WO2022253316A1 - 一类喹喔啉衍生物及其制备和用途 - Google Patents

一类喹喔啉衍生物及其制备和用途 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)
French (fr)
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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/zh

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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.

Abstract

本发明提供了喹喔啉衍生物及其制备和用途。具体地，本发明提供了一种如下所示的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药。本发明的化合物具有优异活性的PGK1激酶抑制活性。

Description

一类喹喔啉衍生物及其制备和用途 技术领域
本发明属于医药领域。具体涉及一类喹喔啉衍生物及其制备和用途。
背景技术
Warburg效应是肿瘤细胞重要的特征之一，其代表了肿瘤细胞对葡萄糖的利用方式由氧化磷酸化到糖酵解的转变。正常细胞是通过线粒体氧化磷酸化途径获得ATP能量，而肿瘤细胞处于失控的***增殖中，对能量的需求尤为旺盛。即使在氧浓度正常的情况下，快速增殖的肿瘤细胞依然会优先选择无氧酵解的途径获得能量。肿瘤代谢途径的改变被认为是肿瘤发生和发展的重要的驱动力之一。
磷酸甘油酸激酶1(phosphoglycerate kinase 1，PGK1)是糖酵解途径中的关键代谢酶，它催化1,3-二磷酸甘油酯(1,3-BPG)转变成3-磷酸甘油酯(3-PG)并生成糖酵解途径中的第一个ATP，在细胞能量代谢中发挥着重要功能。近年来研究结果表明，PGK1与肿瘤的发生发展密切相关。2016年一项研究表明，肝癌病人的严重程度与其中PGK1蛋白的表达量正相关。敲减pgk1基因后，肝癌细胞株的糖酵解能力下降，产能减少，细胞的增殖受到抑制，成瘤能力减弱。结果提示PGK1可能成为肝癌治疗中的一个分子靶标。同时，PGK1与多种恶性肿瘤的多药耐药现象相关。例如，PGK1是乳腺癌患者生存率低的预测因子，也是紫杉醇治疗耐药的一种新的预后生物标志物。不仅如此，PGK1在胰腺癌、结直肠癌、神经母细胞瘤、脑胶质瘤等多种其它恶性肿瘤中的表达也显著上调。由此可见，靶向PGK1可能是恶性肿瘤治疗的有效策略。
尽管靶向PGK1抑制剂的研究在恶性肿瘤治疗上具有很大的潜力，但是PGK1抑制剂研究尚处于起步阶段。
综上所述，本领域迫切需要开发一类新的靶向PGK1抑制剂
发明内容
本发明的目的就是提供一类新的靶向PGK1抑制剂。
在本发明的第一方面，提供了一种式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药；
Figure PCTCN2022096880-appb-000001
其中，
X选自下组：N或CH；
A选自下组：不存在(化学键)、取代或未取代的C1-C3亚烷基、
Figure PCTCN2022096880-appb-000002
R a选自下组：H、取代或未取代的C1-C3烷基；
R 1和R 2各自独立地选自下组：H、取代或未取代的C1-C6烷基(较佳地，C1-C3烷基)、卤素(较佳地，为Cl)、氰基、N(R c) 2、
Figure PCTCN2022096880-appb-000003
未取代或被一个或多个R s1所取代的C6-C10芳环、未取代或被一个或多个R s1所取代的5-10元杂芳环；
R s1各自独立地选自下组：卤素、取代或未取代的C1-C3烷基、氰基；
R b选自下组：H、未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地，C1-C3烷基)、
Figure PCTCN2022096880-appb-000004
R c各自独立地选自下组：H、取代或未取代的C1-C3烷基；
R s2各自独立地选自下组：羟基、取代或未取代的C1-C3烷氧基、卤素、取代或未取代的C1-C3烷基、氰基；
R 3选自下组：H、取代或未取代的C1-C6烷基(较佳地，C1-C3烷基)、N(R d) 2；
R d各自独立地选自下组：H、取代或未取代的C1-C3烷基；
R 4选自下组：未取代或被一个或多个R s3所取代的C1-C6(较佳地，C1-C3烷基)、未取代或被一个或多个R s3所取代的C4-C10环烷基、未取代或被一个或多个R s3所取代的4-10元杂环烷基、未取代或被一个或多个R s3所取代的C6-C10芳基、未取代或被一个或多个R s3所取代的5-10元杂芳基；
R s3各自独立地选自下组：羟基、取代或未取代的C1-C3烷基、卤素、取代或未取代的C1-C3烷基酰基、取代或未取代的C1-C3烷氧基、取代或未取代的C1-C3卤代烷基、取代或未取代的C1-C3羟基烷基；
除非特别说明，所述的取代是指基团中一个或多个氢任选地被选自下组的取代基取代：羟基、卤素、C1-C3烷基、C1-C3卤代烷基、氨基(-NH 2)、-N(C1-C3烷基) 2、-NH(C1-C3烷基)、氰基。
在另一优选例中，X为CH。
在另一优选例中，A为
Figure PCTCN2022096880-appb-000005
在另一优选例中，R a选自下组：H、C1-C3烷基。
在另一优选例中，R a选自下组：H、甲基。
在另一优选例中，A选自下组：不存在或
Figure PCTCN2022096880-appb-000006
其中，R a选自下组：H、C1-C3烷基。
在另一优选例中，A为
Figure PCTCN2022096880-appb-000007
其中，R a选自下组：H、C1-C3烷基。
在另一优选例中，A选自下组：不存在、-NH-、-N(CH 3)-。
在另一优选例中，A选自下组：-NH-、-N(CH 3)-。
在另一优选例中，R 1和R 2是不同的基团。
在另一优选例中，R 1和R 2中的至少一个为卤素(如Cl)。
在另一优选例中，R 1为卤素。
在另一优选例中，R 1和R 2各自独立地选自下组：卤素、
Figure PCTCN2022096880-appb-000008
在另一优选例中，R 1和R 2之一为卤素，另一个为
Figure PCTCN2022096880-appb-000009
在另一优选例中，R 1为卤素且R 2为
Figure PCTCN2022096880-appb-000010
在另一优选例中，R b为未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地C1-C3烷基)。
在另一优选例中，R s2各自独立地选自下组：羟基、取代或未取代的C1-C3烷氧。
在另一优选例中，R s2为羟基。
在另一优选例中，R b为C1-C6羟基烷基，较佳地，C1-C3羟基烷基；更佳地，R b为-CH 2OH。
在另一优选例中，R 1和R 2各自独立地选自下组：卤素、
Figure PCTCN2022096880-appb-000011
且R b为未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地C1-C3烷基)。
在另一优选例中，R 1和R 2各自独立地选自下组：卤素、
Figure PCTCN2022096880-appb-000012
R b为未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地C1-C3烷基)，且R s2各自独立地选自下组：羟基、取代或未取代的C1-C3烷氧基。
