WO2022253316A1 - Dérivé de quinoxaline, sa préparation et son utilisation - Google Patents

Dérivé de quinoxaline, sa préparation et son utilisation Download PDF

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WO2022253316A1
WO2022253316A1 PCT/CN2022/096880 CN2022096880W WO2022253316A1 WO 2022253316 A1 WO2022253316 A1 WO 2022253316A1 CN 2022096880 W CN2022096880 W CN 2022096880W WO 2022253316 A1 WO2022253316 A1 WO 2022253316A1
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compound
substituted
unsubstituted
alkyl
group
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PCT/CN2022/096880
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English (en)
Chinese (zh)
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张翱
高大明
邢莉
王凯华
宋子兰
陈婷婷
肖若璇
丁春勇
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上海交通大学
中国科学院分子细胞科学卓越创新中心
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Publication of WO2022253316A1 publication Critical patent/WO2022253316A1/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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the invention belongs to the field of medicine. It specifically relates to a class of quinoxaline derivatives and their preparation and use.
  • the Warburg effect is one of the important characteristics of tumor cells, which represents the transformation of tumor cells' utilization of glucose from oxidative phosphorylation to glycolysis.
  • Normal cells obtain ATP energy through the mitochondrial oxidative phosphorylation pathway, while tumor cells are in uncontrolled division and proliferation, and have a particularly strong demand for energy. Even in the case of normal oxygen concentration, rapidly proliferating tumor cells still prefer anaerobic glycolysis to obtain energy.
  • Alteration of tumor metabolic pathways is considered to be one of the important driving forces of tumorigenesis and progression.
  • Phosphoglycerate kinase 1 is a key metabolic enzyme in the glycolysis pathway, which catalyzes the conversion of 1,3-bisphosphoglyceride (1,3-BPG) into 3-phosphoglyceride (3- PG) and generate the first ATP in the glycolytic pathway, which plays an important role in cellular energy metabolism.
  • PGK1 is closely related to the occurrence and development of tumors.
  • a 2016 study showed that the severity of liver cancer patients is positively correlated with the expression of PGK1 protein. After knocking down the pgk1 gene, the glycolytic ability of the liver cancer cell line decreased, the production capacity decreased, the cell proliferation was inhibited, and the tumorigenic ability was weakened.
  • PGK1 may become a molecular target in the treatment of liver cancer.
  • PGK1 is associated with multidrug resistance of various malignant tumors.
  • PGK1 is a predictor of poor survival in breast cancer patients and a novel prognostic biomarker of resistance to paclitaxel therapy.
  • the expression of PGK1 is also significantly up-regulated in various other malignant tumors such as pancreatic cancer, colorectal cancer, neuroblastoma, and glioma.
  • targeting PGK1 may be an effective strategy for the treatment of malignant tumors.
  • the purpose of the present invention is to provide a new class of targeted PGK1 inhibitors.
  • a compound of formula I or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, optical isomer, racemate, deuterated Derivatives, solvates or hydrates, metabolites or prodrugs;
  • X is selected from the group consisting of N or CH;
  • A is selected from the group consisting of absent (chemical bond), substituted or unsubstituted C1-C3 alkylene,
  • R a is selected from the group consisting of H, substituted or unsubstituted C1-C3 alkyl
  • R 1 and R 2 are each independently selected from the group consisting of H, substituted or unsubstituted C1-C6 alkyl (preferably, C1-C3 alkyl), halogen (preferably, Cl), cyano, N(R c ) 2 ⁇ C6-C10 aromatic ring unsubstituted or substituted by one or more R s1 , 5-10 membered heteroaromatic ring unsubstituted or substituted by one or more R s1 ;
  • R s1 are each independently selected from the group consisting of halogen, substituted or unsubstituted C1-C3 alkyl, cyano;
  • R b is selected from the group consisting of H, unsubstituted or C1-C6 alkyl (preferably, C1-C3 alkyl) substituted by one or more R s2 ,
  • Each R c is independently selected from the following group: H, substituted or unsubstituted C1-C3 alkyl;
  • R s2 are each independently selected from the following group: hydroxyl, substituted or unsubstituted C1-C3 alkoxy, halogen, substituted or unsubstituted C1-C3 alkyl, cyano;
  • R 3 is selected from the following group: H, substituted or unsubstituted C1-C6 alkyl (preferably, C1-C3 alkyl), N(R d ) 2 ;
  • R d is independently selected from the following group: H, substituted or unsubstituted C1-C3 alkyl;
  • R 4 is selected from the group consisting of C1-C6 unsubstituted or substituted by one or more R s3 (preferably, C1-C3 alkyl), C4- unsubstituted or substituted by one or more R s3 C10 cycloalkyl, 4-10 membered heterocycloalkyl unsubstituted or substituted by one or more R s3 , C6-C10 aryl unsubstituted or substituted by one or more R s3 , unsubstituted or substituted by 5-10 membered heteroaryls substituted by one or more R s3 ;
  • Each R s3 is independently selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C3 alkyl, halogen, substituted or unsubstituted C1-C3 alkylacyl, substituted or unsubstituted C1-C3 alkoxy, substituted Or unsubstituted C1-C3 haloalkyl, substituted or unsubstituted C1-C3 hydroxyalkyl;
  • substitution means that one or more hydrogens in the group are optionally substituted by a substituent selected from the following group: hydroxyl, halogen, C1-C3 alkyl, C1-C3 haloalkyl, amino (- NH 2 ), -N(C1-C3 alkyl) 2 , -NH(C1-C3 alkyl), cyano.
