WO2025007113A2 - Inhibiteurs du complexe mitochondrial i à inhibition réduite de la phosphodiestérase - Google Patents

Inhibiteurs du complexe mitochondrial i à inhibition réduite de la phosphodiestérase Download PDF

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WO2025007113A2
WO2025007113A2 PCT/US2024/036369 US2024036369W WO2025007113A2 WO 2025007113 A2 WO2025007113 A2 WO 2025007113A2 US 2024036369 W US2024036369 W US 2024036369W WO 2025007113 A2 WO2025007113 A2 WO 2025007113A2
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pharmaceutically acceptable
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WO2025007113A3 (fr
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Nicholas Denko
Mark MITTON-FRY
Ben HAINES
Martin BENEJ
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Ohio State Innovation Foundation
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
    • 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
    • C07D401/10—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 aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This disclosure relates to compounds for treating medical disorders, and more particularly to inhibitors of mitochondrial complex I which are useful in treating cancers, such as by sensitizing cancers to radiation therapy.
  • Mitochondrial complex I inhibitors such as papaverine and SMV-32 have been previously shown to sensitive tumors to radiation therapy (see Proc. Natl. Acad. Sci. 2018, 115(49), El 1561).
  • papaverine also inhibits PDElOa, and this off-target activity is believed to lead to side effects that limit the dose that can be administered clinically.
  • SMV- 32 partially overcomes this liability, but there is a clear need for additional compounds which further dissociate mitochondrial complex I inhibition from PDElOa inhibition.
  • the present disclosure provides compounds which are useful as mitochondrial complex I inhibitors which also show limited inhibition of phosphodiesterases (particularly PDElOa). Also provided are methods of using the compounds described herein in the treatment of medical disorders.
  • a compound is provided of Formula I or a pharmaceutically acceptable salt thereof; wherein all variables are as defined herein.
  • a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • a method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.
  • a method of sensitizing a cancer to radiation therapy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein prior to or concurrently with the radiation therapy.
  • the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate, larger or smaller, as desired, reflecting tolerances, conversion factors, rounding, measurement error, and the like, and other factors known to those of skill in the art such that equivalent results or effects are obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, as used herein, “about” and “at or about” mean the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred.
  • an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. Where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless expressly stated otherwise.
  • the term “therapeutically effective amount” refers to an amount sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the particular compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts.
  • the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to permanently halt the progression of the disease. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease.
  • the desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset.
  • the effective daily dose can be divided into multiple doses for administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the individual physician can adjust the dosage in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the invention (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. However, a patient may insist on a lower or tolerable dose for medical reasons, psychological reasons, or virtually any other reason.
  • a response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent.
  • Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response.
  • the amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound or pharmaceutical composition, changing the disclosed compound or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more dose administrations daily for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • subject can refer to a vertebrate organism, such as a mammal (e.g., human). “Subject” can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof.
  • treating and “treatment” generally refer to obtaining a desired pharmacological or physiological effect.
  • the effect can be but does not necessarily have to be prophylactic in preventing or partially preventing a disease, symptom, or condition such as a cancer.
  • the effect can be therapeutic regarding a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition.
  • treatment as used herein can include any treatment of a disorder in a subject, particularly a human.
  • treatment can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment.
  • Those in need of treatment i.e., subjects in need thereof
  • treating can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, or condition.
  • Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.
  • dose can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration.
  • terapéutica can refer to treating, healing, or ameliorating a disease, disorder, condition, or side effect or decreasing the rate of advancement of a disease, disorder, condition, or side effect.
  • the compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R-) or (5-) configuration. The compounds provided herein may either be enantiomerically pure, or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo.
  • Compounds described herein may contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless states to the contrary, all such possible isomers are contemplated, as well as mixtures of such isomers.
  • Compounds described herein may also present as an equilibrium of tautomers. For example, ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated.
  • a dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable.
  • a pyridyl group substituted by oxo is a pyridine.
  • a stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month.
  • a stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use.
  • a stable moiety or substituent group is one that does not degrade, react or fall apart within the period necessary for use.
  • Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art.
  • Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the invention and includes, but is not limited to: alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • “ ? ” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond.
  • the specific point of attachment to the non-depicted chemical entity can be specified by inference.
  • Alkyl is a straight chain or branched saturated aliphatic hydrocarbon group.
  • the alkyl is C1-C2, C1-C3, or Ci-Ce (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length).
  • the specified ranges as used herein indicate an alkyl group with length of each member of the range described as an independent species.
  • Ci-Cealkyl indicates an alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species
  • Ci-C4alkyl indicates an alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species.
  • Co- Cnalkyl is used herein in conjunction with another group, for example (C3-C7cycloalkyl)Co- C4alkyl, or -Co-C4(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (Coalkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms.
  • Alkyls can also be attached via other groups such as heteroatoms, as in -0-Co-C4alkyl(C3-C7cycloalkyl).
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3 -methylpentane, 2,2- dimethylbutane, and 2, 3 -dimethylbutane.
  • the alkyl group is optionally substituted as described herein.
  • alkyl as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent alkyl, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • Cycloalkyl is a saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion.
  • Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments, the cycloalkyl group is optionally substituted as described herein.
  • cycloalkyl as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent cycloalkyl, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • Alkenyl is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain.
  • Non-limiting examples include C2-C4alkenyl and C2-Cealkenyl (i.e., having 2, 3, 4, 5, or 6 carbons).
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkenyl include, but are not limited to, ethenyl and propenyl. In one embodiment, the alkenyl group is optionally substituted as described herein.
  • alkenyl as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent alkenyl, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • Alkynyl is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-Cealkynyl (i.e., having 2, 3, 4, 5, or 6 carbons).
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described above for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3 -pentynyl, 4-pentynyl, 1 -hexynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl, and 5-hexynyl.
  • the alkynyl group is optionally substituted as described herein.
  • alkynyl as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent alkynyl, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • Alkoxy is an alkyl group as defined above covalently bound through an oxygen bridge (-O-).
  • alkoxy include, but are not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3 -pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3 -methylpentoxy.
  • an “alkylthio” or “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-).
  • the alkanoyl group is optionally substituted as described herein.
  • Halo or “halogen” indicates, independently, any of fluoro, chloro, bromo or iodo.
  • Aryl indicates an aromatic group containing only carbon in the aromatic ring or rings.
  • the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members.
  • such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si and S, to form, for example, a 3, 4-methylenedi oxyphenyl group.
  • Aryl groups include, for example, phenyl and naphthyl, including 1 -naphthyl and 2- naphthyl.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described herein.
  • the term “aryl” as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent aryl, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • heterocycle refers to saturated and partially saturated heteroatomcontaining ring radicals, where the heteroatoms may be selected from N, O, and S.
  • the term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions.
  • saturated heterocycle groups including saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6- membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl].
  • saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl
  • partially saturated heterocycle radicals include, but are not limited, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl.
  • partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[l,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1, 2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,
  • Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring.
  • Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical.
  • Representative examples include, but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.
  • heterocycle as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent heterocycle, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • Heteroaryl refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring which contains from 1 to 4, or in some embodiments 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some embodiments from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have from 5 to 6 ring atoms.
  • bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is groups containing 8 or 10 ring atoms in which one 5-, 6-, or 7-membered aromatic ring which contains from 1 to 4 heteroatoms selected from N, O, S, B, or P is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is an aromatic ring.
  • the total number of S and O atoms in the heteroaryl ring exceeds 1, these heteroatoms are not adjacent to one another within the ring. In one embodiment, the total number of S and O atoms in the heteroaryl ring is not more than 2.
  • the total number of S and O atoms in the heteroaryl ring is not more than 1.
  • heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl,
  • heteroaryl as used herein is not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent heteroaryl, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person.
  • a “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include salts which are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts.
  • Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)I-4-COOH, and the like, or using a different acid that produced the same counterion.