在另一优选例中，R 1为卤素且R 2为
Figure PCTCN2022096880-appb-000013
且R b为未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地C1-C3烷基)。
在另一优选例中，R 1为卤素且R 2为
Figure PCTCN2022096880-appb-000014
R b为未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地C1-C3烷基)，且R s2各自独立地选自下组：羟基、取代或未取代的C1-C3烷氧基。
在另一优选例中，R 3选自下组：H、C1-C3烷基、N(R d) 2；其中，R d各自独立地选自下组：H、C1-C3烷基。
在另一优选例中，R 3选自下组：H、C1-C3烷基、NH(C1-C3烷基)。
在另一优选例中，R 3为H或C1-C6烷基(较佳地，C1-C3烷基)。
在另一优选例中，R 4选自下组：未取代或被一个或多个R s3所取代的C1-C6烷基(较佳地，C1-C3烷基)、未取代或被一个或多个R s3所取代的C4-C6环烷基、未取代或被一个或多个R s3所取代的5-6元杂环烷基、未取代或被一个或多个R s3所取代的苯基、未取代或被一个或多个R s3所取代的5-6元杂芳基。
在另一优选例中，R 4选自下组：未取代或被一个或多个R s3所取代的5-6元杂环烷基、未取代或被一个或多个R s3所取代的5-6元杂芳基。
在另一优选例中，R 4中，所述杂环烷基为饱和含氧杂环烷基；较佳地，5-6元含1或2个氧杂原子的杂环烷基。
在另一优选例中，R 4中，所述杂芳基为含硫杂芳基。
在另一优选例中，R 4中，所述杂芳基为五元含硫杂芳基。
在另一优选例中，R s3各自独立地选自下组：羟基、C1-C3烷基、卤素、C1-C3烷基酰基、C1-C3烷氧基、C1-C3卤代烷基、C1-C3羟基烷基。
在另一优选例中，当R 4为未取代或被一个或多个R s3所取代的C4-C10环烷基(较佳地，C4-C6环烷基)、未取代或被一个或多个R s3所取代的4-10元杂环烷基(较佳地，5-6元杂环烷基)时，式I化合物如式I-1或式I-2所示；
Figure PCTCN2022096880-appb-000015
在另一优选例中，所述的化合物中，A、X、R 1、R 2、R 3、R 4、R a、R b、R c、R d、R s1、R s2和R s3各自独立地为实施例中或表1中所述具体化合物(如化合物S1-S35)中所对应的基团。
在另一优选例中，所述式I化合物为选自下表1中的化合物，
表1
Figure PCTCN2022096880-appb-000016
Figure PCTCN2022096880-appb-000017
Figure PCTCN2022096880-appb-000018
或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药。
在本发明的第二方面中，提供了一种药物组合物，包括(i)治疗有效量的如第一方面所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药，和(ii)任选的药学上可接受的载体、赋形剂或稀释剂。
在另一优选例中，所述的药物组合物是用于***的药物组合物，或用于治疗能量代谢酶(优选为PGK1酶)活性相关疾病的药物组合物。
在本发明的第三方面中，提供了一种如第一方面所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药的制备方法，
所述制备方法为方法一或方法二。
在另一优选例中，所述方法一包括步骤：
Figure PCTCN2022096880-appb-000019
v)使化合物ie脱除保护基，然后再与R 4COOH进行缩合反，从而得到化合物if；
vi)任选地使化合物if脱去保护基，从而得到式I化合物；
各式中，R 1'为R 1或被保护基团保护的R 1，R 2'为R 2或被保护基团保护的R 2；
且A、X、R 1、R 2、R 3和R 4如第一方面中定义。
在另一优选例中，方法一中，当R 1或R 2为含羟基的基团，且相应的R 1'或R 2'为羟基被保护(较佳地形成酯从而被保护)的R 1或R 2时，步骤vi)为：在碱性条件下使化合物if进行水解，从而得到化合物ig-1和ig-2。
在另一优选例中，所述方法二包括步骤：
Figure PCTCN2022096880-appb-000020
ii)在惰性溶剂中，在Pd催化下，使化合物iia-1或化合物iia-2或它们的混合物与R b-C≡CH或R 5-B(OH) 2进行偶联反应，从而得到式I化合物；
其中，R 5为未取代或被一个或多个R s1所取代的C6-C10芳环或未取代或被一个或多个R s1所取代的5-10元杂芳环；式I化合物中，R 1和R 2之一为
Figure PCTCN2022096880-appb-000021
未取代或被一个或多个R s1所取代的C6-C10芳环或未取代或被一个或多个R s1所取代的5-10元杂芳环，且另一个如第一方面中定义；A、X、R 3和R 4如第一方面中定义。
在另一优选例中，方法二中，化合物iia-1中R 1和化合物iia-2中R 2为Cl。
在本发明的第四方面中，提供了一种如第一方面所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药，或者如第二方面所述的药物组合物在制备(i)PGK1抑制剂和/或(ii)用于治疗或预防与PGK1相关疾病的药物中的用途。
在另一优选例中，所述与PGK1相关疾病包括：癌症、细胞异常增殖、形态变化、糖代谢异常、运动功能亢进、肿瘤生长、糖尿病，或其组合。
在另一优选例中，所述癌症包括：肝癌、胃癌、结直肠癌、乳腺癌、膀胱癌、胰腺癌、胰腺导管腺癌、神经母细胞瘤、***癌，或其组合。
在本发明的第五方面中，提供了一种治疗或预防治疗或预防与PGK1相关疾病的方法，包括步骤：向需要的对象施用治疗有效量的如第一方面所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药，或如第二方面所述的药 物组合物。
在另一优选例中，所述与PGK1相关疾病包括：癌症、细胞异常增殖、形态变化、糖代谢异常、运动功能亢进、肿瘤生长、糖尿病、炎症、免疫性疾病，或其组合。
在另一优选例中，所述癌症包括：肝癌、胃癌、结直肠癌、乳腺癌、膀胱癌、胰腺癌、胰腺导管腺癌、神经母细胞瘤、***癌，或其组合。
在另一优选例中，所述对象为哺乳动物，较佳地，为人。
在本发明的第六方面中，提供了一种抑制PGK1活性的方法，包括步骤：使PGK1与如第一方面所述的式I化合物接触，从而抑制PGK1的活性。
在另一优选例中，所述的方法是体外非治疗性的。
在本发明的第七方面中，提供了一种抑制细胞增殖活性的方法，包括步骤：在如第一方面所述的式I化合物的存在下培养细胞，从而抑制细胞的增殖活性。
在另一优选例中，所述方法是体外非治疗性的。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
发明人经过广泛而深入地研究。发现将现有喹唑啉类PGK1抑制剂的母核替换为喹喔啉得到一类具有新颖母核结构的PGK1抑制剂依然具有对PGK1抑制活性，甚至部分优选的化合物具有显著增强对PGK1抑制活性，从而获得了一类作为PGK1抑制剂结构新颖的以喹喔啉为母核的喹喔啉衍生物。基于此，发明人完成了本发明。
术语
除非另有定义，术语“烷基”，本身或作为另一取代基的一部分，是指具有指定碳原子数的直链或支链烃基(即，C1-C6表示1-6个碳)。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基等。
