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WO2018187414A1 - Inhibiteurs d'interactions mtor-rictor - Google Patents

Inhibiteurs d'interactions mtor-rictor Download PDF

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Publication number
WO2018187414A1
WO2018187414A1 PCT/US2018/026005 US2018026005W WO2018187414A1 WO 2018187414 A1 WO2018187414 A1 WO 2018187414A1 US 2018026005 W US2018026005 W US 2018026005W WO 2018187414 A1 WO2018187414 A1 WO 2018187414A1
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compound
mmol
ethyl acetate
hexane
mhz
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PCT/US2018/026005
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English (en)
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Joseph F. GERA
Alan LICHTENSTEIN
Michael E. Jung
Jihye Lee
Brent Holmes
Angelica BENAVIDES-SERRATO
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The Regents Of The University Of California
United States Government Represented By The Department Of Veterans Affairs
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Publication of WO2018187414A1 publication Critical patent/WO2018187414A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/30—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/18—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms

Definitions

  • Glioblastomas are highly malignant and invasive tumors, properties which prevent total surgical resection, and render these neoplasms refractory to chemotherapeutic interventions (1). Prognosis for patients is very poor and most succumb to the disease within a year (2). Patients that do survive typically develop significant long-term toxicities as a result of high-dose chemotherapies ultimately leading to drug resistance (3). Thus, the development of novel therapeutic options based on the biology of these heterogeneous tumors is necessary while circumventing resistance mechanisms. However, current efforts utilizing mTOR inhibitors as a potential targeted therapeutic for the treatment of glioblastoma have failed in the clinic. Accordingly, new mTOR inhibitors are needed.
  • the present invention provides compounds having the structure of formula I or a pharmaceutically acceptable salt thereof:
  • R 1 is aryl, heteroaryl, or heterocyclyl
  • R 2 is alkyl, aryl or heteroaryl
  • R 3 is alkyl, aryl, or heteroaryl
  • X is C(R 4 R 5 ), N(R 4 ), or O; Y is S or O; and
  • R 4 and R 5 are independently selected from H or alkyl.
  • Exemplary compounds of Formula (I) include the compounds depicted in Table I.
  • the invention further relates to pharmaceutical compositions of the subject compounds, as well as methods of using these compounds or compositions in the treatment of cancer, such as prostate cancer.
  • FIGs. 1A-1C Identification of compounds that inhibit mTORC2 activity in glioblastoma cells.
  • FIG. 1A JR-AB2-000 inhibits mTORC2 in vitro kinase activity.
  • FIG. IB JR-AB2-000 blocks binding of Rictor to mTOR in LN229 cells. Cells were treated with 5 mM Antimycin (control compound), 50 nM JR-AB2-000 or 20 nM rapamycin for 15 min and mTOR immunoprecipitated.
  • FIG. 1C shows
  • mTORC2 signaling is inhibited in GBM lines following 24 h exposure to JR-AB2-000.
  • LN229 or U87 cells were treated with 100 nM of inhibitor as shown and lysates
  • FIGs. 2A-2E Anti-GBM effects of JR-AB2-000 in cell lines.
  • FIG. 2A Inhibition of GBM cell line proliferation following culture with JR-AB2-000 (black, 0 nM; blue, 0.5 ⁇ ; red, 1 ⁇ ; green, 2 ⁇ ) for the indicated time points. Data represent mean ⁇ S.D. of three independent experiments.
  • FIG. 2B JR-AB2-000 exposure inhibits anchorage-independent growth. Cells were suspended in soft agar to evaluate anchorage independent growth in the presence of the indicated concentrations of inhibitor and colonies counted after 14 days of growth. Data represent mean +S.D. of three independent experiments.
  • FIG. 2A Inhibition of GBM cell line proliferation following culture with JR-AB2-000 (black, 0 nM; blue, 0.5 ⁇ ; red, 1 ⁇ ; green, 2 ⁇ ) for the indicated time points. Data represent mean ⁇ S.D. of three independent experiments.
  • FIG. 2B JR-AB2-000 exposure inhibits anchor
  • FIG. 2C Migration of U87 and LN229 cells in the presence of the indicated concentration of JR-AB2-000. Cells were seeded into Boyden chambers and allowed to migrate towards BSA (white bars), vitronectin (grey bars) or fibronectin (black bars) (*, O.05). Data represent mean +S.D. of three independent experiments.
  • FIG. 2D Invasive potential of U87 or LN229 cells in the presence of the indicated concentrations of JR-AB2-000 migrating through matrigel. Data represent mean +S.D. of three independent experiments.
  • FIG. 2E Cell-cycle phase distributions were determined on the indicated lines treated with JR-AB2-000 as shown. Percent apoptotic cells as determined via annexin V-FITC staining are also shown below each graph. One of three experiments with similar results is shown.
  • FIGs. 3A-3F Sensitivity to JR-AB2-000 is dependent on Rictor or SIN1 expression.
  • FIG. 3A Steady-state Rictor expression levels in GBM lines. Lysates from the indicated lines were immunoblotted for Rictor and actin levels.
  • FIG. 3C XTT proliferation assays performed on eleven GBM lines with increasing concentration of JR-AB2-000 at 72 h.
  • FIG. 3D Correlation between JR-AB2-000 sensitivity and icso determined for all GBM cell lines treated with JR- AB2-000 for 72 h and shown as means of 3-5 individual experiments. Relative Rictor expression was obtained from (B) above.