  • inorganic acids such as hydrochloric, hydrobromic,
  • Suitable counterions found in pharmaceutically acceptable salts described herein include, but are not limited to, cations such as calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, potassium, procaine, sodium, triethylamine, and zinc, and anions such as acetate, aspartate, benzenesulfonate, besylate, bicarbonate, bitartrate, bromide, camsylate, carbonate, chloride, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, hexanoate, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methyl sulfate, mucate, napsylate, nitrate, octanoate, oleate, pa
  • the present disclosure provides compounds which are inhibitors of mitochondrial complex I. Unlike the previously described inhibitor papaverine, the presently disclosed compounds also show limited inhibition of phosphodiesterases (particularly PDElOa), reducing off-target activity which leads to side effects.
  • a compound is provided of Formula I or a pharmaceutically acceptable salt thereof; wherein: R 1 and R 2 are each independently selected from H or -O-(Ci-Ce alkyl), wherein at least one or R 1 and R 2 is H;
  • X 1 and X 2 are each independently selected from N or C(R 4 ), wherein at least one or X 1 and X 2 is N;
  • R 3 is 5- to 10-membered monocyclic or bicyclic aryl optionally substituted with one or more groups (for example, 1, 2, 3, or 4 groups) selected from R 5 ;
  • R 4 is independent selected at each occurrence from H or halo
  • R 5 is selected from hydrogen, halo, nitro, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, R X O-(CO-C 3 alkyl)-, R x S-(Co-C 3 alkyl)-, (R’T 'NXCo-Cs alkyl)-, R x O-C(0)-(Co-C 3 alkyl)-, R X S-C(0)-(CO-
  • R x and R y are independently selected at each occurrence from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-Cealkynyl, (C3-C7cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;
  • R z is independently selected at each occurrence from hydrogen, halo, Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-Cealkynyl, (C3-C7cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, -OR X , -SR X , and -NR ⁇ , each of which may be optionally substituted with one or more Y groups (for example, 1, 2, 3, or 4 groups) as allowed by valency; and
  • Y is independently selected at each occurrence from alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, phospho, thiol, or combinations thereof.
  • R 1 is H. In some aspects of Formula I, R 1 is -O(Ci-Ce alkyl). In some aspects of Formula I, R 1 is -OCH3.
  • R 2 is H. In some aspects of Formula I, R 2 is -O(Ci-Ce alkyl). In some aspects of Formula I, R 2 is -OCH3.
  • R 1 is -OCH3 and R 2 is H. In some aspects of Formula I, R 1 is H and R 2 is -OCH3. In some aspects of Formula I, R 1 and R 2 are each H.
  • X 1 is N. In some aspects of Formula I, X 1 is C(R 4 ).
  • X 2 is N. In some aspects of Formula I, X 2 is C(R 4 ).
  • X 1 is N and X 2 is C(R 4 ). In some aspects of Formula I, X 1 is C(R 4 ) and X 2 is N.
  • R 4 is H. In some aspects of Formula I, R 4 is halo. In some aspects of Formula I, R 4 is selected from fluoro, chloro, bromo, and iodo. In some aspects of Formula I, R 4 is fluoro.
  • X 1 and X 2 are each N.
  • the compound of Formula I is selected from the group consisting of
  • R 3 is phenyl or 1 -naphthyl optionally substituted with one or more groups (for example, 1, 2, 3, or 4 groups) selected from R 5 .
  • R 3 is selected from the group consisting of:
  • R 3 is phenyl substituted with one group selected from
  • R 5 wherein R 5 is phenyl optionally substituted with one or more groups (for example, 1, 2, 3, or 4 groups) selected from Y.
  • R 3 is selected from the group consisting of: In some aspects of Formula I, R 3 is selected from the group consisting of:
  • Representative examples of compounds of Formula I include, but are not limited to:
  • a compound selected from:
  • a compound selected from:
  • the present disclosure also includes compounds described herein with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., enriched.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2 H, 3 H, n C, 13 C, 15 N, 17 O, 18 O, 18 F, 31 P’ 32 P, 35 S, 36 C1, and 125 I, respectively.
  • isotopically labeled compounds can be used in metabolic studies (with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients.
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • an 18 F labeled compound may be particularly desirable for PET or SPECT studies.
  • Isotopically labeled compounds of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • isotopes of hydrogen for example deuterium ( 2 H) and tritium ( 3 H) may optionally be used anywhere in described structures that achieves the desired result.
  • isotopes of carbon e.g., 13 C and 14 C, may be used.
  • the isotopic substitution is replacing hydrogen with a deuterium at one or more locations on the molecule to improve the performance of the molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc.
  • the deuterium can be bound to carbon in allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a betadeuterium kinetic isotope effect).
  • Isotopic substitutions for example deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium.
  • the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest.
  • deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance, and in an embodiment is enough to alter a detectable property of the compounds as a drug in a human.
  • the compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one embodiment, the invention includes a solvated form of the active compound.
  • solvate refers to a molecular complex of a compound of the present invention (including a salt thereof) with one or more solvent molecules.
  • solvents are water, ethanol, dimethyl sulfoxide, acetone and other common organic solvents.
  • hydrate refers to a molecular complex comprising a disclosed compound and water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, de-acetone, or de-DMSO.
  • a solvate can be in a liquid or solid form.
  • a “prodrug” as used herein means a compound which when administered to a host in vivo is converted into a parent drug.
  • the term “parent drug” means any of the presently described compounds herein.
  • Prodrugs can be used to achieve any desired effect, including to enhance properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including to increase the half-life of the drug in vivo.
  • Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug.
  • Non-limiting examples of prodrug strategies include covalent attachment of removable groups, or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others.
  • the prodrug renders the parent compound more lipophilic.
  • a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner.
  • non-limiting embodiments include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, dihydroxy compound, or other compound that has at least two functional groups that can link the parent compound with another prodrug moiety and is typically biodegradable in vivo.
  • a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, dihydroxy compound, or other compound that has at least two functional groups that can link the parent compound with another prodrug moiety and is typically biodegradable in vivo.
  • 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound.
  • Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a
  • a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug.
  • the amino acid can be used alone or covalently linked (straight, branched or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity, or other drug delivery or pharmacokinetic properties.
  • the amino acid can be any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid.
  • the compounds as used in the methods described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art.
  • the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art including, for example, oral and parenteral routes of administering.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection.
  • Administration of the active components of their compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art.
  • compositions comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort may be useful in a variety of medical and nonmedical applications.
  • pharmaceutical compositions comprising an active compound and an excipient may be useful for the treatment or prevention of a cancer in a subject in need thereof.
  • “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use.
  • carrier or “pharmaceutically acceptable carrier” can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents.
  • carrier encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations and as described further herein.
  • Excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • General considerations in formulation and/or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
  • excipients include, but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum
  • the excipients may be chosen based on what the composition is useful for.
  • the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intraci sternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray.
  • the active compounds disclosed herein are administered topically.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • cross-linked poly(vinyl-pyrrolidone) crospovidone
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol
  • carbomers e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), di ethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Pol oxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • Exemplary binding agents include starch (e.g.
  • cornstarch and starch paste examples include gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g.
  • acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, NeoIone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline, Ringer
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buck
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyl dodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • composition may further comprise a polymer.
  • exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (ELEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar
  • epsilon. -caprolactone-co-glycolide)- carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid/acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxidepropylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), polyanhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N-[Methoxy(Poly ethylene glycol)-1000], 1,2-Distearoyl-sn-glycero- 3-Phosphoethanolamine-N-[Met
  • composition may further comprise an emulsifying agent.
  • emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g.
  • acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.
  • carboxy polymethylene polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), polyvinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Pol oxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • the emulsifying agent is cholesterol.
  • Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable compositions for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol.
  • acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the particles are suspended in a carrier fluid comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween 80.
  • the injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
  • Solid compositions include capsules, tablets, pills, powders, and granules.
