WO2023280136A1 - Dérivé de pyrazino pyrazino quinolinone substitué par un trideutérométhyle, son procédé de préparation et son utilisation en médecine - Google Patents

Dérivé de pyrazino pyrazino quinolinone substitué par un trideutérométhyle, son procédé de préparation et son utilisation en médecine Download PDF

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WO2023280136A1
WO2023280136A1 PCT/CN2022/103800 CN2022103800W WO2023280136A1 WO 2023280136 A1 WO2023280136 A1 WO 2023280136A1 CN 2022103800 W CN2022103800 W CN 2022103800W WO 2023280136 A1 WO2023280136 A1 WO 2023280136A1
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cancer
group
compound
aryl
cycloalkyl
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PCT/CN2022/103800
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English (en)
Chinese (zh)
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陈友喜
程超英
向清
朱明江
叶成
钱文建
陈磊
戴露媚
吴恩国
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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 CN202280006447.2A priority Critical patent/CN116249683A/zh
Publication of WO2023280136A1 publication Critical patent/WO2023280136A1/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
    • A61K31/4985—Pyrazines or piperazines 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems

Definitions

  • the present invention relates to a deuteromethyl-substituted pyrazinopyrazinoquinolinone derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and its therapeutic agent, especially as a K-Ras GTPase inhibitor use.
  • RAS represent a group of closely related monomeric globular proteins (21 kDa molecular weight) of 189 amino acids that are associated with the plasma membrane and bind GDP or GTP. Under normal development or physiological conditions, RAS is activated by receiving growth factors and various other extracellular signals, and is responsible for regulating cell growth, survival, migration and differentiation. RAS functions as a molecular switch, the on/off state of RAS protein is determined by nucleotide binding, the active signaling conformation binds GTP, and the inactive conformation binds GDP. When the RAS contains bound GDP it is dormant or resting or off and is "inactive". When cells are exposed to certain growth-promoting stimuli in response, RAS is induced to convert bound GDP to GTP.
  • GTPase activating proteins GTPase activating proteins
  • RAS proteins contain a G domain responsible for the enzymatic activity of RAS—guanine nucleotide binding and hydrolysis (GTPase reaction). It also includes a C-terminal extension containing the so-called CAAX box, which can be post-translationally modified and targets the protein to the membrane.
  • the G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop).
  • P-loop represents the pocket in the protein that binds nucleotides, and this is the rigid part of the domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, threo amino acid 26 and lysine 16).
  • the G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein, since this dynamic part switches between the resting and loaded states This capability is often expressed as a "spring-loaded” mechanism.
  • the main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the ⁇ -phosphate of GTP, which maintains the switch I and switch II regions in their active conformations, respectively. Following hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.
  • KRAS mutations are prevalent in the three most deadly cancer types in the United States: pancreatic cancer (95%), colorectal cancer (45%), and lung cancer (25%), including multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer KRAS mutations are also found in other cancer types, including diffuse large B-cell lymphoma, rhabdomyosarcoma, squamous cell carcinoma of the skin, cervical cancer, testicular germ cell carcinoma, and in breast cancer, ovarian cancer and brain cancer. Rarely found ( ⁇ 2%).
  • KRAS G12C is the most common mutation, accounting for nearly half of all KRAS mutations, followed by G12V and G12D.
  • the increased mutation frequency of specific alleles is mostly from the classic smoking-induced mutations (G:C to T:A substitutions), resulting in KRAS G12C (GGT to TGT) and G12V (GGT to GTT) mutation.
  • KRAS mutations including G12C
  • other known driver oncogenic mutations in NSCLC including EGFR, ALK, ROS1, RET, and BRAF
  • KRAS mutations often co-occur with certain co-mutations, such as STK11, KEAP1, and TP53, which cooperate with mutated RAS to transform cells into highly malignant and aggressive tumor cells.
  • KRAS inhibitors At present, there is fierce competition for the clinical development of KRAS inhibitors at home and abroad.
  • the KRAS enzyme inhibitor MRTX-849 developed by Mirati Therapeutics Inc. has entered the second clinical phase for the prevention and treatment of advanced solid tumors, metastatic colorectal cancer and metastasis.
  • Non-small cell lung cancer and other diseases There are also other KRAS inhibitors under development, including AMG-510 (Amgen Inc, phase 3).
  • AMG-510 Amgen Inc, phase 3
  • KRAS inhibitors significantly control and alleviate disease progression in patients with non-small cell lung cancer, and significantly reduce tumor size in patients with advanced lung and colorectal cancer.