  • FIG. 3E Sensitivity of U87, U87shRictor and U87-Rictor GBM cells to JR-AB2-000 treated with the indicated concentrations at 72 h. Data represent mean ⁇ S.D. of three independent experiments. *, P ⁇ 0.05
  • FIG. 3F Sensitivity of wt SIN1 and SINl-null MEFs to increasing concentrations of JR-AB2-000 at 48 h. Data represent mean ⁇ S.D. of three independent experiments. *, P ⁇ 0.05
  • FIG. 4 JR-AB-011 binds to Rictor and prevents Rictor-mTOR association.
  • the Kon, Koff and Kd were calculated by simultaneous nonlinear regression using a 1 : 1 binding model and BIAevaluation 3.1 software.
  • FIGs. 5A-5B JR-AB-011 binds to Rictor and prevents Rictor-mTOR association.
  • FIG. 5A Competitive binding curves of Rictor-mTOR association in the absence or presence of JR-AB2-011 or JR-AB2-000 as indicated (left panel). Analysis of selectivity of JR-AB2-01 1 (middle panel) or JR-AB2-000 (right panel) binding to Rictor, Raptor, mLST8 or Deptor as shown. Samples were preincubated with inhibitors and Rictor, Raptor, mLST8 or Deptor proteins as indicated and run over sensor chip containing immobilized mTOR. The ic5o values were calculated using the response units at the dissociation phase.
  • FIG. 5A Competitive binding curves of Rictor-mTOR association in the absence or presence of JR-AB2-011 or JR-AB2-000 as indicated (left panel). Analysis of selectivity of JR-AB2-01 1 (middle panel) or JR-AB2-000 (right panel) binding
  • myc-Rictor was incubated with inhibitor for 1 h followed by incubation with FLAG agarose beads coupled to mTOR-Flag (mTOR-Flag beads).
  • mTOR-Flag beads binding of myc-Rictor to mTOR-Flag beads (Rictor-mTOR-Flag beads) was detected by immunoblotting with an anti-myc mAb.
  • the amount of protein bound to FLAG agarose beads was detected with an anti-Flag mAb (loading control). Immunoblots were quantified via densitometric analyses and graphs are shown to the right of the blots. Three independent experiments were performed and one representative result is shown.
  • FIGs. 6A-6C Effects of JR-AB2-011 treatment on GBM tumor growth in mice.
  • FIG. 6A Tumor burden of SCID mice implanted with LN229 cells and treated with the indicated schedules of vehicle (top trace), JR-AB2-011 (4 mg/kg/d) (middle trace) and JR- AB2-011 (20 mg/kg/d) (bottom trace) for ten consecutive days and tumor growth assessed every two days following initiation of treatment (start, day 0).
  • *, P ⁇ 0.05 significantly different from vehicle, JR-AB2-011 (4 mg/kg/d) and JR-AB2-011 (20 mg/kg/d).
  • FIG. 6B Overall survival of subcutaneous LN229 tumors receiving the indicated treatment schedules of vehicle (left trace), JR-AB2-011 (4 mg/kg/d) (middle trace) and JR-AB2-011 (20 mg/kg/d) (right trace).
  • FIG. 6C Apoptotic cells were identified by TUNEL assays of sections prepared from harvested tumors at day 12 following initiation of treatment regimens (left panel). Data are expressed as the number of positive apoptotic bodies divided by high power field (hpf; 10-12 hpf/tumor). Values are means +S.D , *, P ⁇ 0.05. Phospho-S 473 -AKT/total AKT protein ratio levels in tumors (middle panel).
  • Values are means ⁇ S.D , *, P ⁇ 0.05, significantly different from vehicle, JR-AB2-011 (4 mg/kg/d) and JR-AB2-011 (20 mg/kg/d).
  • Phospho-T 389 -S6K/total S6K protein ratio levels in tumors Values are means ⁇ S.D., *, P ⁇ 0.05, significantly different from vehicle, JR-AB2-01 1 (4 mg/kg/d) and JR-AB2-01 1 (20 mg/kg/d). Protein levels were quantified by Western analyses of harvested tumors from mice with the corresponding treatments as indicated and described in "Material & Methods".
  • FIGs. 8A-8B Kinetics and dose-response of JR-AB2-000 mediated-inhibition of mTORC2 signaling in LN229 cells.
  • FIG. 8A LN229 cells were treated with JR-AB2-000 (1 ⁇ ) for the indicated time points and lysates immunoblotted for the indicated proteins.
  • FIG. 8B LN229 cells were treated with JR-AB2-000 at the indicated concentrations for 2.5 h and protein lysates immunoblotted for the indicated proteins.
  • FIG. 9. Treatment of U87 and LN229 GBM cells with JR-AB2-01 1 (1 ⁇ ) for 24 h and lysates immunoblotted for the indicated proteins.
  • FIG. 10. Peripheral blood RBC and WBC counts in mice (5 mice/group) treated with daily IP injections (10 days) of 0, 4 or 20 mg/kg/d of JR-AB2-011. Data are expressed as percent of control mice that received vehicle only and assigned 100 %.
  • the present invention provides compounds as described herein.
  • the compounds described herein are useful as cancer therapeutics, in particular as inhibitors of the interaction between Rictor and mTORC2, and inhibitors of mTORC2 signaling.
  • the compounds described herein do not substantially affect mTORCl signaling (e.g., affect mTORCl with an ICso at least 10 times or preferably even at least 100 times their ICso for mTORC2).
  • the present invention provides compounds having the structure of formula I or pharmaceutically acceptable salts thereof:
  • R 1 is aryl, heteroaryl, or heterocyclyl
  • R 2 is alkyl, aryl or heteroaryl
  • R 3 is alkyl, aryl, or heteroaryl
  • X is C(R 4 R 5 ), N(R 4 ), or O;
  • Y is S or O
  • R 4 and R 5 are independently selected from H or alkyl.
  • R 1 is not 3-methylisothiazolyl.
