WO2022228509A1 - Dérivé de pyrrolopyrimidine, son procédé de préparation et son utilisation - Google Patents

Dérivé de pyrrolopyrimidine, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2022228509A1
WO2022228509A1 PCT/CN2022/089850 CN2022089850W WO2022228509A1 WO 2022228509 A1 WO2022228509 A1 WO 2022228509A1 CN 2022089850 W CN2022089850 W CN 2022089850W WO 2022228509 A1 WO2022228509 A1 WO 2022228509A1
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Prior art keywords
alkyl
compound
halogen
cycloalkyl
substituted
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PCT/CN2022/089850
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English (en)
Chinese (zh)
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谢雨礼
樊后兴
钱立晖
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微境生物医药科技(上海)有限公司
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Priority to CN202280031800.2A priority Critical patent/CN117222649A/zh
Publication of WO2022228509A1 publication Critical patent/WO2022228509A1/fr

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    • 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 invention relates to the field of medicinal chemistry, and more particularly, to a compound with Wee-1 kinase inhibitory effect, a preparation method thereof, and the use of the compound in the preparation of antitumor drugs.
  • Wee-1 protein kinase is an important negative regulator of cell cycle checkpoints.
  • Cell cycle checkpoints include the G1 phase checkpoint for the transition from G1 (cell quiescence) to S phase (DNA synthesis phase), the G2 phase checkpoint for the transition from G2 (preparation for cell division) to M (cell division), and the M Spindle checkpoint for the transition from metaphase (mid-phase) to anaphase (anaphase).
  • Wee-1 protein kinase plays an important role in the G2 phase checkpoint.
  • the entry of cells into M phase depends on the kinase activity of CDK1.
  • Wee-1 inhibits the activity of CDK1 by phosphorylating Tyr 15 of CDK1 protein, preventing cells from entering M phase (cell division phase).
  • Polo kinase kinase phosphorylates Wee-1, activates the degradation of Wee-1 protein, and promotes cell entry into M phase.
  • Wee-1 kinase activity determines the activity of the G2 checkpoint, which in turn regulates the transition of cells from G2 to M phase.
  • Cell cycle checkpoints are mainly activated after DNA damage and play an important role in DNA repair in cells. Normal activation of cell cycle checkpoints arrests the cell cycle and promotes DNA repair. Inhibit the function of checkpoints, DNA damage cannot be repaired, and cells undergo apoptosis. Compared with normal cells, various tumor cells mainly rely on the activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to the impaired function of p53, an important protein of the G1 phase checkpoint. Therefore, inhibiting the G2 phase checkpoint can selectively kill tumor cells.
  • Wee-1 kinase determines the repair or death of tumor cells after DNA damage, and inhibition of Wee-1 activity can promote unrepaired tumor cells after DNA damage to enter M period, induce apoptosis.
  • Wee-1 is also involved in DNA synthesis, DNA homology repair, post-translational modification of chromosomal histones and other functions closely related to tumorigenesis and development.
  • Wee-1 expression is greatly elevated in a large number of tumors including liver, breast, cervical, melanoma and lung cancer.
  • the high expression of Wee-1 is positively correlated with tumor development and poor prognosis, suggesting that Wee-1 kinase may be involved in tumor occurrence and development.
  • Studies in in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors.
  • AstraZeneca's Wee-1 inhibitor AZD1775 (MK-1775, Adavosertib) has entered the phase 2 clinical research stage, and more than 30 clinical trials are under development.
  • Patents related to AZD1775 include US20070254892, WO2007126122, EP2213673, WO2008133866, WO2011034743 and the like.
  • Abbott and Abbvie have also conducted research on Wee-1 inhibitors, and related patents mainly include US2012220572, WO2013126656, WO2013012681, WO2013059485, WO2013013031 and so on.
