WO2021083383A1 - Composé cyclique fusionné contenant de l'azote en tant que régulateur de sting, son procédé de préparation et son utilisation - Google Patents

Composé cyclique fusionné contenant de l'azote en tant que régulateur de sting, son procédé de préparation et son utilisation Download PDF

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WO2021083383A1
WO2021083383A1 PCT/CN2020/125965 CN2020125965W WO2021083383A1 WO 2021083383 A1 WO2021083383 A1 WO 2021083383A1 CN 2020125965 W CN2020125965 W CN 2020125965W WO 2021083383 A1 WO2021083383 A1 WO 2021083383A1
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group
membered
alkyl
compound
cycloalkyl
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万惠新
查传涛
马金贵
沈竞康
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上海凌达生物医药有限公司
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Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a class of nitrogen-containing fused ring STING regulator compounds, preparation methods and uses.
  • Interferon gene stimulating protein is a transmembrane protein, usually in the 152-173 region (dimerization domain) to form a dimer and is in a state of self-inhibition. STING is an important component of the human innate immune system and the body's first line of defense against the invasion of external pathogens such as bacteria and viruses. It plays an important role in maintaining the body's homeostasis, resisting external infections, and preventing tumors and autoimmune diseases.
  • STING activators can be used as vaccine adjuvants or immune activators.
  • STING STING-related vascular disease
  • SAVI infantile-onset STING-related vascular disease
  • SLE systemic erythema Lupus
  • abnormal cGAS/STING activation can induce more common diseases, such as non-alcoholic steatohepatitis (NASH), chronic obstructive pulmonary disease (COPD), age-related macular degeneration (AMD) and Parkinson's Disease.
  • NASH non-alcoholic steatohepatitis
  • COPD chronic obstructive pulmonary disease
  • AMD age-related macular degeneration
  • Parkinson's Disease Parkinson's Disease.
  • Cyclic dinucleotide (CDN) compounds are the only agonists discovered so far that can directly activate both murine and human STING protein.
  • One of the technical problems to be solved by the present invention is to provide a novel STING protein regulator for preparing therapeutic drugs for tumors, immune diseases, antiviral and degenerative diseases.
  • R 1 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, 5-10 membered aryl Group or heteroaryl group, acyl group, sulfonyl group, sulfone group, sulfoxide group, etc.;
  • R 2 is selected from amino, amide, C1-C10 alkyl, 5-10 membered aryl or heteroaryl, C3-C6 cycloalkyl or heterocycloalkyl;
  • a 4- to 10-membered saturated or partially unsaturated ring system can be formed through carbon chains or heteroatoms; or any Ra on M6 and M7 can be combined with any group on R1
  • a 3-10 membered saturated or partially unsaturated ring system is formed through carbon chains or heteroatoms.
  • One or more hydrogen atoms on any of the above groups may be substituted by substituents selected from the following group: including but not limited to deuterium, halogen, C1-C8 alkyl; wherein, the heteroaryl includes 1- 3 heteroatoms selected from the group: N, O, P or S, the heterocycloalkyl group contains 1-3 heteroatoms selected from the group: N, O, P or S, the ring
  • the system includes a saturated or partially unsaturated ring system such as a spiro ring, a bridged ring, a condensed ring, and a fused ring.
  • the ring system may be further substituted with a C1-C6 alkyl group, a hydroxyl group, an amino group, a halogen, an alkoxy group, etc.
  • the compound of general formula (I) is preferably selected from the compound represented by the following general formula (II), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, or mutual Tautomers, solvates, polymorphs or prodrugs:
  • Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, Ra7 are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carbonyl, amide, ester, urea, sulfone, sulfoxide, sulfonyl , Sulfinyl group, sulfinimide group, C1-C6 alkyl group, C1-C6 alkoxy group, C2-C6 alkenyl group, C2-C6 alkynyl group, C3-C6 cycloalkyl group, C3 -C6 heterocycloalkyl, 5-10 membered aryl or heteroaryl; and any two adjacent Ra 1-7 can form a 4-10 membered saturation or part through a carbon chain or a heteroatom
  • An unsaturated ring system; or any one of Ra 1-7 can form a 3-10 membered saturated or partially unsaturated ring system with any group on R1 through a carbon chain or a heteroatom;
  • R1, R2 are
  • it is preferably a compound represented by the following general formula (III), or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, or solvent Compounds, polymorphs or prodrugs:
  • R2a, R2b, R2c, Ra4, Ra6, R1' are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carbonyl, amide, ester, urea, sulfone, and sulfoxide.
  • Ma8 is independently selected from NRa8, O, S(O)p, C(Ra8)q, wherein Ra8 is selected from hydrogen , Halogen, C1-C6 alkyl, p is selected from 0-2, q is selected from 1-2;
  • any one or more hydrogens on the above groups can be substituted by groups selected from the following group: -ORm, -NRmRn, -NRmCORn, -CO2Rm, -OCORm, -CONRmRn, -SO2NRmRn, -NRmSO2Rn, -SRm,- SORm, -SO2Rm, -OCONRmRn, -NRpCONRmRn;
  • Rm and Rn are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl hydroxy, C1-C6 alkyl alkoxy, C1 -C6 alkylamino or substituted amino, C1-C6 alkyl cyclic amino, C3-C6 cycloalkyl or heterocycloalkyl, 5-8 membered aryl or heteroaryl;
  • Rm and Rn, R2c and R2b can be respectively connected through carbon atoms or heteroatoms to form a 3-12 membered monocyclic or polycyclic alkyl group, a 3-12 membered monocyclic or polycyclic heterocycloalkyl group, and a 3-12 membered A spiro ring or fused ring alkyl group and a 3-12 membered spiro ring or fused ring heterocycloalkyl group;
  • R 1 , Ra 4 , and Ra 6 are as defined above.
  • the compounds of general formulae (I), (II), (III) and (IV), or pharmaceutically acceptable salts thereof, or enantiomers or diastereomers thereof A conformer, tautomer, solvate, polymorph or prodrug, characterized in that the compound includes but is not limited to the following structure:
  • a method for preparing the compound of general formula I characterized in that the method comprises steps a-c:
  • X is a leaving group such as halogen and sulfonate, and the other groups are as defined above.
  • the steps a), b), and c) are each performed in a solvent, and the solvent is selected from the group consisting of water, methanol, ethanol, isopropanol, butanol, ethylene glycol, and ethylene glycol.
  • Ether N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, toluene, methylene chloride, 1,2-dichloroethane, acetonitrile, N,N-dimethylformamide, N,N-dimethyl Acetamide, dioxane, or a combination thereof.
  • the inorganic base is selected from the group consisting of sodium hydride, potassium hydroxide, sodium acetate, potassium acetate, potassium tert-butoxide, sodium tert-butoxide, potassium fluoride, cesium fluoride, potassium phosphate, potassium carbonate, carbonic acid Potassium hydrogen, sodium carbonate, sodium hydrogen carbonate, or a combination thereof;
  • the organic base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] Undec-7-ene (DBU), lithium hexamethyldisilazide, sodium hexamethyldisilazide, lutidine, or a combination thereof.
  • Another object of the present invention is to provide a medicine and composition for treating or preventing tumors, viral infections, autoimmune diseases and degenerative diseases.
  • the technical solutions to achieve the above objectives are as follows:
  • a pharmaceutical composition for the treatment or prevention of the above-mentioned diseases which is composed of the nitrogen-containing heterocyclic compound represented by the above-mentioned general formula (I), or a pharmaceutically acceptable salt thereof, or an enantiomer or diastereomer thereof Isomers, tautomers, solvates, polymorphs or prodrugs and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide a use of the above-mentioned compound.
  • the nitrogen-containing heterocyclic compounds represented by the general formula (I), or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, tautomers, solvates, Polymorphs or prodrugs are used to prepare drugs for the treatment of STING protein-dependent diseases, especially for tumors, viral infections, immune diseases, and inflammatory diseases, and are a new class of therapeutic drugs with a new mechanism of action.
