, and amino groups may replace any suitable hydrogen on the phenyl ring.
[0059] As a suffix, the term“substituted” as used herein in relation to a first structure, molecule or group, followed by one or more variables or names of chemical groups, refers to a second structure, molecule or group that results from replacing one or more hydrogens of the first structure, molecule or group with the one or more variables or named chemical groups. For example, a“phenyl substituted by nitro” refers to nitrophenyl.
[0060] The term“available”, as in“available hydrogen atoms” or“available atoms” refers to atoms that would be known to a person skilled in the art to be capable of replacement by a substituent.
[0061] The term “optionally substituted” refers to groups, structures, or molecules that are unsubstituted or are substituted with one or more substituents.
[0062] The term“amine” or“amino,” as used herein, whether it is used alone or as part of another group, refers to radicals of the general formula -NRR', wherein R and R' are each independently selected from hydrogen or a alkyl group, such as Ci- 6alkyl.
[0063] The term“halo” or“halogen” as used herein, whether it is used alone or as part of another group, refers to a halogen atom and includes fluoro, chloro, bromo and iodo.
[0064] acac as used herein refers to acetylacetonate.
[0065] The term“atm” as used herein refers to atmosphere.
[0066] The term“aq.” as used herein refers to aqueous.
[0067] The terms“Boc” and“t-Boc” as used herein refer to the group tert- butoxycarbonyl.
[0068] DCM as used herein refers to dichloromethane.
[0069] DIPEA as used herein refers to N,N-diisopropylethylamine
[0070] DMF as used herein refers to dimethylformamide.
[0071] DMSO as used herein refers to dimethylsulfoxide.
[0072] EDCI.HC1 as used herein refers to N-[3-(dimethylamino)propyl]-N'- ethylcarbodiimide hydrochloride.
[0073] EDC as used herein refers to l-ethyl-3-(3- dimethylaminopropyl)carbodiimide.
[0074] Et20 as used herein refers to diethylether. [0075] EtOAc as used herein refers to ethyl acetate.
[0076] Et as used herein refers to the group ethyl.
[0077] Fmoc as used herein refers to the group 9-fluorenylmethyloxycarbonyl.
[0078] The term“hr(s)” as used herein refers to hour(s).
[0079] The term“min(s)” as used herein refers to minute(s).
[0080] HOBt as used herein refers to N-hydroxybenzotriazole.
[0081] HBTU as used herein refers to 0-(benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate.
[0082] MeOH as used herein refers to methanol.
[0083] Me as used herein refers to the group methyl.
[0084] t-BuLi as used herein refers to tert-butyllithium.
[0085] ON as used herein refers to overnight.
[0086] RT as used herein refers to room temperature.
[0087] TEA as used herein refers to triethylamine.
[0088] TFA as used herein refers to trifluoroacetic acid.
[0089] THF as used herein refers to tetrahydrofuran.
[0090] t-Bu as used herein refers to the group tertiary butyl.
[0091] SPE as used herein refers to solid phase extraction, for example using columns containing silica gel for mini-chromatography.
[0092] The term“protecting group” or“PG” and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in“Protective Groups in Organic Chemistry” McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., “Protective Groups in Organic Synthesis”, John Wiley & Sons, 3rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).
[0093] The term“cell” as used herein refers to a single cell or a plurality of cells and includes a cell either in a cell culture or in a subject.
[0094] The term“subject” as used herein includes all members of the animal kingdom including mammals, and suitably refers to humans. Thus the methods of the present application are applicable to both human therapy and veterinary applications. In an embodiment, the subject is a mammal. In another embodiment, the subject is human.
[0095] The term“pharmaceutically acceptable” means compatible with the treatment of subjects, for example humans.
[0096] The term“pharmaceutically acceptable carrier” means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to a subject. One non -limiting example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration.
[0097] The term“pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.
[0098] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound. Basic compounds that form an acid addition salt include, for example, compounds comprising an amine group. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acids, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include mono-, di- and tricarboxylic acids. Illustrative of such organic acids are, for example, acetic, trifluoroacetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, mandelic, salicylic, 2-phenoxybenzoic, p- toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts such as but not limited to oxalates may be used, for example in the isolation of compounds of the application for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
[0099] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound. Acidic compounds that form a basic addition salt include, for example, compounds comprising a carboxylic acid group. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxide as well as ammonia. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. [See, for example, S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19] The selection of the appropriate salt may be useful so that an ester functionality, if any, elsewhere in a compound is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.
[00100] In general, prodrugs will be functional derivatives of the compounds of the application which are readily convertible in vivo into the compound from which it is notionally derived. Prodrugs of the compounds of the application may be, for example, conventional esters formed with available hydroxy, thiol, amino or carboxyl groups. For example, available OH or N¾ groups in the compounds of the application may be acylated using an activated acid in the presence of a base, and optionally, in inert solvent (e.g. an acid chloride in pyridine). Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C8-C24) esters, acyloxymethyl esters, carbamates and amino acid esters. In certain instances, the prodrugs of the compounds of the application are those in which the hydroxyl and/or amino groups in the compounds is masked as groups which can be converted to hydroxyl and/or amino groups in vivo. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in“Design of Prodrugs” ed. H. Bundgaard, Elsevier, 1985.
[00101] The term“solvate” as used herein means a compound, or a salt or prodrug of a compound, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a“hydrate”. The formation of solvates of the compounds of the application will vary depending on the compound and the solvate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of suitable conditions to form a particular solvate can be made by a person skilled in the art.
[00102] The term“treating” or“treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission (whether partial or total), whether detectable or undetectable.“Treating” and“treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.“Treating” and“treatment” as used herein also include prophylactic treatment. For example, a subject with early cancer can be treated to prevent progression, or alternatively a subject in remission can be treated with a compound or composition described herein to prevent recurrence. Treatment methods comprise administering to a subject a therapeutically effective amount of one or more of the compounds of the application and optionally consist of a single administration, or alternatively comprise a series of administrations. For example, the compounds of the application may be administered at least once a week. However, in another embodiment, the compounds may be administered to the subject from about one time per three weeks, or about one time per week to about once daily for a given treatment. In another embodiment, the compounds are administered 2, 3, 4, 5 or 6 times daily. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and/or the activity of the compounds of the application, and/or a combination thereof. It will also be appreciated that the effective dosage of the compound used for the treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required. For example, the compounds are administered to the subject in an amount and for a duration sufficient to treat the patient.
[00103] “Palliating” a disease or disorder means that the extent and/or undesirable clinical manifestations of a disease, disorder or condition are lessened and/or time course of the progression is slowed or lengthened, as compared to not treating the disorder.
[00104] The term“prevention” or“prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a patient becoming afflicted with a disease, disorder or condition mediated by survivin inhibition or manifesting a symptom associated with a disease, disorder or condition mediated by survivin inhibition.
[00105] The term“disease, disorder or condition” as used herein refers to a disease, disorder or condition treatable by inhibition of survivin activity and particularly using a survivin inhibitor, such as a compound of the application herein described.
[00106] The term“mediated by survivin” as used herein means that the disease, disorder or condition to be treated is affected by, modulated by and/or has some biological basis, either direct or indirect, that includes aberrant survivin activity, in particular, increased survivin activity and the like. These diseases respond favorably when survivin activity associated with the diseases is blocked by one or more of the present compounds.
[00107] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of one or more compounds of the application that is effective, at dosages and for periods of time necessary to achieve the desired result. For example in the context of treating a disease, disorder or condition mediated by survivin inhibition, an effective amount is an amount that, for example, increases survivin inhibition compared to the survivin inhibition without administration of one or more compounds of the application. In an embodiment, effective amounts may vary according to factors such as the disease state, age, sex and/or weight of the subject. In a further embodiment, the amount of a given compound or compounds that will correspond to an effective amount will vary depending upon various factors, such as the given drug(s) or compound(s), the pharmaceutical formulation, the route of administration, the type of condition, disease or disorder, the identity of the subject being treated, and the like, but can nevertheless be routinely determined by one skilled in the art. The effective amount is one that following treatment therewith manifests as an improvement in or reduction of any disease symptom. When the disease is cancer, amounts that are effective can cause a reduction in the number, growth rate, size and/or distribution of tumours.
[00108] The term“administered” as used herein means administration of a therapeutically effective amount of one or more compounds or compositions of the application to a cell either in cell culture or in a subject.
[00109] The term“neoplastic disorder” as used herein refers to a disease, disorder or condition characterized by cells that have the capacity for autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. The term“neoplasm” as used herein refers to a mass of tissue resulting from the abnormal growth and/or division of cells in a subject having a neoplastic disorder. Neoplasms can be benign (such as uterine fibroids and melanocytic nevi), potentially malignant (such as carcinoma in situ ) or malignant (i.e. cancer). Exemplary neoplastic disorders include but are not limited to carcinoma, sarcoma, metastatic disorders (e.g., tumors arising from the prostate), hematopoietic neoplastic disorders, (e.g., leukemias, lymphomas, myeloma and other malignant plasma cell disorders), metastatic tumors and other cancers. Prevalent cancers include breast, prostate, colon, lung, liver, brain, ovarian and pancreatic cancers.
[00110] The term“cancer” as used herein refers to cellular-proliferative disease states.