  • the present invention provides a compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • n 0 or 1
  • n 0 or 1
  • v 1, 2 or 3;
  • R 1 is H or halogen
  • R 2a and R 2b are independently H or C1-C3 alkyl, or R 2a and R 2b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
  • R 3a and R 3b are independently H or C1-C3 alkyl, or R 3a and R 3b together with the C atom to which they are attached form a C3-C6 cycloalkyl;
  • R 4 is halogen, CN, C1-C6 alkyl, C1-C6 alkoxy, N(C1-C6 alkyl) 2 , NH(C1-C6 alkyl), C1-C6 alkylthio, C2-C6 alkene base, C2-C6 alkynyl, C3-C6 cycloalkyl or (4-12 membered) heterocycloalkyl, the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3- C6 cycloalkyl and (4-12 membered) heterocycloalkyl can be optionally substituted with 1-3 of the following groups: H, halogen, OH, CN, C1-C3 alkyl, C3-C6 cycloalkyl, C1-C3 alkoxy, halogen substituted C1-C3 alkyl, CN substituted C1-C3 alkyl, OH substituted C1-C
  • R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The sulfur atom forms (3-10 membered) heterocycloalkyl;
  • each R is independently H, halogen, CN, C1 - C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy;
  • R 8 and R 9 are independently H, C1-C6 alkyl or C3-C6 cycloalkyl, or R 8 and R 9 together with the N atom to which they are attached form a (4-7 membered) heterocycloalkyl, the ( 4-7 membered) heterocycloalkyl can be substituted with 1-3 of the following groups: H, halogen, OH, CN or C1-C3 alkyl.
  • the compound of general formula (1) has the structure shown in general formula (1A):
  • n 0 or 1
  • n 0 or 1
  • v 1, 2 or 3;
  • R 1 is H or halogen
  • R 5 and R 6 are independently C1-C3 alkyl, deuterated C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl and C3-C6 cycloalkyl, or R 5 and R 6 together with which they are attached The atoms form (3-10 membered) heterocycloalkyl;
  • each R is independently H, halogen, CN, C1 - C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, halogen-substituted C1-C6 alkyl, or halogen-substituted C1-C6 alkoxy;
  • R 8 and R 9 are independently H, C1-C6 alkyl or C3-C6 cycloalkyl, or R 8 and R 9 together with the N atom to which they are attached form a (4-7 membered) heterocycloalkyl, the ( 4-7 membered) heterocycloalkyl can be substituted with 1-3 of the following groups: H, halogen, OH, CN or C1-C3 alkyl.
  • R 4 is Me, Et, CF 3 , CHF 2 , F, Cl, Br, I, CN, OMe, OEt, CN, SMe, SEt , OCF 3 , NMe 2 , NHMe,
  • the compound of general formula (1) or general formula (1A) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and/or excipient, and general formula (1) and or general formula (1A) of the present invention, or Its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1), or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition of the present invention Use in the preparation of medicines for treating, regulating or preventing diseases mediated by Wee-1.
  • Another object of the present invention also provides a method for treating, regulating or preventing related diseases mediated by Wee-1, comprising administering to a subject a therapeutically effective amount of the formula (1) of the present invention
  • the compound, or each isomer, each crystal form, pharmaceutically acceptable salt, hydrate or solvate or the above-mentioned pharmaceutical composition comprising administering to a subject a therapeutically effective amount of the formula (1) of the present invention.
  • the inventors have found through sufficient research that the compound represented by the general formula (1) has a strong Wee-1 inhibitory activity and a combined administration activity with the chemotherapeutic drug Gemcitabine (GMC).
  • the compounds of the invention may have better effects when used in combination with chemotherapeutic drugs.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or well-known techniques combined with methods incorporated herein.
  • the 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 with 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.
  • the compounds described herein are according to methods well known in the art.
  • the conditions of the method such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction and the like are not limited to the following explanations.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily carried out by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula (1), wherein the compound of the general formula (1) can be prepared by the following method A:
  • Method A includes the following steps: firstly, compound A1 and A2 are subjected to a coupling reaction to form compound A3, and compound A3 and compound B3 are further reacted to form the target compound (1).
  • R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , m, n and v are as defined above, Z is Br, I or -B(OH) 2 .
  • “Pharmaceutically acceptable” as used herein refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound and is relatively non-toxic, ie, administered to a subject, does not cause undesired biological effects or Interacts in a detrimental manner with any of the components it contains.
  • pharmaceutically acceptable salt refers to a compound in which it exists in a form that does not cause significant irritation to the administered organism and that does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound of general formula (1) with an acid, such as inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, etc.