  • X is CH.
  • A is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R a is selected from the following group: H, C1-C3 alkyl.
  • R a is selected from the group consisting of H and methyl.
  • A is selected from the group: absent or Wherein, R a is selected from the following group: H, C1-C3 alkyl.
  • A is wherein, R a is selected from the following group: H, C1-C3 alkyl.
  • A is selected from the group consisting of absent, -NH-, -N(CH 3 )-.
  • A is selected from the following group: -NH-, -N(CH 3 )-.
  • R 1 and R 2 are different groups.
  • At least one of R 1 and R 2 is halogen (such as Cl).
  • R 1 is halogen
  • R 1 and R 2 are each independently selected from the following group: halogen,
  • one of R1 and R2 is halogen, and the other is
  • R 1 is halogen and R 2 is
  • R b is C1-C6 alkyl (preferably C1-C3 alkyl) which is unsubstituted or substituted by one or more R s2 .
  • R s2 are each independently selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C3 alkoxy.
  • R s2 is hydroxyl
  • R b is C1-C6 hydroxyalkyl, preferably, C1-C3 hydroxyalkyl; more preferably, R b is -CH 2 OH.
  • R 1 and R 2 are each independently selected from the following group: halogen, And R b is C1-C6 alkyl (preferably C1-C3 alkyl) which is unsubstituted or substituted by one or more R s2 .
  • R 1 and R 2 are each independently selected from the following group: halogen, R b is C1-C6 alkyl (preferably C1-C3 alkyl) unsubstituted or substituted by one or more R s2 , and each R s2 is independently selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C3 alkoxy.
  • R 1 is halogen and R 2 is And R b is C1-C6 alkyl (preferably C1-C3 alkyl) which is unsubstituted or substituted by one or more R s2 .
  • R 1 is halogen and R 2 is R b is C1-C6 alkyl (preferably C1-C3 alkyl) unsubstituted or substituted by one or more R s2 , and each R s2 is independently selected from the group consisting of hydroxyl, substituted or unsubstituted C1-C3 alkoxy.
  • R 3 is selected from the following group: H, C1-C3 alkyl, N(R d ) 2 ; wherein, each R d is independently selected from the following group: H, C1-C3 alkyl.
  • R 3 is selected from the following group: H, C1-C3 alkyl, NH (C1-C3 alkyl).
  • R 3 is H or C1-C6 alkyl (preferably, C1-C3 alkyl).
  • R 4 is selected from the following group: unsubstituted or substituted by one or more R s3 C1-C6 alkyl (preferably, C1-C3 alkyl), unsubstituted or substituted by one or C4-C6 cycloalkyl substituted by multiple R s3 , 5-6 membered heterocycloalkyl unsubstituted or substituted by one or more R s3 , benzene unsubstituted or substituted by one or more R s3 Base, 5-6 membered heteroaryl unsubstituted or substituted by one or more R s3 .
  • R 4 is selected from the group consisting of 5-6 membered heterocycloalkyl unsubstituted or substituted by one or more R s3 , 5-membered unsubstituted or substituted by one or more R s3 -6 membered heteroaryl.
  • the heterocycloalkyl group is a saturated oxygen-containing heterocycloalkyl group; preferably, a 5-6 membered heterocycloalkyl group containing 1 or 2 oxygen heteroatoms.
  • the heteroaryl is a sulfur-containing heteroaryl.
  • the heteroaryl is a five-membered sulfur-containing heteroaryl.
  • R s3 are each independently selected from the following group: hydroxyl, C1-C3 alkyl, halogen, C1-C3 alkyl acyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 Hydroxyalkyl.
  • R 4 when R 4 is unsubstituted or substituted by one or more R s3 C4-C10 cycloalkyl (preferably, C4-C6 cycloalkyl), unsubstituted or substituted by one or more
  • R s3 C4-C10 cycloalkyl preferably, C4-C6 cycloalkyl
  • R s3 When a 4-10 membered heterocycloalkyl group (preferably, 5-6 membered heterocycloalkyl group) substituted by R s3 , the compound of formula I is as shown in formula I-1 or formula I-2;
  • each of A, X, R 1 , R 2 , R 3 , R 4 , R a , R b , R c , R d , R s1 , R s2 and R s3 are independently the corresponding groups in the specific compounds (such as compounds S1-S35) described in the examples or in Table 1.