  • R 2 is not 3,4-dimethylphenyl.
  • R 3 is not 3,4-dichlorophenyl.
  • X is not (H). In s compound is not
  • R 1 is 5-membered heteroaryl or heterocyclyl, e.g., thiazolyl, isothiazolyl, oxazolyl, 4,5-dihydrooxazolyl, 4,5-dihydrothiazolyl, benzothiazolyl, benzoxazolyl, pyridyl, or phenyl.
  • R 1 is selected from thiazolyl, oxazolyl, 4,5-dihydrooxazolyl, 4,5-dihydrothiazolyl, benzothiazolyl, benzoxazolyl, pyridyl, or phenyl.
  • R 1 is substituted with one or more alkyl moieties.
  • R 1 is 3-methylisothiazolyl:
  • R 2 is heteroaryl or heterocyclyl. In other embodiments, R 2 is phenyl.
  • R 2 is substituted with one or more R 6 ; each R 6 independently selected from N(R 7 R 8 ), alkyl, alkoxy, or halo; wherein R 7 and R 8 are independently selected from alkyl.
  • R 2 is halophenyl, such as 4-bromophenyl or 4- fluorophenyl.
  • R 3 is heteroaryl or heterocyclyl. In other embodiments, R 3 is phenyl.
  • R 3 is optionally substituted with one or more R 9 ; each R 9 independently selected from N(R 10 R U ), alkyl, alkoxy, or halo; wherein R 10 and R u are independently selected from alkyl.
  • R 3 is halophenyl, such as 3,4-dichlorophenyl.
  • X is N(R 4 ), preferably N(H).
  • Y is O. In other embodiments, Y is S.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable excipient.
  • the present invention provides the use of a compound or composition as disclosed herein for inhibiting or preventing the formation of mTORC2 in a cell.
  • the compound or composition does not substantially inhibit or prevent the formation of mTORCl in the cell.
  • the present invention provides the use of a compound or composition as disclosed herein for treating a mammal suffering from cancer, such as glioblastoma.
  • the present invention provides a method for inhibiting or preventing the formation of mTORC2 in a cell, comprising contacting the cell with a compound or composition as disclosed herein. In some such embodiments, the formation of mTORCl in the cell is not substantially inhibited or prevented.
  • the present invention provides a method for treating a mammal suffering from cancer, comprising administering a compound or composition as disclosed herein.
  • the cancer is glioblastoma.
  • the present invention provides methods of treating proliferative diseases, such as glioblastoma, methods of inhibiting the interaction between Rictor and mTORC2, and methods of inhibiting mTORC2 signaling.
  • proliferative diseases such as glioblastoma
  • methods of inhibiting the interaction between Rictor and mTORC2 and methods of inhibiting mTORC2 signaling.
  • compounds of the invention are prodrugs of the compounds described herein.
  • a hydroxyl in the parent compound is presented as an ester or a carbonate, or a carboxylic acid present in the parent compound is presented as an ester.
  • the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl or carboxylic acid).
  • compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. In certain embodiments, compounds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomers. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.
  • the present invention provides pharmaceutical compositions comprising a compound of Formula I.
  • the pharmaceutical compositions further comprise a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions may be for use in treating or preventing a condition or disease as described herein.
  • the present invention relates to methods of treatment with a compound of Formula I.
  • the therapeutic preparation may be enriched to provide predominantly one enantiomer or isomer of a compound.
  • enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g. , in the composition or compound mixture.
  • composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.
  • the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound.
  • a diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.
  • the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above, and one or more pharmaceutically acceptable excipients.
  • the compounds of this invention may be used in treating the conditions described herein, in the form of the free base, salts (preferably pharmaceutically acceptable salts), solvates, hydrates, prodrugs, isomers, or mixtures thereof. All forms are within the scope of the disclosure. Acid addition salts may be formed and provide a more convenient form for use; in practice, use of the salt form inherently amounts to use of the base form.
  • the acids which can be used to prepare the acid addition salts include preferably those which produce, when combined with the free base, pharmaceutically acceptable salts, that is, salts whose anions are non-toxic to the subject organism in pharmaceutical doses of the salts, so that the beneficial properties inherent in the free base are not vitiated by side effects ascribable to the anions.
  • Pharmaceutically acceptable salts within the scope of the disclosure include those derived from the following acids; mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.
  • the compounds of the present invention can be formulated as pharmaceutical compositions and administered to a subject in need of treatment, for example a mammal, such as a human patient, in a variety of forms adapted to the chosen route of administration, for example, orally, nasally, intraperitoneally, or parenterally (e.g., by intravenous,
  • Parenteral administration may be by continuous infusion over a selected period of time.
  • the described compounds may be administered to a patient in a variety of forms depending on the selected route of
  • compositions containing the compounds of the disclosure can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle.
  • suitable vehicles are described, for example, in Remington's
  • compositions include, albeit not exclusively, solutions of the substances in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • a composition comprising a compound of the present disclosure may also contain adjuvants, such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin. A person skilled in the art would know how to prepare suitable formulations.
  • compounds of the invention may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier; or by inhalation or insufflation. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier
  • the compounds may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • the compounds may be combined with a fine inert powdered carrier and inhaled by the subject or insufflated.
  • compositions and preparations should contain at least 0.1% of compounds of formula la or lb.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a given unit dosage form.
  • the amount of the compounds in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • compositions comprising a compound of the present disclosure for oral administration include capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water- in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and the like, each containing a predetermined amount of the compound of the present disclosure as an active ingredient.
  • inert base such as gelatin and glycerin, or sucrose and acacia
  • one or more compositions comprising the compound of the present disclosure may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, gum tragacanth, corn starch, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose
  • the pharmaceutical compositions 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 sugars, as well as high molecular weight polyethylene glycols and the like.
  • Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the compounds may be incorporated into sustained-release preparations and devices.
  • the compounds may be incorporated into time release capsules, time release tablets, and time release pills.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and
  • emulsifiers such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • Suspensions in addition to the active compounds, salts and/or prodrugs thereof, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions suitable for parenteral administration may comprise the compound of the present disclosure in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • the compounds may be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the compounds or their salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations can contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the compounds which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the compounds may be applied in pure form. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Other solid carriers include nontoxic polymeric nanoparticles or microparticles.
  • Useful liquid carriers include water, alcohols or glycols or water/alcohol/glycol blends, in which the compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds to the skin are known to the art; for example, see Jacquet et al. (U. S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U. S. Pat. No. 4,559,157) and Wortzman (U. S. Pat. No. 4,820,508), all of which are hereby incorporated by reference.
  • Useful dosages of the compounds of formulas I and II 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; for example, see U. S. Pat. No. 4,938,949, which is hereby incorporated by reference.
  • the concentration of the compounds in a liquid composition, such as a lotion can be from about 0.1-25% by weight, or from about 0.5-10% by weight.
  • the concentration in a semi-solid or solid composition such as a gel or a powder can be about 0.1- 5% by weight, or about 0.5-2.5% by weight.
  • the amount of the compounds required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • Effective dosages and routes of administration of agents of the invention are conventional.
  • the exact amount (effective dose) of the agent will vary from subject to subject, depending on, for example, the species, age, weight and general or clinical condition of the subject, the severity or mechanism of any disorder being treated, the particular agent or vehicle used, the method and scheduling of administration, and the like.
  • a therapeutically effective dose can be determined empirically, by conventional procedures known to those of skill in the art. See, e.g., The Pharmacological Basis of Therapeutics, Goodman and Gilman, eds., Macmillan Publishing Co., New York.
  • an effective dose can be estimated initially either in cell culture assays or in suitable animal models. The animal model may also be used to determine the appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • a therapeutic dose can also be selected by analogy to dosages for comparable therapeutic agents.
  • Treatment may involve daily or multi-daily doses of compound(s) over a period of a few days to months, or even years.
  • a suitable dose will be in the range of from about 0.001 to about 100 mg/kg, e.g., from about 0.01 to about 100 mg/kg of body weight per day, such as above about 0.1 mg per kilogram, or in a range of from about 1 to about 10 mg per kilogram body weight of the recipient per day.
  • a suitable dose may be about 1 mg/kg, 10 mg/kg, or 50 mg/kg of body weight per day.
  • the compounds of Formula I are conveniently administered in unit dosage form; for example, containing 0.05 to 10000 mg, 0.5 to 10000 mg, 5 to 1000 mg, or about 100 mg of active ingredient per unit dosage form.
  • the compounds can be administered to achieve peak plasma concentrations of, for example, from about 0.5 to about 75 ⁇ , about 1 to 50 ⁇ , about 2 to about 30 ⁇ , or about 5 to about 25 uM.
  • Exemplary desirable plasma concentrations include at least or no more than 0.25, 0.5, 1, 5, 10, 25, 50, 75, 100 or 200 ⁇ .
  • plasma levels may be from about 1 to 100 micromolar or from about 10 to about 25 micromolar. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the compounds, optionally in saline, or orally administered as a bolus containing about 1-100 mg of the compounds.
  • Desirable blood levels may be maintained by continuous infusion to provide about 0.00005-5 mg per kg body weight per hour, for example at least or no more than 0.00005, 0.0005, 0.005, 0.05, 0.5, or 5 mg/kg/hr.
  • such levels can be obtained by intermittent infusions containing about 0.0002-20 mg per kg body weight, for example, at least or no more than 0.0002, 0.002, 0.02, 0.2, 2, 20, or 50 mg of the compounds per kg of body weight.
  • the compounds may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator.
  • the dosage of the compounds and/or compositions of the disclosure can vary depending on many factors such as the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of the treatment and the type of concurrent treatment, if any, and the clearance rate of the compound in the subject to be treated.
  • One of skill in the art can determine the appropriate dosage based on the above factors.
  • the compounds of the disclosure may be administered initially in a suitable dosage that may be adjusted as required, depending on the clinical response.
  • HED (mg/kg) mouse dose (mg/kg) x 0.08 may be employed (see Estimating the Safe Starting Dose in Clinical Trials for Therapeutics in Adult Healthy Volunteers, December 2002, Center for Biologies Evaluation and Research).
  • agent is used herein to denote a chemical compound (such as an organic or inorganic compound, a mixture of chemical compounds), a biological macromolecule (such as a nucleic acid, an antibody, including parts thereof as well as humanized, chimeric and human antibodies and monoclonal antibodies, a protein or portion thereof, e.g., a peptide, a lipid, a carbohydrate), or an extract made from biological materials such as bacteria, plants, fungi, or animal (particularly mammalian) cells or tissues.
  • Agents include, for example, agents whose structure is known, and those whose structure is not known. The ability of such agents to inhibit AR or promote AR degradation may render them suitable as "therapeutic agents" in the methods and compositions of this disclosure.
  • a “patient,” “subject,” or “individual” are used interchangeably and refer to either a human or a non-human animal These terms include mammals, such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • mammals such as humans, primates, livestock animals (including bovines, porcines, etc.), companion animals (e.g., canines, felines, etc.) and rodents (e.g., mice and rats).
  • Treating a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results.
  • beneficial or desired results including clinical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e. not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • administering or "administration of a substance, a compound or an agent to a subject can be carried out using one of a variety of methods known to those skilled in the art.