如本文所用，术语“环烷基”是指具有指定环原子数(例如，C4-C10环烷基)并且完全饱和的或在环顶之间具有不超过一个双键的烃环，优选为完全饱和的环。“环烷基”可以是单环(如环丙基、环丁基、环己基等)，也可指双环和多环烃环(如并环、螺环、稠环、桥环等)。术语“杂环烷基，在本文中也可称为“杂环基”，是指含有一至五个选自N、O和S的杂原子作为环原子的环烷基，其中氮和硫原子任选被氧化，且氮原子任选被季铵化。杂环烷基可以是单环、双环或多环体系。 一般地，杂环基通常包括5-12个环原子(即5-12元杂环烷基)，优选地，包括5-7个环原子(即5-7元杂环基)并含有1、2、3或4个杂环原子。杂环烷基的非限制性例子包括吗啉环、哌啶环、哌嗪环、N-烷基或酰基取代的哌嗪环、高哌嗪环、N-烷基或酰基取代的高哌嗪环、吡咯、四氢吡咯、7H-嘌呤、四氢呋喃、四氢吡喃等。杂环烷基可以经环碳或杂原子(如环N)连接于分子的其余部分。
术语"烷氧基"以其常规意义使用，指代经氧原子连接于分子的其余部分的那些烷基。此外，对于二烷基氨基，烷基部分可以相同或不同，也可和与各烷基相连的氮原子组合形成3-7元环。因此，-N(R a) 2所示基团表示包括哌啶基、吡咯烷基、吗啉基、氮杂环丁烷基(azetidinyl)等。
除非另有定义，术语“芳基”表示多不饱和的(通常芳香性)的烃基，其可以是单环或稠合在一起或共价连接的多环(最多三环)。一般地，芳基是指具有6-10个环原子全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，且所述的基团具有共轭的π电子体系。所述芳基环可以与杂环烷基、杂芳基或环烷基环稠合，非限制性实施例含苯并咪唑、苯并噻唑、苯并恶唑、苯并异恶唑、苯并吡唑、喹啉、苯并吲哚、苯并二氢呋喃。术语"杂芳基"是指含有1至4个选自N、O和S的杂原子和5至14个环原子的杂芳族体系，其中氮和硫原子任选被氧化，氮原子任选被季铵化。一般地，杂芳基具有5-10个环原子即5-10元杂芳基，优选地，具有5-6个环原子即5或6元杂芳基。杂芳基可通过杂原子连接于分子的其余部分。芳基的非限制性例子包括苯基和萘基。所述芳基(环)可以与杂环烷基、杂芳基或环烷基环稠合，非限制性实例包括苯并咪唑、苯并噻唑、苯并恶唑、苯并异恶唑、苯并吡唑、喹啉、苯并吲哚、苯并二氢呋喃等。杂芳基的非限制性例子包括呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等等。所述的杂芳基可以稠合于芳基、杂环烷基或者环烷基环上，其中与母体结构连接在一起的环为杂芳基环。
如本文所用，术语“杂原子”意在包括氧(O)、氮(N)和硫(S)。
对于本文提供的化合物，从取代基(通常为R基团)到芳香环(例如苯，吡啶等)的中心的键将被理解为是指在芳香环的任何可用顶点提供连接的键。在一些实施例中，该描述也包括稠合在芳环上的环上的连接。例如，绘制到吲哚苯部分的中心的键将表示与吲哚的六元或五元环部分的任何可用顶点连接的键。
如本文所用，术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。类似地，术语“卤代”是指基团中一个或多个氢或全部的氢被如上定义的相同或不同的卤素所取代。
除非特别说明，本发明所描述的结构式意在包括所有的光学异构和立体异构形式(如对映异构体、非对映异构体，几何异构体或构象异构体)：例如含有不对称中心的R、S构型。因此本发明的化合物的单个立体化学异构体、对映异构 体、非对映异构体或几何异构体或构象异构体的混合物都属于本发明的范围。
如本文所用，术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此，术语“主要由...组成”和“由...组成”包含在术语“含有”中。
如本文所用，术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和***反应)，即有合理的效益/风险比的物质。
如本文所用，术语“治疗有效剂量”是指药物的任何如下所述的量，当单独使用或与另一种治疗剂组合使用该量的药物时，可促进疾病消退，疾病消退表现为疾病症状的严重度降低、无疾病症状期的频率和持续时间增加、或者防止由患病导致的障碍或失能。本发明药物的“治疗有效剂量”也包括“预防有效剂量”，“预防有效剂量”是药物的任何如下所述的量，当将该量的药物单独施用或者与另一种治疗剂组合施用于具有发生疾病的风险或者遭受疾病复发的受试者时，可抑制疾病的发生或复发。
喹喔啉衍生物
本发明涉及具有磷酸甘油酸激酶1(PGK1)抑制活性的一类喹喔啉衍生物及其药学上可接受的盐或药学上可接受的溶剂化合物、其制备方法及其在制备预防或治疗与生物体内和PGK相关的细胞异常增殖、形态变化以及糖代谢异常、运动功能亢进、炎症、免疫性疾病等相关的疾病，尤其是用于治疗或预防肿瘤生长与转移和糖尿病的药物中的用途。
如本文所用，术语“本发明化合物”或者“喹喔啉衍生物”或者“喹喔啉类化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
其中，术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。在本发明中，所述的药学上可接受的盐没有特别的限制，优选包括：无机酸盐、有机酸盐、烷基磺酸盐和芳基磺酸盐；所述无机酸盐包括盐酸盐、氢溴酸盐、硝酸盐、硫酸盐、磷酸盐等；所述有机酸盐包括甲酸盐、乙酸盐、丙酸盐、苯甲酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐等；所述烷基磺酸盐包括甲基磺酸盐、乙基磺酸盐等；所述芳基磺酸盐包括苯磺酸盐、对甲苯磺酸盐等。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。在本发明中，所述通式(I)表示的化合物的药学上可接受的溶剂合物没有特别的限制，优选包括：通式(I)表示的化合物与水、乙醇、异丙醇、***、丙酮等的溶剂合物。
此外，本发明化合物还包括式I所示的化合物的前药。术语“前药”包括其本 身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式I的一类化合物，或式I的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
本发明的目的是提供一类结构新颖，且具有优异活性的PGK1激酶抑制剂。
具体地，本发明提供了一种如下式所示的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药。
Figure PCTCN2022096880-appb-000022
其中，R 1、R 2、R 3、R 4、X和A如第一方面中定义。
在一个具体实施例中，
X选自氮原子或CH；和/或
A选自直键或
Figure PCTCN2022096880-appb-000023
和/或其中R a选自氢、C1-C3烷基；和/或
R 1和R 2各自独立地选自氢、卤素、氰基、取代或未取代的氨基，
Figure PCTCN2022096880-appb-000024
取代或未取代的6～10元芳环，取代或未取代的5～10元杂芳环。其中R b选自氢、C1-C3烷基、
Figure PCTCN2022096880-appb-000025
C1-C3烷基可进一步被羟基、卤素、氰基取代。所述取代可选自卤素、C1-C3烷基、氰基；和/或
R 3选自氢，氨基，C1-C3烷基氨基；和/或
R 4选自取代或未取代的C1-C3烷基，取代或未取代的饱和或不饱和的4-10元环烷基，取代或未取代的5～10元杂芳环基，取代或未取代的4～10元杂环基。所述5～10元杂芳环基、4～10元杂环基包含选自O、N、S中的1-3个杂原子。所述的取代基团进一步被一个或多个选自下组的取代基取代：羟基，C1-C3烷基，卤素，C1-C3烷基酰基。其中所述C1-C3烷基可进一步被羟基、卤素、氨基、氰基取代。