  • KRAS inhibitors A series of patent applications for KRAS inhibitors have been published, including WO2020047192, WO2019099524, and WO2018217651. The research and application of KRAS inhibitors have made some progress, but there is still huge room for improvement, and it is still necessary to continue research and develop new ones. KRAS inhibitors.
  • the object of the present invention is to provide a tetracyclic derivative shown in general formula (I), or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:
  • Ring A is selected from aryl, heteroaryl or fused rings
  • R 5 , R 6 and R 7 are each independently selected from a 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 is selected from 0, 1 or 2;
  • r is selected from 0, 1 or 2.
  • the compound described in general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof wherein ring A is selected from phenyl, naphthyl, pyridyl , benzothiazolyl or benzothienyl, preferably benzothiazolyl or benzothienyl.
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a method for preparing the compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, the method comprising:
  • the compound of general formula (IA) and the compound of general formula (IB) carry out Suzuki coupling reaction under the effect of palladium catalyst and basic reagent, further remove protecting group, obtain general formula (IC) compound, general formula (IC) compound and Acryloyl chloride is reacted under basic conditions, and the protective group is optionally further removed to obtain a compound of general formula (I);
  • X 1 is a leaving group, preferably bromine
  • M is selected from -B(OH) 2 , -BF 3 K or
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • Ring A, R 1 and m are as defined in general formula (I).
  • the present invention provides a compound described in general formula (IC) or its stereoisomer, tautomer and pharmaceutically acceptable salt thereof,
  • ring A, R 1 and m are defined as described in general formula (I).
  • Typical compounds of general formula (IC) include, but are not limited to:
  • the present invention provides a pharmaceutical composition containing an effective dose of the compound described in general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers, excipients or combinations thereof.
  • the present invention provides a method for inhibiting K-Ras GTPase, wherein said method comprises, administering to a patient a pharmaceutical composition, said pharmaceutical composition containing an effective dose of the general formula (I) The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carrier, excipient or their combination, wherein K-Ras GTPase is preferably KRAS G12C enzyme.
  • the present invention also provides a compound described in general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, or its pharmaceutical composition in the preparation for the treatment of KRAS mutation-mediated wherein the disease mediated by the KRAS mutation is preferably selected from cancer, wherein the cancer is preferably selected from pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct cancer , gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, skin squamous cell carcinoma, cervical cancer, testicular germ cell carcinoma, more preferably pancreatic cancer, colorectal cancer and lung cancer; wherein the lung cancer is preferably Non-small cell lung cancer, wherein the KRAS mutation is preferably a KRAS G12C mutation.
  • the cancer is preferably selected from pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct
  • the present invention provides a compound described in general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of K-Ras GTP
  • K-Ras GTPase inhibitor is preferably KRAS G12C inhibitor.
  • Another aspect of the present invention relates to a method for preventing and/or treating diseases mediated by KRAS mutations, which comprises administering to patients a therapeutically effective dose of the compound described in general formula (I) or its tautomer, internal Racemate, racemate, enantiomer, diastereomer or mixture thereof or pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising it, wherein the KRAS mutation is preferably KRAS G12C mutation .
  • the present invention also provides a compound described in general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of medicines for treating cancer
  • the cancer is preferably selected from pancreatic cancer, colorectal cancer, lung cancer, multiple myeloma, uterine cancer, bile duct cancer, gastric cancer, bladder cancer, diffuse large B-cell lymphoma, rhabdomyosarcoma, skin squamous cell Cancer, cervical cancer, testicular germ cell cancer, more preferably pancreatic cancer, colorectal cancer and lung cancer; wherein said lung cancer is preferably non-small cell lung cancer.
  • 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.
  • 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.
  • Alkylene is a divalent alkyl group. It is preferably a C 1 -C 10 alkylene group, more preferably a C 1 -C 6 alkylene group, particularly preferably a C 1 -C 4 alkylene group. Examples of alkylene groups include, but are not limited to, methylene, ethylene, -CH( CH3 )2n - propylene, and the like. Alkylene 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.
  • “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.
  • 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,
  • 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.