  • propionic acid oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • references to pharmaceutically acceptable salts include solvent addition forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric amounts of solvent 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.
  • the organic solvent used includes, but is not limited to, tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In sum, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • compounds of general formula (1) are prepared in various forms including, but not limited to, amorphous, comminuted and nano-particle size forms.
  • the compound of the general formula (1) includes a crystalline form and can also be a polymorph.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to dominate.
  • compounds of general formula (1) may exist in chiral centers and/or axial chirality and are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds Enantiomeric forms, and cis-trans isomers occur.
  • Each chiral center or axial chirality will independently produce 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 present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • a deuterated compound can be formed by replacing a hydrogen atom with deuterium, and the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. It has the advantages of stability, enhanced efficacy, and prolonged half-life of drugs in vivo. All alterations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 6 carbon atoms. Preference is given to lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 ) CH , iPr , nPr , iBu , nBu or tBu .
  • alkylene refers to a divalent alkyl group as defined above.
  • alkylene groups include, but are not limited to, methylene and ethylene.
  • alkenyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preference is given to lower alkenyl groups containing 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methpropenyl.
  • alkynyl refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl, are preferred.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic), and if the carbocyclic ring contains at least one double bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkyl” alkenyl", or if the carbocycle contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”.
  • Cycloalkyl groups may include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spiro rings. In some embodiments, the cycloalkyl group is monocyclic.
  • the cycloalkyl group is monocyclic or bicyclic.
  • the ring-forming carbon atoms of a cycloalkyl group can optionally be oxidized to form oxo or thiol groups.
  • Cycloalkyl also includes cycloalkylene.
  • the cycloalkyl group contains 0, 1 or 2 double bonds.
  • cycloalkyl groups contain 1 or 2 double bonds (partially unsaturated cycloalkyl groups).
  • cycloalkyl groups can be fused to aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused to aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused to aryl and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and cycloalkyl groups.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinyl, norcarbenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexane and the like.
  • alkoxy refers to an alkyl group bonded to the remainder of the molecule through an ether oxygen atom.
  • Representative alkoxy groups are alkoxy groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy.
  • alkoxy includes unsubstituted and substituted alkoxy, especially alkoxy substituted with one or more halogens.
  • Preferred alkoxy groups are selected from OCH3 , OCF3, CHF2O , CF3CH2O , i - PrO, n- PrO , i- BuO, n- BuO or t- BuO.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one independently selected from boron, phosphorus , nitrogen, sulfur, oxygen and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond May be referred to as "heterocycloalkynyl".
  • Heterocycloalkyl groups may include monocyclic, bicyclic, spirocyclic, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • a heterocycloalkyl group is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of heterocycloalkyl groups can be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (eg C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring carbon atom or a ring heteroatom.
  • the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds.
  • moieties having one or more aromatic rings fused to (ie, sharing a bond with) the heterocycloalkyl ring such as piperidine, morpholine, azacyclotriene or Benzo derivatives of thienyl and the like.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached via any ring-forming atom, including a ring-forming atom 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, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyri
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen-substituted appearing before a group name indicates that the group is partially or fully halogenated, that is, substituted with F, Cl, Br or I in any combination, preferably replaced by F or Cl.
  • 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 cyclic structure.
  • membered is meant to denote the number of backbone atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule.
  • a chemical moiety is generally considered to be a chemical entity contained in or attached to a molecule.
  • acceptable refers to a formulation component or active ingredient that does not have undue deleterious effects on the health of the general target of treatment.
  • treatment include alleviating, inhibiting or ameliorating the symptoms or conditions of a disease; inhibiting the development of complications; ameliorating or preventing the underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the development of a disease or condition; alleviating a disease or symptom; reducing a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating symptoms caused by a disease or symptom.
  • a compound or pharmaceutical composition when administered, results in amelioration, especially improvement in severity, delay in onset, slow progression, or reduction in duration of a disease, symptom or condition. Whether fixed or temporary, continuous or intermittent, the conditions attributable to or associated with the administration.
  • 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 are thus available as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomeric compounds in the form of enantiomers.
  • the number of asymmetric centers that can exist depends on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce 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 present invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound Wait.