  • the compound of formula I is a compound selected from the following table 1,
  • a pharmaceutical composition comprising (i) a therapeutically effective amount of the compound of formula I as described in the first aspect, or a pharmaceutically acceptable salt or enantiomer thereof , diastereoisomers, optical isomers, racemates, deuterated derivatives, solvates or hydrates, metabolites or prodrugs, and (ii) optionally a pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutical composition is a pharmaceutical composition for treating tumors, or a pharmaceutical composition for treating diseases related to energy metabolism enzyme (preferably PGK1 enzyme) activity.
  • energy metabolism enzyme preferably PGK1 enzyme
  • a compound of formula I as described in the first aspect or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, optical isomer thereof , racemates, deuterated derivatives, solvates or hydrates, metabolites or prodrugs,
  • the preparation method is method one or method two.
  • said method one includes the steps of:
  • R 1 ' is R 1 or R 1 protected by a protecting group
  • R 2 ' is R 2 or R 2 protected by a protecting group
  • step vi) is: hydrolyze compound if under basic conditions to obtain compounds ig-1 and ig-2.
  • the second method includes the steps of:
  • R 5 is a C6-C10 aromatic ring unsubstituted or substituted by one or more R s1 or a 5-10 membered heteroaromatic ring unsubstituted or substituted by one or more R s1 ; in the compound of formula I, One of R1 and R2 is A C6-C10 aromatic ring unsubstituted or substituted by one or more R s1 or a 5-10 membered heteroaromatic ring unsubstituted or substituted by one or more R s1 , and the other is as defined in the first aspect; A, X, R3 and R4 are as defined in the first aspect.
  • R 1 in compound iia-1 and R 2 in compound iia-2 are Cl.
  • a compound of formula I as described in the first aspect or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, optical isomer thereof , racemate, deuterated derivative, solvate or hydrate, metabolite or prodrug, or the pharmaceutical composition as described in the second aspect is used in the preparation of (i) PGK1 inhibitor and/or (ii) Use in medicines for treating or preventing diseases related to PGK1.
  • the PGK1-related diseases include: cancer, abnormal cell proliferation, morphological changes, abnormal glucose metabolism, hyperkinesia, tumor growth, diabetes, or a combination thereof.
  • the cancer includes: liver cancer, gastric cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, neuroblastoma, prostate cancer, or a combination thereof.
  • a method for treating or preventing diseases related to PGK1 comprising the steps of: administering a therapeutically effective amount of the compound of formula I as described in the first aspect to a subject in need, or its pharmaceutically acceptable salts, enantiomers, diastereomers, optical isomers, racemates, deuterated derivatives, solvates or hydrates, metabolites or prodrugs thereof, or The pharmaceutical composition as described in the second aspect.
  • the PGK1-related diseases include: cancer, abnormal cell proliferation, morphological changes, abnormal glucose metabolism, hyperkinesia, tumor growth, diabetes, inflammation, immune diseases, or a combination thereof.
  • the cancer includes: liver cancer, gastric cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, neuroblastoma, prostate cancer, or a combination thereof.
  • the subject is a mammal, preferably a human.
  • a method for inhibiting the activity of PGK1 comprising the step of contacting PGK1 with the compound of formula I as described in the first aspect, thereby inhibiting the activity of PGK1.
  • the method is non-therapeutic in vitro.
  • a method for inhibiting cell proliferation activity comprising the step of culturing cells in the presence of the compound of formula I as described in the first aspect, thereby inhibiting cell proliferation activity.
  • the method is non-therapeutic in vitro.
  • the inventors have studied extensively and intensively. It was found that replacing the core of the existing quinazoline PGK1 inhibitors with quinoxaline to obtain a class of PGK1 inhibitors with a novel core structure still has inhibitory activity against PGK1, and even some preferred compounds have significantly enhanced inhibitory activity against PGK1 , thus obtaining a class of quinoxaline derivatives with novel structures as PGK1 inhibitors. Based on this, the inventors have completed the present invention.
  • alkyl refers to a straight or branched chain hydrocarbon group having the indicated number of carbon atoms (ie, C1-C6 means 1-6 carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl and the like.
  • cycloalkyl refers to a hydrocarbon ring having a specified number of ring atoms (for example, C4-C10 cycloalkyl) and is fully saturated or has no more than one double bond between ring tips, preferably fully saturated ring.
  • Cycloalkyl can be a single ring (such as cyclopropyl, cyclobutyl, cyclohexyl, etc.), and can also refer to bicyclic and polycyclic hydrocarbon rings (such as fused rings, spiro rings, fused rings, bridged rings, etc.).
  • heterocycloalkyl which may also be referred to herein as “heterocyclyl”, refers to a cycloalkyl group containing as ring atoms one to five heteroatoms selected from N, O and S, wherein nitrogen and sulfur atoms are optionally It is selected to be oxidized, and the nitrogen atom is optionally quaternized.
