WO2023001229A1 - Dérivé pyrimidocyclique, son procédé de préparation et son utilisation - Google Patents

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

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Publication number
WO2023001229A1
WO2023001229A1 PCT/CN2022/107001 CN2022107001W WO2023001229A1 WO 2023001229 A1 WO2023001229 A1 WO 2023001229A1 CN 2022107001 W CN2022107001 W CN 2022107001W WO 2023001229 A1 WO2023001229 A1 WO 2023001229A1
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cycloalkyl
alkyl
pharmaceutically acceptable
group
tautomer
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PCT/CN2022/107001
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English (en)
Chinese (zh)
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张盼盼
何智鹏
苟俊
程超英
郭静
叶成
钱文建
陈磊
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浙江海正药业股份有限公司
上海昂睿医药技术有限公司
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Priority to CN202280049444.7A priority Critical patent/CN117769556A/zh
Publication of WO2023001229A1 publication Critical patent/WO2023001229A1/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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the invention relates to a pyrimidocyclic derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its use as a therapeutic agent, especially as an SOS1 inhibitor.
  • RAS genes are widely found in various eukaryotic organisms such as mammals, fruit flies, fungi, nematodes and yeasts, and have important physiological functions in various life systems.
  • the mammalian RAS gene family has three members, namely H- RAS, K-RAS and N-RAS, each RAS gene has a similar structure, and all of them are composed of four exons, which are distributed on the DNA with a total length of about 30 kb.
  • Their encoded products are monomeric globular proteins with a relative molecular mass of 21kDa.
  • the activation and inactivation state of RAS protein has a significant impact on the life processes such as cell growth, differentiation, proliferation and apoptosis.
  • This protein is a membrane-bound guanine nucleotide-binding protein with weak GTPase activity and regulates RAS through GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities
  • GAPs GTPase-activating proteins
  • GEFs guanine nucleotide exchange factors
  • the active state when the RAS protein combines with GTP to form RAS-GTP, it is the active state, and the GTPase activating protein can dephosphorylate RAS-GTP into RAS-GDP, and then inactivate it; the inactivated RAS-GDP is in the guanine Under the action of nucleotide exchange factors, it is transformed into active RAS-GTP, thereby activating a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR.
  • the RAS gene is also closely related to various human diseases, especially in cancer.
  • RAS is a frequently mutated oncogene, and the KRAS subtype gene mutation accounts for 86% of the total number of RAS gene mutations, and about 90% of pancreatic cancers. 30%-40% of colon cancer and 15-20% of lung cancer have different degrees of KRAS gene mutation.
  • this target has always been the focus of drug research and development workers. Since the announcement of the clinical results of AMG-510, which directly acts on the KRAS-G12C target, research on KRAS inhibitors has set off a wave of upsurge at home and abroad.
  • SOS Seon of sevenless homolog
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • hSOS1 and hSOS2 SOS homologues
  • the hSOS1 protein is 150kDa in size and is a multi-structural protein domain consisting of 1333 amino acids, including an N-terminal protein domain (HD), multiple homology domains, a helical linker (HL), a RAS exchange sequence (REM) and a rich Proline C-terminal domain.
  • HD N-terminal protein domain
  • HL helical linker
  • REM RAS exchange sequence
  • RAS protein on hSOS1 There are two binding sites for RAS protein on hSOS1, namely the catalytic site and the allosteric site.
  • the catalytic site binds to the RAS protein on the RAS-GDP complex to promote the exchange of guanine nucleotides
  • the allosteric site binds The RAS protein on the RAS-GTP complex further enhances the catalytic effect, and then participates in and activates the signal transduction of RAS family proteins.
  • SOS1 alterations in SOS1 have also been implicated in cancer.
  • inherited SOS1 mutations have also been implicated in the pathogenesis of RAS disorders such as Noonan Syndrome (NS), Heart-Face-Skin Syndrome (CFC) and Type 1 Hereditary Gingival Fiber Tumor etc.
  • SOS1 is also a GEF for activation of the GTPase RAC1 (Ras-associated C3 botulinum toxin substrate 1). Like RAS family proteins, RAC1 has been implicated in the pathogenesis of a variety of human cancers and other diseases.