  • the tumors are each independently selected from: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia , Lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.
  • the immune diseases and inflammatory diseases are independently selected from the rejection of transplanted organs, gout, rhinitis, alopecia, Alzheimer's disease, appendicitis, atherosclerosis, asthma, arthritis, allergic dermatitis, shellfish Chett's disease, bullous skin disease, cholecystitis, chronic idiopathic thrombocytopenic purpura, chronic obstructive pulmonary disease, liver cirrhosis, degenerative joint disease, dermatitis, dermatomyositis, eczema, enteritis, encephalitis, Gastritis, nephritis, Hashimoto's thyroiditis, hepatitis, hypophysitis, inflammatory bowel disease, irritable bowel syndrome, Kawasaki disease, meningitis, multiple sclerosis, myocarditis, myasthenia gravis, mycosis fungoides, muscle Inflammation, nephritis, osteomyelitis, pan
  • the inventor prepared a class of compounds with a novel structure as shown in formula I, and found that it has better STING protein binding activity, and the compound is at a lower concentration (as low as ⁇ 1nmol /L), it can specifically bind to the STING protein, and can regulate the release of the STING pathway or inhibit downstream cytokines such as IFN- ⁇ , IL 6, TNF, etc., so it can be used to regulate the activity of the STNG pathway and treat related diseases Such as tumor, inflammation, antiviral, etc. Based on the above findings, the inventor completed the present invention.
  • the manufacturer's instructions for the use of the kit can be used, or the reaction and purification can be carried out in a manner known in the art or the instructions of the present invention.
  • the above-mentioned techniques and methods can be implemented according to the descriptions in a number of summary and more specific documents cited and discussed in this specification according to conventional methods well-known in the art.
  • groups and their substituents can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH2O- is equivalent to -OCH2-.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the simplified notation does not include the carbons that may be present in the substituents of the group.
  • halogen refers to fluorine, chlorine, bromine or iodine
  • hydroxyl refers to the -OH group
  • hydroxyalkyl refers to an alkane as defined below substituted by a hydroxyl (-OH)
  • nitro refers to -NO 2
  • cyano refers to -CN
  • amino refers to -NH 2
  • substituted amino Refers to an amino group substituted with one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, and heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylamido, aralkyl Alkylamino, heteroaralkylamino; "carboxy” refers to -COOH.
  • alkyl means only composed of carbon atoms and hydrogen atoms without unsaturation.
  • a bond a straight or branched hydrocarbon chain group having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl and decyl, etc.
  • alkenyl means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 One, more preferably 2 to 6) carbon atoms and a straight or branched hydrocarbon chain group connected to the rest of the molecule through a single bond, such as but not limited to vinyl, propenyl, allyl, but- 1-alkenyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl, etc.
  • alkynyl means consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, A straight or branched hydrocarbon chain group having 2 to 14 (preferably 2 to 10, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as but not limited to ethynyl , Prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, etc.
  • cycloalkyl means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting of only carbon atoms and hydrogen atoms, which may include condensed
  • the ring system, bridged ring system or spiro ring system has 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, and it is saturated or unsaturated and can be passed through any suitable
  • the carbon atom of is connected to the rest of the molecule by a single bond. Unless specifically indicated otherwise in this specification, the carbon atoms in the cycloalkyl group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H- Indenyl, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzene And cyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl , Fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl
  • heterocyclic group means a group consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Stable 3- to 20-membered non-aromatic cyclic group.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or more ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; in the heterocyclic group
  • the nitrogen, carbon, or sulfur atoms of may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom and through a single bond.
  • one or more rings may be aryl or heteroaryl groups as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the group is more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged ring or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]non Alkyl-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutanyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxopentyl, tetrahydroisoquinolinyl, decahydro
  • aryl means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms).
  • the aryl group can be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and can also be fused with the above-defined cycloalkyl or heterocyclic group, provided that the aryl group passes through The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to the above-defined alkyl group substituted by the above-defined aryl group.
  • heteroaryl means having 1 to 15 carbon atoms (preferably having 1 to 10 carbon atoms) and 1 to 6 selected from nitrogen in the ring A 5- to 16-membered conjugated ring system group of heteroatoms of, oxygen and sulfur.
  • heteroaryl groups can be monocyclic, bicyclic, tricyclic or more cyclic ring systems, and can also be fused with cycloalkyl or heterocyclic groups as defined above, provided that the hetero The aryl group is connected to the rest of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atoms in the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably contains 1 to 4 selected heteroatoms.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, naphthyl, naphthyridinyl, quinoxalinyl, pterridinyl, carbazolyl, carboline, phenanthridinyl, phenanthrolinyl, acridine Group, phena
  • heteroarylalkyl refers to the above-defined alkyl group substituted by the above-defined heteroaryl group.
  • optional or “optionally” means that the event or condition described later may or may not occur, and the description includes both occurrence and non-occurrence of the event or condition.
  • optionally substituted aryl group means that the aryl group is substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.
  • part refers to specific fragments or functional groups in a molecule.
  • the chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.
  • Steps refer to compounds that consist of the same atoms and are bonded by the same bonds, but have different three-dimensional structures.
  • the present invention will cover various stereoisomers and mixtures thereof.
  • the compound of the present invention contains an olefinic double bond, unless otherwise specified, the compound of the present invention is intended to include E- and Z-geometric isomers.
  • Tautomer refers to an isomer formed by transferring a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention will also be included in the scope of the present invention.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may contain one or more chiral carbon atoms, and therefore may produce enantiomers, diastereomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • racemates, diastereomers or enantiomers can be selected as raw materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic acid or an organic acid that can retain the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include, but are not limited to, formate, acetate, and 2,2-dichloroacetate , Trifluoroacetate, propionate, caproate, caprylate, caprate, undecylenate, glycolate, gluconate, lactate, sebacate, hexanoate Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , Cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate,
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include but are not limited to the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including natural substituted amines, cyclic amines and basic ion exchange resins , Such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethyl
  • Polymorphs refer to different solid crystal phases produced by the presence of two or more different molecular arrangements in certain compounds of the present invention in a solid state. Certain compounds of the present invention may exist in more than one crystal form, and the present invention is intended to include various crystal forms and mixtures thereof.
  • solvate refers to an aggregate comprising one or more molecules of the compound of the present invention and one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate.
  • the solvent may be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, etc., and corresponding solvated forms.
  • the compound of the present invention can form a real solvate, but in some cases, it can also retain only the indeterminate water or a mixture of water and a part of the indeterminate solvent.
  • the compound of the present invention can be reacted in a solvent or precipitated or crystallized from the solvent. Solvates of the compounds of the present invention are also included in the scope of the present invention.
  • the present invention also includes prodrugs of the above-mentioned compounds.
  • the term “prodrug” means a compound that can be converted into the biologically active compound of the invention under physiological conditions or through solvolysis. Therefore, the term “prodrug” refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention.
  • the prodrug When administered to an individual in need, the prodrug may not be active, but is converted into the active compound of the invention in the body.
  • the prodrug is usually rapidly transformed in the body to produce the parent compound of the present invention, for example, by hydrolysis in the blood.
  • Prodrug compounds generally provide advantages in solubility, tissue compatibility, or sustained release in mammalian organisms.
  • Prodrugs include known amino protecting groups and carboxyl protecting groups.
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for the delivery of a biologically active compound to a mammal (such as a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredients and then exert the biological activity.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention, and is relatively non-toxic, that is, the substance can be administered to an individual without causing undesirable biological activity. Reacts or interacts in an undesirable manner with any components included in the composition.
  • pharmaceutically acceptable carriers include, but are not limited to, any adjuvants, carriers, excipients, glidants, and sweeteners that are approved by relevant government regulatory agencies as acceptable for human or livestock use. , Diluents, preservatives, dyes/colorants, flavors, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the "tumor” and “disorders related to abnormal cell proliferation” in the present invention include, but are not limited to, leukemia, gastrointestinal stromal tumor, histocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, Lung adenocarcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, cervical cancer, ovarian cancer, bowel cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc. disease.