在另一优选例中，所述的化合物中，X、A、R 1、R 2、R 3、R 4中任一个分别为实施例中所述具体化合物中所对应的基团。
优选的，本发明通式(I)所示的喹喔啉类化合物选自下表1中的化合物：
表1
Figure PCTCN2022096880-appb-000026
Figure PCTCN2022096880-appb-000027
Figure PCTCN2022096880-appb-000028
制备方法
本发明还提供了一种如本发明第一方面所述的式I化合物的制备方法。下面更具体地描述本发明式I结构化合物的制备方法。但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
本发明的化合物可通过例如方法一或二制备。
在另一优选例中，所述方法一和方法二如第二方面中定义。
在另一优选例中，方法一包括如下步骤：
Figure PCTCN2022096880-appb-000029
i)化合物iiia-1或iiia-2或它们的混合物与碱性亲核试剂(如
Figure PCTCN2022096880-appb-000030
)发生取代反应，得到化合物iiib-1或iiib-2或它们的混合物；
ii)化合物iiib-1或iiib-2或它们的混合物在惰性溶剂中与炔试剂(如R b-C≡CH)通过Pd催化偶联反应并任选地分离，得到化合物iiic-1和/或iiic-2；
iii)化合物iiic-1和/或iiic-2脱除保护基然后再与不同的羧酸(如R 4COOH)通过缩合反应得到化合物iiid-1和/或iiid-2；
iv)任选地使化合物iiid-1和/或iiid-2在碱性条件下水解分别得到化合物iiie-1和iiie-2(即式I化合物，其中，R 1或R 2之一为Cl，另一个为
Figure PCTCN2022096880-appb-000031
)；
其中，除非特别说明，各基团如第一方面中定义。在另一优选例中，当方法一中，R 3为H时，所述方法一为方法一(1)，并包括如下步骤：
Figure PCTCN2022096880-appb-000032
i)化合物ia与乙醛酸乙酯发生关环反应得到化合物ib；
ii)化合物ib在氯代试剂作用下得到化合物ic-1或ic-2或它们的混合物；
iii)使化合物ic-1或ic-2或它们的混合物与碱性亲核试剂(如
Figure PCTCN2022096880-appb-000033
)发生取代反应得到化合物id-1或id-2或它们的混合物；
iv)使化合物id-1或id-2或它们的混合物在惰性溶剂中与炔试剂(如R b-C≡CH或被保护基保护的R b-C≡CH)通过Pd催化偶联反应并任选地分离，得到化合物ie-1和/或ie-2；
v)化合物ie-1和/或ie-2脱除保护基然后再与不同的羧酸(如R 4COOH)通过缩合反应分别得到化合物if-1和/或if-2；
vi)任选地使化合物if-1和/或if-2在碱性条件下水解分别得到化合物ig-1和/或ig-2(即式I化合物，其中，R 1或R 2之一为Cl，另一个为
Figure PCTCN2022096880-appb-000034
)；
其中，除非特别说明，各基团如第一方面中定义。
制备方法二：
Figure PCTCN2022096880-appb-000035
i)化合物id-1或id-2或它们的混合物脱除保护基然后再与不同的羧酸(如R 4COOH)通过缩合反应并任选地分离，得到iia-1和/或iia-2的混合物；
ii)iia-1和/或iia-2的混合物在惰性溶剂中与不同的硼酸(如R 5-B(OH) 2，其中R 5如前定义)或不同的炔试剂(如R b-C≡CH)通过Pd催化偶联反应，得到化合物iib-1和/或iib-2(即式I化合物，其中，R 1和R 2之一为Cl，另一个为
Figure PCTCN2022096880-appb-000036
未取代或被一个或多个R s1所取代的C6-C10芳环或未取代或被一个或多个R s1所取代的5-10元杂芳环(即R 5))。
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。
药物组合物和施用方法
由于本发明化合物具有优异的对磷酸甘油酸激酶1(PGK1)抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与磷酸甘油酸激酶1(PGK1)相关的的疾病。根据现有技术，本发明化合物可用于治疗以下疾病：癌症、细胞异常增殖、形态变化、糖代谢异常、运动功能亢进、肿瘤生长、糖尿病，或其组合；其中，所述癌症包括：肝癌、胃癌、结直肠癌、乳腺癌、膀胱癌、胰腺癌、胰腺导管腺癌、神经母细胞瘤、***癌，或其组合。
本发明还提供了式I化合物(喹喔啉衍生物)或其异构体或其药剂学上可接受的盐、酯、前药或水合物的用途，其作为PGK1抑制剂，在制备预防和/或治疗与PGK1相关疾病的药物中的用途，与PGK1相关疾病包括各种癌症(肝癌、胃 癌、结直肠癌、乳腺癌、膀胱癌、胰腺癌及神经母细胞瘤等)。
本发明还提供了一种药物组合物，包括治疗有效量的如本发明第一方面中所述的化合物，或其药用盐、其前药、其水合物或溶剂合物，和任选的药学上可接受的载体、赋形剂或稀释剂等。
在另一优选例中，所述的药物组合物是用于***的药物组合物，或用于治疗能量代谢酶(优选为PGK1酶)活性相关疾病的药物组合物。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-500mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022096880-appb-000037
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的 包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.本发明的化合物(尤其是优选的化合物)对PGK1具有很强的抑制活性，在人肝癌SNU739或HepG2细胞上显示出较强的增殖抑制活性。
具体如下：
1.1特拉唑嗪(如下所示)在高浓度(2.5-25μM)下抑制PGK1，本发明的优选化合物对PGK1的抑制IC 50值小于100nM；
1.2.本发明的优选化合物对人肝癌SNU739或HepG2具有显著的增殖抑制活性。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
一、制备实施例
对于以下实施例，可以使用本领域技术人员已知的标准操作和纯化方法。除非另有规定，否则原料通常是从市售来源可获得的。商购的溶剂和试剂一般在不进一步纯化的情况下使用，无水溶剂均通过标准方法处理，其他试剂为市售分析纯。除非另有说明，所有温度以℃(摄氏度)表示，室温或环境温度是指20～25℃。产品的纯化除说明外均使用硅胶(200～30目)柱色谱法。化合物的结构通过核磁共振谱(NMR)来确定。核磁共振氢谱位移(δ)以百万分之一(ppm)的单位给出。核磁共振氢谱用Varian MercuryAMX300型仪测定，氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)、氘代二甲基亚砜(d6-DMSO)为溶剂，四甲基硅烷(TMS)为内标。
缩写
DIPEA：N,N-二异丙基乙胺
TBTU：O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸
TFA：三氟醋酸
DAST：二乙胺基三氟化硫
Pd 2(dba) 3：三(二亚苄基丙酮)二钯
Xantphos：4,5-双二苯基膦-9,9-二甲基氧杂蒽
DMF：N,N-二甲基甲酰胺
制备实施例1 化合物S1的制备