II. Compounds and Compositions of the Application
[00111] Compounds of the present application were prepared and were found to inhibit uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin. In particular, compounds of the present application exhibited activity as survivin inhibitors, and are therefore useful in therapy, for example for the treatment of neoplastic disorders such as cancer.
[00112] Accordingly, the present application includes a compound of Formula I or a compound of Formula II or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
Figure imgf000022_0001
wherein:
Ri is - H or Ci-6alkyl,
R2 is selected from the group consisting of H, CN, Ci-ioalkyl, C2-ioalkenyl, C2- loalkynyl, Ci-iohaloalkyl, Ci-iocyanoalkyl, O-Ci-ioalkyl, 0-C2-ioalkenyl, O-C2- loalkynyl, C3-iocycloalkyl, heterocycloalkyl, Ce-ioaryl, heteroaryl, Ci-ealkylene-O-Ci- 6alkyl, Ci-6alkylene-0-Ci-6haloalkyl, C2-6alkenylene-0-Ci-6haloalkyl, C2-ealkynylene- 0-Ci-6haloalkyl, Ci-6alkylene-C3-8cycloalkyl, Ci-6alkylene-heterocycloalkyl, Ci- 6alkylene-aryl, Ci-6alkylene-heteroaryl, wherein any cyclic moiety is optionally substituted with Ci-4alkyl or is optionally fused to a further 5- to 7-membered heterocycloalkyl;
X- is a counter anion;
A is Co-ealkylene, O, S, SO, SO2 or NR3;
R3 is H or Ci-ealkyl; n is 0, 1, 2 or 3; and
Xi, X2, X3 are the same or different and is selected from H, halogen andCi-6alkyl, provided that at least one of X1, X2 and X3 is F.
[00113] In an embodiment, R1 is Ci-6alkyl. In another embodiment, R1 is selected from methyl, ethyl, propyl, isopropyl, vec-butyl and /-butyl. In a further embodiment, R1 is selected from methyl, ethyl and propyl. In yet a further embodiment, R1 is methyl.
[00114] In an embodiment, R2 is selected from:
(i) Ci-ioalkyl;
(ii) C2-ioalkenyl;
(iii) C2-ioalkynyl;
(iv) substituted or unsubstituted C6-i4aryl;
(v) substituted or unsubstituted Ci-6alkylene-C6-2oaryl;
(vi) substituted or unsubstituted heteroaryl;
(vii) substituted or unsubstituted C3-iocycloalkyl; and
(viii) substituted or unsubstituted C3-ioheterocycloalkyl,
wherein the substituent is Ci-4alkyl.
[00115] In another embodiment, R2 is selected from:
(i) Ci-ealkyl;
(ii) C2-ealkenyl;
(iii) C2-ealkynyl;
(iv) substituted or unsubstituted Ce-ioaryl;
(v) substituted or unsubstituted Ci-4alkylene-C6-ioaryl;
(vi) a substituted or unsubstituted 5- or 6-membered heteroaryl;
(vii) substituted or unsubstituted C3-scycloalkyl; and
(viii) substituted or unsubstituted C3-8heterocycloalkyl,
wherein the substituent is Ci-4alkyl. [00116] In a further embodiment, R2 is selected from:
(i) Ci-ealkyl;
(ii) a substituted or unsubstituted 5- or 6-membered heteroaryl;
(iii) C3-8heterocycloalkyl; and
(iv) substituted or unsubstituted Ci-4alkylene-C6-ioaryl,
wherein the substituent Ci-4alkyl.
[00117] In an embodiment, R2 is selected from Ci-6alkyl. In another embodiment, R2 is /-butyl. In a further embodiment, R2 is methyl.
[00118] In an embodiment, R2 is selected from an unsubstituted 5- or 6- membered heteroaryl, a 5- or 6-membered heteroaryl substituted with a Ci-4alkyl and C3-8heterocycloalkyl.
[00119] In an embodiment, R2 is selected from pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl, furazanyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3- thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,4-oxadiazolyl,
1.3.4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4 oxadiazolyl.
[00120] In an embodiment, R2 is selected from indolyl, indobnyl, isoindobnyl, quinobnyl, tetrahydroquinobnyl, isoquinobnyl, tetrahydroisoquinobnyl, 1,4- benzodioxanyl, coumarinyl, dihydrocoumarinyl, benzofuranyl, 2,3- dihydrobenzofuranyl, isobenzofuranyl, chromenyl, chromanyl, isochromanyl, xanthenyl, phenoxathiinyl, thianthrenyl, indobzinyl, isoindolyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazobnyl, cinnobnyl, pteridinyl, phenanthridinyl, perimidinyl, phenanthrobnyl, phenazinyl, phenothiazinyl, phenoxazinyl, 1,2-benzisoxazolyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benzimidazolyl, benztriazolyl, thioxanthinyl, carbazolyl, carbobnyl and acridinyl.
[00121] In an embodiment, R2 is selected from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,
1.2.4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4- oxadiazolyl. [00122] In an embodiment, R2 is selected from pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
[00123] In an embodiment, R2 is an unsubstituted 5- or 6-membered heteroaryl, a 5-membered heteroaryl substituted with a Ci-4alkyl or a 6-membered heterocycloalkyl.
[00124] In an embodiment, R2 is an unsubstituted 5- or 6-membered heteroaryl or a 5- or 6-membered heteroaryl substituted with a Ci-4alkyl. In another embodiment, R2 is an unsubstituted 5-membered heteroaryl. In a further embodiment, R2 is an unsubstituted 6-membered heteroaryl. In an embodiment, R2 is a 5-membered heteroaryl, substituted with a Ci-4alkyl. In another embodiment, R2 is a 5-membered heteroaryl, substituted with a methyl.
[00125] In an embodiment, R2 is a substituted or unsubstituted Ci-4alkylene-C6- loaryl, wherein the substituent is Ci-4alkyl. In another embodiment, R2 is substituted or unsubstituted Ci-2alkylene-C6-ioaryl, wherein the substituent is Ci-4alkyl. In a further embodiment, R2 is substituted Ci-2alkylene-C6-ioaryl, wherein the substituent is methyl.
[00126] In an embodiment, R2 is selected from:
(i) substituted or unsubstituted thiazolyl;
(ii) substituted or unsubstituted isothiazolyl;
(iii) substituted or unsubstituted oxazolyl;
(iv) substituted or unsubstituted isooxazolyl;
(v) substituted or unsubstituted thiophenyl;
(vi) substituted or unsubstituted furanyl;
(vii) substituted or unsubstituted 1,2,4-triazolyl;
(viii) substituted or unsubstituted pyridyl;
(ix) substituted or unsubstituted pyrazinyl;
(x) substituted or unsubstituted pyrimidinyl; and
(xi) substituted or unsubstituted 1,2,4-triazinyl, wherein the substituents for thiazolyl, isothiazolyl, oxazolyl, isooxazolyl, thiophenyl, furanyl, 1 ,2,4-triazolyl, pyridyl, pyrazinyl, pyrimidinyl and 1,2,4-triazinyl are independently selected from a Ci-4alkyl such as a methyl.
[00127] In another embodiment R2 is selected from:
(i) substituted or unsubstituted isoxazolyl;
(ii) substituted or unsubstituted isothiazolyl;
(iii) substituted or unsubstituted furanyl;
(iv) substituted or unsubstituted thiophenyl;
(v) substituted or unsubstituted oxazolyl;
(vi) substituted or unsubstituted thiazolyl;
(vii) substituted or unsubstituted pyrazolyl; and
(viii) substituted or unsubstituted imidazolyl,
wherein the substituents for isoxazolyl, isothiazolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrazolyl and imidazolyl are independently selected from a Ci-4alkyl such as a methyl.
[00128] In another embodiment, R2 is selected from:
(i) substituted or unsubstituted isoxazolyl;
(ii) substituted or unsubstituted furanyl; and
(iii) substituted or unsubstituted thiazolyl,
wherein the substituents for isooxazolyl, furanyl and thiazolyl are independently selected from a Ci-4alkyl such as a methyl.
[00129] In another embodiment, R2 is selected from:
Figure imgf000026_0001
wherein < represents the point of atachment with the remainer of the compound. [00130] In a further embodiment, R2 is selected from:
Figure imgf000027_0001
wherein ' represents the point of attachment with the remainer of the compound.
[00131] In an embodiment, X1, X2 and X3 are the same or different and are selected from H, F, and Ci-4alkyl, provided that at least one of X1, X2 and X3 is F. In another embodiment, X1, X2 and X3 are the same or different and are selected from H and F, provided that at least one of X1, X2 and X3 is F. In a further embodiment, one or two of X1, X2 and X3 are F and the other of X1, X2 and X3 is H. In yet a further embodiment, two of X1, X2 and X3 are F and the other one of X1, X2 and X3 is H. In yet a further embodiment, X1, X2 and X3 are F.