  • the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.
  • the active compound is admixed with an excipient and any needed preservatives or buffers as may be required.
  • the ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the particles in a polymer matrix or gel.
  • the present disclosure also provides methods for treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.
  • the methods can further comprise administering one or more additional therapeutic agents, for example anti-cancer agents or anti-inflammatory agents. Additionally, the method can further comprise administering a therapeutically effective amount of ionizing radiation to the subject.
  • Methods of killing a cancer or tumor cell comprising contacting the cancer or tumor cell with an effective amount of a compound or composition as described herein.
  • the compounds can inhibit mitochondrial complex I.
  • the methods can further include administering one or more additional therapeutic agents or administering an effective amount of ionizing radiation.
  • the disclosed methods can optionally include identifying a patient who is or can be in need of treatment of an oncological disorder.
  • the patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow pig, or horse, or other animals having an oncological disorder.
  • the subject can receive the therapeutic compositions prior to, during, or after surgical intervention to remove part or all of a tumor.
  • a method for sensitizing a cancer to radiation therapy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • neoplasia or “cancer” is used throughout this disclosure to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated.
  • neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant, hematogenous, ascitic and solid tumors.
  • the cancers which may be treated by the compositions disclosed herein may comprise carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastomas.
  • Carcinomas which may be treated by the compositions of the present disclosure include, but are not limited to, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, giant cell carcinoma, gigantocellulare, glandular carcinoma,
  • sarcomas which may be treated by the compositions of the present disclosure include, but are not limited to, liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors (including Ewing's sarcoma of bone, extraskeletal or non-bone) and primitive neuroectodermal tumors (PNET), synovial sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, malignant mesenchymoma, alveolar soft-part sarcoma, epithelioid sarcoma, clear cell s
  • compositions of the present disclosure may be used in the treatment of a lymphoma.
  • Lymphomas which may be treated include mature B cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, precursor lymphoid neoplasms, Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders.
  • NK natural killer
  • Representative mature B cell neoplasms include, but are not limited to, B-cell chronic lymphocytic leukemia/small cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenstrom macroglobulinemia), splenic marginal zone lymphoma, hairy cell leukemia, plasma cell neoplasms (such as plasma cell myeloma/multiple myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, and heavy chain diseases), extranodal marginal zone B cell lymphoma (MALT lymphoma), nodal marginal zone B cell lymphoma, follicular lymphoma, primary cutaneous follicular center lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, Epstein-Barr virus-positive DLBCL of the elderly, lyphomatoid granulomato
  • Representative mature T cell and NK cell neoplasms include, but are not limited to, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, lycosis fungoides/Sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders (such as primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma.
  • T-cell prolymphocytic leukemia T-cell large granular lymphocyte leukemia
  • aggressive NK cell leukemia
  • Representative precursor lymphoid neoplasms include B-lymphoblastic leukemia/lymphoma not otherwise specified, B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities, or T- lymphoblastic leukemia/lymphoma.
  • Representative Hodgkin lymphomas include classical Hodgkin lymphomas, mixed cellularity Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma.
  • compositions of the present disclosure may be used in the treatment of a leukemia.
  • leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia, adult T-cell leukemia, clonal eosinophilias, and transient myeloproliferative disease.
  • ALL acute lymphoblastic leukemia
  • CLL chronic lymphocytic leukemia
  • AML acute myelogenous leukemia
  • CML chronic myelogenous leukemia
  • HCL hairy cell leukemia
  • T-cell prolymphocytic leukemia T-cell prolymphocytic leukemia
  • adult T-cell leukemia clonal eosinophilias
  • compositions of the present disclosure may be used in the treatment of a germ cell tumor, for example germinomatous (such as germinoma, dysgerminoma, and seminoma), non germinomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma) and mixed tumors.
  • germinomatous such as germinoma, dysgerminoma, and seminoma
  • non germinomatous such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma
  • mixed tumors for example germinomatous (such as germinoma, dysgerminoma, and seminoma), non germinomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma) and mixed
  • compositions of the present disclosure may be used in the treatment of blastomas, for example hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme.
  • Representative cancers which may be treated include, but are not limited to: bone and muscle sarcomas such as chondrosarcoma, Ewing’s sarcoma, malignant fibrous histiocytoma of bone/osteosarcoma, osteosarcoma, rhabdomyosarcoma, and heart cancer; brain and nervous system cancers such as astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, medulloblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, and visual pathway and hypothalamic glioma; breast cancers including invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, male breast
  • Compounds and compositions disclosed herein can be locally administered at one or more anatomical sites, such as sites of unwanted cell growth (such as a tumor site or benign skin growth, e.g., injected or topically applied to the tumor or skin growth), optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent.
  • a pharmaceutically acceptable carrier such as an inert diluent
  • Compounds and compositions disclosed herein can also be systemically administered, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent, or an assimilable edible carrier for oral delivery.
  • the active compound can be incorporated into sustained release preparations and/or devices.
  • compounds, agents, and compositions disclosed herein can be administered to a patient in need of treatment prior to, subsequent to, or in combination with other antitumor or anticancer agents or substances (e.g., chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cytotoxic agents, etc.) and/or with radiation therapy and/or with surgical treatment to remove a tumor.
  • antitumor or anticancer agents or substances e.g., chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cytotoxic agents, etc.
  • compounds, agents, and compositions disclosed herein can be used in methods of treating cancer wherein the patient is to be treated or is or has been treated with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosphamide or ifosfamide, antimetabolites such as 5 -fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, anti angiogenic agents such as angiostatin, antiestrogens such as tamoxifen, and/or other anti-cancer drugs or antibodies, such as, for example, imatinid or trastuzumab.
  • mitotic inhibitors such as taxol or vinblastine
  • alkylating agents such as cyclophosphamide or ifosfamide
  • antimetabolites such as 5 -fluorouracil or hydroxyurea
  • DNA intercalators such as
  • chemotherapeutic agents include, but are not limited to, altretamine, bleomycin, bortezomib, busulphan, calcium folinate, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, liposomal doxorubicin, lomustine, melphalan, mercaptopurine, methotrex
  • immunotherapeutic agents include, but are not limited to, alemtuzumab, cetuximab, gemtuzumab, iodine 131 tositumomab, rituximab, and trastuzumab.
  • Cytotoxic agents include, for example, radioactive isotopes and toxins of bacterial, fungal, plant, or animal origin. Also disclosed are methods of treating an oncological disorder comprising administering an effective amount of a compound described herein prior to, subsequent to, and/or in combination with administration of a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, or radiotherapy.
  • the active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result.
  • the exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like.
  • the active ingredient, whether the active compound itself, or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the active ingredient may be administered by any route.
  • the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • routes including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, enteral, sublingual;
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.
  • an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art.
  • Aspect 1 A compound of Formula I or a pharmaceutically acceptable salt thereof; wherein:
  • R 1 and R 2 are each independently selected from H or -O-(Ci-Ce alkyl), wherein at least one or R 1 and R 2 is H;
  • X 1 and X 2 are each independently selected from N or C(R 4 ), wherein at least one or X 1 and X 2 is N;
  • R 3 is 5- to 10-membered monocyclic or bicyclic aryl optionally substituted with one or more groups selected from R 5 ;
  • R 4 is independent selected at each occurrence from H or halo
  • R 5 is selected from hydrogen, halo, nitro, cyano, azido, Ci-Ce alkyl, Ci-Ce haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(Co-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(Co-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, R X O-(CO-C 3 alkyl)-, R x S-(Co-C 3 alkyl)-, (R’TC'NXCo-Cs alkyl)-, R x O-C(0)-(Co-C 3 alkyl)-, R X S-C(0)-(CO-C
  • R x and R y are independently selected at each occurrence from hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, C2-Cealkenyl, C2-Cealkynyl, (C3-C7cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency;
  • R z is independently selected at each occurrence from hydrogen, halo, Ci-Cealkyl, Ci- Cehaloalkyl, C2-Cealkenyl, C2-Cealkynyl, (C3-C7cycloalkyl)-(Co-C3 alkyl)-, (4- to 6- membered heterocycle)-(Co-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(Co-C3 alkyl)-, -OR X , -SR X , and -NR x R y , each of which may be optionally substituted with one or more Y groups as allowed by valency; and
  • Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, phospho, thiol, or combinations thereof.