Figure PCTCN2022096880-appb-000038
步骤1：称量化合物1a(243mg，1当量)于单口瓶中，加入乙醇做溶剂，然后再向里加乙醛酸乙酯(50％甲苯溶液，222mg，1.2当量)，加毕升至80℃下反应2小时。反应结束后，冷却至室温，由大量固体析出，抽滤，得1b和1c的混合物。
Figure PCTCN2022096880-appb-000039
步骤2：称量1b和1c的混合物(1.385g，1当量)于单口瓶中，加入三氯氧磷(4.2mL，10当量)，DIPEA(3.0mL，4当量)，110℃下反应4小时。反应完全后，减压蒸馏出部分三氯氧磷，然后将反应液倒入冰水中，饱和碳酸氢钠溶液中和，乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得1d和1e的混合物。
Figure PCTCN2022096880-appb-000040
步骤3：称量1d和1e的混合物(486mg，1当量)、1f(482mg，1.5当量)于单口瓶中，向里加1,4-二氧六环溶剂，再加入DIPEA(0.74mL，3当量)，100℃下反应3小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得1g和1h的混合物。
Figure PCTCN2022096880-appb-000041
步骤4：称量1g和1h的混合物(168mg，1当量)、PdCl 2(PPh 3) 2(23mg，0.1当量)、CuI(13mg，0.2当量)于单口瓶中，向里加四氢呋喃溶剂，再加入乙酸丙炔酯(66μL，2当量)、DIPEA(0.60mL，4当量)，氮气保护，80℃下加热反应5小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗， 无水硫酸钠干燥后拌样上柱，得化合物1i和1j。化合物1i的分析数据： 1H NMR(400MHz,CDCl 3)δ8.57(s,1H),8.00(s,1H),7.67(s,1H),4.99(s,2H),4.71(d,J＝13.4Hz,2H),4.33(br,1H),3.06(t,J＝12.4Hz,2H),2.72(s,3H),2.16(s,3H),1.84(d,J＝12.7Hz,2H),1.73(t,J＝13.6Hz,2H),1.48(s,9H).化合物1j的分析数据： 1H NMR(400MHz,CDCl 3)δ8.56(s,1H),7.88(s,1H),7.82(s,1H),4.99(s,2H),4.67(d,J＝13.4Hz,2H),4.40–4.21(m,1H),3.05(t,J＝12.7Hz,2H),2.72(s,3H),2.16(s,3H),1.83(d,J＝9.8Hz,2H),1.78–1.68(t,J＝7.7Hz,2H),1.48(s,9H).
Figure PCTCN2022096880-appb-000042
步骤5：称量化合物1j(78mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(0.12mL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(29mg，1.5当量)，TBTU(106mg，2当量)，DIPEA(0.14mL 5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物1k。化合物1k的分析数据： 1H NMR(400MHz,CDCl 3)δ8.53(s,1H),7.85(s,1H),7.78(s,1H),4.96(s,2H),4.78–4.69(m,1H),4.68–4.56(m,3H),4.00–3.79(m,2H),3.07(t,J＝12.0Hz,2H),2.89(s,2H),2.77(s,1H),2.13–2.17(m,1H),2.13(s,3H),2.09–1.84(m,5H),1.80–1.66(m,3H).
Figure PCTCN2022096880-appb-000043
步骤6：称量化合物1k(73mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(13mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S1。化合物S1的分析数据：
1H NMR(400MHz,CD 3OD)δ8.70(d,J＝3.0Hz,1H),7.82(s,1H),7.72(s,1H),4.84(d,J＝7.5Hz,0.4H),4.82–4.69(m,2.6H),4.68–4.60(m,0.6H),4.49(s,2H),4.27–4.19(m,0.4H),4.02–3.82(m,2H),3.18–3.04(m,2H),2.92(s,1.8H),2.78(s,1.2H),2.27–2.07(m,1.5H),2.03–1.73(m,6.5H).
制备实施例2 化合物S2的制备
Figure PCTCN2022096880-appb-000044
步骤1：称量化合物1i(63mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(99μL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(23mg，1.5当量)，TBTU(86mg，2当量)，DIPEA(0.11mL 5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物2a。化合物2a的分析数据： 1H NMR(400MHz,CDCl 3)δ8.99(s,1H),8.42(s,1H),8.09(s,1H),5.42(s,2H),5.21–5.06(m,4H),4.36(d,J＝36.2Hz,2H),3.54(t,J＝14.8Hz,2H),3.34(s,2H),3.22(s,1H),2.63(br,1H),2.58(s,3H),2.37–2.31(m,4H),2.24–2.14(m,4H).
Figure PCTCN2022096880-appb-000045
步骤2：称量化合物2a(53mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(9mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S2。化合物S2的分析数据： 1H NMR(400MHz,d6-DMSO)δ8.89(s,1H),7.93(s,1H),7.67(s,1H),5.42(t,J＝6.0Hz,1H),4.81–4.74(m,2.5H),4.63(dd,J＝7.3,5.9Hz,0.5H),4.59–4.52(m,0.5H),4.38(d,J＝6.0Hz,2H),4.22–4.16(m,0.5H),3.81–3.70(m,2H),3.17–3.04(m,2H),2.83(s,1.7H),2.64(s,1.3H),2.12–1.94(m,2H),1.90–1.66(m,5H),1.62–1.59(m,1H).
制备实施例3 化合物S3的制备
化合物S3的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为噻吩-2-甲酸，化合物S3的分析数据： 1H NMR(400MHz,CD 3OD)δ8.72(s,1H),7.83(s,1H),7.74(s,1H),7.65(d,J＝5.0Hz,1H),7.47(d,J＝3.5Hz,1H),7.17–7.10(m,1H),4.80(d,J＝13.3Hz,2H),4.60(br,1H),4.49(s,2H),3.06(br,5H),2.04–1.90(m,4H).
