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WO2023030388A1 - Composé de 5-fluoro-7h-pyrrolo[2,3-d]pyrimidines servant d'inhibiteur de wee-1 - Google Patents

Composé de 5-fluoro-7h-pyrrolo[2,3-d]pyrimidines servant d'inhibiteur de wee-1 Download PDF

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Publication number
WO2023030388A1
WO2023030388A1 PCT/CN2022/116219 CN2022116219W WO2023030388A1 WO 2023030388 A1 WO2023030388 A1 WO 2023030388A1 CN 2022116219 W CN2022116219 W CN 2022116219W WO 2023030388 A1 WO2023030388 A1 WO 2023030388A1
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Prior art keywords
heterocycloalkyl
cycloalkyl
och
membered
compound
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Ceased
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PCT/CN2022/116219
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English (en)
Chinese (zh)
Inventor
谢雨礼
吴应鸣
钱立晖
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Wigen Biomedicine Technology Shanghai Co Ltd
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Wigen Biomedicine Technology Shanghai Co Ltd
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Priority to CN202280052786.4A priority Critical patent/CN117751123A/zh
Publication of WO2023030388A1 publication Critical patent/WO2023030388A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the compound of general formula (1) has one of the following structures:
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula (1) are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of general formula (1) is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • ring A is named as an independent group (not combined with other rings).
  • ring A is fused with an adjacent group.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 )CH, iPr , nPr , iBu , nBu or tBu .
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • a heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azepine or Benzo derivatives such as thienyl.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuryl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any ring structure.
  • member is meant to indicate the number of skeletal atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • Active ingredient refers to the compound represented by the general formula (1), and the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula (1).
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • administering means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
  • the compound or pharmaceutical composition of the general formula (1) of the present invention can generally be used to inhibit Wee-1 kinase, and thus can be used to treat one or more diseases related to Wee-1 kinase activity. Therefore, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase-mediated disorder, the method comprising administering a compound of general formula (1) of the present invention, or a pharmaceutical agent thereof, to a patient in need thereof. steps on an acceptable composition.
  • the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative syndrome) and solid tumors (such as carcinoma of the prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancer and osteosarcoma, and stromal tumors), etc.
  • hematological malignancies leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative syndrome
  • solid tumors such as carcinoma of the prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancer and osteosarcoma, and stromal tumors
  • the hematologic malignancies and solid tumors include, but are not limited to, leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, ovarian cancer, Head and neck cancer, stomach cancer, mesothelioma or all cancer metastases.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesam
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • Step 1 the synthesis of compound int_A-1-2:
  • Int_A-1-1 hydrochloride (10.0 g, 46.10 mmol) was dissolved in TfOH (50.0 mL), and NIS (15.7 g, 69.88 mmol) was added under nitrogen protection at 0°C. The reaction was stirred at room temperature for 16 hours. LC-MS monitoring showed the reaction was complete. Cool the reaction solution to room temperature, pour the reaction solution into ice water, adjust the pH value to 8-9 with dilute NaOH solution, filter to obtain a black solid int_A-1-2 (14g, 46.0mmol, crude product), the crude product can be used directly react in the next step.
  • Step 2 the synthesis of compound int_A-1-3:
  • the target intermediates A-2 to A-9 in Table 1 can be obtained.
  • Step 1 the synthesis of compound int_B-1-2:
  • Step 2 the synthesis of compound int_B-1-3:
  • reaction solution was cooled to room temperature, quenched by pouring into ice water, the aqueous phase was extracted with ethyl acetate (200mL*3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography ( Silica Flash Column, Eluent of 0-10% Ethyl acetate/Petroleum ether gradient) to obtain a yellow solid (14g, yield: 72.5%).
  • the mixture was poured into ice water, the aqueous phase was extracted with ethyl acetate (200 mL*3), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product (14.51 g).
  • the crude product can be directly used in the next reaction.
  • Int_B-1-8 (5.3 g, 24.76 mmol) was dissolved in dichloromethane (60 mL), and DMP (21.00 g, 49.52 mmol) was added. The mixture was reacted at room temperature for 5 hours. The reaction solution was filtered, and the filtrate was adjusted to pH 7-8 with saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with dichloromethane (150 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography ( Silica Flash Column, Eluent of 0-50% Ethyl acetate/Petroleum ether gradient) to obtain a green oil (4g, yield: 76.2%).
  • Int_B-1 (10g, 41.30mmol) was subjected to chiral resolution by prep SFC (SFC chiral resolution conditions: instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250mm*50mm, 10um ); mobile phase: A: CO 2 , B: isopropanol (0.05% diethylamine); gradient: B%: 15%-15%; flow rate: 200mL/min; column temperature: 40 °C), will segment The solution was concentrated under reduced pressure and freeze-dried to obtain yellow oil B-2 (peak 1, 4.2g, yield: 42%) and yellow oil B-3 (peak 2, 4.2g, yield: 42%).
  • SFC chiral resolution conditions instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250mm*50mm, 10um ); mobile phase: A: CO 2 , B: isopropanol (0.05% diethylamine); gradient: B%: 15%-15%; flow rate: 200mL/min; column temperature:
  • the target intermediates B-5 to B-36 in Table 2 can be obtained.
  • Step 1 the synthesis of compound int_5-2:
  • Step 1 the synthesis of compound int_6-2:
  • the target compounds 1-4 and 7-52 in Table 3 can be obtained.
  • Example 53 The compound of the present invention inhibits the recombinant protein Wee-1 enzyme activity test in vitro
  • the inhibitory effect of compounds on the enzyme activity of recombinant protein Wee-1 was determined by HTRF method. details as follows.
  • DMSO or serially diluted compound (up to 200nM, 1:5 serial dilution) and recombinant protein were incubated in kinase buffer at 37°C for 30 minutes, after adding Fluorescein-PolyGAT and ATP, the substrate was added to start the reaction. After reacting at room temperature for 90 minutes, add the antibody and detection solution, continue to incubate at room temperature for 60 minutes, and read the fluorescence value (excitation wavelength: 340nm, emission wavelength: 495nm and 520nm. Calculate the ratio of fluorescence intensity at 520nm/495nm, compare it with the DMSO group, and then Compound inhibition percentages and IC50 were calculated. Results are shown in Table 4 below.
  • +++ means IC 50 less than or equal to 10nM