  • Aspect 2 The compound of aspect 1, or a pharmaceutically acceptable salt thereof, wherein R 1 is -OCH3 and R 2 is H.
  • Aspect 4 The compound of aspect 1, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each H.
  • Aspect 5 The compound of any one of aspects 1-4, or a pharmaceutically acceptable salt thereof, wherein X 1 is N and X 2 is C(R 4 ).
  • Aspect 6 The compound of any one of aspects 1-4, or a pharmaceutically acceptable salt thereof, wherein X 1 is C(R 4 ) and X 2 is N.
  • Aspect 8 The compound of any one of aspects 1-6, or pharmaceutically acceptable salt thereof, wherein R 4 is halo.
  • Aspect 9 The compound of any one of aspects 1-6, or pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.
  • Aspect 10 The compound of any one of aspects 1-4, or pharmaceutically acceptable salt thereof, wherein X 1 and X 2 are each N.
  • Aspect 11 The compound of any one of aspects 1-10, or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl or 1 -naphthyl optionally substituted with one or more groups selected from R 5 .
  • Aspect 12 The compound of any one of aspects 1-11, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of:
  • Aspect 13 The compound of aspect 1 selected from the group consisting of:
  • a pharmaceutical composition comprising a compound of any one of aspects 1-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Aspect 15 A method of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 14.
  • a method of sensitizing a cancer to radiation therapy in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 14 prior to or concurrently with the radiation therapy.
  • reaction contents were then diluted and transferred to a separatory funnel using ethyl acetate and water. Phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered through cotton, and concentrated in vacuo to afford the crude residue. Purification of the crude residue could be carried out by recrystallization from either ethanol or ethyl acetate for these substrates.
  • the crude residue (assumed the mass equated to 1.0 equiv. alcohol) was transferred to an oven-dried round bottom flask equipped with a stir bar and dissolved in anhydrous pyridine (0.05 M).
  • Benzoyl chloride (1.60 equiv.) was added to the reaction solution under nitrogen.
  • the reaction solution was left to stir overnight at room temperature under a nitrogen atmosphere. After stirring overnight, TLC commonly demonstrated consumption of the limiting reagent, and the reaction was quenched with distilled water and the reaction contents concentrated in vacuo to remove pyridine.
  • the remaining residue was transferred to a separatory funnel using ethyl acetate and water and the phases separated.
  • aqueous phase was extracted twice with ethyl acetate; the combined organic phases were washed with saturated NaCl, dried over anhydrous sodium sulfate, filtered through cotton, and concentrated in vacuo to afford the crude residue.
  • Crude residues were dissolved in DCM, adsorbed onto silica, and purified through flash chromatography with an appropriate column using the noted eluent gradient to obtain the desired benzoate unless otherwise noted.
  • Anhydrous dimethylacetamide (DMA) was added to the contents of the reaction vessel via syringe under nitrogen. After the DMA solution was prepared, the contents of the activation vessel were taken up into an appropriate syringe, the needle was quickly removed, and then it was equipped with a needle attached to a nylon 0.45 pM syringe filter. The activation vessel contents were then added to the reaction vessel contents in DMA through the filter. The combined reaction vessel contents were sparged with nitrogen for 15 minutes and the sparged solution was tightly sealed with parafilm immediately afterwards. Irradiation and processing: Irradiation of the combined reaction vessel was performed immediately after sparging using a 456 nm PR160 Kessil light held ⁇ 5-7 cm from the wall of the vessel.
  • the vessel was open to the air, diluted with ethyl acetate, and transferred to a separatory funnel.
  • the reaction contents were washed with saturated sodium bicarbonate solution and water, then the aqueous phase was extracted twice with ethyl acetate and the combined organic phases were further washed with water and saturated NaCl solution.
  • the washed organic phase was dried over anhydrous sodium sulfate, filtered through cotton, and concentrated in vacuo to afford the crude residue. Crude residues were dissolved in DCM, adsorbed onto silica, and purified through flash chromatography with an appropriate column using the specified eluent gradient to obtain the desired product unless otherwise noted.
  • General procedure E modification Deoxygenative arylation in parallel: To facilitate more expedient analog synthesis by reacting substrates in parallel, the following changes were made to general procedure E: Three times the calculated amount of alcohol and NHC precursor (for one individual reaction) were weighed into a vessel and placed under a nitrogen atmosphere. Activation with pyridine and the selected solvent were carried out as noted in general procedure E. Upon completed activation and 10 minutes of stirring, the contents of the activation vessel were completely transferred through a nylon 0.45 pM syringe filter into a separate flask under nitrogen. The filtered contents were then evenly partitioned between the selected substrates under nitrogen.
  • Compound 1 was prepared following general procedure A using 4-chloro-6,7- dimethoxyquinazoline (0.3496 mg, 1.56 mmol, 1.0 equiv.), 3,4-dimethoxybenzaldehyde (0.3109 mg, 1.87 mmol, 1.20 equiv.), 1,3-dimethylimidazolium iodide (38 mg, 0.17 mmol, 0.11 equiv.), and sodium hydride (57-63% mineral oil dispersion) (97.5 mg, 2.44 mmol, 1.56 equiv.) in THF (21 mL, 0.07 M). Reaction completion was suggested by TLC after 30 minutes of heating and was cooled and quenched with water (2 mL) after 45 minutes.
  • Compound R1 was prepared following general procedure C using 1 (100.7 mg, 0.28 mmol, 1.0 equiv.), sodium borohydride (16.1 mg, 0.43 mmol, 1.5 equiv.), THF: MeOH (1 : 1, 6 mL, 0.05 M), benzoyl chloride (45 pL, 0.39 mmol, 1.4 equiv.), and pyridine (4 mL, 0.07 M).
  • Step one borohydride reduction
  • step two benzoyl chloride addition to the intermediate alcohol
  • Workup was performed using 20 mL of water and organic phase in each phase separation.
  • Compound 2 was prepared following general procedure C using R1 (67.5 mg, 0.15 mmol, 1.0 equiv.), ammonium formate (92.2 mg, 1.5 mmol, 10.0 equiv.), and 10% Pd/C (8.9 mg, 59 mg/ 1 mmol Rl) in ethyl acetate (240 pL) and ethanol (3.2 mL). Reaction completion was suggested by TLC after stirring in an oil bath set to 70 °C for 18 hours and the reaction contents were filtered through a pad of celite to give the crude residue. Crude residue purified via flash chromatography on silica eluting with a 70 to 90 percent ethyl acetates in hexanes gradient.
  • Compound 3 was prepared following general procedure A using 4-chloro-6,7- dimethoxyquinazoline (299.7 mg, 1.33 mmol, 1.00 equiv.), 1-napthaldehyde (220 uL, 1.62 mmol, 1.22 equiv), 1,3-dimethylimidazolium iodide (22.5 mg, 0.10 mmol, 0.08 equiv.), and sodium hydride (57-63% mineral oil dispersion) (85.1 mg, 2.13 mmol, 1.60 equiv.) in THF (18 mL, 0.07 M). Reaction completion was suggested by TLC after 30 minutes of heating and was cooled and quenched with water (2 mL) after 45 minutes.
  • Compound R2 was prepared following general procedure B using 3 (200.7 mg, 0.58 mmol, 1.0 equiv.), sodium borohydride (32.9 mg, 0.87 mmol, 1.5 equiv.), THF: MeOH (1 : 1, 12 mL, 0.05 M), benzoyl chloride (100 pL, 0.86 mmol, 1.5 equiv.), and pyridine (12 mL, 0.05 M).