  • the heterocycloalkyl group can be a monocyclic, bicyclic or polycyclic ring system.
  • the heterocyclyl group usually includes 5-12 ring atoms (that is, 5-12 membered hetero Cycloalkyl), preferably, includes 5-7 ring atoms (ie, 5-7 membered heterocyclyl) and contains 1, 2, 3 or 4 heterocyclic atoms.
  • Non-limiting examples of heterocycloalkyl include Line ring, piperidine ring, piperazine ring, N-alkyl or acyl substituted piperazine ring, homopiperazine ring, N-alkyl or acyl substituted homopiperazine ring, pyrrole, tetrahydropyrrole, 7H-purine , tetrahydrofuran, tetrahydropyran, etc.
  • the heterocycloalkyl group can be attached to the rest of the molecule via a ring carbon or a heteroatom (eg, ring N).
  • alkoxy is used in its conventional sense to refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom.
  • the alkyl moieties can be the same or different, and can also combine with the nitrogen atom connected to each alkyl group to form a 3-7 membered ring. Therefore, the group represented by -N(R a ) 2 includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl (azetidinyl) and the like.
  • aryl denotes a polyunsaturated (usually aromatic) hydrocarbon group which may be a single ring or multiple rings (up to three rings) fused together or linked covalently.
  • an aryl group refers to a full-carbon monocyclic or fused polycyclic (that is, a ring sharing adjacent pairs of carbon atoms) group with 6-10 ring atoms, and the group has a conjugated ⁇ -electron system .
  • the aryl ring can be fused to a heterocycloalkyl, heteroaryl or cycloalkyl ring, non-limiting examples include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzo Pyrazole, quinoline, benzoindole, benzodihydrofuran.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms selected from N, O and S and 5 to 14 ring atoms, wherein the nitrogen and sulfur atoms are optionally oxidized, the nitrogen atom is optionally is quaternized.
  • the heteroaryl group has 5-10 ring atoms, ie, a 5-10 membered heteroaryl group, preferably, has 5-6 ring atoms, ie, a 5- or 6-membered heteroaryl group.
  • a heteroaryl can be attached to the rest of the molecule through a heteroatom.
  • Non-limiting examples of aryl include phenyl and naphthyl.
  • the aryl (ring) may be fused to a heterocycloalkyl, heteroaryl or cycloalkyl ring
  • non-limiting examples include benzimidazole, benzothiazole, benzoxazole, benzisoxazole, benzo Pyrazole, quinoline, benzindole, benzodihydrofuran, etc.
  • Non-limiting examples of heteroaryl include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl group may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring.
  • heteroatom is intended to include oxygen (O), nitrogen (N) and sulfur (S).
  • a bond from a substituent (typically an R group) to the center of an aromatic ring will be understood to mean a bond providing attachment at any available vertex of the aromatic ring.
  • the description also includes on-ring linkages fused to aromatic rings.
  • a bond drawn to the center of the benzene moiety of an indole would represent a bond to any available vertex of the six- or five-membered ring portion of the indole.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • halo refers to a group in which one or more hydrogens or all hydrogens are replaced by the same or different halogens as defined above.
  • the structural formulas described herein are intended to include all optical isomeric and stereoisomeric forms (such as enantiomers, diastereomers, geometric isomers or conformational isomers): for example R, S configuration with an asymmetric center. Mixtures of individual stereochemical isomers, enantiomers, diastereomers or geometric or conformational isomers of the compounds of the present invention are therefore within the scope of the present invention.
  • the term “comprises”, “comprises” or “comprises” means that various ingredients can be used together in a mixture or composition of the present invention. Accordingly, the terms “consisting essentially of” and “consisting of” are included in the term “comprising”.
  • the term "pharmaceutically acceptable” ingredient refers to a substance suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic reactions), ie having a reasonable benefit/risk ratio.
  • the term "therapeutically effective dose” refers to any amount of a drug which, when used alone or in combination with another therapeutic agent, promotes regression of disease as manifested by disease symptoms decrease in the severity of disease, increase the frequency and duration of disease-free symptom-free periods, or prevent impairment or disability resulting from disease.
  • a “therapeutically effective dose” of a drug of the present invention also includes a “prophylactically effective dose", a “prophylactically effective dose” being any amount of a drug as described below, when the amount of the drug is administered alone or in combination with another therapeutic agent In subjects at risk of developing a disease or suffering from a disease recurrence, the occurrence or recurrence of the disease can be inhibited.
  • the present invention relates to a class of quinoxaline derivatives with phosphoglycerate kinase 1 (PGK1) inhibitory activity and their pharmaceutically acceptable salts or pharmaceutically acceptable solvates, their preparation methods and their use in the preparation of prevention or treatment and PGK-related cell abnormal proliferation, morphological changes, abnormal glucose metabolism, hyperkinesia, inflammation, immune diseases and other related diseases in vivo, especially for the use of drugs for the treatment or prevention of tumor growth and metastasis and diabetes.