  • the present invention provides that the compounds or pharmaceutical compositions of 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 disorders associated with Wee-1 kinase activity. Accordingly, in certain embodiments, the present invention provides a method for treating a Wee-1 kinase mediated disorder comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof A step of.
  • Cancers that can be treated with the compounds of the present invention include, but are not limited to, hematological malignancies (leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes) and solid tumors (cancers such as prostate, breast , lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor) and so on.
  • hematological malignancies leukemias, lymphomas, myeloma including multiple myeloma, myelodysplastic syndromes and myelodysplastic syndromes
  • solid tumors cancers such as prostate, breast , lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, and stromal tumor
  • the compounds of the present invention and their pharmaceutically acceptable salts can be prepared into various formulations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the safe and effective dose of the compound is determined according to the age, disease condition, course of treatment and other specific conditions of the object to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gelling substances, which are suitable for human use and which must be of sufficient purity and sufficiently low toxicity .
  • “Compatibility” as used herein means that the components of the composition can be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds.
  • pharmacologically acceptable excipients or carrier moieties are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween) ), wetting agents (such as sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose,
  • the compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators such as quaternary amine compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea
  • Solid dosage forms such as tablets, dragees, capsules, pills and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active compound may also be in microencapsulated form 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 employed 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, and the like.
  • inert diluents conventionally employed 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, dimethylform
  • compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances and the like.
  • suspending agents such as 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 excipients include water, ethanol, polyols and suitable mixtures thereof.
  • Dosage forms for topical administration of the compounds 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 that 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 suitable for mammals (such as human beings) in need of treatment, and the dose is the effective dose considered pharmaceutically, for a 60kg body weight, the daily dose is
  • the administration dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also take into account the route of administration, the patient's health and other factors, which are all within the skill of the skilled physician.
  • the melting point was measured with X-4 melting point apparatus, and the thermometer was not calibrated; 1 H-NMR was recorded with a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shift was expressed in ⁇ (ppm); the silica gel used for separation was 200-300 if not specified The proportions of the eluents are all volume ratios.
  • Ar represents argon; ClCH 2 CH 2 Cl represents 1,2-dichloroethane; Cs 2 CO 3 represents cesium carbonate; CuI represents cuprous iodide; DCM represents dichloromethane; dioxane stands for 1,4-dioxane; EA stands for ethyl acetate; h stands for hours; K 2 CO 3 stands for potassium carbonate; LC-MS stands for liquid phase-mass spectrometry; mL stands for milliliters; MeOH stands for methanol; min stands for minutes; MS stands for mass spectrum; NaBH 3 CN stands for sodium cyanoborohydride; NMR stands for nuclear magnetic resonance ; Xantphos stands for 4,5-bisdiphenylphosphino-9,9-dimethylxanthene; TEA stands for triethylamine.
  • intermediates A3-2 to A3-11 can be obtained.
  • 6-Nitro-3,4-dihydronaphthalene-2(1H)-one (1.7 g, 8.9 mmol) was dissolved in ClCH 2 CH 2 Cl (40 mL), pyrrolidine (1.264 g, 17.8 mmol), HOAc ( 1.6 g, 26.7 mmol), under argon protection, NaBH 3 CN (1.675 g, 26.7 mmol) was added under an ice-water bath, the reaction was carried out at room temperature overnight, monitored by LC-MS, and the reaction was completed. After passing through a reversed-phase column, a pink solid product B2-1 (1.1 g, yield 50%) was obtained, LC-MS: 247.3 [M+H] + .
  • intermediates B3-2 to B3-45 can be obtained.
  • Example 56 Determination of the compound of the present invention inhibiting Wee-1 enzyme activity
  • serially diluted compounds and enzymes were mixed, incubated at room temperature (25° C.) for 15 minutes, centrifuged at 1000 rpm for 1 minute to mix, and 5 ⁇ L of substrate was added to initiate the reaction. After 60 minutes of reaction at room temperature, 5 ⁇ L of ADP-GLO reagent was added, mixed by centrifugation at 1000 rpm for 1 minute, and incubated at room temperature for 60 minutes, and then 10 ⁇ L of kinase detection reagent was added to incubate for 60 minutes to detect chemiluminescence. Compared with the DMSO group, the percentage of compound inhibited enzyme activity was calculated, and then IC 50 was calculated.