  • Deuterated alkyl refers to a group in which the alkyl group is optionally further substituted by one or more deuterium atoms, wherein alkyl is as defined herein.
  • Deuteroalkyl is preferably deuteromethyl, including: monodeuteromethyl, dideuteromethyl and trideuteromethyl, preferably trideuteromethyl.
  • Hydroalkyl means an alkyl group optionally further substituted with one or more hydroxy groups, wherein alkyl is as defined herein.
  • 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
  • TFA trifluoroacetic acid
  • X-PHOS Pd G2 refers to chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino- 1,1'-biphenyl)]palladium(II).
  • 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 5 , R 6 and R 7 are each independently selected from a 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 preparation method of the compound described in general formula (I) of the present invention or its stereoisomer, tautomer or its pharmaceutically acceptable salt comprises the following steps:
  • the compound of general formula (IA) and the compound of general formula (IB) carry out Suzuki coupling reaction under the effect of palladium catalyst and basic reagent, further remove protecting group, obtain general formula (IC) compound, general formula (IC) compound and Acryloyl chloride is reacted under basic conditions, and the protective group is optionally further removed to obtain a compound of general formula (I);
  • X 1 is a leaving group, preferably bromine
  • M is selected from -B(OH) 2 , -BF 3 K or
  • PG is a protecting group, preferably tert-butoxycarbonyl
  • Ring A, R 1 and m are defined as described in general formula (I).
  • 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 cooled to room temperature, concentrated under reduced pressure, and the obtained residue was sequentially subjected to silica gel column chromatography (eluent: system A) and preparative high performance liquid chromatography (preparation conditions: separation column AKZONOBEL Kromasil; 250 ⁇ 21.2mm I.D.
  • Test example 1 determination of the covalent binding ability of the compound of the present invention and KRAS G12C protein
  • the following method is used to determine the covalent binding ability of the compound of the present invention to recombinant human KRAS G12C protein under in vitro conditions.
  • reaction buffer (20mM HEPES, 150mM NaCl, 1mM MgCl 2 , 1mM DTT) to prepare recombinant human KRAS G12C protein (aa1-169) at a concentration of 4 ⁇ M for use.
  • the test compound was dissolved in DMSO to prepare a 10 mM stock solution, which was then diluted with reaction buffer for later use.
  • reaction buffer final concentration of the reaction system is 3 ⁇ M
  • reaction buffer final concentration of the reaction system is 3 ⁇ M
  • 25 ⁇ L of 4 ⁇ M recombinant human KRAS G12C protein 25 ⁇ L of 4 ⁇ M recombinant human KRAS G12C protein, at room temperature
  • 5 ⁇ L of acetic acid was added to stop the reaction and the samples were transferred to injection vials.
  • the compound of the present invention has a better covalent binding rate with KRAS G12C protein under the condition of 3 ⁇ M and 5 min.
  • Test example 2 compound of the present invention is to NCI-H358 cell proliferation inhibitory assay
  • NCI-H358 cells (containing KRAS G12C mutation) were purchased from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin, 100 ⁇ g/mL streptomycin and 1mM Sodium Pyruvate middle. cell viability through Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573) 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 1000nM to 0.015nM .
  • Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 800 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 has good proliferation inhibitory effect on NCI-H358 (human non-small cell lung cancer) cells.
  • Test example 3 the determination of the compound of the present invention to p-ERK1/2 inhibitory activity in NCI-H358 cells
  • the following method is used to determine the inhibitory activity of the compounds of the present invention on p-ERK1/2 in NCI-H358 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.
  • NCI-H358 cells (containing KRAS G12C mutation) were purchased from the Cell Resource Center, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
  • NCI-H358 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. NCI-H358 cells were plated in a 96-well plate at 30,000 per well, and the culture medium was complete medium, and cultured overnight at 37° C. in a 5% CO 2 incubator.
  • test compound was dissolved in DMSO to prepare a 10 mM stock solution, then diluted with RPMI 1640 basal medium, and 90 ⁇ L 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 1000nM-0.015nM, and cultured in a cell incubator for 3 hours and 40 minutes. Subsequently, 10 ⁇ L of hEGF prepared with RPMI 1640 basal medium (purchased from Roche, product number 11376454001) was added to make the final concentration 5 nM, and placed in an incubator for 20 minutes.
  • the compound of the present invention has a better inhibitory effect on the proliferation of p-ERK1/2 in NCI-H358 cells.
  • Test example 4 the hERG potassium ion channel inhibitory activity of the compound of the present invention
  • the cells used in this experiment are CHO cell lines transfected with hERG cDNA and stably expressing hERG channels (provided by Sophion Bioscience, Denmark), and the cell generation is P17.