  • PGK1 phosphoglycerate kinase 1
  • the term "compound of the present invention” or “quinoxaline derivative” or “quinoxaline compound” refers to a compound represented by formula I.
  • the term also includes the various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula I.
  • the term "pharmaceutically acceptable salt” refers to a salt formed by the compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • the pharmaceutically acceptable salts are not particularly limited, and preferably include: inorganic acid salts, organic acid salts, alkyl sulfonates and aryl sulfonates; the inorganic acid salts include hydrochloric acid Salt, hydrobromide, nitrate, sulfate, phosphate, etc.; said organic acid salts include formate, acetate, propionate, benzoate, maleate, fumarate, Succinate, tartrate, citrate, etc.; the alkylsulfonate includes methanesulfonate, ethylsulfonate, etc.; the arylsulfonate includes benzenesulfonate, p-toluenesulfonic acid salt etc.
  • solvate refers to a complex in which a compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination between the compound of the present invention and water.
  • the pharmaceutically acceptable solvate of the compound represented by the general formula (I) is not particularly limited, and preferably includes: the compound represented by the general formula (I) and water, ethanol, isopropanol, ether , Acetone and other solvates.
  • the compounds of the present invention also include prodrugs of the compounds represented by formula I.
  • prodrug includes itself may be biologically active or inactive, when administered in an appropriate manner, it undergoes metabolism or chemical reactions in the human body to convert into a class of compounds of formula I, or formula I A salt or solution of a compound.
  • the prodrugs include (but are not limited to) carboxylates, carbonates, phosphates, nitrates, sulfates, sulfone esters, sulfoxide esters, amino compounds, carbamates, azo compounds of the compounds , phosphoramide, glucoside, ether, acetal and other forms.
  • the purpose of the present invention is to provide a class of PGK1 kinase inhibitors with novel structure and excellent activity.
  • the present invention provides a compound of formula I shown in the following formula, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, optical isomer, racemate, Deuterated derivatives, solvates or hydrates, metabolites or prodrugs.
  • R 1 , R 2 , R 3 , R 4 , X and A are as defined in the first aspect.
  • X is selected from a nitrogen atom or CH;
  • A is selected from the direct key or And/or wherein R a is selected from hydrogen, C1-C3 alkyl; and/or
  • R and R are each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted amino, A substituted or unsubstituted 6-10 membered aromatic ring, a substituted or unsubstituted 5-10 membered heteroaromatic ring.
  • R b is selected from hydrogen, C1-C3 alkyl, C1-C3 alkyl can be further substituted by hydroxyl, halogen, cyano. The substitution may be selected from halogen, C1-C3 alkyl, cyano; and/or
  • R is selected from hydrogen, amino, C1-C3 alkylamino; and/or
  • R 4 is selected from substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted saturated or unsaturated 4-10 membered cycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl ring group, substituted or unsubstituted Substituted 4-10 membered heterocyclic group.
  • the 5- to 10-membered heteroaryl ring group and the 4- to 10-membered heteroaryl ring group contain 1-3 heteroatoms selected from O, N, and S.
  • Said substituent group is further substituted by one or more substituents selected from the group consisting of hydroxyl, C1-C3 alkyl, halogen, and C1-C3 alkylacyl. Wherein said C1-C3 alkyl can be further substituted by hydroxyl, halogen, amino, cyano.
  • any one of X, A, R 1 , R 2 , R 3 and R 4 is the corresponding group in the specific compound described in the examples.
  • the quinoxaline compound shown in the general formula (I) of the present invention is selected from the compounds in the following table 1:
  • the present invention also provides a preparation method of the compound of formula I as described in the first aspect of the present invention.
  • the preparation method of the compound of formula I of the present invention is described in more detail below. But these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
  • the compounds of the present invention can be prepared by methods one or two, for example.
  • the method 1 and method 2 are as defined in the second aspect.
  • method one includes the following steps:
  • compound iiid-1 and/or iiid-2 optionally hydrolyzing compound iiid-1 and/or iiid-2 under basic conditions to obtain compound iiie-1 and iiie-2 (i.e. compound of formula I, wherein, R 1 or R 2 One of Cl, another for );
  • each group is as defined in the first aspect.
  • R3 is H
  • said method one is method one (1), and comprises the following steps:
  • compound ia undergoes a ring-closing reaction with ethyl glyoxylate to obtain compound ib;
  • compound ib obtains compound ic-1 or ic-2 or a mixture thereof under the action of a chlorination reagent
  • each group is as defined in the first aspect.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature.
  • the reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
  • compositions and methods of administration are provided.