  • compound IC50 (nM) compound IC50 (nM) compound IC50 (nM) compound IC50 (nM) 1 1.56 2 1.98 3 2.16 4 2.37 5 2.48 7 1.75 9 2.62 10 2.37 11 2.73 12 2.05 13 2.29 14 2.58 32 2.17 33 2.32 33 2.59 34 1.97 35 2.16 36 2.41 37 2.82 42 1.72 43 2.74 44 2.59 45 2.65 53 2.15 54 2.47 MK-1775 4.32
  • R 4 is H, alkyl, alkoxy or heterocycloalkane Base, etc.
  • the compounds have strong inhibitory activity against Wee-1 kinase, such as compound 1 and compound 42, the activity is about 2 times higher than that of the control drug MK-1775.
  • 3000/well MIA PaCa-2 cells were plated in a 384-well plate, and after overnight adherence, DMSO or compounds with a maximum concentration of 5 ⁇ M, 1:5 serial dilution were added. Cell survival was assessed by measuring intracellular ATP content 72 hours after dosing. The percent inhibition of cell survival by the compounds compared to the DMSO group was calculated and IC50 values were calculated and the results are shown in Table 5 below.
  • Example 58 In vitro anti-proliferative activity of the compound of the present invention combined with gemcitabine (Gemcitabine, GMC) on MIA PaCa-2 cells
  • the compounds of the present invention all have strong anti-proliferative activities on MIA PaCa-2 cells, such as the IC 50 of the anti-proliferative activities of Compound 1, Compound 2, Compound 7, Compound 36 and Compound 42 on MIA PaCa-2 cells Less than 100nM, compared with the control drug MK-1775, it increased by more than 10 times.
  • the compounds of the present invention have stronger combined activity with GMC, such as compound 1, compound 2, compound 10, compound 12, compound 13, compound 32 and compound 42, the IC 50 is less than 2nM.
  • the compound of the present invention has strong combined activity with GMC, which indicates that it may have better effect in clinical combination with chemotherapeutic drugs.

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Abstract

La présente invention concerne un dérivé de pyrrolopyrimidine, son procédé de préparation et son utilisation. La présente invention concerne en particulier un composé représenté par la formule générale (1) ; un procédé de préparation associé ; et une utilisation du composé de formule générale (1), et des isomères, des formes cristallines et des sels pharmaceutiquement acceptables de celui-ci, le procédé de préparation associé et une utilisation en tant qu'inhibiteur de Wee-1 dans la préparation d'un médicament antitumoral.
PCT/CN2022/089850 2021-04-30 2022-04-28 Dérivé de pyrrolopyrimidine, son procédé de préparation et son utilisation WO2022228509A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2213673A1 (fr) * 2007-10-23 2010-08-04 Banyu Pharmaceutical Co., Ltd. Dérivé de dihydropyrazolopyrimidinone substitué par pyridone
CN106458914A (zh) * 2014-03-28 2017-02-22 常州捷凯医药科技有限公司 作为axl抑制剂的杂环化合物
WO2018011569A1 (fr) * 2016-07-12 2018-01-18 Almac Discovery Limited Composés de pyrazolopyrimidinone inhibant la wee -1
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
WO2020192581A1 (fr) * 2019-03-22 2020-10-01 首药控股(北京)有限公司 Inhibiteur de wee1 ainsi que sa préparation et son utilisation
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

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2213673A1 (fr) * 2007-10-23 2010-08-04 Banyu Pharmaceutical Co., Ltd. Dérivé de dihydropyrazolopyrimidinone substitué par pyridone
CN106458914A (zh) * 2014-03-28 2017-02-22 常州捷凯医药科技有限公司 作为axl抑制剂的杂环化合物
WO2018011569A1 (fr) * 2016-07-12 2018-01-18 Almac Discovery Limited Composés de pyrazolopyrimidinone inhibant la wee -1
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
WO2020192581A1 (fr) * 2019-03-22 2020-10-01 首药控股(北京)有限公司 Inhibiteur de wee1 ainsi que sa préparation et son utilisation
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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