  • preventive include reducing the likelihood of the occurrence or exacerbation of a disease or condition in a patient.
  • treatment and other similar synonyms include the following meanings:
  • an effective amount refers to at least one agent or compound that is sufficient to relieve one or more symptoms of the disease or condition being treated after administration ⁇ The amount.
  • the result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired changes in the biological system.
  • the "effective amount” for treatment is the amount of the composition containing the compound disclosed herein that is required to provide significant disease relief clinically. Techniques such as dose escalation tests can be used to determine the effective amount suitable for any individual case.
  • administration refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral route, transduodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • Those skilled in the art are familiar with the application techniques that can be used for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceuticals (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
  • the compounds and compositions discussed herein are administered orally.
  • drug combination refers to drug treatments obtained by mixing or combining more than one active ingredient. It includes fixed and non-fixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • non-fixed combination refers to the simultaneous administration, combination or sequential administration of at least one compound described herein and at least one synergistic agent to a patient in the form of separate entities. These also apply to cocktail therapy, such as the administration of three or more active ingredients.
  • the functional group of the intermediate compound may need to be protected by an appropriate protecting group.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , Tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable sulfhydryl protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protective groups is detailed in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymer resin.
  • Step 1 Dissolve methyl 4-iodo-3-methoxybenzoate (3.2g, 11.0mmol) and 5-bromo-2-chloropyridine-4-amine (2.5g, 12.1mmol) in N, N -In dimethylformamide (DMF) (30mL), under the protection of nitrogen, add palladium acetate (747.6mg, 3.34mmol), cesium carbonate (14.5g, 44.5mmol) and 4,5-bis(diphenylphosphine) )-9,9-dimethylxanthene (Xantphos) (341.8mg, 0.59mmol), reacted overnight at 115°C.
  • DMF N, N -In dimethylformamide
  • Step 2 Dissolve 4-((5-bromo-2-chloropyridin-4-yl)amino)-3-methoxybenzoic acid methyl ester (365mg, 0.99mmol) in DMF (10mL) under nitrogen protection , Sodium acetate (533.1 mg, 6.50 mmol) and bis(triphenylphosphine) palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 ) (140.4 mg, 0.20 mmol) were added, and reacted overnight at 125°C.
  • the third step Combine 3-chloro-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester (500mg, 1.72mmol) and 1,3-dimethyl- 5-pyrazole pinacol borate (453.3mg, 2.04mmol) dissolved in dioxane and water (20mL/4mL), add sodium carbonate (720.8mg, 6.8mmol) and tetratriphenylphosphine under nitrogen protection Palladium (Pd(PPh 3 ) 4 ) (196.5 mg, 0.17 mmol) was reacted at 90 degrees overnight.
  • Step 1 Dissolve methyl 3-hydroxy-4-iodobenzoate (9.3g, 33.5mmol) and 3-morpholinopropyl methanesulfonate (15.0g, 67.3mmol) in DMF (100mL), add carbonic acid Potassium (13.8g, 100.0mmol), react at room temperature overnight. After eluting with ethyl acetate, the filtrate and washing liquid were concentrated under reduced pressure, and purified by column chromatography to obtain methyl 4-iodo-3-(3-morpholinopropoxy)benzoate (12.3 g, white solid).
  • Step 2 Combine methyl 4-iodo-3-(3-morpholinopropoxy)benzoate (12.3g, 30.4mmol) and 5-bromo-2-chloropyridine-4-amine (6.9g, 33.5mmol) ) was dissolved in DMF (150 mL), and under the protection of nitrogen, palladium acetate (680.5 mg, 3.04 mmol), cesium carbonate (29.6 g, 90.8 mmol) and Xantphos (1.75 g, 3.04 mmol) were added and reacted at 100°C overnight.
  • Step 3 Dissolve methyl 4-((5-bromo-2-chloropyridin-4-yl)amino)-3-(3-morpholinopropoxy)benzoate (12.0g, 24.84mmol) in DMF (100 mL), under the protection of nitrogen, add sodium acetate (8.15 g, 99.36 mmol) and Pd(PPh 3 ) 2 Cl 2 (1.74 g, 2.48 mmol), and react overnight at 120°C.
  • the fourth step Combine 3-chloro-6-(3-morpholinepropoxy)-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester (220mg, 0.55mmol) and 1, 3-Dimethyl-5-pyrazole pinacol borate (169.7mg, 0.76mmol) was dissolved in dioxane and water (20mL/4mL), and sodium carbonate (233.8mg, 2.2mmol) was added under nitrogen protection React with Pd(PPh 3 ) 4 (63.6 mg, 0.055 mmol) at 100°C overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain Intermediate A3 (120 mg, white solid).
  • Step 1 Dissolve methyl 4-amino-3-methoxybenzoate (6.0g, 33.15mmol) and 2,4-dichloro-5-iodopyrimidine (11.8g, 43.10mmol) in 2-pentanol (100mL), add N,N-diisopropylethylamine (DIEA) (12.8g, 99.22mmol), and react overnight at 130°C.
  • DIEA N,N-diisopropylethylamine
  • the reaction solution was cooled to room temperature, filtered, and the solid was slurried and purified with methanol to obtain methyl 4-((2-chloro-5-iodopyrimidin-4-yl)amino)-3-methoxybenzoate (9.4g, white solid) .
  • LC-MS m/z 420.0/422.0 [M+H] + .
  • Step 2 Dissolve 4-((2-chloro-5-iodopyrimidin-4-yl)amino)-3-methoxybenzoic acid methyl ester (9.4g, 22.4mmol) in DMF (100mL) and protect with nitrogen Next, sodium acetate (7.4 g, 90.2 mmol) and bis(triphenylphosphine) palladium(II) chloride (Pd(PPh 3 ) 2 Cl 2 ) (1.57 g, 2.24 mmol) were added, and reacted overnight at 120°C.
  • the third step Combine 2-chloro-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxylic acid methyl ester (200mg, 0.69mmol) and 1,3-dimethyl- 5-pyrazole pinacol borate (233.3mg, 1.05mmol) dissolved in dioxane and water (20mL/4mL), add sodium carbonate (300.8mg, 2.84mmol) and Pd(PPh 3 ) under nitrogen protection 4 (196.5mg, 0.17mmol), react at 100°C overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain Intermediate B1 (160 mg, white solid).
  • the first step Dissolve methyl 4-amino-3-hydroxybenzoate (80mg, 0.48mmol) and 3-morpholinoprop-1-ol (73mg, 0.50mmol) in tetrahydrofuran (THF) (25mL), add Diisopropyl azodicarboxylate (DIAD) (194 mg, 0.96 mmol) and triphenylphosphine (PPh 3 ) (180 mg, 0.70 mmol) were reacted overnight at room temperature. The reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain methyl 4-amino-3-(3-morpholinopropoxy)benzoate (70 mg, white solid). LC-MS: m/z 295.2 [M+H] + .
  • DIAD Diisopropyl azodicarboxylate
  • PPh 3 triphenylphosphine
  • the first step Dissolve methyl 3-hydroxy-4-nitrobenzoate (33.0g, 167.5mmol) in DMF (300mL), add potassium carbonate (69.4g, 502.5mmol), reduce the temperature to zero, slowly Add p-methoxybenzyl chloride (PMB-Cl) (31.5g, 201.0mmol) dropwise, react at 80°C for 1h. LC-MS showed that the reaction was complete.
  • PMB-Cl p-methoxybenzyl chloride
  • Step 2 Dissolve the yellow solid (2.0g, 6.3mmol) of the previous step in methanol and water (20mL/2mL), add iron powder (1.76g, 31.5mmol) and ammonium chloride (1.70g, 31.5mmol), React at 75 degrees overnight.
  • LC-MS showed that the reaction was complete. After filtering through diatomaceous earth twice, it was spin-dried to obtain a white solid, which was slurried with water (20mL) to obtain methyl 4-amino-3-((4-methoxybenzyl)oxo)benzyl Ester (white solid, 1.6 g).
