WO2023250157A1 - Inhibiteurs de mycobacterium tuberculosis lipoamide déshydrogénase - Google Patents

Inhibiteurs de mycobacterium tuberculosis lipoamide déshydrogénase Download PDF

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WO2023250157A1
WO2023250157A1 PCT/US2023/026103 US2023026103W WO2023250157A1 WO 2023250157 A1 WO2023250157 A1 WO 2023250157A1 US 2023026103 W US2023026103 W US 2023026103W WO 2023250157 A1 WO2023250157 A1 WO 2023250157A1
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mmol
mixture
methyl
stirred
compound
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PCT/US2023/026103
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WO2023250157A9 (fr
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John Ginn
Ruslana Bryk
Carl F. Nathan
Alexander PACHECO
Chenguang Yu
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Cornell University
Tri-Institutional Therapeutics Discovery Institute
The Scripps Research Institute
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Publication of WO2023250157A1 publication Critical patent/WO2023250157A1/fr
Publication of WO2023250157A9 publication Critical patent/WO2023250157A9/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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 chain containing hetero atoms as chain links
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds

Definitions

  • Tuberculosis infected 10 million and killed 1.5 million people in 2018. It remains a worldwide health crisis due to rising drug resistance and emerging risk factors, such as diabetes. Resistance of Mycobacterium tuberculosis (Mtb) to all first line anti-TB drugs is prevalent and calls for new strategies to develop effective therapeutics.
  • the BPaL regimen recently approved by the FDA for the treatment of extensively drug resistant (XDR) and nonresponsive multidrug resistant (MDR) TB features are, for the first time in many decades, drugs against new Mtb targets and with novel modes of action. Nevertheless, more inhibitors against previously unexplored targets are urgently needed to sustain the TB drag pipeline and to shorten and diversify drag regimens, as resistance is already detected to components of BPaL.
  • the present disclosure provides compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein:
  • X is N or CR a
  • R a is H, alkyl, cycloalkyl, halo, or cyano
  • R 1 is H, alkyl, cycloalkyl, halo, or cyano
  • R 2 is H, alkyl, cycloalkyl, halo, or cyano; either: a) R 3 is H or alkyl, R 4 is H or alkyl; and R 3 is a bond or C1-C2 alkylene; b) R- 1 and R 4 combine to form a 4 or 5 membered beterocyclyl; and R 5 is a bond or
  • R 4 is H or alkyl; and R J and R 3 combine to form a 4 or 5-membered beterocyclyl;
  • A is -NHC(O)R 6 or R 6 ;
  • R 6 is a heteroaryl or phenyl and is optionally substituted by R 7 ;
  • R 7 is allcyl, alkenyl, alkynyl, cycloalkyl, halo, heteroaryl, beterocyclyl, amide, or phenyl.
  • the present disclosure provides methods of inhibiting the growth or killing of Mycobacterium tuberculosis in vitro, comprising contacting Mycobacterium tuberculosis with a compound disclosed herein.
  • the present disclosure provides methods of treating tuberculosis, comprising administering to a subject in need thereof a compound disclosed herein.
  • Lipoamide dehydrogenase fulfills multiple metabolic functions and a unique antioxidant function in Mtb. It is a component of tire pyruvate, alpha-ketoglutarate and branched chain ketoacid dehydrogenase complexes involved in the breakdown of ketoacids coupled to the production of energy-rich acyl-CoA intermediates and NADH. In the reverse direction, Lpd supplies reducing equivalents from NADH through the lipoylated E2 cores of metabolic complexes to the thioredoxin-like adaptor AhpD and the peroxiredoxin AhpC to detoxify reactive nitrogen and oxygen intermediates.
  • Mtb lacking Lpd fails to grow on carbohydrates as a sole carbon source in vitro, cannot establish TB infection in mice, is highly susceptible to reactive nitrogen intermediates, and accumulates a ⁇ 100-fold excess of intracellular pyruvate, alanine, valine, leucine, isoleucine and their corresponding ketoacids 4 .
  • the dependence of Mtb on Lpd for virulence and persistence provides genetic validation of Lpd as a target, but chemical validation remains to be achieved.