[00132] In an embodiment, X- is any suitable counter anion. In an emdodiment, X- is a halide. In an emdodiment, X- is iodide, chloride or bromide. In an emdodiment, X- is chloride or bromide. In an embodiment, X- is carbonate, bicarbonate, sulfate, nitrate, phosphate, acetate, trifluoroacetate, propionate, glycolate, lactate, lactobionate, pyruvate, malonate, succinate, glutamate, gluconate, gluceptate, fumarate, malate, maleate, mandelate, mucate, napsylate, tartrate, teoclate, bitartrate, citrate, ascorbate, maleic, hydroxymaleic, benzoate, besylate, camsylate, hexanoate, hydroxynaphthoate, octanoate, oleate, decanoate, edetate, esylate, isethionate, hydroxybenzoate, pamoate, pantothenate, polygalacturonate, phenylacetate, cinnamate, mandelate, salicylate, stearate, 2-phenoxybenzate, benzenesulfonate, tosylate, mesylate ethanesulfonate or 2-hydroxyethanesulfonate. In an embodiment, X- is chloride, mesylate, bromide, acetate or fumarate.
[00133] In an embodiment, A is Co-4alkylene or O. In an embodiment, A is CH2 or O.
[00134] In an embodiment R3 is H or Ci-4alkyl. In an embodiment R3 is H or
CH3.
[00135] In an embodiment, n is 1 or 2. In an embodiment, n is 2.
[00136] In an embodiment, the compound of the present application is selected from the compounds of Examples 2(a)-(j) as illustrated below or a pharmaceutically acceptable salt, solvate and/or prodrug thereof: 3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(pyrazin-2- ylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(2- pyridylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(3 - pyridylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
l,3-bis[2-(difluoromethoxy)ethyl]-2-methyl-benzo[f]benzimidazol-3-ium- 4,9- dione bromide;
1-[2-(difluoromethoxy)ethyl]-2-methyl-3-(4,4,4- trifluorobutyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
2-methyl-l,3-bis(4,4,4-trifluorobutyl)benzo[f]benzimidazol-3-ium-4,9- dione bromide;
2-methyl-3-(3-pyridylmethyl)-l -(4,4,4- trifluorobutyl)benzo[f]benzimidazol- 3-ium-4,9-dione bromide;
1-[2-(difluoromethoxy)ethyl]-2-methyl-3-(3,3,3- trifluoropropyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide; and
2-methyl-l,3-bis(3,3,3-trifluoropropyl)benzo[f]benzimidazol-3-ium-4,9- dione bromide,
or a salt, solvate or prodrug thereof.
Preparation of Compounds
[00137] Compounds of the present application can be prepared by various synthetic processes. The choice of particular structural features and/or substituents may influence the selection of one process over another. The selection of a particular process to prepare a given compound of Formula I or Formula II is within the purview of the person of skill in the art. Some starting materials for preparing compounds of the present application are available from commercial chemical sources. Other starting materials, for example as described below, are readily prepared from available precursors using straightforward transformations that are well known in the art. [00138] The compounds of Formula I and II generally can be prepared according to the process illustrated in Scheme I and Scheme II. Variables in the following schemes are as defined above for Formula I and II unless otherwise specified.
Figure imgf000029_0001
c
Scheme I
[00139] As shown in Scheme I, the compounds of the present application can be prepared, for example, by coupling an amine with 2,3-dichloronaphthalene-l,4- dione to give intermediate A. Subsequent acylation of intermediate A with acylating agents such as anhydrides provide the intermediate B. Coupling of B with amines affords intermediate C which is subsequently cyclized into the compounds of Formula I upon treatment with an acid HX, in a methanolic solution. The symmetrical compounds of Formula II are prepared in a similar fashion as outlined in Scheme II.
Figure imgf000029_0002
Scheme II
[00140] Amines are obtained from commercial sources or prepared by methods known in the art. [00141] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in“ Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in“Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “ Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or,“ Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by one skilled in the art.
Compositions
[00142] The compounds of the present application are suitably formulated in a conventional manner into compositions using one or more carriers. Accordingly, the present application also includes a composition comprising one or more compounds of the application and a carrier. The compounds of the application are suitably formulated into pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a pharmaceutical composition comprising one or more compounds of the application and a pharmaceutically acceptable carrier. In embodiments of the application the pharmaceutical compositions are used in the treatment of any of the diseases, disorders or conditions described herein.
[00143] The compounds of the application are administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, a compound of the application is administered by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration and the pharmaceutical compositions formulated accordingly. In some embodiments, administration is by means of a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of suitable compositions are described, for example, in Remington’s Pharmaceutical Sciences (2000 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
[00144] Parenteral administration includes systemic delivery routes other than the gastrointestinal (GI) tract, and includes, intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (for example, by use of an aerosol), intrathecal, rectal and topical (including the use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may be by continuous infusion over a selected period of time.
[00145] In some embodiments, a compound of the application is orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it is enclosed in hard or soft shell gelatin capsules, or it is compressed into tablets, or it is incorporated directly with the food of the diet. In some embodiments, the compound is incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, com starch, sodium citrate and salts of phosphoric acid. Pharmaceutically acceptable excipients include binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fdlers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). In some embodiments, the tablets are coated by methods well known in the art. In the case of tablets, capsules, caplets, pellets or granules for oral administration, pH sensitive enteric coatings, such as Eudragits™ designed to control the release of active ingredients are optionally used. Oral dosage forms also include modified release, for example immediate release and timed-release, formulations. Examples of modified-release formulations include, for example, sustained-release (SR), extended- release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), employed, for example, in the form of a coated tablet, an osmotic delivery device, a coated capsule, a microencapsulated microsphere, an agglomerated particle, e.g., as of molecular sieving type particles, or, a fine hollow permeable fiber bundle, or chopped hollow permeable fibers, agglomerated or held in a fibrous packet. In some embodiments, timed-release compositions are formulated, e.g. liposomes or those wherein the active compound is protected with differentially degradable coatings, such as by microencapsulation, multiple coatings, etc. Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. For oral administration in a capsule form, useful carriers or diluents include lactose and dried com starch.
[00146] In some embodiments, liquid preparations for oral administration take the form of, for example, solutions, syrups or suspensions, or they are suitably presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and/or emulsions are administered orally, the compound of the application is suitably suspended or dissolved in an oily phase that is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Such liquid preparations for oral administration are, for example, prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols. [00147] It is also possible to freeze-dry the compounds of the application and use the lyophilizates obtained, for example, for the preparation of products for injection.
[00148] In some embodiments, a compound of the application is administered parenterally. For example, solutions of a compound of the application are prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. In some embodiments, dispersions are prepared in glycerol, liquid polyethylene glycols, DMSO and mixtures thereof with or without alcohol, and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. A person skilled in the art would know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the application are usually prepared, and the pH’s of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids are, for example, delivered by ocular delivery systems known to the art such as applicators or eye droppers. In some embodiments, such compositions include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzyl chromium chloride, and the usual quantities of diluents or carriers. For pulmonary administration, diluents or carriers will be selected to be appropriate to allow the formation of an aerosol.
[00149] In some embodiments, the compounds of the application are formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection, for example, presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the compositions take such forms as sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and optioanlly contain formulating agents such as suspending, stabilizing and/or dispersing agents. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. Alternatively, the compounds of the application are suitably in a sterile powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen -free water, before use. [00150] In some embodiments, compositions for nasal administration are conveniently formulated as aerosols, drops, gels and powders. For intranasal administration or administration by inhalation, the compounds of the application are conveniently delivered in the form of a solution, dry powder formulation or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device. Alternatively, the sealed container is a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal after use. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which is, for example, a compressed gas such as compressed air or an organic propellant such as fluorochlorohydrocarbon. Suitable propellants include but are not limited to dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to deliver a metered amount. In some embodiments, the pressurized container or nebulizer contains a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the application and a suitable powder base such as lactose or starch. In some embodiments, the aerosol dosage forms take the form of a pump-atomizer.
[00151] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein ingredient compound of the application is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerine. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
[00152] Suppository forms of the compounds of the application are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include but are not limited to theobroma oil (also known as cocoa butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol. See, for example: Remington's Pharmaceutical Sciences , 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533 for further discussion of suppository dosage forms.
[00153] In some embodiments, a compound of the application is coupled with soluble polymers as targetable drug carriers. Such polymers include, for example, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, in some embodiments, a compound of the application is coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, poly cyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
[00154] A compound of the application including pharmaceutically acceptable salts, solvates and/or prodrugs thereof is suitably used on their own but will generally be administered in the form of a pharmaceutical composition in which the one or more compounds of the application (the active ingredient) is in association with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will comprise from about 0.05 wt% to about 99 wt% or about 0.10 wt% to about 70 wt%, of the active ingredient, and from about 1 wt% to about 99.95 wt% or about 30 wt% to about 99.90 wt% of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.
[00155] A compound of the application is either used alone or in combination with other known agents useful for treating diseases, disorders or conditions mediated by survivin inhibition. When used in combination with other agents useful in treating diseases, disorders or conditions mediated by survivin inhibition, it is an embodiment that a compound of the application is administered contemporaneously with those agents. As used herein,“contemporaneous administration” of two substances to a subject means providing each of the two substances so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances in the presence of each other, and can include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administration of the other, if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, two substances will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition that contains both substances. It is a further embodiment of the present application that a combination of agents is administered to a subject in a non- contemporaneous fashion. In an embodiment, a compound of the present application is administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present application provides a single unit dosage form comprising one or more compounds of Formula I and/or one or more compounds of Formula II, an additional therapeutic agent, and a pharmaceutically acceptable carrier.