  • Step 3 Dissolve the white solid compound of the previous step (3.0g, 10.2mmol), 2,4-dichloro-5-iodopyrimidine (5.58g, 20.4mmol) in 2-pentanol (10mL), and then add DIEA (5.22g, 40.8mmol), reacted overnight at 130°C. After filtration, the solid was slurried with methanol to obtain methyl 4-((2-chloro-5-iodopyrimidin-4-yl)amino)-3-((4-methoxybenzyl)oxo)benzoate ( 3.5g).
  • Step 4 Dissolve the compound (2.0g, 3.8mmol) obtained in the previous step in DMF (30mL), add sodium acetate (2.06g, 15.2mmol), and then add PdCl 2 (PPh 3 ) 2 Cl 2 (266mg, 0.38) mmol), under the protection of nitrogen, react at 120°C overnight. Add water (60mL) and ethyl acetate (60mL), column chromatography to obtain methyl 2-chloro-8-((4-methoxybenzyl)oxo)-9H-pyrimido[4,5-b ]Indole-6-carboxylate (1.3g) LC-MS[M+H]+: m/z 398.4.
  • the first step the 4-amino-3-iodo-5-methoxybenzoic acid methyl ester (1.0g, 3.3mmol) and (2,6-dichloropyridin-3-yl)boronic acid (1.26g, 6.6mmol) ) was added to DMF (50mL), under the protection of nitrogen, added palladium acetate (Pd(OAc) 2 ) (74mg, 0.33mmol), triphenylphosphine (PPh 3 ) (86mg, 0.33mmol) and triethylamine (TEA) ) (1.0g, 9.9mmol), heat to 85 degrees and react for 5 hours.
  • Pd(OAc) 2 palladium acetate
  • PPh 3 triphenylphosphine
  • TAA triethylamine
  • Step 2 Dissolve methyl 4-amino-3-(2,6-dichloropyridin-3-yl)-5-methoxybenzoate (420mg, 1.29mmol) in DMF (20mL), add 18- Crown-6 (680mg, 2.57mmol) and sodium hydride (NaH) (60% in mineral oil, 206mg, 5.15mmol), under the protection of nitrogen, heated to 100°C for 2h.
  • reaction solution was cooled to room temperature, quenched with water (50 mL), extracted three times with ethyl acetate (50 mL), combined the organic phases, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 2-chloro-8-methoxy-9H -Pyrido[2,3-b]indole-6-carboxylic acid methyl ester (142 mg, white solid).
  • the third step Combine 2-chloro-8-methoxy-9H-pyrido[2,3-b]indole-6-carboxylic acid methyl ester (273mg, 0.94mmol) and 1,3-dimethyl- 5-Pyrazole pinacol borate (278mg, 1.18mmol) was dissolved in dioxane and water (30mL/5mL), and sodium carbonate (398mg, 3.75mmol) and tetrakis(triphenylphosphine) were added under nitrogen protection ) Palladium (Pd(PPh 3 ) 4 ) (100 mg, 0.09 mmol), react at 85°C overnight.
  • Step 1 Dissolve compound (E)-2-(4-bromobut-2-en-1-yl)isoindoline-1,3-dione (17g, 60.93mmol) in DMF (200ml) Then added potassium acetate (11.9g, 121.86mmol), protected by nitrogen, added to 80°C, reacted for 16h, cooled to room temperature, poured into 600mL water, and then extracted with ethyl acetate (200mL*2), the organic layer was saturated with Washed with ammonium chloride (500mL), saturated brine (500mL), dried, and passed through the column to obtain (E)-4-(1,3-dioxoisoindolin-2-yl)but-2-ene- 1-yl acetate (white solid, 13.6 g).
  • Step 2 Dissolve the product from the previous step (13.6g, 52.5mmol) in methanol (1.3L), then add sodium methoxide (0.28g, 5.25mmol), stir at room temperature for 16h, then add 14mL 1N HCl to quench, spin dry After passing through the column, (E)-2-(4-hydroxybut-2-en-1-yl)isoindoline-1,3-dione (white solid, 10.6g) was obtained.
  • 1 H-NMR 400MHz, DMSO-d 6 ): ⁇ 8.29-7.61(m,4H), 5.66(q,2H), 4.71(t,1H), 4.30-4.00(m,2H), 3.89(dd ,2H).
  • Step 3 Dissolve the product from the previous step (10.6g, 48.85mmol) in dichloromethane (150mL), then add imidazole (6.65g, 97.7mmol) and N,N-dimethylaminopyridine (DMAP) (1.2 g,9.77mmol), stir for 5min, add tert-butyldiphenylchlorosilane (14mL, 53.37mmol) at room temperature, add 200mL of water, stir for 4h, separate the layers, dry the organic layer, spin dry, and pass the column to obtain (E)-2-(4-((tert-butyldiphenylsilyl)oxy)but-2-en-1-yl)isoindoline-1,3-dione (white solid, 21 g).
  • imidazole 6.65g, 97.7mmol
  • DMAP N,N-dimethylaminopyridine
  • Step 4 Dissolve the product from the previous step (21g, 46.15mmol) in ethanol (500mL), add hydrazine hydrate (content 80%, 5.3ml, 184.6mmol), reflux for 16h, cool, filter, and spin-dry the filtrate. Water (200 mL) and ethyl acetate (200 mL) were added, and the layers were separated. The organic layer was washed with water, dried, and spin-dried to obtain (E)-4-((tert-butyldiphenylsilyl)oxy)butan-2- En-1-amino (colorless transparent liquid, 15g).
  • Step 5 Dissolve the product from the previous step (3.5g, 16.4mmol) and methyl 6-chloro-5-nitronicotinic acid ester (5.9g, 18.03 mmol) in dioxane (60mL) and keep at room temperature DIEA (8.1mL, 49.2mmol) was added, stirred at room temperature for 3h, the reaction solution was poured into water (200mL), and extracted with ethyl acetate (300mL), the organic layer was washed with saturated brine, dried, spin-dried, and passed through the column to obtain Methyl (E)-6-((4-((tert-butyldiphenylsilyl)oxy)but-2-en-1-yl)amino)-5-nitronicotinate (yellow solid, 6.3 g).
  • Step 6 Dissolve the product from the previous step (1.5g, 0.97mmol) in methanol/tetrahydrofuran/water (25mL/25mL/25mL), add ammonium chloride (1.6g, 29.7mmol) and add zinc powder (1.93g, 29.7mmol), stirred at room temperature for 3h, filtered, the filtrate was poured into water, extracted with ethyl acetate, and then the organic layer was washed with saturated brine, dried, and spin-dried to obtain methyl (E)-5-amino-6-(( 4-((tert-butyldiphenylsilyl)oxy)but-2-en-1-yl)amino)nicotinate (red-brown sticky substance, 1.4g).
  • Step 7 Dissolve the product from the previous step (200mg, 0.42mmol) in dichloromethane/anhydrous methanol (3mL/3mL), add cyanogen bromide (108mg, 1.0mmol) at room temperature, and then stir at room temperature for 16h. Saturated sodium bicarbonate solution (50 mL) was added to the reaction solution, stirred for 1 h, and extracted with dichloromethane (50 mL).
  • Step 1 Dissolve intermediate A1 (190mg, 0.54mmol) and (E)-1,4-dibromobut-2-ene (58.3mg, 0.27mmol) in DMF (10mL), add cesium carbonate (531.5mg) , 1.62mmol) and sodium iodide (162mg, 1.08mmol), react overnight at room temperature.
  • reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 5,5'-(butyl-2-ene-1,4-diyl)(E)-bis(3-(1,3-dimethyl-1H- Pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester) (75 mg, white solid).
  • LC-MS m/z 753.4 [M+H] + .
  • Step 2 Add 5,5'-(butyl-2-ene-1,4-diyl)(E)-bis(3-(1,3-dimethyl-1H-pyrazol-5-yl) )-6-Methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester) (75mg, 0.10mmol) was dissolved in methanol (10mL), and 2N sodium hydroxide (NaOH) was added (5mL), react at 100°C overnight.