制备实施例4 化合物S4的制备
化合物S4的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为4,5-二氯噻吩-2-甲酸，化合物S4的分析数据： 1H NMR(400MHz,CDCl 3)δ8.57(s,1H),7.90 (s,1H),7.80(s,1H),7.16(s,1H),4.73–4.70(m,3H),4.60(s,2H),3.13(d,J＝13.1Hz,2H),3.06(s,3H),1.92(d,J＝10.0Hz,3H),1.84(d,J＝10.3Hz,1H).
制备实施例5 化合物S5的制备
化合物S5的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为4-乙酰基噻吩-2-甲酸(合成方法参见专利WO2001096286)，化合物S5的分析数据： 1H NMR(400MHz,d6-DMSO)δ8.91(s,1H),8.65(d,J＝1.1Hz,1H),7.96(s,1H),7.75(br,1H),7.70(s,1H),5.47(br,1H),4.78(d,J＝13.1Hz,2H),4.54(br,1H),4.40(s,2H),3.04(d,J＝22.0Hz,5H),2.52(s,3H),1.82(br,4H).
制备实施例6 化合物S6的制备
化合物S6的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为4-(羟甲基)噻吩-2-羧酸，化合物S6的分析数据： 1H NMR(400MHz,d6-DMSO)δ8.92(s,1H),7.96(s,1H),7.70(s,1H),7.50(s,1H),7.40(s,1H),5.48(t,J＝6.0Hz,1H),5.20(t,J＝5.7Hz,1H),4.77(d,J＝13.0Hz,2H),4.54(s,1H),4.47(d,J＝5.6Hz,2H),4.40(d,J＝6.0Hz,2H),3.07(t,J＝12.0Hz,2H),2.97(s,3H),1.89–1.73(m,4H).
制备实施例7 化合物S7的制备
Figure PCTCN2022096880-appb-000046
化合物7a的合成方法参见化合物1k；
步骤1：称量化合物7a(82mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，冰浴下加入DAST(31μL，1.5当量)，室温下反应0.5小时。反应完全后，用碳酸氢钠中和反应液，然后二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物7b。化合物7b的分析数据： 1H NMR(400MHz,CDCl 3)δ8.58(s,1H),7.89(s,1H),7.83(s,1H),7.47(s,1H),7.37(s,1H),5.35(d,J＝47.8Hz,2H),4.99(s,2H),4.71(d,J＝13.1Hz,3H),3.16–3.00(m,5H),2.16(s,3H),1.96–1.82(m,4H).
Figure PCTCN2022096880-appb-000047
步骤6：称量化合物7b(30mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(5mg，2当量)，室温下反应3小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S7。化合物S7的分析数据： 1H NMR(400MHz,CDCl 3)δ8.57(s,1H),7.90(s,1H),7.80(s,1H),7.48(s,1H),7.38(s,1H),5.35(d,J ＝47.9Hz,2H),4.73–4.69(m,3H),4.60(s,2H),3.12(d,J＝12.0Hz,2H),3.06(s,3H),2.08(br,1H),1.94(d,J＝10.8Hz,2H),1.86(d,J＝10.2Hz,1H).
制备实施例8 化合物S8的制备
化合物S8的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为4-二氟甲基噻吩-2-甲酸(合成方法参见文献European Journal ofMedicinal Chemistry,2018,159,23-34)，化合物S8的分析数据： 1H NMR(400MHz,CDCl 3)δ8.57(s,1H),7.89(s,1H),7.80(s,1H),7.67(s,1H),7.43(s,1H),6.67(t,J＝56.2Hz,1H),4.71(d,J＝13.3Hz,3H),4.60(d,J＝4.8Hz,2H),3.12(d,J＝12.4Hz,2H),3.06(s,3H),2.01(t,J＝6.4Hz,1H),1.90(dd,J＝33.1,11.6Hz,4H).
制备实施例9 化合物S9的制备
Figure PCTCN2022096880-appb-000048
称量化合物S5(48mg，1当量)于单口瓶中，加入乙醇作溶剂，然后冰浴下向里加硼氢化钠(11mg，3当量)，加毕升至室温下反应6小时。反应结束后，向反应液中加水和乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S9。化合物S9的分析数据： 1H NMR(400MHz,CDCl 3)δ8.57(s,1H),7.89(s,1H),7.79(s,1H),7.38(s,1H),7.33(s,1H),5.00–4.91(m,1H),4.71(d,J＝13.2Hz,3H),4.60(d,J＝6.2Hz,2H),3.11(d,J＝13.3Hz,2H),3.05(s,3H),2.04(t,J＝6.3Hz,1H),1.95(d,J＝14.8Hz,3H),1.86(d,J＝10.9Hz,2H),1.53(d,J＝6.4Hz,3H).
制备实施例10 化合物S10的制备
Figure PCTCN2022096880-appb-000049
称量化合物S5(135mg，1当量)于单口瓶中，加入四氢呋喃作溶剂，氮气保护，然后冰浴下向里甲基溴化镁(3M四氢呋喃溶液，0.38mL，3当量)，加毕升至室温下反应8小时。反应结束后，向反应液中饱和氯化铵溶液淬灭，然后加水和乙酸乙酯萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S10。化合物S10的分析数据： 1H NMR(600MHz,d6-DMSO)δ8.91(s,1H),7.96(s,1H),7.70(s,1H),7.45(d,J＝4.4Hz,2H),5.46(t,J＝6.0Hz,1H),5.11(s,1H),4.78(d,J＝13.3Hz,2H),4.51(br,1H),4.40(d,J＝6.0Hz,2H),3.05(br,2H),2.97(br,3H),1.87–1.80(m,4H),1.43(s,6H).
制备实施例11 化合物S11的制备
化合物S11的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为1,4-二氧六环-2-甲酸，化合物S11的分析数据：
1H NMR(400MHz,CD 3OD)δ8.72(d,J＝5.0Hz,1H),7.83(d,J＝2.5Hz,1H),7.74(d,J＝2.7Hz,1H),4.78(d,J＝13.1Hz,2H),4.65–4.57(m,0.6H),4.53(dd,J＝9.4,2.7Hz,0.4H),4.49(s,2H),4.41(dd,J＝9.4,2.7Hz,0.6H),4.24–4.17(m,0.4H),3.90–3.71(m,4H),3.70–3.59(m,2H),3.19–3.05(m,2H),2.95(s,1.7H),2.76(s,1.3H),1.98–1.78(m,3H),1.74(d,J＝12.7Hz,1H).
制备实施例12 化合物S12的制备
Figure PCTCN2022096880-appb-000050
称量化合物S7(24mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，冰浴下加入DAST(10μL，1.5当量)，室温下反应0.5小时。反应完全后，用碳酸氢钠中和反应液，然后二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S12。化合物S12的分析数据： 1H NMR(400MHz,CDCl 3)δ8.59(s,1H),7.91(s,1H),7.84(s,1H),7.48(s,1H),7.37(s,1H),5.41(s,1H),5.33(s,1H),5.29(s,1H),5.22(s,1H),4.73–4.70(m,3H),3.13(d,J＝15.2Hz,2H),3.06(s,3H),1.96–1.85(m,4H).