  • the object of the present invention is to provide a pyrimidocyclic derivative shown in general formula (I), or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • W is selected from N or CH
  • V is selected from N, -CR 2 ;
  • L is selected from a bond or -CH2- ;
  • X is selected from -O- or -N(R 3 )-;
  • Y is selected from -C(O)- or -CH 2 -;
  • Z is selected from -O- or -N(R 5 )-;
  • Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl or 9-10 membered fused ring;
  • R 2 is selected from fluorine atom, hydroxyl group, cyano group, methoxyl group or amino group
  • R 4 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-10 membered heterocyclic group; wherein said alkyl, cycloalkyl or heterocyclic group is optionally further replaced by one or more R A replaced;
  • R 5 is selected from hydrogen atom, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected from one or more halogen, cyano, Substituents of hydroxy, amino, C 1 -C 3 alkoxy or C 1 -C 3 hydroxyalkyl;
  • R 9 , R 10 and R 11 are each independently selected from hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , carboxyl or carboxylate substituents;
  • n 1, 2 or 3.
  • the compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound represented by general formula (II) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • ring A, R 1 , W, X, Y, Z, L and m are as defined in general formula (I).
  • the compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof is the compound represented by general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • the compound represented by general formula (II) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof it is general formula (II-1), (II- 2), the compound shown in (II-3) or (II-4) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • ring A, R 1 , R 5 , W, X and m are as defined in general formula (II).
  • the compound represented by the general formula (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof it is the general formula (III-1), (III- 2), the compound represented by (III-3) or (III-4) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • ring A, R 1 , R 2 , R 5 , W, X and m are as defined in general formula (III).
  • X is selected from -N(R 3 )-;
  • R 3 is selected from -C(O)R 4 ;
  • R 4 is as described in the general formula (I).
  • X is selected from -N(R 3 )-;
  • R 3 is selected from -C(O)R 4 ;
  • R4 is selected from methyl or cyclopropyl.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a pharmaceutical composition, which contains effective doses of general formula (I), (II), (III), (II-1), (II-2), (II) -3), (II-4), (III-1), (III-2), (III-3) or (III-4) compound or its stereoisomer, tautomer or Its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier, excipient or their combination.
  • the present invention provides a kind of general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), ( The compound described in III-2), (III-3) or (III-4) or its stereoisomer, tautomer or its pharmaceutically acceptable salt, or its pharmaceutical composition is used in the preparation of SOS1 inhibitor use in .
  • the present invention also provides a general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), Compounds described in (III-2), (III-3) or (III-4) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in the preparation of Use in medicine for SOS1-mediated diseases, wherein the SOS1-mediated diseases are preferably RAS family protein signaling pathway-dependent cancers, cancers caused by SOS1 mutations, or hereditary diseases caused by SOS1 mutations; wherein The disease mediated by SOS1 is preferably lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, heart face skin syndrome, hereditary gingival fibroma type I, embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, or
  • the present invention further provides a general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), Compounds described in (III-2), (III-3) or (III-4) or their stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof are used in the preparation and treatment of RAS Use in medicine for cancers related to family protein signaling pathway dependence, cancers caused by SOS1 mutations or hereditary diseases caused by SOS1 mutations.
  • the present invention provides a kind of general formula (I), (II), (III), (II-1), (II-2), (II-3), (II-4), (III-1), ( The compound described in III-2), (III-3) or (III-4) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of the treatment of lung cancer, Pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, Noonan syndrome, cardiofacial skin syndrome, hereditary gingival fibroma type I, embryonal Use in medicine for rhabdomyosarcoma, Sertoli cell testicular tumor or cutaneous granulosa cell tumor.
  • the pharmaceutical formulations of the present invention can be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonarily, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intravesically, intradermally , intraperitoneally, subcutaneously, subkeratinally or by inhalation.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixir. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets.
  • the formulations of the invention are suitably presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form generally refers to that amount of the compound which produces a therapeutic effect.
  • Dosage forms for the topical or transdermal administration of a compound of this invention may include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, in admixture with any preservatives, buffers or propellants which may be required.
  • the compound of the present invention when administered to humans and animals in the form of medicine, the compound can be provided alone or in the form of a pharmaceutical composition containing Active ingredient, such as 0.1% to 99.5% (more preferably, 0.5% to 90%) active ingredient.
  • Active ingredient such as 0.1% to 99.5% (more preferably, 0.5% to 90%) active ingredient.