  • a compound or an agent can be administered, intravenously, arterially, intradermally, intramuscularly, intraperitoneally, subcutaneously, ocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intraspinally, intracerebrally, and transdermally (by absorption, e.g., through a skin duct).
  • a compound or agent can also appropriately be introduced by rechargeable or biodegradable polymeric devices or other devices, e.g., patches and pumps, or formulations, which provide for the extended, slow or controlled release of the compound or agent.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.
  • a compound or an agent is administered orally, e.g., to a subject by ingestion.
  • the orally administered compound or agent is in an extended release or slow release formulation, or administered using a device for such slow or extended release.
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either
  • a “therapeutically effective amount” or a “therapeutically effective dose” of a drug or agent is an amount of a drug or an agent that, when administered to a subject will have the intended therapeutic effect.
  • the full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a therapeutically effective amount may be administered in one or more administrations.
  • the precise effective amount needed for a subject will depend upon, for example, the subject's size, health and age, and the nature and extent of the condition being treated, such as cancer or MDS. The skilled worker can readily determine the effective amount for a given situation by routine experimentation.
  • acyl is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.
  • acylamino is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbylC(0)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(0)0-, preferably alkylC(0)0-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto.
  • alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.
  • alkyl refers to saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., Ci- 30 for straight chains, C3-30 for branched chains), and more preferably 20 or fewer.
  • alkyl as used throughout the specification, examples, and claims is intended to include both unsubstituted and substituted alkyl groups, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2- trifluoroethyl, etc.
  • Cx- y or "C x -C y ", when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain.
  • Coalkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a Ci-6alkyl group for example, contains from one to six carbon atoms in the chain.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.
  • amide refers to a group wherein R 9 and R 10 each independently represent a hydrogen or hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by wherein R 9 , R 10 , and R 10 ' each independently represent a hydrogen or a hydrocarbyl group, or R 9 and R 10 taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.
  • aminoalkyl refers to an alkyl group substituted with an amino group.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • the ring is a 5- to 7- membered ring, more preferably a 6-membered ring.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • rt-recognized refers to a group wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl group.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbocycle refers to a non-aromatic saturated or unsaturated ring in which each atom of the ring is carbon.
  • a carbocycle ring contains from 3 to 10 atoms, more preferably from 5 to 7 atoms.
  • Carbocyclylalkyl refers to an alkyl group substituted with a carbocycle group.
  • carbonate is art-recognized and refers to a group -OCO2-.
  • esters refers to a group -C(0)OR 9 wherein R 9 represents a hydrocarbyl group.
  • ether refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.
  • ethers include, but are not limited to, heterocycle-O-heterocycle and aiyl-O- heterocycle.
  • Ethers include "alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heteroaryl and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is
  • heteroaromatic e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclylalkyl refers to an alkyl group substituted with a heterocycle group.
  • heterocyclyl refers to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms.
  • heterocyclyl and “heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.
  • lower when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer atoms in the substituent, preferably six or fewer.
  • acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).
  • polycyclyl refers to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are "fused rings".
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • sulfate is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.
  • sulfonamide is art-recognized and refers to the group represented by the general formulae wherein R 9 and R 10 independently represents hydrogen or hydrocarbyl.
  • sulfoxide is art-recognized and refers to the group-S(O)-.
  • sulfonate is art-recognized and refers to the group SO3H, or a
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic mo
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(0)SR 9 or -SC(0)R 9 wherein R 9 represents a hydrocarbyl.
  • thioether is equivalent to an ether, wherein the oxygen is replaced with a sulfur.
  • urea is art-recognized and may be represented by the general formula wherein R 9 and R 10 independently represent hydrogen or a hydrocarbyl.
  • modulate includes the inhibition or suppression of a function or activity (such as cell proliferation) as well as the enhancement of a function or activity.
  • compositions, excipients, adjuvants, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is suitable for or compatible with the treatment of patients.
  • pharmaceutically acceptable acid addition salt means any non-toxic organic or inorganic salt of any base compounds represented by Formula I.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate.
  • Illustrative organic acids that form suitable salts include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluene sulfonic and methanesulfonic acids.
  • Either the mono or di-acid salts can be formed, and such salts may exist in either a hydrated, solvated or substantially anhydrous form.
  • the acid addition salts of compounds of Formula I are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms.
  • the selection of the appropriate salt will be known to one skilled in the art.
  • Other non-pharmaceutically acceptable salts e.g., oxalates, may be used, for example, in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable basic addition salt means any non-toxic organic or inorganic base addition salt of any acid compounds represented by Formula I or any of their intermediates.
  • Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide.
  • Illustrative organic bases which form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine and picoline or ammonia. The selection of the appropriate salt will be known to a person skilled in the art.
  • stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration, said R and S notation is used in correspondence with the rules described in Pure Appl. Chem. (1976), 45, 1 1-30.
  • the disclosure contemplates all stereoisomeric forms such as enantiomeric and diastereoisomeric forms of the compounds, salts, prodrugs or mixtures thereof (including all possible mixtures of stereoisomers). See, e.g., WO 01/062726.
  • Prodrug or “pharmaceutically acceptable prodrug” refers to a compound that is metabolized, for example hydrolyzed or oxidized, in the host after administration to form the compound of the present disclosure (e.g., compounds of formula I).
  • Typical examples of prodrugs include compounds that have biologically labile or cleavable (protecting) groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, or
  • prodrugs using ester or phosphoramidate as biologically labile or cleavable (protecting) groups are disclosed in U. S. Patents 6,875,751, 7,585,851, and 7,964,580, the disclosures of which are incorporated herein by reference.