  • the compound of the present invention has excellent inhibitory activity on phosphoglycerate kinase 1 (PGK1), the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and compounds containing the present invention
  • the pharmaceutical composition whose main active ingredient is the compound of the invention can be used for treating, preventing and alleviating diseases related to phosphoglycerate kinase 1 (PGK1).
  • the compound of the present invention can be used to treat the following diseases: cancer, abnormal cell proliferation, morphological changes, abnormal glucose metabolism, hyperkinesia, tumor growth, diabetes, or a combination thereof; wherein, the cancer includes: liver cancer, gastric cancer , colorectal cancer, breast cancer, bladder cancer, pancreatic cancer, pancreatic ductal adenocarcinoma, neuroblastoma, prostate cancer, or a combination thereof.
  • the present invention also provides the use of the compound of formula I (quinoxaline derivatives) or its isomers or pharmaceutically acceptable salts, esters, prodrugs or hydrates thereof as PGK1 inhibitors in the preparation of prophylaxis and /or use in medicines for treating diseases related to PGK1, including various cancers (liver cancer, gastric cancer, colorectal cancer, breast cancer, bladder cancer, pancreatic cancer, neuroblastoma, etc.).
  • the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of the compound as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate or a solvate thereof, and optionally Pharmaceutically acceptable carrier, excipient or diluent etc.
  • the pharmaceutical composition is a pharmaceutical composition for treating tumors, or a pharmaceutical composition for treating diseases related to energy metabolism enzyme (preferably PGK1 enzyme) activity.
  • energy metabolism enzyme preferably PGK1 enzyme
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-500 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • calcium sulfate such
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 20-500 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • the compounds of the present invention (especially the preferred compounds) have strong inhibitory activity on PGK1, and show strong growth inhibitory activity on human liver cancer SNU739 or HepG2 cells.
  • terazosin (as shown below) inhibits PGK1 at a high concentration (2.5-25 ⁇ M), and the preferred compound of the present invention has an inhibitory IC value of less than 100 nM to PGK1;
  • Preferred compounds of the present invention have significant growth inhibitory activity against human liver cancer SNU739 or HepG2.
  • the proton nuclear magnetic resonance spectrum was measured with a Varian MercuryAMX300 instrument, deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), deuterated dimethyl sulfoxide (d6-DMSO) as solvents, tetramethylsilane (TMS) is the internal standard.
  • DIPEA N,N-Diisopropylethylamine
  • Step 1 Weigh compound 1a (243 mg, 1 equivalent) into a single-necked bottle, add ethanol as a solvent, and then add ethyl glyoxylate (50% toluene solution, 222 mg, 1.2 equivalents) to it, and heat up to 80°C The reaction was carried out for 2 hours. After the reaction was completed, it was cooled to room temperature, a large amount of solids were precipitated, and filtered by suction to obtain a mixture of 1b and 1c.
  • ethyl glyoxylate 50% toluene solution, 222 mg, 1.2 equivalents
  • Step 2 Weigh the mixture of 1b and 1c (1.385g, 1 equivalent) into a single-necked bottle, add phosphorus oxychloride (4.2mL, 10 equivalents), DIPEA (3.0mL, 4 equivalents), and react at 110°C for 4 hours . After the reaction is complete, part of the phosphorus oxychloride is distilled off under reduced pressure, then the reaction solution is poured into ice water, neutralized with a saturated sodium bicarbonate solution, extracted with ethyl acetate, the organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and mixed with The sample was applied to the column to obtain a mixture of 1d and 1e.
  • Step 3 Weigh the mixture of 1d and 1e (486mg, 1eq), 1f (482mg, 1.5eq) in a single-necked bottle, add 1,4-dioxane solvent, and then add DIPEA (0.74mL, 3eq ), reacted at 100°C for 3 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain a mixture of 1g and 1h.
  • Step 4 Weigh the mixture of 1g and 1h (168 mg, 1 equivalent), PdCl 2 (PPh 3 ) 2 (23 mg, 0.1 equivalent), CuI (13 mg, 0.2 equivalent) in a single-necked bottle, add tetrahydrofuran solvent to it, and then add Propargyl acetate (66 ⁇ L, 2 equivalents), DIPEA (0.60 mL, 4 equivalents), under nitrogen protection, was heated at 80° C. for 5 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compounds 1i and 1j.
  • Step 5 Weigh compound 1j (78 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add TFA (0.12 mL, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofuranic acid (29mg, 1.5eq), TBTU (106mg, 2eq), DIPEA (0.14mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 6 Weigh compound 1k (73 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (13 mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S1. Analytical data for compound S1:
  • Step 1 Weigh compound 1i (63 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add TFA (99 ⁇ L, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofuranic acid (23mg, 1.5eq), TBTU (86mg, 2eq), DIPEA (0.11mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 2 Weigh compound 2a (53 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (9 mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction, water and dichloromethane were added to the reaction liquid for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S2.