  • Step one borohydride reduction
  • step two benzoyl chloride addition to the intermediate alcohol
  • Workup was performed using 30 mL of water and organic phase in each phase separation.
  • Compound 4 was prepared following general procedure C using R2 (100 mg, 0.22 mmol, 1.0 equiv.), ammonium formate (143.1 mg, 2.27 mmol, 10.3 equiv.), and 10% Pd/C (10.9 mg, 50mg/ 1 mmol R2) in ethyl acetate (240 pL) and ethanol (3.2 mL). Reaction completion was suggested by TLC after stirring for 4 hours in an oil bath set to 70 °C and the reaction solution was filtered through a pad of celite to give the crude material. The crude residue was purified via flash chromatography on silica eluting with a 55 to 60 percent ethyl acetates in hexanes gradient.
  • Compound 3 was prepared following general procedure A using 4-chloro-6,7- dimethoxyquinazoline (500 mg, 2.23 mmol, 1.0 equiv.), p-Anisaldehyde (325 pL, 2.67 mmol, 1.20 equiv.), 1,3-Dimethylimidazolium iodide (53.9 mg, 0.20 mmol, 0.07 equiv.), and sodium hydride (57-63% mineral oil dispersion) (144.5 mg, 3.61 mmol, 1.35 equiv.) in THF (30 mL, 0.09 M). Reaction completion was suggested by TLC after Jackpot of heating and cooled/quenched with water (2 mL) after 90 minutes of heating.
  • Compound 7 was prepared following general procedure E using 4-chloro-6,7- dimethoxyquinazoline (115.0 mg, 0.51 mmol, 1.0 equiv.), sodium acetate (74.5 mg, 0.91 mmol, 1.78 equiv.), [l,l’-biphenyl]-3-ylmethanol (165.0 mg, 0.89 mmol, 1.75 equiv.), NHC-1 BF4 (324.0 mg, 0.82 mmol, 1.60 equiv.), pyridine (66 pL, 0.82 mmol, 1.61 equiv.), phthalimide (19.6 mg, 0.13 mmol, 0.26 equiv.), Ni(dtbbpy)Br2 (20.1 mg, 41.3 pmol, 0.081 equiv.), and Ir(ppy)2(dtbbpy)PFe (7.7 mg, 8.4 pmol, 0.017 equiv.) in TBME (5 mL, 0.16 M
  • Compound 8 was prepared following general procedure E with the following modifications: The alcohol was used as the limiting reagent with the halide in excess. Alcohol activation was achieved by first combining the alcohol and pyridine under nitrogen and subsequently adding NHC-1 BF4 in five portions over 10 minutes under a constant stream of nitrogen in a Schlenk flask.
  • Compound R4 was prepared following general procedure E using 4-chloro-6,7- dimethoxyquinazoline (230 mg, 1.02 mmol, 1.0 equiv.), sodium acetate (169.0 mg, 2.06 mmol, 2.01 equiv.), [3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanol (421.0 mg, 1.80 mmol, 1.76 equiv.), NHC-1 BF4 (647 mg, 1.64 mmol, 1.60 equiv.), pyridine (135 pL, 1.68 mmol, 1.64 equiv.), phthalimide (33.1 mg, 0.23 mmol, 0.22 equiv.), Ni(dtbbpy)Br2 (36.9 mg, 75.8 pmol, 0.074 equiv.), and Ir(ppy)2(dtbbpy)PFe (14.7 mg, 16.1 pmol,
  • Compound 9 was prepared following general procedure F using R4 (38.0 mg, 93 pmol, 1.00 equiv.), 4-bromotoluene (23 pL, 0.19 mmol, 2.00 equiv.), CS2CO3 (75.8 mg, 0.23 mmol, 2.49 equiv.), XPhos (4.3 mg, 9 pmol, 0.01 equiv.), and Pd(OAc)2 (1.2 mg, 5 pmol, 0.06 equiv.) in 9: 1 dioxane: water (1.4 mL, 0.07 M). The crude residue was purified by flash chromatography on silica eluting with a 50 to 65 percent ethyl acetate in hexanes gradient.
  • Compound 10 was prepared following general procedure F using R4 (50.0 mg, 0.12 mmol, 1.00 equiv.), 4-bromoanisole (31 pL, 0.25 mmol, 2.01 equiv.), CS2CO3 (100.0 mg, 0.31 mmol, 2.50 equiv.), and Pd(dppf)C12 DCM adduct (3.0 mg, 3.7 pmol, 0.03 equiv.) in 9: 1 dioxane: water (1.6 mL, 0.08 M). The crude residue was purified by flash chromatography on silica eluting with a 50 to 60 percent ethyl acetate in hexanes gradient.
  • Compound 11 was prepared following general procedure F using R4 (51.0 mg, 0.13 mmol, 1.00 equiv.), 3-bromoanisole (34 pL, 0.27 mmol, 2.13 equiv.), CS2CO3 (102.0 mg, 0.31 mmol, 2.50 equiv.), and Pd(PPh3)4 (4.3 mg, 3.8 pmol, 0.03 equiv.) in 9: 1 dioxane: water (1.7 mL, 0.07 M). The crude residue was purified by flash chromatography on silica eluting with a 70 to 80 percent ethyl acetate in hexanes gradient.
  • Compound 12 was prepared following general procedure F using R4 (60.0 mg, 0.15 mmol, 1.00 equiv.), 2-bromoanisole (37 pL, 0.30 mmol, 2.01 equiv.), CS2CO3 (120.0 mg, 0.37 mmol, 2.50 equiv.), XPhos (7.0 mg, 14.7 pmol, 0.01 equiv.), and Pd(OAc)2 (1.6 mg, 7.1 pmol, 0.05 equiv.) in 9: 1 dioxane: water (2.0 mL, 0.08 M). The crude residue was purified by flash chromatography on silica eluting with a 70 to 100 percent ethyl acetate in hexanes gradient.
  • Compound 13 was prepared following general procedure F using R4 (60.0 mg, 0.15 mmol, 1.00 equiv.), 4-bromoveratrole (43 pL, 0.30 mmol, 2.02 equiv.), CS2CO3 (122.0 mg, 0.37 mmol, 2.53 equiv.), XPhos (7.1 mg, 14.9 pmol, 0.10 equiv.), and Pd(OAc)2 (1.9 mg, 8.5 pmol, 0.06 equiv.) in 9: 1 dioxane: water (2.0 mL, 0.08 M). The crude residue was purified by flash chromatography on silica eluting with a 20 to 40 percent acetone in hexanes gradient.
  • Compound 14 was prepared following general procedure F using R4 (73.7 mg, 0.18 mmol, 1.00 equiv.), 4-bromopyridine hydrochloride (71.3 mg, 0.37 mmol, 2.02 equiv.), CS2CO3 (298.0 mg, 0.91 mmol, 5.03 equiv.), and Pd(PPh3)4 (10.5 mg, 9.1 pmol, 0.05 equiv.) in 9:1 dioxane: water (2.3 mL, 0.07 M). The crude residue was purified by flash chromatography on silica eluting with a 40 to 55 percent acetone in hexanes gradient.
  • Compound 15 was prepared following general procedure F using R4 (66.0 mg, 0.16 mmol, 1.00 equiv.), 3 -bromopyridine (24 pL, 0.25 mmol, 1.53 equiv.), CS2CO3 (134.0 mg, 0.41 mmol, 2.53 equiv.), and Pd(PPh3)4 (5.8 mg, 5.0 pmol, 0.03 equiv.) in 9: 1 dioxane: water (2 mL, 0.08 M). The crude residue was purified by flash chromatography on silica eluting with a 30 to 60% acetone in hexanes gradient.