  • Examples of pharmaceutically acceptable carriers include, but are not limited to: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as carboxy Sodium methylcellulose, ethylcellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and Suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol , mannitol and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers such as magnesium hydroxide and aluminum hydroxide; (15) seaweed
  • antioxidants examples include, but are not limited to: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; ( 2) Oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like
  • Oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluen
  • Solid dosage forms may include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or the following Any one of: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; (2) binders, such as carboxymethylcellulose, alginate, Gelatin, polyvinylpyrrolidone, sucrose, and/or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retarders, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorption (9) lubricants
  • fillers or bulking agents such as starch, lactose, sucrose, glucose, mannito
  • Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzene Methanol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, THF, polyethylene glycol Fatty acid esters of diols and sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as water or other solvents
  • solubilizers and emulsifiers such as ethanol, isopropanol
  • Suspensions in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and gum tragacanth and mixtures thereof.
  • suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide oxide, bentonite, agar and gum tragacanth and mixtures thereof.
  • Ointments, pastes, creams and gels may contain, in addition to the active compounds, excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyesters, etc. Glycol, polysiloxane, bentonite, silicic acid, talc and zinc oxide or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • the sprays can contain other customary propellants, such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons, such as butane and propane.
  • “Bond” means that the indicated substituent does not exist, and the two end portions of the substituent are directly connected to form a bond.
  • Alkyl when used as a group or a part of a group refers to a C 1 -C 20 straight chain or branched aliphatic hydrocarbon group. It is preferably C 1 -C 10 alkyl, more preferably C 1 -C 6 alkyl.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups can be optionally substituted or unsubstituted.
  • Alkynyl refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C 2 -C 10 alkynyl, more preferably C 2 -C 6 alkynyl, most preferably C 2 -C 4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.
  • Cycloalkyl refers to saturated or partially saturated monocyclic, fused, bridged and spiro carbocyclic rings. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclohexenyl. Cycloalkyl groups can be optionally substituted or unsubstituted.
  • “Spirocycloalkyl” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one carbon atom (called a spiro atom) shared between the single rings.
  • the ring contains one or more Aromatic systems with double bonds, but none of the rings have fully conjugated ⁇ electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro cycloalkyl group is divided into single spiro, double spiro or polyspiro cycloalkyl, preferably single spiro and double spiro cycloalkyl, preferably 4-membered/5-membered, 4-membered Yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan.
  • spirocycloalkyl include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” refers to a 5 to 18-membered, full-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms with each other, and one or more rings may contain one or more double bonds, Aromatic systems where none of the rings have fully conjugated pi-electrons, preferably 6 to 12, more preferably 7 to 10 membered. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthrenyl.
  • “Bridged cycloalkyl” refers to a 5- to 18-membered full-carbon polycyclic group that contains two or more ring structures and shares two carbon atoms that are not directly connected to each other.
  • One or more rings may contain one or more Aromatic systems with multiple double bonds but none of the rings having fully conjugated pi electrons are preferably 6 to 12 membered, more preferably 7 to 10 membered. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged cycloalkyl include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bis Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably in this application and all refer to non-aromatic heterocyclic groups in which one or more atoms forming the ring are heteroatoms, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic rings, condensed rings, bridged rings, and spiro rings. It preferably has a 5 to 7 membered monocyclic ring or a 7 to 10 membered bi- or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, piperidinyl , 2-oxopiperidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl .
  • a heterocyclyl group can be substituted or unsubstituted.
  • “Spiroheterocyclic group” refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the single rings.
  • the ring contains one or more double bonds, but no Aromatic systems with a ring having fully conjugated ⁇ -electrons, in which one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) r (where r is selected from 0, 1 or 2), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group can be divided into single spiroheterocyclyl, double spiroheterocyclyl or polyspiroheterocyclyl, preferably single spiroheterocyclyl and double spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • spiroheterocyclyl include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl, Heteraspiro[3.5]nonyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with each other.
  • One or more rings may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron aromatic systems in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2) and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0]hexyl, octahydrobenzo[b][1,4]dioxine or
  • “Bridged heterocyclic group” refers to a polycyclic group with 5 to 14 members, 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, and one or more rings can be Aromatic systems containing one or more double bonds, but none of the rings have fully conjugated ⁇ -electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclyl include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-azabicyclo[2.2.2]octyl Cyclo[3.3.2]decyl.
  • Aryl means a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion.
  • aryl includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are C 6 -C 10 aryl groups, more preferred aryl groups are phenyl and naphthyl, most preferably naphthyl.
  • Aryl groups can be substituted or unsubstituted.
  • Heteroaryl refers to an aromatic 5 to 6 membered monocyclic ring or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Bicyclic heteroaryl is preferred.
  • heteroaryl examples include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, Thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiazolyl Adiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl , Indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl.