[00156] The dosage of a compound of the application varies depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated. One of skill in the art can determine the appropriate dosage based on the above factors. In some embodiments, a compound of the application is administered initially in a suitable dosage that is optionally adjusted as required, depending on the clinical response. Dosages will generally be selected to maintain a serum level of a compound of the application from about 0.01 pg/cc to about 1000 pg/cc, or about 0.1 pg/cc to about 100 pg/cc. As a representative example, oral dosages of one or more compounds of the application will range between about 1 mg per day to about 1000 mg per day for an adult, suitably about 1 mg per day to about 500 mg per day, more suitably about 1 mg per day to about 200 mg per day. For parenteral administration, a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg will be administered. For oral administration, a representative amount is from about 0.001 mg/kg to about 10 mg/kg, about 0.1 mg/kg to about 10 mg/kg, about 0.01 mg/kg to about 1 mg/kg or about 0.1 mg/kg to about 1 mg/kg. For administration in suppository form, a representative amount is from about 0.1 mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 1 mg/kg. In an embodiment of the application, compositions are formulated for oral administration and the compounds are suitably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of active ingredient per tablet. In embodiments of the application the one or more compounds of the application are administered in a single daily, weekly or monthly dose or the total daily dose is divided into two, three, four, five or daily doses.
[00157] In the above, the term “a compound” also includes embodiments wherein one or more compounds are referenced.
III. Methods and Uses of the Application
[00158] The compounds of the application have been shown to inhibit survivin activity.
[00159] Accordingly, the present application includes a method for suppressing survivin in a cell, either in a biological sample or in a patient, comprising administering an effective amount of one or more compounds of the application to the cell. The application also includes a use of one or more compounds of the application for inhibition of survivin activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of survivin in a cell. The application further includes one or more compounds of the application for use in suppressing survivin in a cell.
[00160] As the compounds of the application have been shown to inhibit survivin activity, the compounds of the application are useful for treating diseases, disorders or conditions mediated by survivin inhibition. Therefore the compounds of the present application are useful as medicaments. Accordingly, the present application includes a compound of the application for use as a medicament.
[00161] The present application also includes a method of treating a disease, disorder or condition that is mediated by survivin suppression comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof.
[00162] The present application also includes a use of one or more compounds of the application for treatment of a disease, disorder or condition mediated survivin inhibition as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a disease, disorder or condition mediated by survivin inhibition. The application further includes one or more compounds of the application for use in treating a disease, disorder or condition mediated by survivin inhibition.
[00163] In an embodiment, the disease, disorder or condition mediated by survivin suppression is a neoplastic disorder. Accordingly, the present application also includes a method of treating a neoplastic disorder comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of a neoplastic disorder as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of a neoplastic disorder. The application further includes one or more compounds of the application for use in treating a neoplastic disorder. In an embodiment, the treatment is in an amount effective to ameliorate at least one symptom of the neoplastic disorder, for example, reduced cell proliferation or reduced tumor mass, among others, in a subject in need of such treatment.
[00164] Compounds of the application have been demonstrated to be effective against the cell lines of a 60 human tumor cell line panel. Therefore in another embodiment of the present application, the disease, disorder or condition mediated by suppressing survivin expression is cancer. Accordingly, the present application also includes a method of treating cancer comprising administering a therapeutically effective amount of one or more compounds of the application to a subject in need thereof. The present application also includes a use of one or more compounds of the application for treatment of cancer as well as a use of one or more compounds of the application for the preparation of a medicament for treatment of cancer. The application further includes one or more compounds of the application for use in treating cancer. In an embodiment, the compound is administered for the prevention of cancer in a subject such as a mammal having a predisposition for cancer.
[00165] In an embodiment, the cancer is selected from, but to limited to: Acute Lymphoblastic Leukemia, Adult; Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; Brain Tumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor, Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; Breast Cancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/Malignant Glioma, Childhood; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths; Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian; Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family of Tumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ Cell Tumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney Cancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, Acute Lymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non- Small Cell; Lung Cancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; Lymphoblastic Leukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma, Cutaneous T-Cell; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's, Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma, Non- Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma, Non- Hodgkin's During Pregnancy; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; Malignant Mesothelioma, Adult; Malignant Mesothelioma, Childhood; Malignant Thymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular; Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome, Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides; Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Childhood Acute; Myeloma, Multiple; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma; Non- Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood; Non- Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineal and Supratentorial Primitive Neuroectodermal Tumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma; Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult; Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; Renal Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma, Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, Soft Tissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft Tissue Sarcoma, Childhood; Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer, Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood; T- Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood; Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of, Childhood; Unusual Cancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macro globulinemia; and Wilms' Tumor. Metastases of the aforementioned cancers can also be treated in accordance with the methods described herein.
[00166] In an embodiment, the cancer is selected from a cancer of the skin, blood, prostate, colorectum, pancreas, kidney, ovary, breast, for example mammary, liver, tongue and lung. In another embodiment, the cancer is selected from leukaemia, lymphoma, non-Hodgkin’s lymphoma and multiple myeloma. In a further embodiment of the present application, the cancer is selected from leukemia, melanoma, lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer and kidney cancer.
[00167] In an embodiment, the disease, disorder or condition mediated by survivin inhibition is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by survivin inhibition. In another embodiment, the uncontrolled and/or abnormal cellular activity that is affected directly or indirectly by survivin inhibition is proliferative activity in a cell. Accordingly, the application also includes a method of inhibiting proliferative activity in a cell, comprising administering an effective amount of one or more compounds of the application to the cell. The present application also includes a use of one or more compounds of the application for inhibition of proliferative activity in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of proliferative activity in a cell. The application further includes one or more compounds of the application for use in inhibiting proliferative activity in a cell.
[00168] The present application also includes a method of inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell, either in a biological sample or in a subject, comprising administering an effective amount of one or more compounds of the application to the cell. The application also includes a use of one or more compounds of the application for inhibition of uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell as well as a use of one or more compounds of the application for the preparation of a medicament for inhibition of uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell. The application further includes one or more compounds of the application for use in inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell.
[00169] The administration of the compound of Formula I or II of the present application in combination with either cisplatin or taxanes has been demonstrated herein to be synergistic ( Clin Cancer Res. 2011; 17 (16):5423-31; Br J Cancer. 2010; 103(1): 36-42). Accordingly, the present application also includes a method of treating a disease, disorder or condition that is mediated by survivin inhibition comprising administering a therapeutically effective amount of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition to a subject in need thereof. The present application also includes a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition for treatment of a disease, disorder or condition mediated by survivin inhibition as well as a use of one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition for the preparation of a medicament for treatment of a disease, disorder or condition mediated by survivin inhibition. The application further includes one or more compounds of the application in combination with another known agent useful for treatment of a disease, disorder or condition mediated by survivin inhibition for use in treating a disease, disorder or condition mediated by survivin inhibition. In an embodiment, the disease, disorder or condition mediated by survivin inhibition is cancer such as multiple myeloma, lymphoma, leukemia, ovarian cancer, brain cancer, lung cancer, pancreatic cancer and brain cancers.
[00170] In a further embodiment, the disease, disorder or condition mediated survivin inhibition is cancer and the one or more compounds of the application are administered in combination with one or more additional cancer treatments. In another embodiment, the additional cancer treatment is selected from radiotherapy, chemotherapy, targeted therapies such as antibody therapies and small molecule therapies such as tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
[00171] The following non-limiting examples are illustrative of the present application:
EXAMPLES
[00172] The introduction of the fluorine atom into molecules may bring about changes in the physical and/or chemical properties of the parent molecules, for example it may result in the enhancement of desirable pharmacokinetic properties and/or biological activities. Replacement of hydrogen atoms may also result in improved thermal and metabolic stability. Improved metabolic stability is generally a desirable feature since the possibility exist that in vivo decomposition may produce toxic effects. The properties of the fluorine atom include its small size, low polarizability, high electronegativity and its ability to form strong bonds with carbon. Accordingly, bioactive compounds containing fluorinated groups such as -OCHF2 are useful.
[00173] The geminal combination of an alkoxy or aryloxy group with a fluorine atom offers the possibility of bonding/nonbonding resonance, which can be formally expressed by the superposition of a covalent and ionic limiting structure. This phenomenon, which reveals itself as a lengthening and weakening of the carbon- halogen bond and a shortening and strengthening of the carbon-oxygen bond is known as the generalized anomeric effect [Schlosser et al. Chem. Rev. 2005, 105, 827-856] Example 1
A. General methods
[00174] All starting materials used herein were commercially available or earlier described in the literature. The ' H and 13C NMR spectra were recorded either on Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for ' H NMR respectively, using TMS or the residual solvent signal as an internal reference, in deuterated chloroform as solvent unless otherwise indicated. All reported chemical shifts are in ppm on the delta-scale, and the fine splitting of the signals as appearing in the recordings is generally indicated, for example as s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiple! Unless otherwise indicated, in the tables below, ' H NMR data was obtained at 400 MHz, using CDCb as the solvent.
[00175] Purification of products was carried out using Chem Elut Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat # 12256018; 12256026; 12256034) or by flash chromatography in silica- filled glass columns.