  • Compound 16 was prepared following general procedure F using R4 (73.2 mg, 0.18 mmol, 1.00 equiv.), 2-bromopyridine (27 pL, 0.28 mmol, 1.54 equiv.), CS2CO3 (170.0 mg, 0.52 mmol, 2.90 equiv.), XPhos Pd G3 (3.2 mg, 3.8 pmol, 0.02 equiv.) in 9: 1 dioxane: water (2.3 mL, 0.08 M). The crude residue was purified by flash chromatography on silica eluting with a 60 to 90 percent ethyl acetate in hexanes gradient.
  • Compound 17 was prepared following general procedure F using R4 (60.0 mg, 0.15 mmol, 1.00 equiv.), 4-bromo-2-methoxypyridine (55.0 mg, 0.29 mmol, 2.00 equiv.), CS2CO3 (120.0 mg, 3.67 mmol, 2.50 equiv.), and Pd(PPh3)4 (8.4 mg, 0.007 mmol, 0.05 equiv.) in 9: 1 dioxane: water (2 mL, 0.08 M). The crude residue was purified by flash chromatography on silica eluting with 40 to 50 percent acetone in hexanes gradient.
  • Compound 18 was prepared following general procedure F using R4 (40.0 mg, 98.5 pmol, 1.00 equiv.), 4-bromobenzyl alcohol (34.5 mg, 0.18 mmol, 1.87 equiv.), CS2CO3 (77.9 mg, 0.24 mmol, 2.43 equiv.), and Pd(PPhs)4 (5.4 mg, 4.7 pmol, 0.05 equiv.) in 9: 1 dioxane: water (1.5 mL, 0.07 M). The crude residue was purified by flash chromatography on silica eluting with a 75 to 95 percent ethyl acetate in hexanes gradient.
  • Compound 19 was prepared following general procedure F using R4 (40.0 mg, 98.5 pmol, 1.00 equiv.), 3-bromobenzyl alcohol (18 pL, 0.15 mmol, 1.52 equiv.), CS2CO3 (66.9 mg, 0.21 mmol, 2.09 equiv.), XPhos (3.5 mg, 7.3 pmol, 0.07 equiv.), and Pd(OAc)2 (1.1 mg,
  • Compound 20 was prepared following general procedure F using R4 (40.0 mg, 98.5 pmol, 1.00 equiv.), 2-bromobenzyl alcohol (36.7 mg, 0.20 mmol, 1.99 equiv.), CS2CO3 (76.0 mg, 0.23 mmol, 2.37 equiv.), and Pd(PPhs)4 (6.2 mg, 5.4 pmol, 0.05 equiv.) in 9: 1 dioxane: water (1.5 mL, 0.07 M). The crude residue was purified by flash chromatography on silica eluting with a 75 to 85 percent ethyl acetate in hexanes gradient.
  • Compound 21 was prepared following general procedure F using R4 (60.0 mg, 0.15 mmol, 1.00 equiv.), (4-bromo-2-methoxyphenyl)methanol (62.7 mg, 0.29 mmol, 1.96 equiv.), CS2CO3 (122.0 mg, 0.38 mmol, 2.54 equiv.), and Pd(PPh3)4 (8.3 mg, 7.2 pmol, 0.05 equiv.) in 9: 1 dioxane: water (2 mL, 0.15 M). The crude residue was purified by flash chromatography on silica eluting with a 30 to 50 percent acetone in hexanes gradient.
  • Compound 22 was prepared following general procedure E using 4-chloro-6,7- dimethoxyquinazoline (110.0 mg, 0.49 mmol, 1.0 equiv.), sodium acetate (74.0 mg, 0.90 mmol, 1.84 equiv.), (3-chlorophenyl)methanol (121.0 mg, 0.85 mmol, 1.73 equiv.), NHC-1 BF4 (310 mg, 0.78 mmol, 1.60 equiv.), pyridine (64 pL, 0.80 mmol, 1.62 equiv.), phthalimide (16 mg, 0.11 mmol, 0.22 equiv.), Ni(dtbbpy)Br2 (18.6 mg, 38.2 pmol, 0.078 equiv.), and Ir(ppy)2(dtbbpy)PFe (6.7 mg, 7.4 pmol, 0.015 equiv.) in TBME (5 mL, 0.16 M for alcohol activation) and DMA (5
  • Compound 24 was prepared following general procedure E with the following modifications: The alcohol was activated using the alternative salt NHC-1 OTf and activation was achieved by adding NHC-1 OTf in five even portions over 10 minutes to a solution of the alcohol in THF under nitrogen. The resultant dark orange homogenous solution required no filtration to transfer.
  • the crude residue was purified via flash chromatography with silica, but this required two purifications to achieve appropriate purity.
  • the first purification eluted with 30 to 40 percent acetone in hexanes, while the second purification eluted with 0 to 1% methanol in DCM.
  • the fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as a light-pink solid. (8.2 mg, 22.9 pmol, 7% yield).
  • reaction solution was irradiated for 20 hours.
  • crude residue was purified via flash chromatography on silica eluting with a 5 to 30 percent acetone in hexanes gradient.
  • fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as a clear semi-solid (33.4 mg, 42% yield).
  • the reaction solution was irradiated for 20 hours.
  • the crude residue was purified via flash chromatography on silica eluting with a 40 to 60 percent ethyl acetate in hexanes gradient. The fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as an off-white solid (32.8 mg, 0.11 mmol, 41% yield).
  • Compound 27 was prepared following general procedure E using 1- bromoisoquinoline (100.0 mg, 0.48 mmol, 1.0 equiv.), sodium acetate (80.4 mg, 0.98 mmol, 2.04 equiv.), (3,4-dimethoxyphenyl) methanol (120 pL, 0.83 mmol, 1.72 equiv.), NHC-1 BF4 (309.0 mg, 0.78 mmol, 1.63 equiv.), pyridine (65 pL, 0.81 mmol, 1.68 equiv.), phthalimide (23.8 mg, 0.16 mmol, 0.34 equiv.), Ni(dtbbpy)Br2 (18.6 mg, 38.2 pmol, 0.080 equiv.), and Ir(ppy)2(dtbbpy)PFe (7.8 mg, 8.5 pmol, 0.018 equiv.) in TBME (2.5 mL, 0.31 M for activation) and DMA (2.5
  • the reaction solution was irradiated for 20 hours.
  • the crude residue was purified via flash chromatography on silica eluting with a 10 to 25 percent ethyl acetate in hexanes gradient.
  • the fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as a light-yellow semi-solid (70.0 mg, 0.22 mmol, 69% yield).
  • the reaction solution was irradiated for 20 hours.
  • the crude residue was purified via flash chromatography on silica eluting with a 0 to 20 percent acetone in hexanes gradient. The fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as a light-yellow solid (43.7 mg, 0.13 mmol, 54% yield).
  • Compound 30 was prepared following general procedure E-IP using 1- bromoisoquinoline (75.8 mg, 0.37 mmol, 1.00 equiv.), sodium acetate (47.8 mg, 0.58 mmol, 1.60 equiv.), [l,l’-biphenyl]-3-ylmethanol (97.4 mg, 0.53 mmol, 1.45 equiv.), NHC-1 BF4 (202.0 mg, 0.51 mmol, 1.40 equiv.), pyridine (43 pL, 0.54 mmol, 1.48 equiv.), phthalimide (24.3 mg, 0.17 mmol, 0.45 equiv.), Ni(dtbbpy)Br2 (13.0 mg, 26.7 pmol, 0.073 equiv.), and Ir(ppy)2(dtbbpy)PFe (5.0 mg, 5.5 pmol, 0.015 equiv.) in THF (3 mL (9 mL /3), 0.