  • the prodrugs of this disclosure are metabolized to produce a compound of Formula I.
  • the present disclosure includes within its scope, prodrugs of the compounds described herein. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" Ed. H. Bundgaard, Elsevier, 1985.
  • phrases "pharmaceutically acceptable carrier” as used herein means a
  • composition or vehicle such as a liquid or solid filter, diluent, excipient, solvent or encapsulating material useful for formulating a drug for medicinal or therapeutic use.
  • log of solubility is used in the art to quantify the aqueous solubility of a compound.
  • the aqueous solubility of a compound significantly affects its absorption and distribution characteristics. A low solubility often goes along with a poor absorption.
  • LogS value is a unit stripped logarithm (base 10) of the solubility measured in mol/liter.
  • mTOR rapamycin
  • PI-3K phosphatidylinositol 3-kinase
  • GBM phosphatidylinositol 3-kinase
  • mTOR is a common element in two separate multicomponent kinase complexes (6,7).
  • the mTOR-mLST8-Raptor complex (mTORC l) integrates signals regulating cell size and growth whereas the mTOR-mLST8-mSINl -Rictor complex
  • mTORC2 regulates cell cycle-dependent cytoskeleton assembly in addition to growth (8).
  • mTORC2 has emerged as a promising target in GBM, as recent data indicate that mTORC2 activity is essential for the transformation and invasive characteristics of these tumors, yet in many normal cells mTORC2 activity appears nonessential (9-11).
  • Mammalian TORC2 is -1.3 MDa and contains two copies of each of six subunits: mTOR, mLST8, Rictor, mSINl, Deptor and PRR5 or its paralog PRR5L (37). Besides mTOR, Rictor is the largest subunit of TORC2. Disruption or RNAi-mediated depletion of Rictor results in the disassembly of TORC2 suggesting that Rictor performs a critical scaffolding function (38). In binding studies both the parent and JR-AB2-011 inhibitors bound to Rictor and prevented the association of mTOR, consistent with the notion that these compounds are able to inhibit assembly of mTORC2.
  • JR-AB2-011 can also result in the disassembly of preformed mTORC2. While unlikely, it cannot be ruled out that JR-AB2-01 1 affects PRR5 function such that mTORC2 activity is impaired. Future mechanistic studies will be required to address these questions.
  • the inhibitors described herein are specific for mTORC2 in that mTORCl was apparently unaffected by exposure, as one of the most well established markers of mTORCl activity, phospho-T 389 -S6K, was monitored as a readout. Additionally, phospho-S 312 and total IRS1 levels were unchanged suggesting that at least the S6K/IRS 1/PI-3K feedback loop remained intact in the presence of JR-AB2-000 (Fig. 8A). MAPK activation is also downstream of this feedback loop and ERK activity was unresponsive to JR-AB2-000 (Fig. 8B).
  • JR-AB2-000 An important determinant of sensitivity to JR-AB2-000 is relative Rictor or SIN1 expression. This is most likely a result of increased mTORC2 formation, as increased expression of these subunits would be expected to promote the nucleation of signaling competent mTORC2 kinases. These inhibitors bind Rictor, and it is possible that post- translational modifications of Rictor, such as phosphorylation or acetylation may additionally be critical determinants of sensitivity for these compounds. Indeed, recent experiments show that glucose-dependent acetylation of Rictor promotes resistance to EGFR, PI-3K or AKT targeted therapies in GBM (39). It is conceivable that such modifications to Rictor may affect the affinity of JR-AB2-01 1 for its putative binding site. Another important consideration is the possibility that JR-AB2-000 or JR-AB2-01 1 bound Rictor may exert effects on several mTORC2-independent signaling cascades regulating cell proliferation and motility (15,40- 42).
  • inhibitors of mTORC2 activity have been identified which target the regulatory subunit Rictor.
  • the compounds and compositions are useful in inhibiting the interaction of the regulatory subunit Rictor with mTOR and in blunting mTORC2 signaling while leaving mTORCl signaling unaffected.
  • These inhibitors have broad anti-GBM effects in vitro and in xenograft experiments, blocking growth, motility and invasive characteristics of GBM cell lines. Sensitivity to the inhibitor is correlated with elevated Rictor or mSINl expression. SPR and mTOR-bead pull-down experiments suggest that JR-AB2-000 and JR- AB2-011 specifically bind to Rictor and block association with mTOR.
  • the SF763 line was obtained from the UCSF Neurosur-gery Tissue Bank and all other lines were from ATCC (Manassas, VA). Normal mature human neurons were obtained from ScienCell (Carlsbad, CA). Wild-type and SIN1- null MEFs were gen-erously provided by Dr. Bing Su (Yale University). Lines were obtained from 2001-2012 and rou-tinely tested to confirm the absence of mycoplasma. Cell authentication by ATCC is done by STR profiling. The myc-Rictor (corrected) and Deptor constructs were gifts from Dr.
  • Recombinant Proteins, Antibodies, Reagents and JR-AB2-000 Structure-activity relationship (SAR) Analog preparation- Proteins were expressed and purified from HEK293 cells using anti-myc, an-ti-HA or anti-Flag Sepharose column chromatography as previously described (23).
  • Recombinant Raptor was from Abeam (Cambridge, MA) and recombinant mLST8 was obtained from Abnova (Walnut, CA).
  • Antibodies were from the following sources.
