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WO2020139701A1 - Composés, compositions et procédés de modulation de l'activité du récepteur des androgènes - Google Patents

Composés, compositions et procédés de modulation de l'activité du récepteur des androgènes Download PDF

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Publication number
WO2020139701A1
WO2020139701A1 PCT/US2019/067511 US2019067511W WO2020139701A1 WO 2020139701 A1 WO2020139701 A1 WO 2020139701A1 US 2019067511 W US2019067511 W US 2019067511W WO 2020139701 A1 WO2020139701 A1 WO 2020139701A1
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Prior art keywords
methyl
mmol
pyrimidine
thieno
compound
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Inventor
Peter Mikochik
Joseph Vacca
David Freeman
Andrew S. Tasker
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Kronos Bio Inc
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Kronos Bio Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the disclosure provides for compounds or salts thereof that modulate the activity of the androgen receptor (AR), alternatively referred to herein as MYC/AR-r elated co-factor (MARC), pharmaceutical compositions comprising such compounds or salts thereof, and methods of using the compounds or salts and/or pharmaceutical compositions for treatment, amelioration, and/or prevention of diseases arising from MYC/AR activity and MYC transcriptional complexes, e.g., prostate cancer.
  • AR androgen receptor
  • Prostate cancer tumors develop resistance to current treatments, especially in therapies that involve targeting the androgen receptor (AR). Treatments generally rely upon continual androgen deprivation therapy via direct AR antagonism (e.g.,
  • enzalutamide bicalutamide
  • adrenal androgen production e.g, abiraterone acetate
  • AR-vs AR splice variants
  • AR-FL full-length AR
  • ARE androgen response elements
  • AR-FL is a steroid receptor transcription factor composed of a N-terminal domain (NTD), a DNA binding domain (DBD), and a C-terminal domain (CTD) comprising a hinge region and a ligand binding domain (LBD).
  • NTD N-terminal domain
  • DBD DNA binding domain
  • CCD C-terminal domain
  • LBD ligand binding domain
  • AR-vs Androgen receptor splice variants arise from alternative splicing of the AR gene by insertion of "intronic" cryptic exons downstream of exons that encode the DNA-binding domain, thereby preventing ligand binding domain (LBD) incorporation and resulting in a shortened AR construct characterized by ligand-independent function.
  • LBD ligand binding domain
  • AR-v7 is the most widely identified and clinically important variant in prostate cancer.
  • AR-v7 is characterized by an unperturbed NTD and DBD with a portion of the NLS and a unique 16-amino acid sequence in its CTD derived from a cryptic exon incorporation.
  • CTCs circulating tumor cells
  • the AR-v7 expression level in primary tumor cells derived from metastatic prostate cancer and CRPC patients is significantly higher than that in cells derived from patients with localized prostate cancer, and consequently higher AR-v7 expression can be correlated to shorter survival likelihood in CRPC patients (p ⁇ 0.001). Qu et al. (2015) Sci Rep, 5: doi: 10.1038/srep07654.
  • the disclosure provides for thienopyrimidines, and derivatives thereof, that are inhibitors of androgen receptor transcriptional activity and MYC/AR- related transcriptional complexes.
  • the disclosure provides for a compound of formula (I):
  • R 1 is a C3-C6 saturated or unsaturated ring, optionally aromatic, optionally
  • heterocyclic optionally forming a fused, spiro, or bridged ring system with 1 to 8 additional ring atoms, wherein 1 to 4 non-adjacent ring atoms may independently be replaced by N, O, or S, and optionally ring atoms independently may be substituted at any position with one or more D, halo, N(R 2 ) 2 , OR 2 or SR 2 wherein R 2 is C1-C3 alkyl, or C1-C2 alkyl optionally substituted with one or more D or F;
  • W 1 is (CFh) n wherein n is an integer from 0 to 3;
  • W 2 is O or NR 8 , wherein R 8 is H, C1-C3 alkyl or alkoxy, or R 8 forms a fused or spiro ring with W 1 or R 1 ;
  • R 3 is H or C1-C4 alkyl, cycloalkyl, alkoxy, hydroxymethyl, or NR 3 2, wherein each R 3 is independently H or methyl;
  • R 4 is H or C1-C4 alkyl, cycloalkyl, or alkoxy
  • R 5 is a 5- or 6-membered aromatic or heteroaromatic ring, attached at any position of the ring, optionally having one or more fused or spiro C4-C6 aromatic, heteroaromatic, aliphatic, or heteroaliphatic rings, and optionally substituted at one or more positions with one or more D, halo, NFh, NHR 9 , OH, OR 9 , SH, or SR 9 , wherein R 9 is C1-C4 alkyl, cycloalkyl or alkoxy; and
  • R 6 is H or C1-C4 alkyl, cycloalkyl, or alkoxy.