  • Compound 31 was prepared following general procedure E using 4-chloro-7- methoxyquinazoline (60.0 mg, 0.31 mmol, 1.0 equiv.), sodium acetate (53.0 mg, 0.65 mmol, 2.10 equiv.), (3,4-dimethoxyphenyl)methanol (77 pL, 0.53 mmol, 1.72 equiv.), NHC-1 BF4 (195.0 mg, 0.50 mmol, 1.60 equiv.), pyridine (40 pL, 0.50 mmol, 1.61 equiv.), phthalimide (10.5 mg, 0.23 mmol, 0.23 equiv.), Ni(dtbbpy)Br2 (11.0 mg, 22.6 pmol, 0.073 equiv.), and Ir(ppy)2(dtbbpy)PFe (4.0 mg, 4.38 pmol, 0.014 equiv.) in 1,4-dioxane (2 mL, 0.25 M for
  • Compound 32 was prepared following general procedure E using 4-chloro-6- methoxyquinazoline (60.0 mg, 0.31 mmol, 1.0 equiv.), sodium acetate (50.5 mg, 0.62 mmol, 2.0 equiv.), (3, 4-dimethoxyphenyl)m ethanol (78 pL, 0.54 mmol, 1.74 equiv.), NHC- 1 BF4 (196.0 mg, 0.50 mmol, 1.61 equiv.), pyridine (40 pL, 0.50 mmol, 1.61 equiv.), phthalimide (12.1 mg, 82.2 pmol, 0.27 equiv.), Ni(dtbbpy)Br2 (11.3 mg, 23.1 pmol, 0.075 equiv.), and Ir(ppy)2(dtbbpy)PFe (4.1 mg, 4.5 pmol, 0.015 equiv.) in TBME (2 mL, 0.25 M for activation) and DMA (2
  • Compound 33 was prepared following general procedure E-IP using 4- chloroquinazoline (60.0 mg, 0.37 mmol, 1.00 equiv.), quinuclidine (64.2 mg, 0.58 mmol, 1.58 equiv.), (3,4-dimethoxyphenyl)methanol (96 pL, 0.66 mmol, 1.81 equiv.), NHC-1 BF4 (245.0 mg, 0.62 mmol, 1.70 equiv.), pyridine (50 pL, 0.62 mmol, 1.70 equiv.), phthalimide (24.2 mg, 0.16 mmol, 0.45 equiv.), Ni(dtbbpy)Br2 (22.1 mg, 45.4 pmol, 0.13 equiv.), and Ir(ppy)2(dtbbpy)PFe (5.5 mg, 6.0 pmol, 0.017 equiv.) in THF (3 mL (9 mL /3), 0.21 M for activation) and D
  • Compound 36 was prepared following general procedure E-IP using 4- chloroquinazoline (60.0 mg, 0.37 mmol, 1.0 equiv.), quinuclidine (68.4 mg, 0.62 mmol, 1.69 equiv.), [l,l’-biphenyl]-3-ylmethanol (121 mg, 0.66 mmol, 1.80 equiv.), NHC-1 BF4 (245.0 mg, 0.62 mmol, 1.70 equiv.), pyridine (50 pL, 0.62 mmol, 1.70 equiv.), phthalimide (11.9 mg, 80.9 pmol, 0.22 equiv.), Ni(dtbbpy)Br2 (14.5 mg, 29.8 pmol, 0.082 equiv.), and Ir(ppy)2(dtbbpy)PFe (5.2 mg, 5.7 pmol, 0.016 equiv.) in THF (2 mL (6 mL /3), 0.31 M
  • Compound 37 was prepared following general procedure E using 4-bromo-6,7- dimethoxyquinoline (75.0 mg, 0.28 mmol, 1.0 equiv.), quinuclidine (56.1 mg, 0.51 mmol, 1.80 equiv.), (3,4-dimethoxyphenyl)methanol (71 pL, 0.49 mmol, 1.73 equiv.), NHC-1 BF4 (177.0 mg, 0.45 mmol, 1.60 equiv.), pyridine (36 pL, 0.45 mmol, 1.60 equiv.), phthalimide (9.5 mg, 64.6 pmol, 0.23 equiv.), Ni(dtbbpy)Br2 (10.2 mg, 21.0 pmol, 0.075 equiv.), and Ir(ppy)2(dtbbpy)PFe (4.2 mg, 4.6 pmol, 0.016 equiv.) in TBME (2 mL, 0.23 M for activation) and D
  • Compound 39 was prepared following general procedure E using 4-bromo-6- methoxyquinoline (119.0 mg, 0.50 mmol, 1.0 equiv.), sodium acetate (82.8 mg, 1.01 mmol, 2.02 equiv.), (3,4-dimethoxyphenyl)methanol (127 pL, 0.88 mmol, 1.75 equiv.), NHC-1 BF4 (316.0 mg, 0.80 mmol, 1.60 equiv.), pyridine (65 pL, 0.81 mmol, 1.61 equiv.), phthalimide (17.4 mg, 0.12 mmol, 0.24 equiv.), Ni(dtbbpy)Br2 (18.1 mg, 37.2 pmol, 0.074 equiv.), and Ir(ppy)2(dtbbpy)PFe (7.4 mg, 8.1 pmol, 0.016 equiv.) in TBME (5 mL, 0.16 M for activation) and D
  • Compound 40 was prepared following general procedure E-IP using 4- bromoquinoline (75.8 mg, 0.37 mmol, 1.00 equiv.), sodium acetate (60.5 mg, 0.74 mmol, 2.02 equiv.), (3,4-dimethoxyphenyl)methanol (96 pL, 0.66 mmol, 1.81 equiv.), NHC-1 BF4 (245.0 mg, 0.62 mmol, 1.70 equiv.), pyridine (50 pL, 0.62 mmol, 1.70 equiv.), phthalimide (23.5 mg, 0.16 mmol, 0.44 equiv.), Ni(dtbbpy)Br2 (16.6 mg, 34.1 pmol, 0.094 equiv.), and Ir(ppy)2(dtbbpy)PFe (4.9 mg, 5.4 pmol, 0.015 equiv.) in THF (3 mL (9 mL /3), 0.21 M for activation) and D
  • Compound 41 was prepared following general procedure E-IP using 4-bromo-6,7- dimethoxyquinoline (82.6 mg, 0.31 mmol, 1.0 equiv.), quinuclidine (65.3 mg, 0.59 mmol, 1.91 equiv.), [l,l’-biphenyl]-3-ylmethanol (108 mg, 0.59 mmol, 1.90 equiv.), NHC-1 BF4 (219.0 mg, 0.55 mmol, 1.80 equiv.), pyridine (45 pL, 0.56 mmol, 1.81 equiv.), phthalimide (10.1 mg, 68.7 pmol, 0.22 equiv.), Ni(dtbbpy)Br2 (11.2 mg, 23.1 pmol, 0.075 equiv.), and Ir(ppy)2(dtbbpy)PFe (4.2 mg, 4.6 pmol, 0.015 equiv.) in TBME (2 mL (6
  • Compound 43 was prepared following general procedure E-IP using 4-bromo-6- methoxyquinoline (73.3 mg, 0.31 mmol, 1.0 equiv.), quinuclidine (63.2 mg, 0.57 mmol, 1.85 equiv.), [l,r-biphenyl]-3-ylmethanol (108.0 mg, 0.59 mmol, 1.90 equiv.), NHC-1 BF4 (219.0 mg, 0.55 mmol, 1.80 equiv.), pyridine (45 pL, 0.56 mmol, 1.81 equiv.), phthalimide (9.8 mg, 66.6 pmol, 0.22 equiv.), Ni(dtbbpy)Br2 (11.3 mg, 23.2 pmol, 0.075 equiv.), and Ir(ppy)2(dtbbpy)PFe (4.1 mg, 4.5 pmol, 0.015 equiv.) in TBME (2 mL (6 mL /3),
  • Compound R5 was prepared following general procedure F using (4-(4,4,5,5-Tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)methanol (6.50 g, 27.8 mmol, 1.00 equiv.), ((4- Bromobenzyl)oxy)(tert-butyl)dimethylsilane (9.2 g, 30.5 mmol, 1.10 equiv.), K2CO3 (7.71 g, 55.8 mmol, 2.01 equiv.), XPhos (527 mg, 1.11 mmol, 0.04 equiv.), and Pd(OAc)2 (128 mg, 0.57 mmol, 0.02 equiv.) in 9: 1 iPOH: water (80 mL, 0.35 M).