制备实施例13 化合物S13的制备
化合物S13的合成路线参见化合物S1，将原料4-N-叔丁氧羰基-4-N-甲基氨基哌啶替换为4-叔丁氧羰基氨基哌啶，将(R)-四氢呋喃甲酸替换为4-(羟甲基)噻吩-2-羧酸。化合物S13的分析数据：
1H NMR(500MHz,d6-DMSO)δ8.91(s,1H),8.30(d,J＝7.8Hz,1H),7.96(s,1H),7.72(d,J＝10.2Hz,2H),7.47(s,1H),5.45(t,J＝6.0Hz,1H),5.17(t,J＝5.5Hz,1H),4.60(d,J＝13.4Hz,2H),4.43(d,J＝5.5Hz,2H),4.40(d,J＝6.0Hz,2H),4.15–4.06(m,1H),3.18(t,J＝12.0Hz,2H),1.93(d,J＝10.3Hz,2H),1.63–1.53(m,2H).
制备实施例14 化合物S14的制备
化合物S14的合成路线参见化合物S1，将原料4-N-叔丁氧羰基-4-N-甲基氨基哌啶替换为4-叔丁氧羰基氨基哌啶。化合物S14的分析数据：
1H NMR(500MHz,CDCl 3)δ8.55(s,1H),7.89(s,1H),7.79(s,1H),6.63(d,J＝8.1Hz,1H),4.59(s,2H),4.49(d,J＝13.8Hz,2H),4.34(dd,J＝8.3,6.0Hz,1H),4.15–4.05(m,1H),3.95–3.84(m,2H),3.34–3.08(m,2H),2.35–2.27(m,1H),2.12–2.02(m,3H),1.95–1.83(m,2H),1.57–1.48(m,3H).
制备实施例15 化合物S15的制备
Figure PCTCN2022096880-appb-000051
步骤1：称量1d和1e的混合物(650mg，1当量)、哌嗪-1-甲酸叔丁酯(559mg，1.5当量)于单口瓶中，向里加1,4-二氧六环溶剂，再加入DIPEA(0.99mL，3当量)，100℃下反应3小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得15a和15b的混合物。
Figure PCTCN2022096880-appb-000052
步骤2：称量15a和15b的混合物(768mg，1当量)、PdCl 2(PPh 3) 2(131mg，0.1当量)、CuI(71mg，0.2当量)于单口瓶中，向里加四氢呋喃溶剂，再加入乙酸丙炔酯(0.37mL，2当量)、DIPEA(1.24mL，4当量)，氮气保护，80℃下加热反应5小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物15c和15d。化合物15c的分析数据： 1H NMR(400MHz,CDCl 3)δ8.54(s,1H),8.01(s,1H),7.68(s,1H),4.99(s,2H),3.85–3.76(m,4H),3.64–3.55(m,4H),2.15(s,3H),1.49(s,9H)；化合物15d的分析数据： 1H NMR(400MHz,CDCl 3)δ8.53(s,1H),7.90(s,1H),7.83(s,1H),4.99(s,2H),3.78–3.72(m,4H),3.63–3.55(m,4H),2.15(s,3H),1.49(s,9H).
Figure PCTCN2022096880-appb-000053
步骤3：称量化合物15d(60mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(0.10mL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(23mg，1.5 当量)，TBTU(87mg，2当量)，DIPEA(0.11mL，5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物15e。化合物15e的分析数据： 1H NMR(400MHz,CDCl 3)δ8.55(s,1H),7.91(s,1H),7.84(s,1H),4.99(s,2H),4.69–4.62(m,1H),3.99–3.83(m,6H),3.80–3.62(m,4H),2.80(s,3H),2.44–2.34(m,1H),2.16(s,3H),2.10–1.99(m,3H).
Figure PCTCN2022096880-appb-000054
步骤4：称量化合物15e(48mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(9mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S15。化合物S15的分析数据： 1H NMR(400MHz,CD 3OD)δ8.69(s,1H),7.83(s,1H),7.73(s,1H),4.79(dd,J＝7.8,6.0Hz,1H),4.49(s,2H),4.01–3.63(m,10H),2.30–2.06(m,2H),2.04–1.91(m,2H).
制备实施例16 化合物S16的制备
Figure PCTCN2022096880-appb-000055
步骤1：称量化合物15c(60mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(0.10mL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(23mg，1.5当量)，TBTU(87mg，2当量)，DIPEA(0.11mL，5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物16a。化合物16a的分析数据： 1H NMR(400MHz,CDCl 3)δ8.56(s,1H),8.03(s,1H),7.70(s,1H),4.99(s,2H),4.68–4.61(m,1H),3.97–3.67(m,10H),2.46–2.34(m,1H),2.15(s,3H),2.11–1.90(m,3H).
Figure PCTCN2022096880-appb-000056
步骤2：称量化合物16a(57mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(11mg，2当量)，室温下反应4小时。 反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S16。化合物S16的分析数据：
1H NMR(400MHz,CD 3OD)δ8.70(s,1H),7.92(s,1H),7.65(s,1H),4.79(dd,J＝7.8,6.0Hz,1H),4.48(s,2H),3.96(dd,J＝14.6,7.0Hz,3H),3.91–3.78(m,5H),3.75–3.65(m,2H),2.26–2.08(m,2H),2.01–1.92(m,2H).
制备实施例17 化合物S17的制备
化合物S17的合成方法参见化合物S15，将(R)-四氢呋喃甲酸替换为4-(羟甲基)噻吩-2-羧酸，化合物S17的分析数据： 1H NMR(400MHz,CD 3OD)δ8.71(s,1H),7.86(s,1H),7.77(s,1H),7.52(s,1H),7.44(s,1H),4.62(s,2H),4.49(s,2H),3.94(s,8H).
制备实施例18 化合物S18的制备
化合物S18的合成方法参见化合物S16，将(R)-四氢呋喃甲酸替换为4-(羟甲基)噻吩-2-羧酸，化合物S18的分析数据： 1H NMR(400MHz,d6-DMSO)δ8.87(s,1H),7.98(s,1H),7.72(s,1H),7.54(s,1H),7.42(d,J＝1.0Hz,1H),5.44(br,1H),5.23(br,1H),4.48(s,2H),4.39(s,2H),3.94(dd,J＝6.6,3.5Hz,4H),3.84(s,4H).
制备实施例19 化合物S19的制备
化合物S19的合成方法参见化合物S15，将(R)-四氢呋喃甲酸替换为(R)-2-三氟甲基-2-羟基丙酸，化合物S19的分析数据： 1H NMR(400MHz,CD 3OD)δ8.71(s,1H),7.86(s,1H),7.78(s,1H),4.49(s,2H),4.24(br,2H),3.87(br,4H),3.84–3.70(m,2H),1.65(s,3H).