  • Heteroaryl groups can be substituted or unsubstituted.
  • “Fused ring” refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring does not have complete conjugation Aromatic system of ⁇ electrons in which the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) r (where r is selected from 0, 1 or 2), and the remaining ring atoms are carbon .
  • the fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:
  • Alkoxy refers to a group of (alkyl-O-). Wherein, alkyl refers to relevant definitions herein. C 1 -C 6 alkoxy is preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
  • Haloalkyl means an alkyl group optionally further substituted with one or more halogens, wherein alkyl is as defined herein.
  • Hydroalkyl means an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • Hydromethyl refers to a group in which the methyl group is optionally further substituted with one or more hydroxy groups.
  • Haloalkoxy refers to a group in which the alkyl group of (alkyl-O-) is optionally further substituted by one or more halogens, wherein alkoxy is as defined herein.
  • Haldroxy means an -OH group.
  • Halogen refers to fluorine, chlorine, bromine and iodine.
  • Amino refers to -NH2 .
  • Cyano refers to -CN.
  • Niro refers to -NO2 .
  • Benzyl means -CH2 -phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylate group refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein the definitions of alkyl and cycloalkyl are as above.
  • DMSO dimethylsulfoxide
  • Ts refers to p-toluenesulfonyl.
  • T3P refers to propylphosphoric anhydride.
  • DPPA diphenylphosphoryl azide
  • DEA diethylamine
  • X-PHOS Pd G2 refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino- 1,1'-biphenyl)]palladium(II).
  • Pd(dppf)Cl 2 refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • R 9 , R 10 and R 11 are each independently selected from hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl , aryl or heteroaryl are optionally further replaced by one or more selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl , carboxyl or carboxylate substituents;
  • r 0, 1 or 2.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and thus exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including but not limited to diastereomers, enantiomers and atropisomers (atropisomers) and geometric (conformational) isomers and Mixtures thereof, such as racemic mixtures, are within the scope of the present invention.
  • structures depicted herein also include all isomeric (eg, diastereoisomers, enantiomers, and atropisomers) and geometric (conformational) isomeric forms of such structures; e.g. , the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
  • isomeric e.g. diastereoisomers, enantiomers, and atropisomers
  • geometric (conformational) isomeric forms of such structures e.g. , the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.
  • the individual stereoisomers of the compounds of the present invention and the pair Mixtures of enantiomers, diastereoisomers and geometric (conformational) isomers are within the scope of the present invention.
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use.
  • the pharmaceutically acceptable salt of the compound represented by formula (I) may be a metal salt or an amine salt with a suitable acid.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically acceptable carriers and excipients. Forming agent.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • the mass spectrum is measured by LC/MS instrument, and the ionization method can be ESI or APCI.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • CD 3 OD deuterated methanol.
  • the solution in the reaction refers to an aqueous solution.
  • reaction solution was lowered to room temperature, concentrated under reduced pressure, added water (10 mL), extracted with dichloromethane (20 mL ⁇ 3), combined the organic phases, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was washed with silica gel Separation and purification by column chromatography (eluent: system B) to obtain 9-methyl-1,2,4a,5-tetrahydro-4H-[1,4]oxazino[4',3':4, 5] [1,4]oxazino[3,2-g]quinazolin-11-ol 1e (256 mg, 0.94 mmol), yield 70%.
  • reaction solution was lowered to room temperature, concentrated under reduced pressure, dichloromethane (20 mL) was added to the obtained residue, the pH was adjusted to alkaline with saturated sodium bicarbonate solution, the insoluble matter was removed by filtration, the layers were separated, the organic phase was collected, and the anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure.
  • Test example 1 the test that the compound of the present invention blocks the combination of SOS1 and KRAS G12C protein
  • the following method is used to determine the ability of the compound of the present invention to block the interaction between SOS1 and KRAS G12C protein under in vitro conditions.
  • This method uses the KRAS-G12C/SOS1 BINDING ASSAY KITS kit (Cat. No. 63ADK000CB16PEG) from Cisbio.
  • Kit instructions for detailed experimental operations, please refer to the kit instructions.
  • the experimental procedure is briefly described as follows: use diluent buffer (Product No. 62DLBDDF) to prepare Tag1-SOS1 and Tag2-KRAS-G12C proteins at a working solution concentration of 5X for later use.
  • the test compound was dissolved in DMSO to prepare a 10 mM stock solution, and then diluted with diluent buffer for use.