  • the reaction mixture was worked up by filtering through a short pad of celite and concentrating.
  • the crude residue was purified by flash chromatography on silica eluting with 10 to 15 percent ethyl acetate in hexanes.
  • the fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as a light brown oil (7.2355 g, 22.0 mmol, 79% yield).
  • Compound R6 was prepared following general procedure E using 4-bromo-6- methoxyquinoline (1.0 g, 4.20 mmol, 1.00 equiv.), sodium acetate (613.0 mg, 7.47 mmol, 1.78 equiv.), R5 (2.14 g, 6.51 mmol, 1.55 equiv.), NHC-1 BF 4 (2.41 g, 6.09 mmol, 1.45 equiv.), pyridine (500 pL, 6.21 mmol, 1.48 equiv.), phthalimide (139.0 mg, 0.95 mmol, 0.23 equiv.), Ni(dtbbpy)Br2 (149.0 mg, 0.31 mmol, 0.073 equiv.), and Ir(ppy)2(dtbbpy)PFe (59.9 mg, 65 pmol, 0.016 equiv.) in THF (24 mL, 0.25 M for activation) and DMA (24 mL
  • Compound 45-Phosphate was prepared from 45 (200.0 mg, 0.56 mmol, 1.00 equiv.) and psi 0 (334.0 mg, 0.79 mmol, 1.41 equiv.) added to an oven dried vial and placed under nitrogen via three evacuation and backfill cycles. Anhydrous DCM (5.6 mL, 0.10 M) was added to the solids via syringe under nitrogen to give a light orange suspension. After 1 minute of stirring, DBU (0.12 mL, 0.80 mmol, 1.43 equiv.) was added in one portion via syringe to give a clear, homogenous orange solution.
  • the resultant solution was stirred for 1 hour before being quenched by addition of pre-mixed ACN (5.7 mL) and distilled water (0.3 mL) followed by DBU (0.25 mL, 1.67 mmol, 2.98 equiv.). After stirring for 15 minutes, the reaction contents were transferred with ethanol to a 100 mL round bottom flask and concentrated to give a dark orange residue.
  • the crude residue was purified via flash chromatography using a Teledyne ISCO 12 g gold spherical silica column, eluting with a 10 to 60 percent ammonia IN methanol in DCM gradient.
  • the fractions corresponding to the desired product were combined and concentrated in vacuo to give the ammonium salt product as a white solid (99.0 mg, 0.23 mmol).
  • the isolated ammonium salt was placed under nitrogen and suspended in anhydrous THF (4.4 mL, 0.05 M) to create a cloudy white suspension.
  • To the stirring suspension was added NaOtBu (2 M in THF, 0.22 mL, 0.44 mmol, 2.00 equiv.) dropwise over five minutes to create additional suspended solid. After addition, the suspension was stirred for an additional 30 minutes before hexanes (4.4 mL) was added in one portion and the suspension was allowed to stir an additional 5 minutes.
  • Compound R7 was prepared following general procedure E using 4-chloro-6- methoxyquinazoline (650 mg, 3.34 mmol, 1.00 equiv.), sodium acetate (438.0 mg, 5.34 mmol, 1.60 equiv.), R5 (1.40 g, 4.26 mmol, 1.28 equiv.), NHC-1 BF 4 (1.58 g, 4.01 mmol, 1.20 equiv.), pyridine (340 pL, 4.22 mmol, 1.26 equiv.), phthalimide (111.0 mg, 0.75 mmol, 0.23 equiv.), Ni(dtbbpy)Br2 (123.0 mg, 0.25 mmol, 0.076 equiv.), and Ir(ppy)2(dtbbpy)PFe (45.3 mg, 50 pmol, 0.015 equiv.) in THF (24 mL, 0.17 M for activation) and DMA (24 mL, 0.07
  • Compound R8 was prepared following general procedure E using 4-bromo-6- methoxyquinoline (250.0 mg, 1.05 mmol, 1.00 equiv.), quinuclidine (179.0 mg, 1.61 mmol, 1.53 equiv.), [3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]methanol (402.0 mg, 1.64 mmol, 1.64 equiv.), NHC-1 BF4 (621 mg, 1.57 mmol, 1.50 equiv.), pyridine (130 pL, 1.61 mmol, 1.54 equiv.), phthalimide (40.0 mg, 0.27 mmol, 0.26 equiv.), Ni(dtbbpy)Br2 (41.0 mg, 84.2 pmol, 0.08 equiv.), and Ir(ppy)2(dtbbpy)PFe (13.0 mg, 14.2 pmol, 0.014
  • the crude residue was purified via liquid loading with DCM onto a Teledyne Isco 12 g gold spherical silica column and eluting with a 60 to 70 percent ethyl acetate in hexanes gradient. The fractions corresponding to the desired product were combined and concentrated in vacuo to give the title compound as a light brown solid (186.0 mg, 0.50 mmol, 47% yield).
  • Compound 47 was prepared following general procedure F using R8 (100.0 mg, 0.27 mmol, 1.00 equiv.), 3-(4-Chlorophenyl)oxetane (50.0 mg, 0.30 mmol, 1.11 equiv.), CS2CO3 (163.0 mg, 0.50 mmol, 1.88 equiv.), XPhos (14.2 mg, 30 pmol, 0.11 equiv.), and Pd(OAc)2 (3.1 mg, 14 pmol, 0.05 equiv.) in 9: 1 dioxane: water (2.5 mL, 0.1 M).
  • Compound 48 was prepared following general procedure F using R8 (106.0 mg, 0.28 mmol, 1.00 equiv.), 4-bromo-l-methylpyrazole (43 pL, 0.43 mmol, 1.51 equiv.), CS2CO3 (199.0 mg, 0.61 mmol, 2.16 equiv.), XPhos (11.4 mg, 24 pmol, 0.08 equiv.), and Pd(OAc)2 (2.9 mg, 13 pmol, 0.05 equiv.) in 9: 1 dioxane: water (3 mL, 0.1 M). The crude residue was purified by flash chromatography on silica eluting with a 15 to 45 percent acetone in hexanes gradient.
  • Compound 49 was prepared following general procedure F using R8 (85.0 mg, 0.23 mmol, 1.00 equiv.), 4-bromo-l-(3-oxetanyl)pyrazole (71.1 mg, 0.35 mmol, 1.55 equiv.), CS2CO3 (157.0 mg, 0.48 mmol, 2.13 equiv.), XPhos (11.0 mg, 23 pmol, 0.10 equiv.), and Pd(OAc)2
  • OCR inhibition Inhibition of the oxygen consumption rate of live EO771 cells at 10 pM.
  • PDElOa inhibition Inhibition of isolated PDElOa at 0.1 pM.
  • compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims.
  • Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims.
  • other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited.
  • a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

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Abstract

La présente divulgation concerne des composés pour le traitement de troubles médicaux, et plus particulièrement des inhibiteurs du complexe mitochondrial I qui sont utiles dans le traitement de cancers, par exemple par sensibilisation de cancers à une radiothérapie.
PCT/US2024/036369 2023-06-29 2024-07-01 Inhibiteurs du complexe mitochondrial i à inhibition réduite de la phosphodiestérase Ceased WO2025007113A2 (fr)

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ZA986732B (en) * 1997-07-29 1999-02-02 Warner Lambert Co Irreversible inhibitiors of tyrosine kinases
AU4317399A (en) * 1998-05-28 1999-12-13 Parker Hughes Institute Quinazolines for treating brain tumor
CA2581516C (fr) * 2004-10-12 2013-06-11 Astrazeneca Ab Derives de quinazoline
US7977346B2 (en) * 2006-01-17 2011-07-12 Guoqing Paul Chen Spiro compounds and methods of use
KR102327054B1 (ko) * 2017-08-29 2021-11-17 기초과학연구원 퀴놀린 유도체 및 alk와 변이된 alk의 저해제로서의 용도

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