  • X is N or CR a
  • R a is H, alkyl, cycloalkyl, halo, or cyano
  • R’ 1 is H, alkyl, cycloalkyl, halo, or cyano
  • R 2 is H, alkyl, cycloalkyl, halo, or cyano; either: a) R 3 is H or alkyl, R 4 is H or alkyl; and R 3 is a bond or C1-C2 alkylene; b) R 3 and R 4 combine to form a 4 or 5 membered heterocyclyl; and R 5 is a bond or
  • R 4 is H or alkyl; and R 3 and R 5 combine to form a 4 or 5-membered heterocyclyl;
  • A is -NHC(O)R 6 or R 6 ;
  • R 1 ' is a heteroaryl or phenyl and is optionally substituted by R 7 ;
  • R 7 is alkyl, alkenyl, alkynyl, cycloalkyl, halo, heteroaryl, heterocyclyl, amide, or phenyl.
  • R a is II or cyano.
  • R 1 is H or Cl.
  • R 2 is H or methyl.
  • R 3 is methyl or ethyl, R 4 is II; and R 3 is a bond or C1-C2 alkylene.
  • R 3 and R 4 combine to fotm a 4 or 5 membered heterocyclyl; and R 3 is a bond or optionally substituted methylene.
  • R 4 is H; and R 3 and R 5 combine to form a 4 or 5 -membered heterocyclyl.
  • R 6 is a 5-10 membered heteroaryl or phenyl, wherein each hydrogen atom in 5-10 membered heteroaryl and phenyl is optionally substituted by R 7 .
  • R'' is C1-3 alkyl, Cc-C?, alkynyl, halo, C1-C3 alkoxy, 5-10 membered heteroaryl, 4-7 membered heterocyclyl, -C(O)N(CJ-C3 alkylk, or phenyl.
  • the compounds are of formula (II): or a pharmaceutically acceptable salt thereof, wherein:
  • X is N or CR a
  • R a is H or cyano
  • R 1 is H or Cl;
  • R 2 is H or methyl; either: a) R 3 is methyl or ethyl, R 4 is H; and R 5 is a bond or C1-C2 alkylene; b) R J and R 4 combine to form a 4 or 5 membered heterocyclyl; and R 5 is a bond or optionally substituted methylene; or c) R 4 is H; and R 3 and R 5 combine to form a 4 or 5-membered heterocyclyl;
  • A is -NHC(O)R 6 or R 6 :
  • R 6 is a 5-10 membered heteroaryl or phenyl, wherein each hydrogen atom in 5-10 membered heteroaryl and phenyl is optionally substituted by R 7 :
  • R' is C1-3 alkyl, C2-C4 alkynyl, halo, C1-C3 alkoxy, 5-10 membered heteroaryl, 4-7 membered heterocyclyl, -C(O)N(CI-C3 alkyl)2, or phenyl.
  • the compounds are of formula ( Illa ) or (Illb) (IHa)
  • (Ulb), or a pharmaceutically acceptable salt thereof is preferably of Formula (Illa) or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , and A are as described herein and R 3 is II or alkyl. In certain preferred embodiments, A is R 6 .
  • the compounds are of formula (IV) or (V) or a pharmaceutically acceptable salt thereof, wherein X, R 1 , R 2 , R 5 , and A are as described herein and m is 1 or 2.
  • R 6 is heteroaryl, for example, a 5-10 membered heteroaryl (e.g., pyrazolyl, isoxazolyl, pyridyl, pyrimidyl, quinolinyl, etc.) or phenyl.
  • each hydrogen atom in heteroaryl (e.g., 5-10 membered heteroaryl) or phenyl is optionally substituted by R z .
  • R 6 can be phenyl and can be optionally substituted by 1, 2, 3, 4, or 5 R'.
  • R 6 is 5-10 membered heteroaryl optionally substituted by at least one R'.
  • R 6 is bicyclic, for example which is optionally substituted by at least one R 7 , and is preferably substituted by at least one R 7 , and more preferably is substituted by one R'.
  • R 6 is monocyclic, for example pyrazolyl, pyridyl, isoxazolyl, triazolyl, imidazolyl, or oxadiazolyl, each of which is optionally substituted by at least one R 7 .