  • W 1 is absent or W 1 is (CH2) n wherein n is an integer from 0 to 3, optionally substituted with methyl, halogen, or hydroxyl
  • W 2 is absent or W 2 is O or NR 8 , wherein R 8 is H, C1-C3 alkyl or alkoxy, or R 8 forms a fused or spiro ring with W 1 or R 1
  • W 1 and W 2 together are (CH2) n O or 0(CH 2 ) n wherein n is an integer from 0 to 3, and R 1 , R 3 , R 4 , R 5 , and R 6 are as defined above.
  • W 1 is O and W 2 is (CH2) n wherein n is an integer from 0 to 3, optionally substituted with methyl, halogen, or hydroxyl, and R 1 , R 3 , R 4 , R 5 , and R 6 are as defined above.
  • the compound may be in the form of a composition including a pharmaceutically acceptable carrier.
  • the disclosure provides for methods of treating, preventing, or ameliorating prostate cancer, including metastatic prostate cancer and castration-resistant prostate cancer (CRPC), by administering an effective amount of a compound or salt of formula (I), or a composition thereof, to a subject in need thereof.
  • CRPC castration-resistant prostate cancer
  • a compound described herein capable of use in compositions or methods described herein comprises, consists of, or consists essentially of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the composition is formulated in a pharmaceutical composition or form.
  • R 1 is a C3-C6 cycloalkyl, optionally substituted with one or more D or halo;
  • W 1 is (CH2) n wherein n is 1;
  • W 2 is O or NH
  • R 3 is methyl, ethyl, cyclopropyl, hydroxymethyl, or NR 3 2, wherein each R 3 is independently H or methyl;
  • R 4 is C1-C4 alkyl
  • R 5 is pyridyl or quinolyl, optionally substituted at any position with methoxy, ethoxy, or C1-C4 alkyl;
  • R 6 is H or methyl.
  • R 1 is cyclopentyl optionally substituted at the 2 or 3 position with one or two F, or R 1 is cyclohexyl optionally substituted at the 2 or 4 position with one or two F; n is 1; R 3 is methyl or ethyl; R 4 is methyl or ethyl; and R 5 is pyridyl optionally substituted at one or more positions with one or more methyl or methoxy.
  • R 1 is cyclopentyl optionally substituted at the 2 or 3 position with one or two F, or R 1 is cyclohexyl optionally substituted at the 2 or 4 position with one or two F;
  • R 5 is pyridyl optionally substituted at one or more positions with one or more methyl or methoxy; and
  • R 6 is H or methyl.
  • Examplary compounds are shown in a Table herein as compounds 1 to 151. Any of the compounds described via formula (I) or shown as specific compounds may be a single stereoisomer or a mixture of possible stereoisomers. For example, if a single chiral carbon is present, the compound may be the (S) or (R) stereoisomer, with respect to the chiral carbon, or the compound may be a non-racemic mixture of (S) and (R) isomers, or the compound may be the (S) isomer alone or the (R) isomer alone. If the compound contains more than one chiral carbon, the compound may be a single diastereomer or a mixture of diastereomers.
  • salt is meant a pharmaceutically acceptable salt, e.g., a hydrochloride salt.
  • a “pharmaceutically acceptable salt” is a salt that retains the activity of the compound without significant adverse effects.