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  • Organic Chemistry (AREA)
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Abstract

L'invention concerne un composé de 5-fluoro-7H-pyrrolo[2,3-d]pyrimidines utilisé en tant qu'inhibiteur de Wee-1, en particulier, un composé représenté par la formule générale (I) et son procédé de préparation, et l'utilisation du composé représenté par la formule générale (I) et des isomères, des formes cristallines, un sel pharmaceutiquement acceptable, un hydrate ou un solvate de celui-ci en tant qu'inhibiteur de Wee-1. Le composé et les isomères, les formes cristallines, le sel pharmaceutiquement acceptable, l'hydrate ou le solvate de celui-ci peuvent être utilisés pour préparer des médicaments pour traiter ou prévenir des maladies associées à une protéine kinase Wee-1.
PCT/CN2022/116219 2021-08-31 2022-08-31 Composé de 5-fluoro-7h-pyrrolo[2,3-d]pyrimidines servant d'inhibiteur de wee-1 Ceased WO2023030388A1 (fr)

Priority Applications (1)

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CN202280052786.4A CN117751123A (zh) 2021-08-31 2022-08-31 作为Wee-1抑制剂的5-氟-7H-吡咯并[2,3-d]嘧啶类化合物

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CN202111013816 2021-08-31

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005107760A1 (fr) * 2004-04-30 2005-11-17 Irm Llc Composes et compositions en tant qu'inducteurs de la differenciation de keratinocytes
CN1918158A (zh) * 2004-02-14 2007-02-21 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN110467615A (zh) * 2018-05-10 2019-11-19 四川科伦博泰生物医药股份有限公司 吡咯并嘧啶类化合物、包含其的药物组合物及其制备方法和用途
CN111718348A (zh) * 2019-03-22 2020-09-29 首药控股(北京)有限公司 Wee1抑制剂及其制备和用途
WO2021074251A1 (fr) * 2019-10-15 2021-04-22 Sentinel Oncology Limited Dérivés de pyrrolo[2,3-d]pyrimidine et leur utilisation dans le traitement du cancer
CN112724144A (zh) * 2019-10-14 2021-04-30 首药控股(北京)有限公司 Wee1抑制剂及其制备和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES3024692T3 (en) * 2018-03-09 2025-06-05 Recurium Ip Holdings Llc Substituted 1,2-dihydro-3h-pyrazolo[3,4-d]pyrimidin-3-ones

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1918158A (zh) * 2004-02-14 2007-02-21 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
WO2005107760A1 (fr) * 2004-04-30 2005-11-17 Irm Llc Composes et compositions en tant qu'inducteurs de la differenciation de keratinocytes
CN110467615A (zh) * 2018-05-10 2019-11-19 四川科伦博泰生物医药股份有限公司 吡咯并嘧啶类化合物、包含其的药物组合物及其制备方法和用途
CN111718348A (zh) * 2019-03-22 2020-09-29 首药控股(北京)有限公司 Wee1抑制剂及其制备和用途
CN112724144A (zh) * 2019-10-14 2021-04-30 首药控股(北京)有限公司 Wee1抑制剂及其制备和用途
WO2021074251A1 (fr) * 2019-10-15 2021-04-22 Sentinel Oncology Limited Dérivés de pyrrolo[2,3-d]pyrimidine et leur utilisation dans le traitement du cancer

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