  • R 7 is alkyl (e.g., C1-3 alkyl (methyl, ethyl, or isopropyl), alkenyl, alkynyl (e.g., C2.-C4 (propargyl)), cycloalkyl, halo (e.g., fluoro, chloro, or bromo), alkoxy (e.g., C1-C3 alkoxy (methoxy)), heteroaryl (e.g., 5-10 membered heteroaryl (pyridyl or triazolyl optionally substituted by phenyl), methylpyrimidonyl, N-methylpyridonyl pyridonyl, pyrimidonyl, or dihydroindenyl)), heterocyclyl (e.g., 4-7 membered heterocyclyl (morpholino, oxetanyl, or tetrahydropyranyl)), amide (e.g., C(O)N(CI-C3
  • R 7 is tetrahydropyranyl, even more preferably 4-tetrahydropyranyl.
  • R 7 is phenyl optionally substituted by hydroxy, C1-C3 alkyl (e.g., methyl or ethyl), C1-C3 haloalkyl (e.g., trifluoromethyl), halo (e.g., fluoro, chloro, or bromo), -OC1-C3 alkyl-N(Ci-C3 alkyl (e.g., -OCftCIXNfMe)?, or a boronate ester or two substituents combine to form C3-C6 cycloalkyl (e.g., cyclopentyl).
  • the boronate ester is
  • A is -NHC(O)R 6 or R 6 . In some embodiments, A is -NHC(O)R 6 . In certain preferred embodiments, A is R 6 .
  • R 3 and R 4 combine to form a 4 or 5 membered heterocyclyl; and R 5 is a bond or optionally substituted methylene; or
  • R 4 is H; and R ' and R"' combine to form a 4 or 5-membered heterocyclyl
  • A is -NHC(O)R 6 , and either:
  • R 3 and R 4 combine to form a 4 or 5 membered heterocyclyl; and R J is a bond or optionally substituted methylene; or
  • R 4 is H; and R J and R 3 combine to form a 4 or 5-membered heterocyclyl.
  • X is N or CR a . In some embodiments, X is N. In certain preferred embodiments, X is CR a . In some embodiments, R a is H, alkyl, cycloalkyl, halo (e.g., chloro), or cyano. In certain preferred embodiments, R a is cyano. In some embodiments, R a is H.
  • R 1 is H, alkyl, cycloalkyl, halo (e.g., chloro), or cyano.
  • R’ 1 is H.
  • R’ 1 is Cl.
  • R 2 is H, alkyl, cycloalkyl, halo (e.g., chloro), or cyano. In some embodiments, R 2 is H. In certain preferred embodiments, R 2 is methyl.
  • R 3 is H or alkyl (e.g., methyl or ethyl) and is preferably methyl.
  • R 4 is H or alkyl (e.g., methyl or ethyl).
  • R 5 is a bond or Ci-Cc alkylene (e.g., methylene). In certain preferred embodiments, R 3 is a bond. In some embodiments, R 5 is Ci-C?. alkylene (e.g., methylene).
  • R 3 and R 4 combine to form a 4- or 5-membered heterocyclyl (e.g. bond or C1-C2 alkylene.
  • R 3 and R 5 combine to form a 4- or 5-membered heterocyclyl (e.g., alkyl.
  • the compound is selected from :
  • compositions comprising a compound disclosed herein and a pharmaceutically acceptable carrier.
  • the present disclosure provides methods of inhibiting or killing Mycobacterium tuberculosis in vitro, comprising contacting Mycobacterium tuberculosis with a compound disclosed herein.
  • the present disclosure provides methods of treating tuberculosis, comprising administering to a subject in need thereof a compound disclosed herein.
  • the subject is a mammal.
  • the subject is a human.
  • compositions and methods of the present invention may be utilized to treat an individual in need thereof.
  • the individual is a mammal such as a human, or a non-human mammal.
  • the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters.
  • the aqueous solution is pyrogen-free, or substantially pyrogen-free.
  • the excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs.
  • the pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.
  • the composition can also be present in a transdermal delivery system, e.g., a skin patch.
  • the composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.
  • a pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention.
  • physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients.