  • the cells were cultured in a medium containing the following components (all derived from Invitrogen): Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 ⁇ g/mL hygromycin B, 100 ⁇ g/mL Geneticin.
  • CHO hERG cells were grown in the culture dish containing the above culture medium and cultured in an incubator at 37°C with 5% CO 2 . 24 to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to round glass slides placed in petri dishes and grown in the same medium and conditions as above. The density of CHO hERG cells on each circular slide needs to be such that most of the cells are independent and single.
  • a fully automated QPatch system (Sophion, Denmark) was used for whole-cell current recordings. Cells were clamped at a voltage of -80 mV. Cell voltage clamps were depolarized to +20 mV to activate hERG potassium channels, and then clamped to -50 mV after 2.5 s to abolish inactivation and generate outward tail currents. The peak tail current was used as a measure of hERG current magnitude.
  • test concentration 30 ⁇ M, followed by 6 concentrations of 30, 10, 3, 1, 0.3 and 0.1 ⁇ M.
  • test data were analyzed by Qpatch analysis software provided by Sophion, Excel and Graphpad Prism, etc.
  • Table 4 shows the inhibitory results of the compounds of the present invention on hERG current.
  • the compound of the present invention is to the inhibitory result of hERG electric current
  • Test example 5 SD rat pharmacokinetic research of compound of the present invention
  • SD rats were given the compound of the present invention via intravenous injection and/or gavage, and the drug concentration in plasma at different times was measured by LC/MS/MS method, and the compound of the present invention was studied in SD rats. pharmacokinetic characteristics.
  • SD rats were divided into intravenous injection group (3 rats/group) and gavage group (3 rats/group) of the compound to be tested.
  • Intravenous injection group administered via dorsal foot vein (administration dose 1 mg/kg, administration volume 5 mL/kg), without fasting.
  • Oral gavage group intragastric administration (administration dose 5 mg/kg, administration volume 10 mL/kg) after fasting overnight, and take food 4 hours after administration.
  • Intravenous injection group Collect about 150 ⁇ L of blood into EDTA-K2 anticoagulant tubes via the jugular vein at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration.
  • Oral gavage group collect about 100 ⁇ L of blood into EDTA-K2 anticoagulant tubes via the jugular vein at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after administration.
  • the blood samples were stored in wet ice, and the plasma was centrifuged within 15 minutes after sampling (centrifugation conditions: 7000 rpm, 4° C., 5 minutes).
  • the collected upper layer plasma was stored at –70°C before analysis.
  • LC-MS/MS was used to determine the content of the compound to be tested in rat plasma after intravenous injection and gavage administration of the compound.
  • Test example 6 the pharmacodynamics test of the compound of the present invention in NCI-H358 cell BALB/c nude mouse subcutaneous transplantation model 1.
  • This test is used to evaluate oral gavage administration for 11 days, once a day, give the compound of the present invention (the compound that retention time is 9.239 minutes in 4 or 5) in NCI-H358 (human non-small cell lung cancer) cell line subcutaneous transplantation BALB/ c Antitumor effect and safety in nude mouse animal model.
  • mice Female, 6-7 weeks (the age of mice at the time of tumor cell inoculation), 12, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd., license number: SCXK (Su) 2019-0009 .
  • NCI-H358 cells were cultured in RPMI 1640 medium containing 10% fetal bovine serum, 1% sodium pyruvate and 1% glutamine. The NCI-H358 cells in the exponential growth phase were collected, and the cells were resuspended in PBS to a suitable concentration for subcutaneous tumor inoculation in nude mice.
  • NCI-H358 cells were inoculated subcutaneously on the right side of the back of female BALB/c nude mice. When the average volume of the tumor reached about 100-150 mm 3 , they were randomly divided into 2 groups according to the size of the tumor.
  • a subcutaneous transplanted tumor model was established. Each treatment group and the vehicle control group were administered orally by gavage for 11 days. Animals were weighed daily, and tumor volume was measured twice a week.
  • TV tumor volume
  • T/C relative tumor proliferation rate
  • TGI relative tumor inhibition rate
  • IR tumor inhibition percentage
  • TV (tumor volume, tumor volume) 1/2 ⁇ a ⁇ b 2 , where a and b represent the length and width of the tumor, respectively;
  • T/C (relative tumor proliferation rate, %) T RTV /C RTV ⁇ 100%, wherein T RTV is the RTV of the treatment group, and C RTV is the RTV of the control group;
  • TGI% (tumor growth inhibition rate) (1-T/C) ⁇ 100%; wherein, T and C are the relative tumor volumes at a specific time point in the treatment group and the control group, respectively.
  • IR (%) (tumor weight inhibition rate) (1-TW t /TW c ) ⁇ 100%, where TW t is the tumor weight of the treatment group, and TW c is the tumor weight of the control group.
  • Tumor volume data are expressed as "mean ⁇ standard error"
  • Tumor volume data are expressed as "mean ⁇ standard error"