  • NaOH sodium hydroxide
  • the third step 5,5'-(butyl-2-ene-1,4-diyl)(E)-bis(3-(1,3-dimethyl-1H-pyrazol-5-yl) )-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid) (30mg, 0.04mmol) was dissolved in DMF (15mL), and ammonium chloride (NH 4 Cl) was added ( 23mg, 0.4mmol), DIEA (51.6mg, 0.4mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU) (30.4mg, 0.08mmol).
  • NH 4 Cl ammonium chloride
  • DIEA 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • Example 2 During the preparation of Example 1, the target compound was simultaneously separated due to side reactions.
  • LC-MS m/z 751.2 [M+H] + .
  • Example 2 During the preparation of Example 1, the target compound was simultaneously separated due to side reactions.
  • LC-MS m/z 779.2 [M+H] + .
  • LC-MS m/z 351.1 [M+H] + .
  • Step 2 Add 3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8- Carboxylic acid (288mg, 0.82mmol) was dissolved in DMF (6mL), ammonium chloride (NH 4 Cl) (440mg, 8.2mmol), DIEA (529mg, 4.1mmol) and HATU (935mg, 2.46mmol) were added and stirred at room temperature for 2 hour. The reaction solution was added with water (30mL), and extracted with ethyl acetate (15mL) for 6 times. The organic phases were combined and concentrated to about 3mL. A solid precipitated out.
  • NH 4 Cl ammonium chloride
  • DIEA 529mg, 4.1mmol
  • HATU 935mg, 2.46mmol
  • the third step Add 3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8- Amide (50mg, 0.14mmol) and (E)-1,4-dibromobut-2-ene (15mg, 0.071mmol) were dissolved in DMF (8mL), cesium carbonate (93mg, 0.29mmol) and sodium iodide ( 24mg, 0.16mmol), stirred at room temperature for 3 hours.
  • Step 1 Dissolve intermediate A1 (190mg, 0.54mmol) and (Z)-1,4-dichlorobut-2-ene (58.3mg, 0.27mmol) in DMF (10mL), add cesium carbonate (531.5mg) , 1.62mmol) and sodium iodide (162mg, 1.08mmol), react overnight at room temperature.
  • reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain 5,5'-(butyl-2-ene-1,4-diyl)(Z)-bis(3-(1,3-dimethyl-1H- Pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester) (75 mg, white solid).
  • LC-MS m/z 753.2 [M+H] + .
  • Step 2 Add 5,5'-(butyl-2-ene-1,4-diyl)(Z)-bis(3-(1,3-dimethyl-1H-pyrazol-5-yl) )-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester) (75mg, 0.10mmol) was dissolved in methanol (10mL), 2N NaOH (5mL) was added, 100 Reaction overnight.
  • the third step 5,5'-(butyl-2-ene-1,4-diyl)(Z)-bis(3-(1,3-dimethyl-1H-pyrazol-5-yl) )-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid) (30mg, 0.04mmol) was dissolved in DMF (15mL), and NH 4 Cl (23mg, 0.4mmol) was added , DIEA (51.6 mg, 0.4 mmol) and HATU (30.4 mg, 0.08 mmol). React overnight at room temperature.
  • Step 1 Dissolve Intermediate A1 (500mg, 1.43mmol) in methanol (20mL), add 2N NaOH (5mL), and react at 100°C overnight.
  • LC-MS m/z 337.1 [M+H] + .
  • Step 2 Add 3-(1,3-dimethyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8-carboxylic acid (430 mg, 1.28 mmol) was dissolved in DMF (25 mL), and NH 4 Cl (728 mg, 13.7 mmol), DIEA (1.6 g, 12.4 mmol) and HATU (728.4 mg, 1.92 mmol) were added. React overnight at room temperature.
  • the third step the 3-(1,3-dimethyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8-amide ( 40mg, 0.12mmol) and 1,4-dibromobutane (12.8mg, 0.06mmol) were dissolved in DMF (10mL), cesium carbonate (118mg, 0.36mmol) and sodium iodide (60mg, 0.40mmol) were added and reacted at room temperature overnight.
  • LC-MS m/z 338.3 [M+H] + .
  • the second step the 2-(1,3-dimethyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b]indole-6-carboxylic acid (120 mg, 0.36 mmol) was dissolved in DMF (15 mL), and NH 4 Cl (199 mg, 3.8 mmol), DIEA (140 mg, 1.08 mmol) and HATU (410.4 mg, 1.08 mmol) were added. React at room temperature for 2 hours.
  • the third step the 2-(1,3-dimethyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimidino[4,5-b]indole-6-amide ( 60mg, 0.18mmol) and (E)-1,4-dibromobut-2-ene (19.3mg, 0.09mmol) were dissolved in DMF (10mL), cesium carbonate (120mg, 037mmol) and sodium iodide (60mg, 0.40mmol), react at room temperature for 1 hour.
  • Example 12 (E)-5-(4-(8-carbamoyl-3-(1,3-dimethyl-1H-pyrazol-5-yl)-6-(3-morpholine propoxy) Yl)-5H-pyridine[4,3-b]indol-5-yl)butyl-2-en-1-yl)-3-(1,3-dimethyl-1H-pyrazole-5- Yl)-6-methoxy-5H-pyridine[4,3-b]indole-8-amide
  • the third step (E)-3-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(4-(3-(1,3-dimethyl-1H-pyridine) (Azol-5-yl)-6-methoxy-8-(methoxycarbonyl)-5H-pyrido[4,3-b]indol-5-yl)butyl-2-en-1-yl) -6-(3-Morpholinepropoxy)-5H-pyrido[4,3-b]indole-8-carboxylic acid methyl ester (120mg, 0.14mmol) was dissolved in methanol (10mL), and 2N NaOH( 5mL), react at 100°C overnight.
  • Example 13 (E)-5-(4-(8-carbamoyl-3-(1,3-dimethyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyridine [4,3-b]Indol-5-yl)butyl-2-en-1-yl)-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6 -Methoxy-5H-pyridine[4,3-b]indole-8-amide
  • the first step the 3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyrido[4,3-b]indole-8- Amide (100mg, 0.29mmol) and (E)-1,4-dibromobut-2-ene (318mg, 1.5mmol) were dissolved in DMF (20mL), cesium carbonate (391mg, 1.2mmol) and sodium iodide ( 50mg, 0.3mmol), stirred at room temperature for 1 hour. The reaction solution was separated by adding water (40 mL) and ethyl acetate (40 mL).
  • Step 2 Add (E)-9-(4-bromobutyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)- 8-Methoxy-9H-pyrido[2,3-b]indole-6-amide (50mg, 0.1mmol) and 3-(1,3-dimethyl-1H-pyrazol-5-yl) -6-Methoxy-5H-pyrido[4,3-b]indole-8-amide (34mg, 0.1mmol) was dissolved in DMF (20mL), cesium carbonate (131mg, 0.4mmol) and sodium iodide were added (16mg, 0.1mmol), stirred at room temperature for 1 hour.
  • Example 12 Using intermediates A and B as raw materials, referring to the synthesis methods of Example 12 and Example 13, the following example compounds were prepared.
  • Example 21 (S)-3-(3-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholine Propoxy)-9H-pyrimido[4,5-b]indol-9-yl)propyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) -3,4-Dihydro-5-oxa-1,2a-acenaphthylene-7-amide
  • Example 25 (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy Yl)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-8-(3-(difluoromethoxy)propoxy)-2- (1-Ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • the first step The compound 3-((4-methoxybenzyl)oxo)propyl-1-ol (1.0g, 5.10mmol) was dissolved in acetonitrile (40mL), and CuI (193.8mg, 1.02 mmol), the temperature was raised to 70°C and 2,2-difluoro-2-(fluorosulfonyl fluoride)acetic acid (1.81g, 10.2mmol) was slowly added, and the reaction was carried out at room temperature for 2 hours.