  • carbohydrates such as glucose, sucrose or dextrans
  • antioxidants such as ascorbic acid or glutathione
  • chelating agents such ascorbic acid or glutathione
  • low molecular weight proteins or other stabilizers or excipients The choice of a pharmaceutically acceptable earner, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.
  • the preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system.
  • the pharmaceutical composition also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.
  • Liposomes for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases '‘pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • Some examples of materials which can serve as pharmaceutically acceptable earners include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oik (10) glycols, such as propylene glycol; (1 1) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum
  • a pharmaceutical composition can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually): subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin).
  • the compound may also be formulated for inhalation.
  • a compound may be simply dissolved or suspended in sterile water.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • Methods of preparing these formulations or compositions include the step of bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients.
  • an active compound such as a compound of the invention
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, 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/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • Compositions or compounds may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable earners, 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 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 quaternary ammonium compounds; (7) wetting agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as paraffin; (6) absorption accelerators, such
  • 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.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfaceactive or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of tire above-described excipients.
  • Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, 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.
  • inert diluents commonly used in the art, such
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Dosage forms for the topical or transdernial administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an 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 an 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 and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdernial patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the active compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous 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 nonaqueous 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.
  • compositions 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 that delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drag then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drag in an oil vehicle.
  • Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide -polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drag in liposomes or microemulsions that are compatible with body tissue.
  • active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • Methods of introduction may also be provided by rechargeable or biodegradable devices.
  • Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinaceous biopharmaceuticals.
  • a variety of biocompatible polymers including hydrogels, including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe tire therapeutically effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • therapeutically effective amount is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effecti ve amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient’s condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention.
  • a larger total dose can be delivered by multiple administrations of the agent.
  • Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).
  • a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • the active compound may be administered two or three times daily.
  • the active compound will be administered once daily.
  • the patient receiving this treatment is any animal in need, including primates, in particular humans; and other mammals such as equines, cattle, swine, sheep, cats, and dogs; poultry; and pets in general.
  • compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent.
  • contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts.
  • contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N-methyl glucamine, hydrabamine, IH-imidazole, lithium, L- lysine, magnesium, 4-(2-hydroxyethyl)morpholine, piperazine, potassium, l-(2- hydroxyethyljpyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts.
  • contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, 1 -hydroxy-2 -naphthoic acid, 2, 2 -di chloroace tic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4- aminosalicylic acid, acetic acid, adipic acid, 1 -ascorbic acid, 1-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsul
  • the pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared.
  • the source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDT'A), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT
  • 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).
  • Treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including cli nical results.
  • treatment is an approach for obtaining beneficial or desired results, including clinical results.
  • Beneficial or desired clinical results can include, but tire 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 phrase “conjoint administration” refers to any form of administration of two or more different therapeutic agents such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are simultaneously effective in the patient, which may include synergistic effects of the two agents).
  • the different therapeutic compounds can be administered either in the same formulation or in separate formulations, either concomitantly or sequentially.
  • an individual who receives such treatment can benefit from a combined effect of different therapeutic agents.
  • 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 effecti ve 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.
  • the terms “optional” or “optionally” mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as weli as instances in which it does not.
  • “optionally substituted alkyl” refers to the alkyl may be substituted as well as where the alkyl is not substituted.
  • substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the term “optionally substituted” refers to the replacement of one to six hydrogen radicals in a given structure with tire radical of a specified substituent including, but not limited to: hydroxyl, hydroxyalkyl, alkoxy, halogen, alkyl, nitro, silyl, acyl, acyloxy, aryl, cycloalkyl, heterocyclyl, amino, aminoalkyl, cyano, haloalkyl, haloalkoxy, -OCO-CH2-O- alkyl, -OP(O)(O-alkyl)2 or ⁇ CH2-OP(O)(O-alkyl)2.
  • “optionally substituted” refers to the replacement of one to four hydrogen radicals in a given structure with the substituents mentioned above. More preferably, one to three hydrogen radicals are replaced by the substituents as mentioned above. It is understood that the substituent can be further substituted.
  • alkyl refers to saturated aliphatic groups, including but not limited to C1-C10 straight-chain alkyl groups or Ci-Cw branched-chain alkyl groups.