  • pharmaceutically acceptable salts include salts of organic or inorganic acids, e.g., hydrochloric acid, sulphuric acid,
  • the salt may contain one or more equivalents of acid per compound, i.e., the compound may be in the form of a dichloride salt.
  • the active compounds disclosed can also be in the form of their hydrates.
  • the term“hydrate” includes, e.g., hemihydrate, monohydrate, dihydrate, trihydrate, and tetrahydrate.
  • the compounds of this disclosure may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present disclosure includes all suitable isotopic variations of the compounds described herein.
  • Alkyl means branched and straight-chain saturated aliphatic hydrocarbons, and specifying the number of carbon atoms as in“C1-C6 alkyl” means all isomers thereof having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement.
  • “C1-C6 alkyl” includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, etc.
  • Cycloalkyl means cyclic saturated aliphatic hydrocarbons of the specified number of carbons.
  • Halo means a halogen substituent, e.g., F, Cl, or Br.
  • an“effective amount” or“therapeutically effective amount” is an amount of the compound or composition that is sufficient to effect beneficial or desired results as described herein when administered to a subject.
  • Effective dosage forms, modes of administration, and dosage amounts may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount will vary with the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered, the age, size, and species of mammal, e.g., human patient, and like factors well known in the arts of medicine and veterinary medicine.
  • a suitable dose will be that amount of the compound that is the lowest dose effective to produce the desired effect with no or minimal side effects.
  • a suitable, non-limiting example of a dosage of the compounds according to the present disclosure is from about 1 ng/kg to about 1000 mg/kg, such as from about 1 mg/kg to about 100 mg/kg, including from about 5 mg/kg to about 50 mg/kg.
  • Other representative dosages of a PI3K inhibitor include about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg.
  • the AR-mediated disease may be a prostate cancer, including metastatic prostate cancer and castration-resistant prostate cancer (CRPC).
  • CRPC castration-resistant prostate cancer
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier and an effective amount of the compounds described herein.
  • a pharmaceutical composition of the present disclosure may be administered in any desired and effective manner: for oral ingestion, or as an ointment or drop for local administration to the eyes, or for parenteral or other administration in any appropriate manner such as intraperitoneal, subcutaneous, topical, intradermal, inhalation,
  • a pharmaceutical composition of the present disclosure may be administered in conjunction with other treatments.
  • a pharmaceutical composition of the present disclosure maybe encapsulated or otherwise protected against gastric or other secretions, if desired.
  • compositions of the disclosure are pharmaceutically acceptable and comprise one or more active ingredients in admixture with one or more pharmaceutically-acceptable carriers and, optionally, one or more other compounds, drugs, ingredients and/or materials.
  • the agents/compounds of the present disclosure are formulated into pharmaceutically- acceptable dosage forms by conventional methods known to those of skill in the art using pharmaceutically acceptable carriers well-known in the art (see, e.g., Remington, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa.) and The National Formulary (American Pharmaceutical Association, Washington, D.C.)) and include sugars (e.g., lactose, sucrose, mannitol, and sorbitol), starches, cellulose preparations, calcium phosphates (e.g., dicalcium phosphate, tricalcium phosphate and calcium hydrogen phosphate), sodium citrate, water, aqueous solutions (e.g., saline, sodium chloride injection,
  • sugars e.g
  • Each pharmaceutically acceptable carrier used in a pharmaceutical composition of the disclosure is "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject.
  • Carriers suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable carriers for a chosen dosage form and method of administration can be determined using ordinary skill in the art.
  • compositions of the disclosure may, optionally, contain additional ingredients and/or materials commonly used in such pharmaceutical compositions.
  • ingredients and materials are well known in the art and include (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium
  • carboxymethyl cellulose and sodium carbonate (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate; (10) suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth; (11) buffering agents; (12) excipients, such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes, paraffins, cocoa butter, starches, tragacanth, cellulose derivatives,
  • inert diluents such as water or other solvents; (14) preservatives; (15) surface-active agents; (16) dispersing agents; (17) control-release or absorption-delaying agents, such as hydroxypropylmethyl cellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monosterate, gelatin, and waxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21) emulsifying and suspending agents; (22), 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, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol
  • compositions suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup, a pastille, a bolus, an electuary or a paste.