Example 2: Representative synthesis of compounds of Formula 1 and compounds of Formula II
Figure imgf000044_0001
Preparation of the Intermediates
(i) 2-(difluoromethoxy)ethanamine
Figure imgf000044_0002
[00176] To a stirred solution of 2-[2-(difluoromethoxy)ethyl]isoindoline-l,3- dione (660 mg, 2.73 mmol) in ethanol (10 mL) at 78 °C was added hydrazine hydrate (266 pL, 5.47 mmol). The mixture was stirred overnight (white precipitate appears). The mixture was concentrated in vacuo to remove some of the ethanol, diluted with diethyl ether and cooled to 0 °C. The solid material was removed via vacuum fdtration, washed with cold diethyl ether. The fdtrate was washed with a small amount of saturated Na2CC>3, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to near dryness. The obtained material was used directly in the subsequent reaction (product was visualized on TLC plate with h stain, elutes with EtOAc).
(ii) 2-[2-(difluoromethoxy)ethyl]isoindoline-l,3-dione
Figure imgf000045_0001
[00177] To a stirred solution of 2-(2-hydroxyethyl)isoindoline-l,3-dione (10 g, 52.3 mmol) in acetonitrile (100 mL) was added copper (I) iodide (1.99 g, 10.4 mmol). The resulting mixture was stirred at 45 °C and treated with 2,2-difluoro-2- fluorosulfonyl-acetic acid (8.11 mL, 78.4 mmol), dropwise, as a solution in acetonitrile (10 mL) over a period of 100 min (bubbling observed). Upon completion of the addition stirring was continued for a further 30 min. The mixture was cooled to room temperature, diluted with diethyl ether and washed with a 1: 1 mixture of brine:water (2x) and brine (2x). The organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo then chromatographed in 10-50% ethyl acetate in hexanes, giving the desired product (8 g, 63%). ¾ NMR (CDCb, 300 MHz): d 7.89-7.84 (m, 2H), 7.75-7.71 (m, 2H), 6.18 (t, 74 Hz, 1H), 4.12 (t, J = 6 Hz, 2H), 3.9 (t, J = 6 Hz, 2H).
(iii) 2-(2-hydroxyethyl)isoindoline-l,3-dione
Figure imgf000045_0002
[00178] A mixture of phthalic anhydride (20 g, 135 mmol) and ethanolamine (8.17 mL, 135 mmol) was warmed to 130 °C and stirred for 40 min (vigorous bubbling observed upon melt formation). The mixture was then allowed to cool to room temperature slowly giving a white solid. The solid material was refluxed to dissolve in ethanol, then recrystallized by cooling slowly to room temperature then to 0 °C. The white crystals were collected via vacuum filtration, giving the desired product (21.6 g, 83%). XH NMR (d6-DMSO, 300 MHz): d 7.88-7.79 (m, 4H), 4.81 (t, J = 4.5 Hz, 1H), 3.65-3.60 (m, 2H), 3.59-3.53 (m, 2H).
(a) Synthesis of 3-[2-(difluoromethoxy)ethyl]-2-methyl-l-(pyrazin-2 ylmethyl) benzo[f]-benzimidazol-3-ium-4,9-dione bromide
Figure imgf000046_0001
STEP 1: Preparation of Difluoromethoxy)ethylamino]naphthalene-l,4-dione
Figure imgf000046_0002
[00179] A mixture of 2,3-dichloronaphthalene-l,4-dione (425 mg, 1.87 mmol), 2-(difluoromethoxy)ethanamine (250 mg, 2.25 mmol) and DIPEA (0.326 mL, 1.87 mmol) in THF was stirred at room temperature for 2 h (turns dark red). The mixture was diluted with diethyl ether and washed with brine (4x). The organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated then chromatographed in 0-25% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving the desired product as a red solid (352 mg, 62%). ' H NMR (de-DMSO, 300 MHz): d 8.17-8.13 (m, 1H), 8.07-8.03 (m, 1H), 7.74 (td, J = 8 Hz, 4 Hz, 1H), 7.64 (td, J = 8 Hz, 4 Hz, 1H), 6.28 (t, J = 74 Hz, 1H), 4.16-4.08 (m, 4H). STEP 2: Preparation of N-(3-chloro-l,4-dioxo-2-naphthyl)-N-[2
(difluoromethoxy)ethyl] acetamide
Figure imgf000047_0001
[00180] To a stirred suspension of 2-chloro-3-[2- (difluoromethoxy)ethylamino]naphthalene-l,4-dione (349 mg, 1.15 mmol) in acetic anhydride (1 mL) at room temperature was added concentrated sulfuric acid (1 drop). The resulting mixture was stirred at room temperature for 1 h (colour changes form dark red to yellow). The mixture was diluted with diethyl ether and washed with brine (lx) and saturated NaHCCh (4x). The organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated giving a yellow solid (375 mg, 94%). ' H NMR (de-DMSO, 300 MHz): d 8.15-8.05 (m, 2H), 7.95-7.89 (m, 2H), 6.54 (t, J = 76 Hz, 1H), 3.95-3.83 (m, 2H), 3.81-3.71 (m, 2H), 1.88 (s, 3H).
STEP 3: N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3-(pyrazin-2- ylmethylamino)-2-naphthyl]acetamide
Figure imgf000047_0002
[00181] To a stirred solution of N-(3-chloro-l,4-dioxo-2-naphthyl)-N-[2-
(difluoromethoxy)ethyl]acetamide (300 mg, 0.87 mmol) in THF (8 mL) was added pyrazin-2-ylmethanamine (0.174 mL, 1.83 mmol) and the resulting mixture was stirred at room temperature for 2 h. The mixture was then diluted with diethyl ether and washed with brine (lx) and a 1 : 1 mixture of brine: water (3x) and brine (lx). The organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated giving the desired product as an orange solid.
STEP 4\ 3-[2-(difluoromethoxy)ethyl]-2-methyl-l-(pyrazin-2- ylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide
Figure imgf000048_0001
[00182] To a stirred suspension of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo- 3-(pyrazin-2-ylmethylamino)-2-naphthyl]acetamide (310 mg, 0.744 mmol) in methanol (3 mL) was added HBr, 48% (141 pL). The resulting mixture was stirred at 65 °C for 4 h (solid material slowly dissolves). The mixture was concentrated in vacuo and the residue was triturated with a 1 :2 mixture of acetone: ethyl acetate, giving the desired product as a fine tan powder, collected via vacuum filtration (359 mg, quantitative). Ή NMR (de-DMSO, 400 MHz): d 8.97-8.95 (m, 1H), 8.66-8.64 (m, 1H), 8.55-8.52 (m, 1H), 8.21-8.17 (m, 1H), 8.14-8.11 (m, 1H), 8.03-7.94 (m, 2H), 6.66 (t, J = 76 Hz, 1H), 6.19 (s, 2H), 5.04 (t, J = 6 Hz, 2H), 4.36 (t, J = 6 Hz, 2H), 2.99 (s, 3H).
(b) 3-[2-(difluoromethoxy)ethyl]-2-methyl-l-(2- pyridylmethyl)benzo[f]benzimida- zol-3-ium-4,9-dione bromide
Figure imgf000048_0002
(i) Preparation of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3-(2- pyridylmethylamino)-2-naphthyl]acetamide
Figure imgf000049_0001
[00183] To a stirred solution of N-(3-chloro-l,4-dioxo-2-naphthyl)-N-[2- (difluoromethoxy)ethyl]acetamide (196 mg, 0.57 mmol) in THF (2 mL) was added 2- pyridylmethanamine (117 pL, 1.14 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was then diluted with diethyl ether and washed with saturated Na2CC>3 (lx), a 1 : 1 mix of water: saturated Na2CC>3 (2x) and brine (lx). The organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo giving the desired product as an orange solid (158 mg, 67%). Isolated material used directly in the subsequent step.
(ii) Preparation of 3-[2-(difluoromethoxy)ethyl]-2-methyl-l-(2- pyridylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide
Figure imgf000049_0002
[00184] To a stirred solution of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3- (2-pyridylmethylamino)-2-naphthyl] acetamide (158 mg, 0.380 mmol) in methanol (2 mL) was added hydrobromic acid, 48% (72 pL) and the resulting mixture was stirred at 65 °C for 4 h. The mixture was then concentrated in vacuo and triturated with a 2: 1 mixture of ethyl acetate: acetone. The resulting suspension was fdtered to collect the desired product as a tan powder (180 mg, quantitative). ' H NMR (de-DMSO, 300 MHz): d 8.45-8.39 (m, 1H), 8.20-8.15 (m, 1H), 8.14-8.08 (m, 1H), 8.02-7.94 (m, 2H), 7.93-7.85 (m, 1H), 7.66-7.60 (m, 1H), 7.40-7.32 (m, 1H), 6.64 (t, J = 76 Hz, 1H), 6.10 (s, 2H), 5.06-4.97 (m, 2H), 4.39-4.31 (m, 2H), 2.94 (s, 3H). (c) 3- [2-(difluoromethoxy)ethyl]-2-methyl-l-(3-pyridylmethyl)benzo [f] benzimidazol-3-ium-4,9-dione bromide
Figure imgf000050_0001
(i) Preparation of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3-(3- pyridylmethylamino)-2-naphthyl]acetamide
Figure imgf000050_0002
[00185] To a stirred solution of N-(3-chloro-l,4-dioxo-2-naphthyl)-N-[2- (difluoromethoxy)ethyl]acetamide (196 mg, 0.57 mmol) in THF (2 mL) was added 3- pyridylmethanamine (116 pL, 1.14 mmol) and the resulting mixture was stirred overnight at room temperature. The mixture was then diluted with diethyl ether and washed with saturated Na2CC>3 (lx), a 1 : 1 mix of water: saturated Na2CC>3 (2x) and brine (lx). The organic phase was dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo giving the desired product as a red oil (209 mg, 88%). Isolated material was used directly in the subsequent reaction.