  • mTOR (#2972, Cell Signaling Technologies, CST), phospho-S 312 -IRSl (#ab66154, Abeam), total IRS1 (#abl31487, Abeam), phospho-T 202 Y204 -ERK (#4370, CST), total ERK (#9102, CST), phospho-S 657 -PKCa (#SAB-4504096, Sigma), total PKCa (#sc-208, Santa Cruz Biotechnology), phospho-T 389 -S6K (#9205, CST), total S6K (#9202, CST), phospho- T 346 -NDRG1 (#3217, CST), total NDRG1 (#abl24689, Abeam), phospho-S 473 -AKT (#9271, CST), total AKT (#9272, CST), Rictor (#A300-459A, Bethyl Laboratories), actin (#ab3280, Abeam), a-GST (#26
  • STK377726 was obtained from Vitas-M Ltd., (Champaign, IL).
  • Protein expression, co-immunoprecipitation and in vitro kinase analyses- Western blot analyses were performed as previously described (14). Briefly, cells were lysed in RIPA (lysis) buffer containing protease inhibitor cocktail and phosSTOP phosphatase inhibitor cocktail (Roche) and extracts resolved by SDS-PAGE. Proteins were transferred to PVDF membranes and incubated with the indicated antibodies. Antigen-antibody complexes were detected using appropriate horseradish peroxidase-conjugated secondary antibodies (GE Healthcare) and enhanced chemiluminescence (Amersham ECL Prime). Co- immunoprecipitations were performed as previously described (26). mTORC2 in vitro kinase assays were performed as described utilizing GST-tagged AKT as a substrate (14).
  • Re-sponse units were measured in the dissociation phase and specific binding was calculated by subtracting the control surface signal from the surfaces with immobilized mTOR.
  • mTOR-Flag binding assays purified myc-Rictor was pre-treated with increasing concentrations of JR-AB2-000 or JR-AB2-011 for lh at 4°C and subsequently added to mTOR-Flag beads and incubated overnight at 4°C. Incubated beads were washed five times and immunoblotted using an anti-myc or anti-Flag antibody as indicated.
  • TUNEL staining of tumor sections was performed using the TACSXL DAB In Situ Apoptosis Detection kit (Trevigen) according to the manufacturer' s instructions (28).
  • Example 2 JR-AB2-000 Inhibition of mTORC2 in vitro kinase activity
  • JR-AB2-000 in a concentration-dependent manner, inhibited mTORC2 in vitro kinase activity. JR-AB2-000 also blocked the association of Rictor with mTOR in immunoprecipitates of mTOR from U87 cells treated with the inhibitor (Fig. IB). The ability of the compound to block rictor-mTOR association was specific as raptor-mTOR binding was unaffected.
  • JR-AB2-000 markedly inhibited phosphorylation of known mTORC2 substrates such as, phospho-S 47 -AKT, phospho-T 346 - DRG1 and phospho-S 657 -PKCa, while having no discernible affect on the levels of phospho- T 389 -S6K, a mTORCl specific phospho-site.
  • JR-AB2-000 inhibited mTORC2 signaling in a concentration- dependent manner with marked inhibition of activity within 2 hours of treatment in GBM cells, while having no significant affects on mTORCl activity.
  • JR-AB2-000 treatment affected cell migration, the ability of JR-AB2-000 treated cells to traverse a vitronectin-coated or fibronectin-coated Boyden chamber was assessed as compared to chambers coated with BSA as a control. In a dose-dependent fashion JR-AB2- 000 significantly inhibited the numbers of cells that migrated towards vitronectin or fibronectin-coated surfaces as compared to control BSA-coated surfaces (Fig. 2C). JR-AB2- 000 was also tested for whether it affected the ability of U87 or LN229 cells to invade Matrigel. As shown in Fig.
  • Rictor expression has been demonstrated to regulate the formation of mTORC2 and its activity (13,14).
  • Rictor expression was varied in these lines and expression levels were quantified via densitometry and normalized to levels observed in U87 cells.
  • Fig. 3B the relative Rictor expression in the lines tested was high in most cases except for H4, U373 and U138 which displayed low Rictor levels and LN229 and M059J in which expression was at intermediate levels.
  • the fold decrease mTORC2 activity was determined by densitometric quantification of immunoblots probed for phospho-S473-AKT abundance in LN229 cells treated with 1 ⁇ analog for 24 h as compared to values obtained with parent compound (JR-AB2-000) under identical conditions.
  • the "Structure" column in Table 2 depicts the structural modifications to JR-AB2-000 that were made, with reference to Scheme A. No significant alterations in p- T389-S6K levels were observed for any of the analogs (1 ⁇ , 24 h) as compared to untreated controls (not shown).
  • the IC50 was determined via XTT proliferation assays as in Figs. 3C and 3D. Data represent mean ⁇ S.D. of three independent experiments. Percent apoptosis was determined for LN229 cells treated with analog (1 ⁇ ) at 48 h via annexin V-FITC staining. One of three experiments with similar results is shown.
  • JR-AB2-011 markedly reduced mT0RC2 signaling (see also Fig. 9) and IC50 while enhancing apoptotic levels in GBM cells compared to the parent compound.
  • JR-AB2-030 also blocked mT0RC2 signaling and lowered the IC50 value while increasing apoptosis levels, albeit to a lesser degree than analog JR-AB2-011.
  • Additional analogs were synthesized shown in Scheme A (modifications to R 3 in Formula (I) and JR-AB2- 027 thru -029). None of these significantly altered mT0RC2 signal blockade or anti-GBM properties as compared to the parent inhibitor.
  • JR-AB2-011 displayed the least toxicity to normal neurons with no significant cytotoxic effects for concentrations up to 10 mM and was chosen for further study.
  • Example 7 JR-AB2-000 and JR-AB2-011 Inhibition of Rictor-mTOR Association
  • JR-AB2-000 surface plasmon resonance (SPR) analyses were performed of JR-AB2-000 binding to either immobilized Rictor, mTOR or mSINl .