  • the “alkyl” group refers to Ci-Ce straight-chain alkyl groups or Ci-Cg branched- chain alkyl groups.
  • the “alkyl” group refers to Ci-C?. straight -chain alkyl groups or C1-C4 branched-chain alkyl groups.
  • alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, 1-pentyl, 2 -pentyl, 3-pentyi, neo-pentyl, 1 -hexyl, 2-hexyl, 3-hexyl, 1 -heptyl, 2-heptyl, 3-heptyl, 4-heptyl, 1 -octyl, 2-octyl, 3-octyl or 4-octyl and the like.
  • the “alkyl” group may be optionally substituted.
  • 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(O)NH-.
  • acyloxy is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.
  • alkoxy refers to an alkyl group having an oxygen attached thereto. Representative 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.
  • C s.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.
  • Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal.
  • a C1-6 alkyl 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 !0 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 includes optionally substituted (i.e., 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.
  • carboxylate is art-recognized and 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 includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • fused carbocycle refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings.
  • an aromatic ring e.g., phenyl
  • a saturated or unsaturated ring e.g., cyclohexane, cyclopentane, or cyclohexene.
  • Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5-cyclooctadiene, 1 ,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct- 3-ene, naphthalene and adamantane.
  • Exemplary' fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-lH- indene and bicyclo[4.1.0]hept-3-ene.
  • “Carbocycles” may be substituted (i.e., are optionally substituted) at any one or more positions capable of bearing a hydrogen atom.
  • 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(O)OR 9 wherein R y 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. Examples of ethers include, but are not limited to, heterocycle- O-heterocycle and aryl-O-heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl - O-alkyl.
  • halo and “halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.
  • heteroalkyl and “heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.
  • heteroaryl and “hetaryl” includes optionally substituted (i.e., substituted or un substituted) 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, pyridone, pyrmidone, 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 optionally substituted (i.e., substituted or unsubstituted) non-aromatic ring structures, preferably 3- to 10- membered rings, more preferably 3- to 7-membered rings, more prefereably 4- to 5 -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 beterocyclyls.
  • Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.
  • groups like methyl, ethoxyethyl, 2 -pyridyl, and even trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a -O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not.
  • 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, hcteroaryls, and/or beterocyclyls) 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 optionally substituted (i.e., are substituted or unsubstituted).
  • each ring of the poly cycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.
  • salt 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 lu 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 pharmaceutically acceptable salt thereof.
  • 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 alkoxy carbonyl, 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 sulfonamide, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.
  • thioalkyl refers to an alkyl group substituted with a thiol group.
  • thioester refers to a group -C(O)SR 9 or -SC(O)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.
  • “Pharmaceutically acceptable salt” or “salt” is used herein to refer to an acid addition salt or a basic addition salt which is sui table for or compatible with the treatment of patients.
  • 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, 11-30.
  • 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.
  • Prodrag or “pharmaceutically acceptable prodrag” 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 dephosphorylated to produce the active compound.
  • 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. II. Bundgaard, Elsevier, 1985.
  • health weight refers to an individual with a body mass index between 18.5 and 24.9.
  • 1-1 1-2 A mixture of 1-1 (460 mg, 1.25 mmol) in a 1:1 mixture of conentrated HCI/EtOAc (15 mL) was stirred at 18 °C for 2 hr. The reaction mixture was filtered and the filter cake was concentrated under reduced pressure to give N-(2-aminoethyl)-N,5-dimethyl-lH-indazole-7- sulfonamide (1-2) (0.35 g, crude) was obtained as a white solid. No further purification was performed.
  • 15-2 (0.0613 mg, 0.266 mmol) and DIEA (0.0687 g, 0.531 mmol) in THF (1 mL) at 25 °C was added 15-2 (0.0500 g, 0.266 mmol) in one portion, then the mixture was stirred at this temperature for 1 hrs.
  • the aqueous phase was extracted with ethyl acetate (10()mL*3) and the combined organic phase was washed with brine (200 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the aqueous phase was extracted with ethyl acetate (20 mL*2) and the combined organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by reversed-phase flash chromatography (0.1 % NHjHjO/MeCN condition) to afford 5-methyl-4- oxo-1 -((2- (trimethylsilyl)ethoxy)methyl)-4,5-dihydro-lH-imidazo[4,5-c]pyridine-2- carbaldehyde (16-5) (0.040 g, 0.125 mmol, 35.1% yield) as a yellow solid.