(ii) Preparation of 3 -[2-(difluoromethoxy)ethyl] -2-methyl- 1 -(3- pyridylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide
Figure imgf000051_0001
[00186] To a stirred solution of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3- (3-pyridylmethylamino)-2-naphthyl] acetamide (209 mg, 0.503 mmol) in methanol was added hydrobromic acid, 48% (95 pL) and the resulting mixture was stirred at 65 °C for 4 h. The mixture was then concentrated in vacuo giving a semi solid which was stirred in acetone. The resulting tan solid was collected via vacuum filtration giving the desired product (212 mg, 88%). ' H NMR (d6-DMSO, 300 MHz): d 8.71- 8.62 (m, 2H), 8.25-8.13 (m, 2H), 8.04-7.97 (m, 2H), 7.96-7.88 (m, 1H), 7.61-7.54 (m, 1H), 6.65 (t, J = 75 Hz, 1H), 6.08 (s, 2H), 5.03-4.95 (m, 2H), 4.38-4.30 (m, 2H), 2.92 (s, 3H).
(d) 1,3-bis [2-(difluoromethoxy)ethyl] -2-methyl-benzo [f] benzimidazol-3-ium-
4,9-dione bromide
Figure imgf000051_0002
(i) Preparation of N-[2-(difluoromethoxy)ethyl]-N-[3-[2 (difluoromethoxy)ethyl- amino] - 1 ,4-di oxo-2 -naphthyl] acetamide
Figure imgf000052_0001
[00187] To a stirred solution of N-(3-chloro-l,4-di oxo-2 -naphthyl)-N-[2- (difluoromethoxy)ethyl] acetamide (375 mg, 1.09 mmol) and DIPEA (208 pL. 1.20 mmol) in THF (5 mL) was added 2-(difluoromethoxy)ethanamine (133 mg, 1.20 mmol) and the resulting mixture was stirred at room temperature for 4 h. The mixture was then diluted with diethyl ether and washed with brine (3x). The organic phase dried over anhydrous sodium sulfate, fdtered and concentrated in vacuo then chromatographed in 20-75% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving the desired product as a red oil (214 mg, 47%). ¾ NMR (CDCb, 400 MHz): d 8.15-8.08 (m, 2H), 7.81-7.76 (m, 1H), 7.72- 7.66 (m, 1H), 6.29 (t, J = 72 Hz, 1H), 6.09 (t, J = 74 Hz, 1H), 4.10-3.91 (m, 4H), 3.89- 3.46 (m, 4H), 1.99 (s, 3H).
(ii) Preparation of l,3-bis[2-(difluoromethoxy)ethyl]-2-methyl- benzo[f]benzimidazol-3-ium-4,9-dione bromide
Figure imgf000052_0002
[00188] To a stirred solution of N-[2-(difluoromethoxy)ethyl]-N-[3-[2- (difluoromethoxy)ethylamino]-l,4-di oxo-2 -naphthyl] acetamide (210 mg, 0.501 mmol) in methanol (2 mL) was added hydrobromic acid, 48% (100 pL) and the resulting mixture was stirred at 65 °C for 3 h. The mixture was then concentrated in vacuo and triturated with diethyl ether giving a sticky gum which slowly formed a fine solid. The suspension was filtered to collect the desired product (130 mg, 52%). ¾ NMR (de-DMSO, 300 MHz): d 8.24-8.14 (m, 2H), 8.05-7.95 (m, 2H), 6.64 (t, J = 75 Hz, 1H), 6.61 (t, J = 75 Hz, 1H), 5.02-4.69 (m, 4H), 4.36-3.80 (m, 4H), 2.91 (s, 3H).
(e) l-[2-(difluoromethoxy)ethyl]-2-methyl-3-(l- phenylethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide
(i) Preparation of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3-(l- phenylethylamino)-2-naphthyl]acetamide
Figure imgf000053_0001
[00189] To a stirred solution of N-(3-chloro-l,4-dioxo-2-naphthyl)-N-[2- (difluoromethoxy)ethyl] acetamide (400 mg, 1.16 mmol) in THF (6 mL) was added 1- phenylethanamine (racemic, 165 pL, 1.28 mmol) and potassium carbonate (321 mg, 2.32 mmol). The resulting suspension was stirred at rrom temperature for 2 h. The mixture was then diluted with diethyl ether and washed with brine (lx), water 2x) and brine (lx). The organic phase was dried, fdtered and concentrated in vacuo then chromatographed in 0 - 50% ethyl acetate in hexanes. The product containing fractions were concentrated in vacuo giving the desired product as a red/orange oil which slowly solidified (150 mg, 30%). ¾ NMR (300 MHz, de-DMSO): 5(ppm): 8.08-8.01 (m, 1H), 7.99-7.90 (m, 1H), 7.88-7.72 (m, 2H), 7.44-7.31 (m, 2H), 7.28- 7.16 (m, 3H), 6.54 (t, J = 76 Hz, 1H), 4.99-4.86 (m, 1H), 4.18-4.05 (m, 1H), 3.99-3.90 (m, 1H), 3.79-3.66 (m, 1H), 3.22-3.09 (m, 1H),1.56 (d, J = 6 Hz, 3H). (ii) Preparation of l-[2-(difluoromethoxy)ethyl]-2-methyl-3-(l- phenylethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide
Figure imgf000054_0001
[00190] To a stirred solution of N-[2-(difluoromethoxy)ethyl]-N-[l,4-dioxo-3- (l-phenylethylamino)-2-naphthyl] acetamide (150 mg, 0.356 mmol) in methanol (2 mL) was added HBR, 48% (66 pL) and the resulting mixture was stirred at 70 °C for 4 h. The mixture was concentrated in vacuo then triturated with acetone and ethyl acetate giving a cloudy suspension. The mixture was fdtered to collect the desired product as a pale yellow solid (135 mg, 77%). ¾ NMR (300 MHz, d6-DMSO): 5(ppm): 8.23-8.10 (m, 2H), 8.03-7.94 (m, 2H), 7.45-7.32 (m, 5H), 7.00-6.89 (m, 1H), 6.61 (t, J = 75 Hz, 1H), 4.99-4.91 (m, 1H), 4.75-4.67 (m, 1H), 4.34-4.27 (m, 1H), 3.87-3.89 (m, 1H), 2.64 (s, 3H), 2.02 (d, J = 6 Hz, 3H).
[00191] In a like manner, the following additional compounds of the application were prepared:
(f) l-[2-(difluoromethoxy)ethyl]-2-methyl-3-(4,4,4-trifluorobutyl)benzo[f] benz- imidazol-3-ium-4,9-dione bromide
Figure imgf000054_0002
[00192] Yellow solid, 73% yield: ¾ NMR (300 MHz, de-DMSO): 5(ppm): 8.26-8.16 (m, 2H), 8.04-7.97 (m, 2H), 6.64 (t, J = 75 Hz, 1H), 4.98-4.90 (m, 2H), 4.78-4.67 (m, 2H), 4.33-4.27 (m, 2H), 2.92 (s, 3H), 2.47-2.38 (m, 2H), 2.11-1.98 (m, 2H). (g) 2-methyl-l,3-bis(4,4,4-trifluorobutyl)benzo[f]benzimidazol-3-ium-4,9- dione bromide
Figure imgf000055_0001
[00193] Yellow solid, 80% yield: ¾ NMR (400 MHz, CDCb): 5(ppm): 8.29- 8.11 (m, 2H), 8.11-7.90 (m, 2H), 4.78-4.55 (m, 4H), 2.56-2.40 (m, 4H), 2.11-1.99 (m, 4H).
(h) 2-methyl-3-(3-pyridylmethyl)- 1-(4,4,4- trifluorobutyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide
Figure imgf000055_0002
[00194] Pale orange solid, 98% yield: ¾ NMR (400 MHz, de-DMSO): 5(ppm): 8.74-8.71 (m, 1H), 8.66 (d, J = 8 Hz, 1H), 8.23-8.19 (m, 1H), 8.15-8.11 (m, 1H), 8.03- 7.95 (m, 3H), 7.64-7.57 (m, 1H), 6.01 (s, 2H), 4.70 (t, J = 8 Hz, 1H), 2.92 (s, 3H), 2.56-2.48 (m, 2H), 2.13-2.05 (m, 2H).
(i) 1- [2-(difluoromethoxy)ethyl]-2-methyl-3-(3,3,3- trifluoropropyl)benzo[f]ben- zimidazol-3-ium-4,9-dione bromide
Figure imgf000055_0003
[00195] Yellow solid, 46% yield: ¾ NMR (300 MHz, de-DMSO): 5(ppm): 8.24-8.16 (m, 2H), 8.05-7.97 (m, 2H), 6.63 (t, J = 75 Hz, 1H), 5.03-4.90 (m, 4H), 4.33-4.27 (m, 2H), 3.11-2.96 (m, 2H), 2.94 (s, 3H).