  • Fig. 4 left-panel
  • JR-AB2-000 selectively bound to Rictor and reached equilibrium rapidly.
  • the KD was determined from steady-state binding associations and was calculated at 1 ⁇ .
  • JR-AB2-000 was unable to bind mTOR or mSINl, another regulatory subunit of mTORC2.
  • mTOR binding to immobilized Rictor was not observed, however in the reverse configuration immobilized mTOR bound Rictor with a calculated Kd of 257 nM (Fig.
  • each of the inhibitors was preincubated with either Raptor (mTORC l subunit), mLST8 or Deptor (both mTORCl & 2 subunits) and these reaction mixtures were passed over immobilized mTOR.
  • Raptor mTORC l subunit
  • mLST8 both mTORCl & 2 subunits
  • JR-AB2-01 1 or JR-AB2-000 significantly affected the binding of Raptor, mLST8 or Deptor to immobilized mTOR (Fig 5 A, middle & right panels).
  • the ability of JR-AB2-011 or JR-AB2-000 to inhibit mTOR-Rictor association was determined by a pull-down assay utilizing Flag-mTOR and myc-Rictor. As shown in Fig.
  • mice were subcutaneously implanted with tumor cells and when tumors were palpable (-200 mm 3 ), mice were randomized into treatment groups receiving vehicle, JR-AB2-011 (4 mg/kg/d) and JR-AB2-011 (20 mg/kg/d). As shown in Fig.
  • mice receiving JR-AB2-011 at either dosing regimen displayed marked inhibition of tumor growth rate (JR-AB2-011 at 4 mg/kg/d; 74% inhibition at end of dosing period; tumor growth delay 10.0 days; JR-AB2-011 at 20 mg/kg/d; 80% inhibition at end of dosing period; tumor growth delay 12.0 days) as compared to mice receiving vehicle alone. Consistent with the effects on xenograft growth, overall survival of mice at either JR-AB2-01 1 dosing regimens were significantly extended relative to vehicle treated mice. Notably, mice tolerated either of these dosing regimens without obvious short or longterm toxicity or weight loss. Blood cell counts were not affected by JR-AB2-011 (Fig. 10).
  • apoptotic cell death was monitored by TUNEL staining of sections from harvested tumors and JR-AB2-01 1 at both dosing regimens markedly enhanced apoptosis, supporting the increases in apoptotic death observed in vitro with the parent compound (Fig 6C, (left panel), see also Fig. 2E).
  • the ratio of phospho-S 47 -AKT to total AKT was significantly reduced in tumors at both doses of JR-AB2-01 1, while the ratio of phospho-T 389 -S6K to total S6K was not significantly altered (Fig. 6C, center and right panels).
  • Antibodies were from the following sources. mTOR (#2972, Cell Signaling Technologies, CST), phospho-S 12 -IRS l (#ab66154, Abeam), total IRS 1
  • Yeast methods Standard techniques were used for yeast manipulations (1). Yeast reagents used are derivatives of the MATCHMAKER Gal4 Two-Hybrid System 3
  • the drug sensitive screening strain AR109D (MATa, trpl-901, leu2-3, 112, ura3- 52, his3-200, gal4A, gal80A, LYS::GAL1UAS-GAL1TATA-HIS3, GAL2UAS-GAL2TATA-ADE2, URA3::MELluAS-MEL ATA-lacZ, avo3::KanMX, tor2::KanMXpRS316::Ypk2 D239A -HA, pdrl:CUPlpro-HXT9, pdr3:CUP lpro-HXTl 1) was derived from AR109 (2). Expression of Ypk2 D23 A (constitutively active Ypk2 (D239A) allele) was well tolerated in this strain and conferred viability in the absence of Avo3 and Tor2 (3).
  • Splitting patterns are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; ddd, doublet of doublets of doubles; dt, doublet of triplets; t, triplet; td, triplet of doublets; q, quartet; sext, sextet; m, multiplet; and br, broad.
  • 13 C NMR spectra were recorded on Bruker Spectrometers at 125 MHz and are reported relative to deuterated solvent signals (CHCb ⁇ 77.0; DMSO ⁇ 40.0 ppm). Data for 13 C spectra are reported in terms of chemical shift. The chemical shifts are reported in parts per million (ppm, ⁇ ).
  • Example 10 Synthetic procedures and Characterization data.
  • 3,4-Dichlorophenyl isothiocyanate 10.
  • thiophosgene 0.2 mL, 2.6 mmol, 1.3 eq
  • triethylamine 0.7 mL, 5.0 mmol, 2.5 eq
  • N-(3,4-Dimethylphenyl)thiazol-2-amine 24.
  • (7) To an isopropanol (25 mL) solution of 3,4-dimethylaniline (606mg, 5.0 mmol, 1.0 eq) and p-toluene sulfonic acid hydrate (476 mg, 2.5 mmol, 0.5 eq) was added 2-bromothiazole (0.68 mL. 7.5 mmol, 1.5 eq) at room temperature, and the mixture was refluxed for 120 h. After the completion of reaction, the mixture was diluted with ethyl acetate (100 mL) and quenched with aq. NaHCCb.
  • DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell 2009; 137(5):873-86 doi 10 1016/j cell.2009.03 046.
  • Wingfield PT Overview of the purification of recombinant proteins. Current protocols in protein science 2015; 80:6.1.-35 doi 10.1002/0471140864.ps0601s80.

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Abstract

La présente invention concerne des composés et des méthodes permettant d'inhiber mTORC2, ainsi que des méthodes de traitement de cancers tels que le glioblastome.
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US11958846B2 (en) 2018-08-17 2024-04-16 Novartis Ag Urea compounds and compositions as SMARCA2/BRM ATPase inhibitors

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