  • These formulations may be prepared by methods known in the art, e.g., by means of conventional pan-coating, mixing, granulation or lyophilization processes.
  • Solid dosage forms for oral administration may be prepared, e.g., by mixing the active ingredient(s) with one or more pharmaceutically-acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, and/or coloring agents.
  • Solid compositions of a similar type maybe employed as fillers in soft and hard-filled gelatin capsules using a suitable excipient.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine.
  • the tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, 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. They may be sterilized by, for example, filtration through a bacteria-retaining filter.
  • compositions may also optionally contain opacifying agents and may be of a composition such that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • the active ingredient can also be in microencapsulated form.
  • Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain suitable inert diluents commonly used in the art.
  • the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions may contain suspending agents.
  • compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more active ingredient(s) with one or more suitable nonirritating carriers which are solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating carriers which are solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Pharmaceutical compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such pharmaceutically-acceptable carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops and inhalants.
  • the active agent(s)/compound(s) may be mixed under sterile conditions with a suitable pharmaceutically-acceptable carrier.
  • the ointments, pastes, creams and gels may contain excipients.
  • Powders and sprays may contain excipients and propellants.
  • compositions suitable for parenteral administrations comprise one or more agent(s)/compound(s) 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 suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.
  • suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents may contain suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.
  • Proper fluidity can be maintained, for example, by the use of coating materials, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain suitable adjuvants, such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption.
  • a drug e.g., pharmaceutical formulation
  • the rate of absorption of the active agent/drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally-administered agent/drug may be accomplished by dissolving or suspending the active agent/drug in an oil vehicle.
  • Injectable depot forms may be made by forming microencapsule matrices of the active ingredient in biodegradable polymers. Depending on the ratio of the active ingredient to polymer, and the nature of the particular polymer employed, the rate of active ingredient release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. The injectable materials can be sterilized for example, by filtration through a bacterial- retaining filter.
  • the formulations may be presented in unit-dose or multi -dose sealed containers, for example, ampules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.
  • a“subject” is a mammal, e.g., a human.
  • categories of mammals within the scope of the present disclosure include, for example, agricultural animals, domestic animals, laboratory animals, etc.
  • agricultural animals include cows, pigs, horses, goats, etc.
  • domestic animals include dogs, cats, etc.
  • laboratory animals include rats, mice, rabbits, guinea pigs, etc.
  • the terms“treat,”“treating,”“treatment” and grammatical variations thereof mean subjecting an individual subject to a protocol, regimen, process or remedy, in which it is desired to obtain a physiologic response or outcome in that subject, e.g., a patient.
  • the methods and compositions of the present disclosure may be used to slow the development of disease symptoms or delay the onset of the disease or condition, or halt the progression of disease development.
  • every treated subject may not respond to a particular treatment protocol, regimen, process or remedy, treating does not require that the desired physiologic response or outcome be achieved in each and every subject or subject, e.g., patient, population. Accordingly, a given subject or subject, e.g., patient, population may fail to respond or respond inadequately to treatment.
  • the terms“ameliorate”,“ameliorating” and grammatical variations thereof mean to decrease the severity of the symptoms of a disease in a subject.
  • the terms“prevent”,“preventing” and grammatical variations thereof mean to administer a compound or composition of the present disclosure to a subject who has not been diagnosed as having the disease or condition at the time of administration, but who could be expected to develop the disease or condition or be at increased risk for the disease or condition.
  • Preventing also includes administration of at least one compound or a composition of the present disclosure to those subjects thought to be predisposed to the disease or condition due to age, familial history, genetic or chromosomal abnormalities, due to the presence of one or more biological markers for the disease or condition and/or due to environmental factors.
  • Scheme 1 shows a synthetic process for making embodiments of formula (I).
  • Scheme 2 shows a synthetic process for making embodiments of formula (I).
  • reaction mixture was quenched with cold water and extracted with CH2CI2 (500 mL x 4).