  • Step 2 Dissolve the crude product of the previous step (10 mg, 0.04 mmol) in methanol (MeOH) (5 mL), add palladium on carbon (2 mg), and react under hydrogen at room temperature overnight.
  • the oily product 3-(difluoromethoxy)propyl-1-ol (4.0 mg) was obtained by filtration and separation.
  • Step 3 Dissolve the crude product of the previous step (4mg, 0.03mmol) in DCM (10mL), then add TEA (9.1mg, 0.09mmol), cool to 0°C and slowly add methylsulfonyl chloride (5.2mg, 0.045mmol) , React at room temperature for 2 hours. It was washed 3 times with saturated sodium carbonate (10 mL) and spin-dried to obtain crude oily 3-(difluoromethoxy)propyl methanesulfonate (4 mg), which was directly used in the next reaction.
  • TEA 9.1mg, 0.09mmol
  • methylsulfonyl chloride 5.2mg, 0.045mmol
  • the fourth step The crude product of the previous step (5mg, 0.006mmol) and (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl) )-8-(3-morpholinopropoxy)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl- 3-Methyl-1H-pyrazol-5-yl)-8-hydroxy-pyrimidine[4,5-b]indole-6-carboxamide (2.5mg, 0.012mmol) dissolved in DMF (5mL), add carbonic acid Cesium (5.9 mg, 0.018 mmol) was reacted at room temperature overnight, extracted with dichloromethane, washed with saturated sodium bicarbonate solution and water, and concentrated to prepare and isolate Example Compound 25 (white solid, 0.6 mg). LC-MS [M+H] + : m/z 960.4.
  • Example 26 (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy Yl)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-8-(3-(4,4-difluoropiperidin-1-yl) Propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • Example 26 (white solid, 6.3 mg) was prepared in the same manner as in Example 25.
  • Example 27 (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy Yl)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-8-(3-(3,3-difluoroazetidine-1 -Yl)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • Example 27 (white solid, 5.5 mg) was prepared in the same manner as in Example 25.
  • Example 28 (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy Yl)-9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole- 5-yl)-8-(3-morpholinopropoxy)-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • the first step the compound 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6 -Formamide (100mg, 0.3mmol) and (E)-1,4-dibromobutyl-2-ene (190.0mg, 0.9mmol) were dissolved in DMF (25mL), cesium carbonate (200mg, 0.6mmol) was added, React at room temperature for 1h.
  • Step 2 Combine the crude product from the previous step (75mg, 0.16mmol) and 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy)- 9H-pyrimidine[4,5-b]indole-6-carboxamide (74 mg, 0.16 mmol) was dissolved in DMF (5 mL), cesium carbonate (104.3 mg, 0.32 mmol) was added, and the reaction was carried out at room temperature overnight.
  • Step 3 Dissolve the crude product of the previous step (20mg, 0.02mmol) in DCM (10mL), add boron tribromide (BBr 3 ) (5mL), and react at 50°C overnight. Quench with methanol and spin dry to obtain crude product (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-hydroxy -9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Yl)-8-(3-morpholinopropoxy)-9H-pyrimidine[4,5-b]indole-6-carboxamide (20 mg). LC-MS [M+H] + : m/z 851.4.
  • Step 4 Dissolve the compound from the previous step (20mg, 0.023mmol) and 3-morpholinopropyl-1-ol (13.29mg, 0.046mmol) in DMF (5mL), add cesium carbonate (22.49mg, 0.069mmol), React overnight at room temperature. Dichloromethane extraction, saturated sodium bicarbonate solution and water washing, concentration, preparation and isolation to obtain Example 28 (white solid, 3.7mg). LC-MS [M+H] + : m/z 978.5.
  • Example 29 (E)-9-(4-(6-amide-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyridine And [2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8 -(3-morpholinopropoxy)-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • the first step the 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b]indole-6- Formamide (50mg, 0.14mmol) and (E)-1,4-dibromobutyl-2-ene (148.4mg, 0.7mmol) were dissolved in DMF (20mL), cesium carbonate (136.9mg, 0.42mmol) was added, React at room temperature for 1h.
  • the second step the compound (20mg, 0.045mmol) obtained in the previous step and 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy )-9H-pyrimidine[4,5-b]indole-6-carboxamide (19 mg, 0.041 mmol) was dissolved in DMF (20 mL), cesium carbonate (58.7 mg, 0.18 mmol) was added, and the reaction was carried out at room temperature for 1 h. Extracted with dichloromethane, washed with saturated sodium bicarbonate solution and water, concentrated, prepared and isolated the compound of Example 29 (white solid, 35.3 mg). LC-MS [M+H] + : m/z 865.5.
  • Example 30 (E)-9-(4-(8-amide-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-(3-morpholinopropoxy) Yl)-5H-pyrido[4,3-b]indol-5-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole- 5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • the first step the 2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-methyl Amide (50 mg, 0.14 mmol) and A (148.4 mg, 0.7 mmol) were dissolved in DMF (20 mL), cesium carbonate (136.9 mg, 0.42 mmol) was added, and the reaction was carried out at room temperature for 1 h.
  • Step 2 Combine the gray solid of the previous step (40mg, 0.09mmol) with 3-(1-ethyl-3-methyl-1H-pyrazole-5-)-6-(3-morpholinopropoxy)- 5H-pyrido[4,3-b]indole-8-carboxamide (38 mg, 0.81 mmol) was dissolved in DMF (20 mL), cesium carbonate (117.4 mg, 0.36 mmol) was added, and the reaction was carried out at room temperature for 1 h. Extracted with dichloromethane, washed with saturated sodium bicarbonate solution and water, concentrated, prepared and isolated Example 30 (white solid, 35.3 mg). LC-MS [M+H] + : m/z 865.5.
  • Example 31 (72 mg, 0.08 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (TFA) (5 mL) was added, and the reaction was heated at 50°C overnight. It was spin-dried, slurried with methanol (10 mL) and filtered to obtain Example 32 (white solid, 42 mg).
  • TFA-d6 trifluoroacetic acid
  • Example 33 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-((4-methyl (Oxybenzyl)oxo)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl- 1H-pyrazol-5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • LC-MS[M+H] + m/z 739.5.
  • Example 35 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxy Propyloxy)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-ene-1-ene)-2-(1-ethyl-3-methyl-1H-pyridine (Azol-5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • Example compound 34 (25.0mg, 0.03mmol) and brominated material (9.3mg, 0.06mmol) were dissolved in DMF (10mL), cesium carbonate (29.1mg, 0.09mmol) was added, and the reaction was carried out at room temperature overnight. Preparative chromatographic separation was achieved.
  • Example 35 (white solid, 2.4 mg). LC-MS[M+H] + : m/z 811.6.
  • Example 36 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-((4-( (Trifluoromethyl)benzyl)oxo)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3- Methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • Example compound 34 (25.0mg, 0.03mmol) and p-trifluoromethylbenzyl chloride (11.6mg, 0.06mmol) were dissolved in DMF (10mL), cesium carbonate (29.3mg, 0.09mmol) was added, and reacted overnight at room temperature to prepare Chromatographic separation gave Example Compound 36 (white solid, 17.1 mg).
  • LC-MS [M+H] + m/z 897.5.
  • Example compound 32 (30.0mg, 0.04mmol) and p-trifluoromethylbenzyl chloride (23.3mg, 0.12mmol) were dissolved in DMF (10mL), cesium carbonate (39.1mg, 0.12mmol) was added and reacted overnight at room temperature to prepare Chromatographic separation gave Example 37 (white solid, 19.8 mg).
  • Example compound 32 (30.0mg, 0.04mmol) and brominated material (18.2mg, 0.12mmol) were dissolved in DMF (10mL), cesium carbonate (39.1mg, 0.12mmol) was added, and the reaction was carried out at room temperature overnight. Preparative chromatographic separation was carried out. Example 38 (white solid, 20.2mg). LC-MS[M+H] + : m/z 869.6.
  • Example 39 (white solid, 12.0 mg) was synthesized.