(j) 2-methyl-l,3-bis(3,3,3-trifluoropropyl)benzo[f]benzimidazol-3-ium-4,9- dione bromide
Figure imgf000056_0001
[00196] Pale green/yellow solid, 60% yield: ¾ NMR (300 MHz, de-DMSO): 5(ppm): 8.28-8.16 (m, 2H), 8.09-7.95 (m, 2H)3.11-2.90 (m, 8H), 1.97 (s, 3H).
Example 3: Biological Testing
(A) Inhibition of Tumor Growth
National Cancer Institute (NCI) screening panel:
[00197] Representative compounds of Formula I were screened using the National Cancer Institute (NCI) screening panel, which consists of a panel of 60 different human tumor cell lines, representing leukemia [CCRF-CEM, HL-60 (TB), K-562, MOLT-4, SR], melanoma [LOX IMVI, MALME-3M, M14, SMDA-MB-435, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257 and UACC-62] and cancers of the lung [A549/ATCC, EKVX, HOP-62, HOP-93, NCI-H226, NCI-H23, NCI-H322M, NCI-H460], colon [COLO 205, HCT-116, HCT-15, HT29, KM12, SW-620], brain [SF-268, SF-295, SF-539, SNB-19, SNB-75, U251], ovary [IGROV1, OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8, NCI/ADR-RES, SK-OV-3], breast [MCF7, MDA-MB-231, BT-549, T-47D, MDA-MB-468], prostate [PC-3, DU-145], and renal [786-0, A498, ACHN, CAKI-1, RXF-393, SN12C, TK-10, UO-31] cancers.
[00198] After 24 h, two plates of each cell line are fixed in situ with TCA, to represent a measurement of the cell population for each cell line at the time of drug addition (Tz). Experimental drugs are solubilised in dimethyl sulfoxide at 400-fold the desired final maximum test concentration and stored frozen prior to use. At the time of drug addition, an aliquot of frozen concentrate is thawed and diluted to twice the desired final maximum test concentration with complete medium containing 50 pg/ml gentamicin. Additional four, 10-fold or ½ log serial dilutions are made to provide a total of five drug concentrations plus control. Aliquots of 100 pi of these different drug dilutions are added to the appropriate microtiter wells already containing 100 mΐ of medium, resulting in the required final drug concentrations.
[00199] Following drug addition, the plates are incubated for an additional 48 h at 37°C, 5% CO2, 95 % air, and 100% relative humidity. For adherent cells, the assay is terminated by the addition of cold TCA (trichloroacetic acid). Cells are fixed in situ by the gentle addition of 50 mΐ of cold 50% (w/v) TCA (final concentration, 10% TCA) and incubated for 60 minutes at 4°C. The supernatant is discarded, and the plates are washed five times with tap water and air dried. Sulforhodamine B (SRB) solution (100 mΐ) at 0.4 % (w/v) in 1% acetic acid is added to each well, and plates are incubated for 10 minutes at room temperature. After staining, unbound dye is removed by washing five times with 1% acetic acid and the plates are air dried. Bound stain is subsequently solubilised with 10 mM trizma base, and the absorbance is read on an automated plate reader at a wavelength of 515 nm. For suspension cells, the methodology is the same except that the assay is terminated by fixing settled cells at the bottom of the wells by gently adding 50 mΐ of 80% TCA (final concentration, 16% TCA). Using the seven absorbance measurements [time zero, (Tz), control growth, (C), and test growth in the presence of drug at the five concentration levels (Ti)], the percentage growth is calculated at each of the drug concentration levels. Percentage growth inhibition is calculated as: [(Ti-Tz)/(C-Tz)] x 100 for concentrations in which T>/=TZ and | (Tj-Tz)/Tz | x 100 for concentrations in which Ti<Tz.
[00200] Three dose response parameters are calculated for each experimental agent. Growth inhibition of 50% (GI50) is calculated from [(Ti-Tz)/(C-Tz)] x 100 = 50, which is the drug concentration resulting in a 50% reduction in the net protein increase (as measured by SRB staining) in control cells during the drug incubation. The drug concentration resulting in total growth inhibition (TGI) is calculated from T; = Tz. The LC50 (concentration of drug resulting in a 50% reduction in the measured protein at the end of the drug treatment as compared to that at the beginning) indicating a net loss of cells following treatment is calculated from [(Ti-Tz)/Tz] x 100 = -50. Values are calculated for each of these three parameters if the level of activity is reached. However, if the effect is not reached or is exceeded, the value for that parameter is expressed as greater or less than the maximum or minimum concentration tested.
[00201] The results obtained from this study shows compounds of Formula I are effective against the cell lines of the 60 human tumor cell lines panel. Inhibition of human cancer cell lines in vitro by representative compounds of Formula I are shown in Table 1 [compound of example 2(a)], Table 2 [compound of example 2(d)], Table 3 [compound of example 2(b)] and Table 4 [compound of example 2(c)]
(B) Inhibition of Tumor Growth in Mouse Xenograft Models:
Efficacy on tumor Growth inhibition in myeloma MM. IS mouse xenograft models :
[00202] The mice were irradiated (200 rads) using a Co60 irradiator source. After 24 hrs, each mouse was inoculated subcutaneously with 5 x 106 MM. IS tumor cells in 0.1 ml PBS for tumor development. Treatments were started when the tumor volume reached 100 mm3. Each treatment group consisted of 10 mice. The test articles of compounds of Formula I were administrated to the tumor-bearing mice according to a specific predetermined regimen. Compound of example 2(a) at dose levels of 50 mg/kg (p.o, qd x 28 days) and 100 mg/kg (p.o, days 1, 3, 5/wk x 4 wks) produced statically significant antitumor activity vs. control with no observed gross adverse effects including reductions in body weight or alterations in behaviour.
[00203] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the present application is not limited to the disclosed examples. To the contrary, the present application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
[00204] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term. Table 1: Results of compound of example 2(a) within the NCI screening panel
Figure imgf000059_0001
Figure imgf000060_0001
Table 2: Results of compound of example 2(d) within the NCI screening panel
Figure imgf000061_0001
Figure imgf000062_0001
Table 3: Results of compound of example 2(b) within the NCI screening panel
Figure imgf000063_0001
Figure imgf000064_0001
Table 4: Results of compound of example 2(c) within the NCI screening panel
Figure imgf000065_0001
Figure imgf000066_0001

Claims

Claims:
1. A compound of Formula I or II, or a pharmaceutically acceptable salt, solvate and/or prodrug thereof:
Figure imgf000067_0001
wherein:
R1 is H or Ci-6alkyl,
R2 is selected from H, CN, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, Ci-iohaloalkyl, Ci- locyanoalkyl, O-Ci-ioalkyl, 0-C2-ioalkenyl, 0-C2-ioalkynyl, C3-iocycloalkyl, heterocycloalkyl, C6-2oaryl, heteroaryl, Ci-ealkylene-O-Ci-ealkyl, Ci-ealkylene-O-Ci- 6haloalkyl, C2-6alkenyl-0-Ci-6haloalkyl, C2-6alkynyl-0-Ci-6haloalkyl, Ci-6alkylene-C3- locycloalkyl, Ci-6alkylene-heterocycloalkyl, Ci-6alkylene-C6-2oaryl, Ci-6alkylene- heteroaryl, wherein any cyclic moiety is optionally substituted with Ci-4alkyl or is optionally fused to a further 5- to 7-membered heterocycloalkyl;
X- is a counter anion;
A is Co-ealkylene, O, S, SO, SO2 or NR3;
R3 is H or Ci-6alkyl;
n is 0, 1, 2 or 3; and
Xi, X2, X3 are the same or different and is selected from H, halogen and Ci-6alkyl, provided that at least one of X1, X2 and X3 is F.
2. The compound of claim 1, wherein R1 is Ci-6alkyl.
3. The compound of claim 2, wherein R1 is selected from methyl, ethyl, propyl and /-butyl.
4. The compound of claim 3, wherein R1 is methyl.
5. The compound of any one of claims 1 to 4, wherein R2 is selected from:
(i) Ci-ioalkyl;
(ii) C2-ioalkenyl; (iii) C2-ioalkynyl;
(iv) substituted or unsubstituted Ce-i4aryl;
(v) substituted or unsubstituted Ci-6alkylene-C6-2oaryl;
(vi) substituted or unsubstituted heteroaryl;
(vii) substituted or unsubstituted C3-iocycloalkyl; and
(viii) substituted or unsubstituted C3-ioheterocycloalkyl, wherein the substituent is Ci-4alkyl.
6. The compound of claim 5, wherein R2 is selected from:
(i) Ci-ealkyl;
(ii) C2-ealkenyl;
(iii) C2-ealkynyl;
(iv) substituted or unsubstituted C6-ioaryl;
(v) substituted or unsubstituted Ci-4alkylene-C6-ioaryl;
(vi) substituted or unsubstituted 5- or 6-membered heteroaryl;
(vii) substituted or unsubstituted C3-scycloalkyl; and
(viii) substituted or unsubstituted C3-8heterocycloalkyl, wherein the substituent is Ci-4alkyl.