  • 17-2 20 To a solution of 17-2 (100 mg, 0.356 mmol) in DMF (3 mL) at 0°C was added TEA (108 mg, 1.07 mmol) followed by a solution of morpholine-4-carbonyl chloride (0.357 mmol) in DCM (1 mL) dropwise under N?.. The mixture was stirred at 20 °C for 12 hr then diluted with NaHCOs (10ml) and extracted with DCM (15ml * 3). The combined organic layers were washed with brine (15ml * 2), dried over NasSCL, filtered, and concentrated under reduced pressttre.
  • the mixture was poured into water (15 mL) and extracted with ethyl acetate (10 mL x 3) then the combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the residue was dissolved in glacial acetic acid (5 mL) and stirred for 2 hours at 50 °C.
  • the mixture was added dropwise into a saturated aqueous solution of sodium bicarbonate (15 mL) then extracted with ethyl acetate (15 mL x 3) and the combined organic layers were washed with brine (15 111L). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was purified by prep-HPLC (column: Phenomenex Gemini -NX Cis 75*30 mm*3 um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B%: 26%-56%, 11.5 min and prep-TLC (petroleum ether/ethyl acetate - 1:1) to afford N-((4- methoxybenzo[djoxazol-2-yl)methyl)-N,5-dimethyl-lH- indazole-7-sulfonamide (26) (0.016 g, 0.041 mmol, 40.5% yield) as a white solid.
  • 28-3 28-4 A solution of 28-3 (0.400 g, 1.32 mmol) in HCl/EtOAc (8 mL, 4N) was stirred at 25 °C for 1 hr. The reaction mixture was filtered and concentrated under reduced pressure to give 2- (azetidin-3-yl)-4-methoxy-lH-ben zimidazole (28-4) (240 mg, 1.09 mmol, 82.3% yield, HO salt) as a whi te solid. No additional purification was performed.
  • aqueous phase was extracted with ethyl acetate (50 mL*3) and the combined organic phase was washed with brine (30 mL*2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford azidobenzene (29-2) (0.500 g, crude) as brown oil which w'as used directly.
  • BHa-MejS (10 M, 0.18 mL) under nitrogen. The mixture was stirred for 30 minutes at 25 °C then heated to 60°C and stirred for 2 hours. The mixture was cooled to 0 °C, then methanol (5 mL) was added and the mixture heated to 60°C stirred for 12 hours. The mixture was poured into water (2.0 mL) and extracted with ethyl acetate (20 mL*3).
  • N,N- dimethylformamide (2 mL) were added 32-3 (0.150 g, 0.897 mmol) followed by T3P (0.856 g, 1.35 mmol, 0.800 mL, 50% in ethyl acetate) and ;V,A'-di isopropylethylamine (0.464 g, 3.59 mmol, 0.625 mL).
  • the resulting mixture was stirred for 1 hour at 25°C then poured into water (20 mL) and extracted with ethyl acetate (20 mL *3). The combined organic layers were washed with brine (20mL*3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure.
  • the solid was purified again by prep-HPLC (column: Phenomenex Gemini-NX Cis 75*30 mm*3 um; mobile phase: [water (10 mm NH4HCO3)-ACN]; B%: 12%-42%, 8 min) and then lyophilized.
  • the solid was dissolved in dichloromethane/methanol (10/1) and washed with an aqueous solution of sodium hydroxide (5 mL*3).
  • 36-3 36 To a mixture of 36-3 (0.100 g, 0.314 mmol) in dimethyl formamide (2 mL) at 0°C was added trimethyl amine (0.219 mL, 1.57 mmol) followed by 1-1 (0.073 g, 0.314 mmol). The mixture was stirred at 0°C for 30 minutes then quenched with 30 mL of water and extracted with ethyl acetate (30 mL*4). The combined organic layer was washed with brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • 43-2 43-3 To a solution of 43-2 (5.50 g, 30.9 mmol) in dimethylformamide (100 mL) was added di-tert- butyl carbonate (10.1 g, 46.3 mmol) and triethylamine (9.37 g, 92.6 mmol). The mixture was stirred at 25 °C for 2 hours then concentrated under reduced pressure.