  • LC-MS [M+H] + m/z 993.7.
  • Example 40 (E)-8-(2-(benzyloxy)ethoxy)-9-(4-(6-acyl-2-(1-ethyl-3-methyl-1H-pyrazole) -5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3- Methyl-1H-pyrazol-5-yl)-9H-pyrimidine[4,5-b]indole-6-amide
  • Example 40 (white solid, 13.3 mg) was synthesized. LC-MS [M+H] + : m/z 873.5.
  • the first step the compound of Example 39 (10.0 mg, 0.01 mmol) was dissolved in TFA (10 mL), and reacted at 90 degrees overnight. LC-MS detected that the reaction was complete, and the crude product (10.0 mg) was obtained by rotary drying and proceed to the next step. LC-MS [M+H] + : m/z 1005.5.
  • Step 2 Dissolve the crude compound (10.0 mg, 0.01 mmol) of the previous step in MeOH/H 2 O (10 mL/1 mL), add potassium carbonate (4.2 mg, 0.03 mmol), and react at room temperature for 4 hours.
  • LCMS detected that the reaction was complete, and preparative chromatography was separated and purified to obtain Example 41 (white solid, 1.5 mg).
  • Example 42 (E)-9-(4-(6-acyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(2-hydroxyethoxy) )-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-amide
  • Example 40 was used as a raw material, and Example 42 (white solid, 2.5 mg) was synthesized by referring to the method of Example 41.
  • Example 43 (E)-9-(4-(6-acyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy Yl)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-8-(3-(diethylamino)propoxy)-2-( 1-Ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrimidine[4,5-b]indole-6-amide
  • Example 43 (white solid, 6.1 mg) was prepared in the same manner as in Example 25.
  • Example 44 (white solid, 2.2 mg) was prepared in the same manner as in Example 25.
  • Example 45 (E)-9-(4-(6-acyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholinopropoxy Yl)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-8-(cyclopropylmethoxy)-2-(1-ethyl- 3-Methyl-1H-pyrazol-5-yl)-9H-pyrimidine[4,5-b]indole-6-amide
  • Example 45 (white solid, 12.0 mg) was prepared in the same manner as in Example 25.
  • LC-MS [M+H] + m/z 906.6.
  • Example 46 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropyl) Oxy)-9H-pyridyl[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole -5-yl)-8-(3-morpholinopropoxy)-9H-pyrimidinyl[4,5-b]indole-6-amide
  • Example 46 (white solid, 19.1 mg) was prepared in the same manner as in Example 25. LC-MS[M+H] + : m/z 909.4. 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 9.83 (s, 1H), 9.72 (s, 1H), 8.50-8.55 (d, 1H ), 8.46 (s, 1H), 8.40 (s, 1H), 8.04-8.08 (m, 2H), 7.61-7.63 (d, 1H), 7.53-7.57 (m, 2H), 7.38-7.46 (m, 2H) ), 6.76 (s, 1H), 6.61 (s, 1H), 5.66 (s, 2H), 5.18-5.23 (m, 4H), 4.52-4.53 (m, 2H), 4.25-4.29 (m, 2H), 3.98-4.07 (m, 8H), 3.58-3.61 (m, 2H), 3.40-3.43 (m, 2H), 2.94-3.17 (m, 4H), 2.51-2.86
  • Example 47 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropyl) Oxy)-9H-pyridyl[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole -5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-amide
  • Example 47 (white solid, 17.5 mg) LC-MS [M+H] + : m/z 796.4.
  • 1 H NMR 400MHz, DMSO-d 6 ): ⁇ 9.47( s,1H),8.51(d,1H),8.42(s,1H),8.37(s,1H),8.01-8.08(m,2H),7.53-7.59(m,3H),7.33-7.42(m, 2H), 6.73 (s, 1H), 6.58 (s, 1H), 5.68-5.87 (m, 2H), 5.18-5.27 (m, 4H), 4.43-4.48 (m, 2H), 4.24-4.29 (m, 2H),4.07-4.10(m,2H),3.98(s,3H),3.45-3.48(m,2H),2.18(s,6H),1.64-1.77(m,2H),1.04-1.12(m, 6H).
  • Example 48 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-methoxy Propoxy)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridine (Azol-5-yl)-8-(3-morpholinopropoxy)-9H-pyrimidinyl[4,5-b]indole-6-carboxamide
  • Example 48 The white solid (44.1mg) of Example 48 was prepared in the same manner as in Example 25. LC-MS [M+H] + : m/z 924.8. 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 9.50 ( d, 2H), 8.47 (d, 2H), 8.44 (d, 2H), 8.08 (d, 2H), 7.56 (d, 2H), 6.76 (d, 2H), 5.62-5.69 (m, 2H), 5.18 -5.19 (m, 4H), 4.52-4.61 (m, 4H), 3.87-4.01 (m, 8H), 3.38-3.41 (m, 4H), 3.17-3.22 (m, 5H), 2.89-2.92 (m, 2H), 2.20 (d, 6H), 1.59-1.61 (m, 2H), 1.22-1.25 (m, 2H), 1.19-1.21 (m, 6H).
  • Example 49 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(2-hydroxyethyl) Oxy)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole- 5-yl)-8-(3-morpholinopropoxy)-9H-pyrimidinyl[4,5-b]indole-6-carboxamide
  • the white solid (30.1mg) of Example 49 was prepared in the same manner as in Example 25.
  • Example 50 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholine) Propoxy)-9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridine (Azol-5-yl)-8-methoxy-9H-pyrimid[4,5-b]indole-6-carboxamide
  • Example 50 (white solid, 6.2 mg) was prepared in the same manner as in Example 25. LC-MS [M+H] + : m/z 865.2.
  • Example 51 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-morpholine) Propoxy)-9H-pyrido[2,3-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridine (Azol-5-yl)-8-(3-hydroxypropoxy)-9H-pyrimido[4,5-b]indole-6-carboxamide
  • Example 51 (white solid, 5.6 mg) was prepared in the same manner as in Example 25. LC-MS [M+H] + : m/z 909.3.
  • Example 52 (E)-9-(4-(8-carbamoyl-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-(3-hydroxypropyl) Oxy)-5H-pyridyl[4,3-b]indol-5-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole -5-yl)-8-(3-morpholinopropoxy)-9H-pyrimidinyl[4,5-b]indole-6-carboxamide
  • Example 52 (white solid, 18.0 mg) was prepared in the same manner as in Example 25. LC-MS [M+H] + : m/z 909.5.
  • Example 53 (E)-9-(4-(8-carbamoyl-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-(3-hydroxypropyl) Oxy)-5H-pyridyl[4,3-b]indol-5-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole -5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • Example 53 (white solid, 18.0 mg) was prepared in the same manner as in Example 25.
  • Example 54 (E)-9-(4-(8-carbamoyl-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-(pyrimidine-2- Methoxy)-5H-pyridyl[4,3-b]indol-5-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H- Pyrazol-5-yl)-8-methoxy-9H-pyrimidine[4,5-b]indole-6-carboxamide
  • Example 54 (white solid, 5.1 mg) was prepared in the same manner as in Example 25. LC-MS [M+H] + : m/z 830.2.
  • Example 55 The light yellow solid (5.0 mg) of Example 55 was prepared by the same method as that of Example 25.
  • Example 56 (E)-9-(4-(6-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-(3-hydroxypropyl) Oxy)-9H-pyrimidine[4,5-b]indol-9-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole- 5-yl)-8-(3-morpholinopropoxy)-9H-pyrimidinyl[4,5-b]indole-6-carboxamide
  • Example 56 The white solid (9.0 mg) of Example 56 was prepared by the same method as that of Example 25.
  • LC-MS[M+H] + m/z 910.3.