  • the percentage inhibition rate of the test compound at each concentration was calculated, and the nonlinear regression analysis was carried out with the concentration of the test compound on the value-inhibition rate by GraphPad Prism 5 software , to obtain the IC50 value of the compound.
  • Test example 2 compound of the present invention is to OCI-AML5 cell proliferation inhibitory assay
  • OCI-AML5 cells containing the SOS1N233Y mutation
  • MEM ⁇ medium containing 10% fetal bovine serum, 100 U penicillin and 100 ⁇ g/mL streptomycin.
  • cell viability through Luminescent Cell Viability Assay Kit was used for determination.
  • test compound is first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with medium to prepare a test sample.
  • concentration of the compound ranges from 10000nM to 0.15nM .
  • Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight at 37°C in a 5% CO2 incubator, and then continued to culture for 120 hours after adding the test compound.
  • the compound of the present invention inhibits the IC50 value of OCI-AML5 cell proliferation
  • the compound of the present invention has a good inhibitory effect on OCI-AML5 cell proliferation inhibition.
  • Test example 3 the assay of compound of the present invention to p-ERK1/2 inhibitory activity in DLD-1 cell
  • the following method is used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in DLD-1 cells.
  • This method uses the Advanced phospho-ERK1/2 (Thr202/tyr204) kit (Cat. No. 64AERPEH) from Cisbio, and the detailed experimental operation can refer to the kit instruction manual.
  • DLD-1 cells (containing the KRAS G13D mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • DLD-1 cells were cultured in RPMI 1640 complete medium containing 10% fetal bovine serum, 100 U penicillin, 100 ⁇ g/mL streptomycin and 1 mM Sodium Pyruvate. DLD-1 cells were plated in 96-well plates at a rate of 30,000 per well, the medium was complete medium, and cultured overnight at 37° C. in a 5% CO2 incubator.
  • test compound was dissolved in DMSO to prepare a 10mM stock solution, then diluted with RPMI 1640 basal medium, and 90uL of RPMI 1640 basal medium containing the corresponding concentration of the test compound was added to each well, and the final concentration of the test compound in the reaction system was The concentration range is 10000nM-0.15nM, and cultured in a cell incubator for 3 hours and 40 minutes. Subsequently, 10 uL of hEGF prepared with RPMI 1640 basal medium (purchased from Roche, product number 11376454001) was added to make the final concentration 5 nM, and cultured in an incubator for 20 minutes.
  • the compounds of the present invention inhibit the IC50 value of ERK phosphorylation in DLD-1 cells
  • the compound of the present invention has a better inhibitory effect on ERK phosphorylation in DLD-1 cells.

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Abstract

La présente invention concerne un dérivé pyrimidocyclique, son procédé de préparation, et une application médicale d'une composition pharmaceutique contenant le dérivé. Plus précisément, la présente invention concerne un dérivé pyrimidocyclique substitué représenté par la formule générale (I), un procédé de préparation de celui-ci et un sel pharmaceutiquement acceptable de celui-ci, et une utilisation de celui-ci en tant qu'agents thérapeutiques, en particulier des inhibiteurs de SOS1. La définition de chaque substituant dans la formule générale (I) est la même que sa définition dans la description.
PCT/CN2022/107001 2021-07-23 2022-07-21 Dérivé pyrimidocyclique, son procédé de préparation et son utilisation WO2023001229A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685531A (zh) * 2020-12-25 2022-07-01 武汉誉祥医药科技有限公司 四并环化合物及其药物组合物和应用
WO2023165438A1 (fr) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 Dérivé tricyclique, son procédé de préparation et son utilisation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2022135610A1 (fr) * 2020-12-25 2022-06-30 武汉誉祥医药科技有限公司 Composé tétracyclique, composition pharmaceutique et utilisation associées

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110167928A (zh) * 2016-12-22 2019-08-23 勃林格殷格翰国际有限公司 作为sos1抑制剂的新型经苄基氨基取代的喹唑啉和衍生物
WO2022135610A1 (fr) * 2020-12-25 2022-06-30 武汉誉祥医药科技有限公司 Composé tétracyclique, composition pharmaceutique et utilisation associées

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114685531A (zh) * 2020-12-25 2022-07-01 武汉誉祥医药科技有限公司 四并环化合物及其药物组合物和应用
WO2023165438A1 (fr) * 2022-03-03 2023-09-07 浙江海正药业股份有限公司 Dérivé tricyclique, son procédé de préparation et son utilisation

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