  • the combined organic phase was washed with saturated NaCl solution (200 mL), followed by drying over anhydrous sodium sulfate.
  • the organic phase was filtered and solvent removed to afford the crude product, which was purified by column chromatography (Combi-flash 230-400 silica gel, EtOAc / CH2CI2) to produce 4- hydroxy-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3-d]pyrimidine-6- carboxamide (4.2g, 12.20 mmol, 51 % yield).
  • Scheme 3 shows a synthetic process for making embodiments of formula (I).
  • Scheme 4 shows a synthetic process for making embodiments of formula (I).
  • Scheme 5 shows a synthetic process for making embodiments of formula (I).
  • the crude compound was purified by silica gel chromatography (20% ethyl acetate / hexane) to produce ethyl 5-cyclopropyl-4-[(4,4-difluorocyclohexyl)methylamino]thieno[2,3- d]pyrimidine-6-carboxylate (200 mg, 0.5057 mmol, 71% yield).
  • Scheme 6 shows a synthetic process for making embodiments of formula (I).
  • Scheme 8 shows a synthetic process for making embodiments of formula (I).
  • Scheme 9 shows a synthetic process for making embodiments of formula (I).
  • Scheme 10 shows a synthetic process for making embodiments of formula (I).
  • Scheme 11 shows a synthetic process for making embodiments of formula (I).
  • reaction mixture was partitioned between CH2CI2 (50ml ml) and water (50 ml), the organic phase set aside, and the aqueous layer extracted with additional CH2CI2 (2 X 20 ml).
  • the combined organic parts were washed with brine solution (50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to get crude compound, which was purified by silica gel chromatography to afford ethyl 2-(6-chloro-5-formyl-pyrimidin-4-yl)sulfanylacetate (2.4 g, 9.206 mmol,
  • reaction mixture was stirred at room temperature for 16 h, at which time it was diluted with water (10 mL), and the organic part extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with cold water (2 x 10 mL) followed by brine solution (20 mL).
  • Scheme 12 shows a synthetic process for making embodiments of formula (I).
  • Scheme 13 shows a synthetic process for making embodiments of formula (I).
  • Scheme 14 shows a synthetic process for making embodiments of formula (I).
  • reaction mixture was quenched with cold water and extracted with CH2CI2 (500 mL x 4).
  • the combined organic phase was washed with saturated NaCl solution (200 mL), followed by drying over anhydrous sodium sulfate.
  • the organic phase was filtered and solvent removed to afford the crude product, which was purified by column chromatography (Combi-flash 230-400 silica gel, EtOAc / CH2CI2) to produce 4- hydroxy-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3-d]pyrimidine-6- carboxamide (4.2g, 12.2 mmol, 51% yield).
  • Scheme 15 shows a synthetic process for making embodiments of formula (I).
  • Scheme 16 shows a synthetic process for making embodiments of formula (I).
  • Scheme 17 shows a synthetic process for making embodiments of formula (I).
  • Scheme 18 shows a synthetic process for making embodiments of formula (I).
  • Scheme 19 shows a synthetic process for making embodiments of the invention.
  • Step 2 To foil-covered flask containing a stirred solution of (ML ⁇ SiOs (139 mg, 0.61 mmol) and AgNCb (26 mg, 0.15 mmol) in Water (5mL) was added spiro[3.3]heptane-2- carboxylic acid (0.01 mL, 0.61 mmol), and the mixture stirred for 15min. N-[(2-methoxy- 4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.30 mmol) dissolved in CH2CI2 (5 mL) was then added, and the combined solution stirred at ambient temperature for 48h in the dark.
  • Scheme 20 shows a synthetic process for making embodiments of formula (I).
  • reaction was stirred for 10 min at this temperature, then allowed to gradually warm to ambient temperature for 16h. After this time, the reaction mixture was quenched with ice cold water and stirred for 20 min, and extracted with ethyl acetate (3 x 50mL) . The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • Scheme 21 shows a synthetic process for making embodiments of formula (I).
  • Example 22 shows a synthetic process for making embodiments of formula (I).
  • Scheme 23 shows a synthetic process for making embodiments of formula (I).