  • Comparative compound 1 The comparative compound 1 was prepared by referring to the synthesis method of Example 4 on page 85 of patent WO2019069275A. LC-MS[M+H] + :850.5m/z. 1 H NMR(400MHz,CD 3 OD): ⁇ 7.59(s,2H),7.27(s,1H),7.25(s,1H),6.61 (s, 1H), 6.59 (s, 1H), 5.80 (br s, 2H), 5.01 (br s, 4H), 4.57-4.61 (m, 4H), 3.97 (br s, 4H), 3.71 (br s) , 5H), 3.12-3.31 (m, 6H), 2.18 (s, 6H), 1.95-1.98 (m, 2H), 1.31-1.39 (m, 6H).
  • Comparative compound 2 The comparative compound 2 was prepared by referring to the synthetic method of Example 1 in patent WO2020028565A1.
  • MS (ESI): m/z 753.0 [M+H].
  • Comparative compound 3 The comparative compound 3 was prepared by referring to the synthesis method of Example 2 in patent WO2020028565A1. LC-MS[M+H] + : m/z 841.4. 1 H NMR (400MHz, DMSO-d 6 ): ⁇ 9.46(s, 2H), 8.40(s, 2H), 8.06(s, 2H), 7.56(s,2H),7.39(s,2H),6.73(s,2H),5.77(s,4H),5.21(s,4H),4.50-4.54(m,6H),4.01-4.05(m, 4H), 3.37-3.39 (m, 4H), 2.17 (s, 6H), 1.59-1.63 (m, 4H), 1.14-1.18 (m, 6H).
  • Test Example 1 Test for the binding activity of the compound of the example and WT hSTING protein
  • the STING protein is reacted with the test compound (initial concentration 10 ⁇ M, ten-fold three-fold dilution) and buffer at 37°C for 30 minutes, then Incubate with 20 ⁇ M fluorescent substrate at 37°C for 30 minutes.
  • the test compound initial concentration 10 ⁇ M, ten-fold three-fold dilution
  • buffer at 37°C for 30 minutes
  • Thermo Scientific Verioskan Flash multi-function reader to use 358nm as excitation light to read the light intensity at 455nm.
  • the measured fluorescence value is compared with the value of the blank well to calculate the competitive binding activity of the sample to the protein.
  • the EC 50 value of the compound was calculated by the Prism software of Graphpad.
  • Test Example 2 Elisa method to detect the release activity test of the compounds of the examples stimulated THP1 cells to IFN ⁇
  • Test steps 1. THP-1 cells are cultured with RPMI1640+10% FBS+0.05mM ⁇ -ME, maintaining the density at 2 ⁇ 10 5 ⁇ 1 ⁇ 10 6 viable cells/mL; collect the cells, discard the old medium, and use Wash the cells once with serum-free medium, centrifuge to remove the supernatant, and resuspend the cells in serum-free medium. Count after staining with trypan blue. When the cell viability is greater than 95%, perform subsequent experiments; use serum-free medium to adjust the cell density to 1.1 ⁇ 10 6 viable cells/mL; add 180 ⁇ L of cell suspension to the wells of the 96-well cell culture plate. The density is 2 ⁇ 10 5 viable cells/well.
  • the cell culture plate is placed in the incubator and incubated for 24hrs; the cell culture plate is centrifuged at 2000g for 5 minutes, and the supernatant is transferred for direct ELISA detection; ELISA test sample
  • the concentration of IFN- ⁇ was calculated according to the standard curve of IFN- ⁇ .
  • the IFN- ⁇ concentration in the cell supernatant is equal to the IFN- ⁇ concentration in the ELISA sample multiplied by the dilution factor; 4.
  • Use GraphPad Prism 5.0 software to analyze the data, use the nonlinear S-curve regression to fit the data to obtain the dose-response curve, and calculate the EC 50 value.
  • Results Most of the compounds of the examples of the present invention stimulate the release activity of THP1 cells to IFN ⁇ with EC 50 values less than 1 uM, the EC 50 values of some examples are even less than 100 nM, and the EC 50 values of some examples are even less than 1 nM, as in Example 16. , 29, 39, 56 etc. (The specific EC 50 data is shown in Table 2, A ⁇ 1nM, 1nM ⁇ B ⁇ 10nM, 10nM ⁇ C ⁇ 100nM, D ⁇ 100nM).
  • Example compounds stimulate the release activity of THP1 cells on IFN ⁇
  • Test Example 3 Elisa method to detect the inhibitory ability of the compounds of the examples on the 2'3'-cGAMP-stimulated THP-1 secretion of IFN- ⁇
  • Test method 1. THP-1 cells are cultured with RPMI1640+10% FBS+0.05mM ⁇ -ME, maintaining the density at 2 ⁇ 10 5 ⁇ 1 ⁇ 10 6 viable cells/mL; collect the cells and discard the old medium before use Wash the cells once with serum-free medium, centrifuge to remove the supernatant, and resuspend the cells in serum-free medium. Count after staining with trypan blue, and perform follow-up experiments when the cell viability is greater than 95%. Use serum-free medium to adjust the cell density to 1.1 ⁇ 10 6 viable cells/mL; add 160 ⁇ L of cell suspension to the wells of a 96-well cell culture plate, and the cell density is 2 ⁇ 10 5 viable cells/well. 2.
  • the concentration of IFN- ⁇ in the ELISA test sample was calculated according to the standard curve of IFN- ⁇ .
  • the concentration of IFN- ⁇ in the cell supernatant is equal to the concentration of IFN- ⁇ in the ELISA sample multiplied by the dilution factor.
  • Example Compound formula (I) a good antagonist STING portion having functional activity, EC 50 of less than 20 uM, as described in Example 11, 18 , 30, 36, 55; Some of the example compounds have an EC 50 of less than 1 uM for 2'3'-cGAMP-stimulated THP-1 secretion of IFN- ⁇ , as shown in Examples 11 and 16.
  • Test Example Four Inhibitory activity of the compounds of the examples on different enzymes
  • the compounds of the examples were respectively interacted with kinases such as GSK3, TBK, CDK, IKK, AMPK, ULK1, etc., to test the inhibitory activity of the compounds on the above-mentioned enzymes.
  • kinases such as GSK3, TBK, CDK, IKK, AMPK, ULK1, etc.

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Abstract

L'invention concerne un composé cyclique fusionné contenant de l'azote représenté par la formule générale I, ou un sel pharmaceutiquement acceptable de celui-ci, ou un énantiomère, un diastéréoisomère, un tautomère, un solvate, un polymorphe, ou un promédicament de celui-ci, et son procédé de préparation et son utilisation en pharmacie, la définition de chaque groupe étant telle que décrite dans la description.
PCT/CN2020/125965 2019-11-02 2020-11-02 Composé cyclique fusionné contenant de l'azote en tant que régulateur de sting, son procédé de préparation et son utilisation WO2021083383A1 (fr)

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US20230212192A1 (en) * 2020-05-28 2023-07-06 Beigene, Ltd. Heterocyclic compounds as sting modulators
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CN109071514A (zh) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 用作蛋白质调节剂的杂环酰胺
WO2019100061A1 (fr) * 2017-11-20 2019-05-23 Silicon Swat, Inc. Dérivés d'acide oxoacridinyle acétique et procédés d'utilisation
WO2020028565A1 (fr) * 2018-07-31 2020-02-06 Incyte Corporation Composés hétéroaryles tricycliques en tant qu'activateurs de sting

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AU2018344902B2 (en) * 2017-10-05 2021-06-03 Glaxosmithkline Intellectual Property Development Limited Modulators of stimulator of interferon genes (STING) useful in treating HIV
WO2019227007A1 (fr) * 2018-05-25 2019-11-28 Incyte Corporation Composés hétérocycliques tricycliques en tant qu'activateurs de sting

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CN109071514A (zh) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 用作蛋白质调节剂的杂环酰胺
WO2019100061A1 (fr) * 2017-11-20 2019-05-23 Silicon Swat, Inc. Dérivés d'acide oxoacridinyle acétique et procédés d'utilisation
WO2020028565A1 (fr) * 2018-07-31 2020-02-06 Incyte Corporation Composés hétéroaryles tricycliques en tant qu'activateurs de sting

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