  • the reaction solution was stirred at 70 °C for 4 hours then cooled to room temperature, quenched with water (50 mL) and ethyl acetate (50 mL), then filtered.
  • the filtrate was diluted with water 20 mL and extracted with ethyl acetate (20 mL*3).
  • the combined organic layers were washed with brine (15 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the mixture was stirred at 95 °C for 12 hours under nitrogen atmosphere.
  • the reaction mixture was cooled to room temperature, quenched by addition of water (20 mL), and then extracted with ethyl acetate (20 mL * 3). The combined organic layers were washed with brine (40 mL * 3), dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue.
  • 54-4 54-5 To a mixture of 54-4 (0.0800 g, 0.302 mmol) and triethylamine (0.092 g, 0.905 mmol) in AyV-dimethy I formamide (2 mL) at 0 °C was added 1-2 (0.105 g, 0.256 mmol). The mixture was stirred at 25 °C for 2 hours then poured into water (25 mL) causing a solid to precipatate.
  • 55-4 55-5 A mixture of 55-4 (0.20 g, 0.593 mmol), tributyi(prop-l-yn-l-yl)stannane (0.488 g, 1.48 mmol) and palladium triphenylphosphane (0.068 g, 0.059 mmol) were taken up into a microwave tube in dioxane (3 mL). The sealed tube was heated to 130 °C for 2 hours under microwave irradiation. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
  • 57-3 57 To a solution of 57-3 (0.19 g, 0.362 mmol) in dichloromethane (2 mL) was added 2,2,2- trifluoroacetic acid (1.54 g, 13.5 mmol). The mixture was stirred at 25 °C for 4 hours then concentrated under reduced pressure.
  • the mixture was stirred at 100 °C for 12 hours then cooled to room temperature and quenched with water (50 mL).
  • the aqueous phase was extracted with ethyl acetate (50 mL*3) and the combined organic phases were washed with brine (50 mL*3), dried with anhydrous sodium sulfate, filtered, and filtrate was concentrated under reduced pressure.
  • Lpd activity was measured by the DTNB assay according to previously published procedures.
  • Lpd was dispensed into the wells, compounds added at specified concentrations, mixed and in certain cases preincubated at RT for 30 min without any other components.
  • Reaction was started by adding assay mix containing the substrates (lipoamide, NADH) and DTNB and the TNB production was recorded over time at RT in the SpectraMax plate reader at 412 nm.
  • Assay mix containing the substrates (lipoamide, NADH) and DTNB
  • TNB production was recorded over time at RT in the SpectraMax plate reader at 412 nm.
  • SpectraMax plate reader for time-dependent measurements compounds were added to wells containing assay mix and the reaction was started by the addition of Lpd protein and TNB production was followed over time in SpectraMax plate reader at 412 nm.
  • Liver microsomes were purchased from Sekisui XenoTech, LLC. (Kansas City, KS).
  • the microsomes (0.2 mg protein/niL) and the compounds (1 pM) were mixed in phosphate buffer (pH /.4).
  • the reactions were initiated by adding an NADPH generating system (a mixture of MgCh, p-NADP + , glucose-6-phosphate, and glucose-6-phosphate dehydrogenase) to the mixtures before incubation.
  • NADPH generating system a mixture of MgCh, p-NADP + , glucose-6-phosphate, and glucose-6-phosphate dehydrogenase
  • Incubations were conducted at 37°C and terminated by adding acetonitrile.
  • the zero-time incubations, which served as the controls, were terminated by adding acetonitrile before adding an NADPH generating system. After the samples were mixed and centrifuged, the compound concentration in the supernatant fractions were measured by LC/MS/MS.

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Abstract

L'invention concerne des composés pour inhiber la lipoamide déshydrogénase (Lpd), et des procédés de traitement de la tuberculose.
PCT/US2023/026103 2022-06-24 2023-06-23 Inhibiteurs de mycobacterium tuberculosis lipoamide déshydrogénase WO2023250157A1 (fr)

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