7. The compound of claim 6, wherein R2 is selected from:
(i) Ci-ealkyl;
(ii) substituted or unsubstituted 5- or 6-membered heteroaryl;
(iii) C3-8heterocycloalkyl; and
(iv) substituted or unsubstituted Ci-4alkylene-C6-ioaryl, wherein the substituent is Ci-4alkyl.
8. The compound of any one of claims 5 to 7, wherein R2 is Ci-6alkyl.
9. The compound of claim 8, wherein R2 is /-butyl.
10. The compound of claim 8, wherein R2 is methyl.
11. The compound of any one of claims 5 to 7, wherein R2 is selected from unsubstituted 5- or 6-membered heteroaryl, substituted 5- or 6-membered heteroaryl and substituted C3-8heterocycloalkyl, wherein the substituent is Ci-4alkyl.
12. The compound of claim 11, wherein R2 is selected from unsubstituted 5- or 6- membered heteroaryl, substituted 5-membered heteroaryl and substituted 6-membered heterocycloalkyl, wherein the substituent is Ci-4alkyl.
13. The compound of claim 12, wherein R2 is unsubstituted 5- or 6-membered heteroaryl or substituted 5- or 6-membered heteroaryl wherein the substituent is Ci- 4alkyl.
14. The compound of claims 11 to 13, wherein R2 is an unsubstituted 5-membered heteroaryl.
15. The compound of claims 11 to 13, wherein R2 is an unsubstituted 6-membered heteroaryl.
16. The compound of claims 11 to 13, wherein R2 is a 5-membered heteroaryl, substituted with a Ci-4alkyl.
17. The compound of claim 16, wherein R2 is a 5-membered heteroaryl, substituted with a methyl.
18. The compound of any one of claims 5 to 7, wherein R2 is substituted or unsubstituted Ci-4alkylene-C6-ioaryl, wherein the substituent is Ci-4alkyl.
19. The compound of claim 18, wherein R2 is substituted or unsubstituted Ci- 2alkylene-C6-ioaryl, wherein the substituent is Ci-4alkyl.
20. The compound of claim 19, wherein R2 is substituted Ci-2alkylene-C6-ioaryl, wherein the substituent is methyl.
21. The compound of claim 1, wherein R2 is selected from:
(i) substituted or unsubstituted thiazolyl;
(ii) substituted or unsubstituted isothiazolyl;
(iii) substituted or unsubstituted oxazolyl;
(iv) substituted or unsubstituted isooxazolyl;
(v) substituted or unsubstituted thiophenyl; (vi) substituted or unsubstituted furanyl;
(vii) substituted or unsubstituted 1,2,4-triazolyl;
(viii) substituted or unsubstituted pyridyl;
(ix) substituted or unsubstituted pyrazinyl;
(x) substituted or unsubstituted pyrimidinyl; and
(xi) substituted or unsubstituted 1,2,4-triazinyl, wherein the substituent is Ci-4alkyl.
22. The compound of claim 21, wherein R2 is selected from:
(i) substituted or unsubstituted isoxazolyl;
(ii) substituted or unsubstituted isothiazolyl;
(iii) substituted or unsubstituted furanyl;
(iv) substituted or unsubstituted thiophenyl;
(v) substituted or unsubstituted oxazolyl;
(vi) substituted or unsubstituted thiazolyl;
(vii) substituted or unsubstituted pyrazolyl; and
(viii) substituted or unsubstituted imidazolyl, wherein the substituent is Ci-4alkyl.
23. The compound of claim 22, wherein R2 is selected from:
(i) substituted or unsubstituted isoxazolyl;
(ii) substituted or unsubstituted furanyl; and
(iii) substituted or unsubstituted thiazolyl,
wherein the substituent is Ci-4alkyl.
24. The compound of claim 1, wherein R2 is selected from:
Figure imgf000071_0001
wherein ' represents the point of attachment with the remainer of the compound.
25. The compound of claim 24, wherein R2 is selected from:
Figure imgf000071_0002
wherein « represents the point of attachment with the remainer of the compound.
26. The compound of any one of claims 1 to 25, wherein X1, X2 and X3 are the same or different and are selected from H, F, and Ci-4alkyl, provided that at least one of X1, X2 and X3 is F.
27. The compound of claim 26, wherein X1, X2 and X3 are the same or different and are selected from H and F, provided that at least one of X1, X2 and X3 is F.
28. The compound of claim 27, wherein one or two of X1, X2 and X3 are F and the other of X1, X2 and X3 is H.
29. The compound of claim 28, wherein two of X1, X2 and X3 are F and the other one of X1, X2 and X3 is H.
30. The compound of any one of claims 1 to 29, wherein is carbonate, bicarbonate, sulfate, nitrate, phosphate, acetate, trifluoroacetate, propionate, glycolate, lactate, lactobionate, pyruvate, malonate, succinate, glutamate, gluconate, gluceptate, fumarate, malate, maleate, mandelate, mucate, napsylate, tartrate, teoclate, bitartrate, citrate, ascorbate, maleic, hydroxymaleic, benzoate, besylate, camsylate, hexanoate, hydroxynaphthoate, octanoate, oleate, decanoate, edetate, esylate, isethionate, hydroxybenzoate, pamoate, pantothenate, polygalacturonate, phenylacetate, cinnamate, mandelate, salicylate, stearate, 2-phenoxybenzate, benzenesulfonate, tosylate, mesylate ethanesulfonate or 2-hydroxyethanesulfonate.
31. The compound of claim 30, wherein X- is chloride, mesylate, bromide, acetate or fumarate.
32. The compound of claim 30, wherein X- is chloride or bromide.
33. The compound of any one of claims 1 to 32, wherein A is Co-4alkylene or O.
34. The compound of claim 33, wherein A is CTh or O.
35. The compound of any one of claims 1 to 34, wherein n is 1 or 2.
36. The compound of claim 1, selected from:
3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(pyrazin-2- ylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(2- pyridylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
3- [2-(difluoromethoxy)ethyl] -2 -methyl- 1 -(3 - pyridylmethyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
l,3-bis[2-(difluoromethoxy)ethyl]-2-methyl-benzo[f]benzimidazol-3-ium- 4,9- dione bromide;
1-[2-(difluoromethoxy)ethyl]-2-methyl-3-(4,4,4- trifluorobutyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide;
2-methyl-l,3-bis(4,4,4-trifluorobutyl)benzo[f]benzimidazol-3-ium-4,9- dione bromide;
2-methyl-3-(3-pyridylmethyl)-l -(4,4,4- trifluorobutyl)benzo[f]benzimidazol- 3-ium-4,9-dione bromide;
1-[2-(difluoromethoxy)ethyl]-2-methyl-3-(3,3,3- trifluoropropyl)benzo[f]benzimidazol-3-ium-4,9-dione bromide; and
2-methyl-l,3-bis(3,3,3-trifluoropropyl)benzo[f]benzimidazol-3-ium-4,9- dione bromide;
or a salt, solvate or prodrug thereof.
37. A pharmaceutical composition comprising one or more compounds of any one of claims 1-36, or a pharmaceutically acceptable salt, and/or solvate thereof, and a pharmaceutically acceptable carrier.
38. The pharmaceutical composition of claim 37 further comprising an additional therapeutic agent.
39. A method for suppressing survivin in a cell, comprising administering an effective amount of one or more compounds of any one of claims 1-36, or a pharmaceutically acceptable salt, and/or solvate thereof, to the cell.
40. A method of inhibiting uncontrolled and/or abnormal cellular activities affected directly or indirectly by survivin inhibition in a cell, comprising administering an effective amount of one or more compounds of any one of claims 1- 36, or a pharmaceutically acceptable salt, and/or solvate thereof, to the cell.
41. A method of treating one or more diseases, disorders or conditions that is mediated by survivin suppression, comprising administering an effective amount of one or more compounds of any one of claims 1-36, or a pharmaceutically acceptable salt, and/or solvate thereof, to a subject in need thereof.
42. The method of claim 41, wherein the disease, disorder or condition that is mediated by survivin inhibition is a disease, disorder or condition associated with an uncontrolled and/or abnormal cellular activity affected directly or indirectly by survivin inhibition.
43. The method of claim 42, wherein the disease, disorder or condition is cancer.
44. The method of claim 43, wherein the one or more compounds of any one of claims 1-36, or a pharmaceutically acceptable salt, and/or solvate thereof, are administered for the prevention of cancer in a subject having a predisposition for cancer.
45. The method of claim 44, wherein the cancer is selected from a cancer of the skin, blood, prostate, colorectum, pancreas, kidney, ovary, breast, liver, tongue and lung.
46. The method of claim 45, wherein the cancer is selected from leukaemia, lymphoma, non-Hodgkin’s lymphoma and multiple myeloma.
47. The method of any one of claims 44, 45 and 46, wherein the one or more compounds of any one or claims 1-36, or a pharmaceutically acceptable salt, and/or solvate thereof, are administered in combination with one or more additional cancer treatments.
48. The method of claim 47, wherein the additional cancer treatment is selected from radiotherapy, chemotherapy and targeted therapies.
49. The method of claim 48, wherein the targeted thereapies are selected from antibody therapies and small molecule therapies.
50. The method of claim 49, wherein the targeted therapies are selected from tyrosine-kinase inhibitors, immunotherapy, hormonal therapy and anti-angiogenic therapies.
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