  • Step 1 Weigh compound 7a (82 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, add DAST (31 ⁇ L, 1.5 equivalents) under ice-cooling, and react at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was neutralized with sodium bicarbonate, then extracted with dichloromethane and water, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, mixed and loaded on the column to obtain compound 7b.
  • Step 6 Weigh compound 7b (30 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (5 mg, 2 equivalents) to it, at room temperature React for 3 hours. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S7.
  • Step 1 Weigh the mixture of 1d and 1e (650 mg, 1 equivalent), piperazine-1-carboxylic acid tert-butyl ester (559 mg, 1.5 equivalents) in a single-necked bottle, add 1,4-dioxane solvent, and then DIPEA (0.99 mL, 3 equivalents) was added and reacted at 100° C. for 3 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain a mixture of 15a and 15b.
  • Step 2 Weigh the mixture of 15a and 15b (768 mg, 1 equivalent), PdCl 2 (PPh 3 ) 2 (131 mg, 0.1 equivalent), CuI (71 mg, 0.2 equivalent) in a single-necked bottle, add tetrahydrofuran solvent to it, and then add Propargyl acetate (0.37mL, 2eq), DIPEA (1.24mL, 4eq), under nitrogen protection, heated at 80°C for 5 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compounds 15c and 15d.
  • Step 3 Weigh compound 15d (60 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add TFA (0.10 mL, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofurancarboxylic acid (23 mg, 1.5 eq), TBTU (87 mg, 2 eq), DIPEA (0.11 mL, 5 eq), and reacted at room temperature for 3 hours.
  • Step 4 Weigh compound 15e (48 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (9 mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S15.
  • Step 1 Weigh compound 15c (60 mg, 1 equivalent) into a one-necked bottle, add dichloromethane solvent, and then add TFA (0.10 mL, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofurancarboxylic acid (23mg, 1.5eq), TBTU (87mg, 2eq), DIPEA (0.11mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 2 Weigh compound 16a (57mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (11mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S16. Analytical data of compound S16:
  • Step 1 Weigh compound 20a (359 mg, 1 equivalent) into a microwave tube, add tetrahydrofuran as a solvent, and then add ethylamine aqueous solution (12mol/L, 0.17mL, 2 equivalents) to it, and microwave for 20 minutes. After the reaction, the mixture was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was loaded onto the column to obtain a mixture of 20b and 20c.
  • Step 2 Weigh the mixture of 20b and 20c (405 mg, 1 equivalent), 1f (471 mg, 1.5 equivalents) in a one-mouth bottle, add 1,4-dioxane solvent, and then add DIPEA (0.55 mL, 3 equivalents ), reacted at 100°C for 16 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain a mixture of 20d and 20e.
  • Step 5 Weigh the mixture of 20d and 20e (582 mg, 1 equivalent), PdCl 2 (PPh 3 ) 2 (74 mg, 0.1 equivalent), CuI (42 mg, 0.2 equivalent) in a single-necked bottle, add tetrahydrofuran solvent to it, and then add Propargyl acetate (0.21 mL, 2 equivalents), DIPEA (0.70 mL, 4 equivalents), under nitrogen protection, was heated at 80°C for 5 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compounds 20f and 20g.
  • Step 6 Weigh compound 20f (65 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add TFA (94 ⁇ L, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofuranic acid (22mg, 1.5eq), TBTU (81mg, 2eq), DIPEA (0.10mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 7 Weigh compound 20h (64 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (11 mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction liquid for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S20.
  • Step 1 Weigh 20 g (65 mg, 1 equivalent) of the compound into a single-necked bottle, add dichloromethane solvent, and then add TFA (94 ⁇ L, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofuranic acid (22mg, 1.5eq), TBTU (81mg, 2eq), DIPEA (0.10mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 2 Weigh compound 21a (52 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (8 mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction liquid for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S21.
  • Step 1 Weigh mixtures 20b and 20c (405 mg, 1 equivalent), piperazine-1-carboxylic acid tert-butyl ester (410 mg, 1.5 equivalents) in a single-necked bottle, add 1,4-dioxane solvent to it, and then add DIPEA (0.55 mL, 3 eq.) was reacted at 100° C. for 16 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was loaded on the column to obtain a mixture of 24a and 24b.
  • Step 2 Weigh the mixture of 24a and 24b (493 mg, 1 equivalent), PdCl 2 (PPh 3 ) 2 (67 mg, 0.1 equivalent), CuI (38 mg, 0.2 equivalent) in a single-necked bottle, add tetrahydrofuran solvent to it, and then add Propynyl acetate (0.19 mL, 2 equivalents), DIPEA (0.63 mL, 4 equivalents), under nitrogen protection, was heated at 80°C for 5 hours. After the reaction was complete, it was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compounds 24c and 24d.
  • Step 3 Weigh compound 24c (64 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add TFA (97 ⁇ L, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofuranic acid (23mg, 1.5eq), TBTU (84mg, 2eq), DIPEA (0.11mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 4 Weigh compound 24e (62mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (11mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction solution for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S24.