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Abstract

La présente invention concerne un dérivé de pyrazino pyrazino quinolinone substitué par un trideutérométhyle, son procédé de préparation et son utilisation en médecine. Plus particulièrement, la présente invention concerne un dérivé de pyrazino pyrazino quinolinone substitué par un trideutériométhyle tel que représenté par la formule générale (I), et son procédé de préparation et un sel pharmaceutiquement acceptable de celui-ci, et son utilisation en tant qu'agent thérapeutique, en particulier en tant qu'inhibiteur de la GTPase KRAS, la définition de chaque substituant dans la formule générale (I) est la même que la définition dans la description.
PCT/CN2022/103800 2021-07-06 2022-07-05 Dérivé de pyrazino pyrazino quinolinone substitué par un trideutérométhyle, son procédé de préparation et son utilisation en médecine WO2023280136A1 (fr)

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CN116249683A (zh) * 2021-07-06 2023-06-09 浙江海正药业股份有限公司 氘甲基取代吡嗪并吡嗪并喹啉酮类衍生物、其制备方法及其在医药上的应用
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof

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US20190177338A1 (en) * 2017-12-08 2019-06-13 Astrazeneca Ab Chemical compounds
WO2021051034A1 (fr) * 2019-09-13 2021-03-18 Biotheryx, Inc. Agents de dégradation de la protéine ras, compositions pharmaceutiques de ceux-ci et leurs applications thérapeutiques
CN114195788A (zh) * 2020-09-17 2022-03-18 苏州闻天医药科技有限公司 一类四环化合物及其用途

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WO2023280136A1 (fr) * 2021-07-06 2023-01-12 浙江海正药业股份有限公司 Dérivé de pyrazino pyrazino quinolinone substitué par un trideutérométhyle, son procédé de préparation et son utilisation en médecine

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US20190177338A1 (en) * 2017-12-08 2019-06-13 Astrazeneca Ab Chemical compounds
WO2021051034A1 (fr) * 2019-09-13 2021-03-18 Biotheryx, Inc. Agents de dégradation de la protéine ras, compositions pharmaceutiques de ceux-ci et leurs applications thérapeutiques
CN114195788A (zh) * 2020-09-17 2022-03-18 苏州闻天医药科技有限公司 一类四环化合物及其用途

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116249683A (zh) * 2021-07-06 2023-06-09 浙江海正药业股份有限公司 氘甲基取代吡嗪并吡嗪并喹啉酮类衍生物、其制备方法及其在医药上的应用
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques

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