  • Scheme 24 shows a synthetic process for making embodiments of formula (I).
  • reaction mixture was then heated at 110 °C for 16h. After completion of the reaction, the reaction was passed through celite, and further eluted with ethyl acetate (2 x 50 mL). The filtrate was washed with water (30 mL), and the organic layer washed with saturated NaCl (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
  • reaction was quenched with ice water and extracted with CH2CI2 (20 mL x 2).
  • CH2CI2 (20 mL x 2).
  • the combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SC>4, filtered, and the solvent removed under reduced pressure.
  • Example 25 shows a synthetic process for making embodiments of formula (I).
  • the flask was degassed under Argon for 5 minutes, then heated at 110 °C for 16h. After completion of the reaction, the catalyst was filtered off through celite, and eluted with ethyl acetate (2 x 20 mL).
  • the mixture was degassed with argon for 5 min, after which time Pd 2 dba 3 (22.3 mg, 0.02 mmol) and XPhos Pd G3 (41.1 mg, 0.05 mmol) were added, and the reaction mixture and further degassed with argon for 5 min.
  • the reaction mixture was heated at 110 °C for 16 h. After that the reaction mixture was filtered through celite, washed with ethyl acetate (2 x 20 mL). The filtrate was washed with water (2 x 20mL), followed by saturated NaCl (20 mL), and the organic phase dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • Scheme 26 shows a synthetic process for making embodiments of formula (I).
  • 22Rvl cells stably expressing the Cignal AR reporter were generated according to the Qiagen Cignal reporter protocol. These cells are seeded in RPMI + 10% charcoal- stripped serum at 20k cells/well in 384 well format (Corning 3570). The next day, cells are induced with R1881 to a final concentration of 1 nM and treated with compounds in half-log, lOpt dose from top concentration 10 mM. All dispenses are performed from lOOOx DMSO stock via the Echo 525 liquid handler. Final assay volume is 50 pL with 0.2% DMSO. 24 hours from treatment, the OneGlo assay is performed according to the Promega protocol. The plate is read using the Envision plate reader.
  • test data shows that the compounds disclosed herein are effective as AR inhibitors and would be suitable candidates for therapy relating to AR-mediated disorders. Results appear in the following Table.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des inhibiteurs de récepteurs androgènes qui sont des dérivés de thiénopyrimidine correspondant à la formule (I), et des sels de ceux-ci, ainsi que des compositions et des procédés de traitement associés.
PCT/US2019/067511 2018-12-28 2019-12-19 Composés, compositions et procédés de modulation de l'activité du récepteur des androgènes Ceased WO2020139701A1 (fr)

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US201862785783P 2018-12-28 2018-12-28
US62/785,783 2018-12-28
US201962934087P 2019-11-12 2019-11-12
US62/934,087 2019-11-12

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100095A1 (fr) * 2005-03-24 2006-09-28 Curacyte Discovery Gmbh Amides d'acide carboxylique substitues, procede pour les preparer et leur utilisation en tant qu'inhibiteurs de liberation de tnf-alpha
US20080004271A1 (en) * 2006-01-17 2008-01-03 Mckenna Jeffrey M Inhibitors of TNFalpha, PDE4 and B-RAF, compositions thereof and methods of use therewith
US20110212103A1 (en) * 2010-02-26 2011-09-01 Boehringer Ingelheim International Gmbh Thienopyrimidines containing a substituted alkyl group for pharmaceutical compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006100095A1 (fr) * 2005-03-24 2006-09-28 Curacyte Discovery Gmbh Amides d'acide carboxylique substitues, procede pour les preparer et leur utilisation en tant qu'inhibiteurs de liberation de tnf-alpha
US20080004271A1 (en) * 2006-01-17 2008-01-03 Mckenna Jeffrey M Inhibitors of TNFalpha, PDE4 and B-RAF, compositions thereof and methods of use therewith
US20110212103A1 (en) * 2010-02-26 2011-09-01 Boehringer Ingelheim International Gmbh Thienopyrimidines containing a substituted alkyl group for pharmaceutical compositions

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