  • Step 1 Weigh compound 24d (60 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add TFA (91 ⁇ L, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofuranic acid (21mg, 1.5eq), TBTU (79mg, 2eq), DIPEA (0.10mL, 5eq), and reacted at room temperature for 3 hours.
  • Step 2 Weigh compound 25a (52 mg, 1 equivalent) in a single-necked bottle, add tetrahydrofuran and water (2:1) as a solvent, and then add lithium hydroxide monohydrate (9 mg, 2 equivalents) to it, at room temperature React for 4 hours. After the reaction was completed, water and dichloromethane were added to the reaction liquid for extraction, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was mixed and put on the column to obtain compound S25. Analytical data of compound S25:
  • Step 1 Weigh 1g and 1h of the mixture (519mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, then add trifluoroacetic acid (TFA, 0.74mL, 10 equivalents), and react at room temperature for 3 hours. After the reaction is complete, the reaction solution is spin-dried. Then dichloromethane was added as a solvent, followed by (R)-tetrahydrofurancarboxylic acid (174mg, 1.5eq), TBTU (642mg, 2eq), DIPEA (0.83mL, 5eq), and reacted at room temperature for 3 hours. After the reaction was complete, it was extracted with dichloromethane and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the sample was loaded on the column to obtain a mixture of 26a and 26b.
  • dichloromethane solvent Trifluoroacetic acid
  • Step 2 Weigh the mixture of 26a and 26b (460 mg, 1 eq), tert-butyl carbamate (138 mg, 1.3 eq), Pd2 (dba) 3 (83 mg, 0.1 eq), Xantphos (110 mg, 0.2 eq), Cesium carbonate (598 mg, 2 equivalents) was added to a single-necked bottle, and 1,4-dioxane was added as a solvent, protected by nitrogen, and heated at 100°C for 6 hours.
  • Step 3 Weigh compound 26d (52 mg, 1 equivalent) into a single-necked bottle, add dichloromethane solvent, and then add trifluoroacetic acid (TFA, 79 ⁇ L, 10 equivalents), and react at room temperature for 5 hours. After the reaction is complete, the reaction solution is spin-dried. Neutralize with saturated sodium bicarbonate solution, extract with dichloromethane and water, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, mix the sample and put it on the column to obtain compound S26.
  • TFA trifluoroacetic acid
  • Embodiment 1 Compound is tested for the inhibitory activity of PGK1 enzyme
  • Dilute ATP detection solution 1:10 with ATP detection diluent In a 96-well white plate, add 100uL of diluted detection solution to each well, react at room temperature for 5min (to remove the influence of background ATP), add 100uL of enzyme activity reaction solution, react for at least 2s, and read the fluorescence value in a chemiluminescence detector.
  • the present invention provides a new class of quinoxaline derivatives as PGK1 inhibitors, among which some preferred compounds have strong inhibitory activity on PGK1, and show strong growth inhibition on human liver cancer SNU739 or HepG2 cells active. Compared with existing PGK1 inhibitors, it has significant advantages.

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Abstract

La présente invention concerne un dérivé de quinoxaline, sa préparation et son utilisation. En particulier, la présente invention concerne un composé représenté par la formule (I) ci-jointe, ou un sel, un énantiomère, un diastéréoisomère, un isomère optique, un racémate, un dérivé deutéré, un solvate, un hydrate, un métabolite ou un promédicament pharmaceutiquement acceptable de celui-ci. Le composé de la présente invention possède une excellente activité inhibitrice de la PGK1 kinase.
PCT/CN2022/096880 2021-06-02 2022-06-02 Dérivé de quinoxaline, sa préparation et son utilisation WO2022253316A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1966500A (zh) * 2005-11-17 2007-05-23 中国科学院上海药物研究所 一类喹喔啉类衍生物、制法及用途
CN101602737A (zh) * 2009-06-11 2009-12-16 浙江大学 苯磺酰基喹喔啉类化合物及制备方法和用途
WO2012045196A1 (fr) * 2010-10-09 2012-04-12 Abbott Laboratories Inhibiteurs de la phosphoglycérate kinase
CN107814792A (zh) * 2016-09-14 2018-03-20 中国科学院上海药物研究所 一类喹唑啉衍生物、其组合物及用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1966500A (zh) * 2005-11-17 2007-05-23 中国科学院上海药物研究所 一类喹喔啉类衍生物、制法及用途
CN101602737A (zh) * 2009-06-11 2009-12-16 浙江大学 苯磺酰基喹喔啉类化合物及制备方法和用途
WO2012045196A1 (fr) * 2010-10-09 2012-04-12 Abbott Laboratories Inhibiteurs de la phosphoglycérate kinase
CN107814792A (zh) * 2016-09-14 2018-03-20 中国科学院上海药物研究所 一类喹唑啉衍生物、其组合物及用途

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