制备实施例20 化合物S20的制备
Figure PCTCN2022096880-appb-000057
化合物20a的合成方法参见专利WO2012045196A。
步骤1：称量化合物20a(359mg，1当量)于微波管中，加入四氢呋喃做溶剂，然后再向里加乙胺水溶液(12mol/L，0.17mL，2当量)，微波反应20分钟。反应结束后，乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得20b和20c的混合物。
Figure PCTCN2022096880-appb-000058
步骤2：称量20b和20c的混合物(405mg，1当量)、1f(471mg，1.5当量)于单口瓶中，向里加1,4-二氧六环溶剂，再加入DIPEA(0.55mL，3当量)，100℃下反应16小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得20d和20e的混合物。
Figure PCTCN2022096880-appb-000059
步骤5：称量20d和20e的混合物(582mg，1当量)、PdCl 2(PPh 3) 2(74mg，0.1当量)、CuI(42mg，0.2当量)于单口瓶中，向里加四氢呋喃溶剂，再加入乙酸丙炔酯(0.21mL，2当量)、DIPEA(0.70mL，4当量)，氮气保护，80℃下加热反应5小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物20f和20g。化合物20f的分析数据： 1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.64(s,1H),5.36(t,J＝5.5Hz,1H),4.97(s,2H),4.17(br,1H),3.67(d,J＝11.6Hz,2H),3.62–3.53(m,2H),2.91(t,J＝11.1Hz,2H),2.80(s,3H),2.14(s,3H),1.93–1.80(m,4H),1.48(s,9H),1.32(t,J＝7.2Hz,3H).化合物20g的分析数据： 1H NMR(400MHz,CDCl 3)δ7.79(s,1H),7.70(s,1H),4.98(s,2H),4.15(br,1H),3.74(d,J＝13.8Hz,2H),3.60–3.52(m,2H),2.91(t,J＝11.8Hz,2H),2.80(s,3H),2.15(s,3H),1.92–1.79(m,4H),1.48(s,9H),1.32(t,J＝7.1Hz,3H).
Figure PCTCN2022096880-appb-000060
步骤6：称量化合物20f(65mg，1当量)于单口瓶中，向里加二氯甲烷溶 剂，再加入TFA(94μL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(22mg，1.5当量)，TBTU(81mg，2当量)，DIPEA(0.10mL 5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物20h。化合物20h的分析数据： 1H NMR(400MHz,CDCl 3)δ7.83(d,J＝3.6Hz,1H),7.65(d,J＝5.9Hz,1H),5.39–5.32(m,1H),4.97(s,2H),4.68–4.59(m,1.7H),4.12(br,0.3H),4.01–3.85(m,2H),3.70(d,J＝13.2Hz,2H),3.63–3.54(m,2H),3.03–2.92(m,4H),2.89(s,1H),2.14(s,3H),2.09–1.76(m,8H),1.32(t,J＝3.5Hz,3H).
Figure PCTCN2022096880-appb-000061
步骤7：称量化合物20h(64mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(11mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S20。化合物S20的分析数据： 1H NMR(400MHz,CD 3OD)δ7.72(s,1H),7.56(d,J＝1.8Hz,1H),4.83–4.79(m,0.5H),4.75–4.72(m,0.5H),4.58–4.51(m,0.5H),4.46(s,2H),4.12–4.03(m,0.5H),4.12–4.03(m,1H),3.91–3.83(m,1H),3.76(d,J＝12.0Hz,2H),3.57(qd,J＝7.1,2.5Hz,2H),3.01(s,1.7H),2.95–2.92(m,2H),2.89(s,1.3H),2.29–2.16(m,2H),2.13–1.92(m,4H),1.84–1.69(m,2H),1.29(td,J＝7.1,2.5Hz,3H).
制备实施例21 化合物S21的制备
Figure PCTCN2022096880-appb-000062
步骤1：称量化合物20g(65mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(94μL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(22mg，1.5当量)，TBTU(81mg，2当量)，DIPEA(0.10mL 5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物21a。化合物21a的分析数据： 1H NMR(400MHz,CDCl 3)δ7.79(d,J＝6.2Hz,1H),7.70(s,1H),5.35(d,J＝7.2Hz,1H),5.17(br,1H),4.98(s,2H),4.65(t,J＝6.5Hz,1H),4.02–3.71(m,4H),3.61–3.51(m,2H),3.03–2.93(m,3.7H),2.89(s,1.3H),2.15(s,3H),2.04–1.73(m,8H),1.31(t,J＝3.8HZ,3H).
Figure PCTCN2022096880-appb-000063
步骤2：称量化合物21a(52mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(8mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S21。化合物S21的分析数据： 1H NMR(400MHz,CD 3OD)δ7.67(d,J＝1.7Hz,1H),7.62(s,1H),4.83–4.79(m,0.5H),4.75–4.72(m,0.5H),4.58–4.51(m,0.5H),4.47(s,2H),4.12–4.03(m,0.5H),3.99–3.92(m,1H),3.89–3.82(m,3H),3.55(qd,J＝6.7,2.4Hz,2H),3.00(s,1.7H),2.94(t,J＝12.4Hz,2H),2.88(s,1.3H),2.29–1.93(m,6H),1.85–1.69(m,2H),1.29(t,J＝6.7Hz,3H).
制备实施例22 化合物S22的制备
化合物S22的合成方法参见化合物S20，将(R)-四氢呋喃甲酸替换为4-(羟甲基)噻吩-2-羧酸，化合物S22的分析数据： 1H NMR(400MHz,CD 3OD)δ7.72(s,1H),7.57(s,1H),7.49(s,1H),7.43(s,1H),4.60(s,2H),4.46(br,3H),3.78(d,J＝11.4Hz,2H),3.57(q,J＝7.1Hz,2H),3.15(br,3H),2.90(br,2H),2.26–2.17(m,2H),1.86(d,J＝11.4Hz,2H),1.29(t,J＝7.1Hz,3H).
制备实施例23 化合物S23的制备
化合物S23的合成方法参见化合物S21，将(R)-四氢呋喃甲酸替换为4-(羟甲基)噻吩-2-羧酸，化合物S23的分析数据： 1H NMR(400MHz,CD 3OD)δ7.67(s,1H),7.63(s,1H),7.49(s,1H),7.43(s,1H),4.60(s,2H),4.47(br,3H),3.85(d,J＝12.8Hz,2H),3.56(q,J＝7.2Hz,2H),3.14(br,3H),2.92(br,2H),2.27–2.16(m,2H),1.86(d,J＝10.9Hz,2H),1.30(t,J＝7.2Hz,3H).
制备实施例24 化合物S24的制备
Figure PCTCN2022096880-appb-000064
步骤1：称量混合物20b和20c(405mg，1当量)、哌嗪-1-甲酸叔丁酯(410mg，1.5当量)于单口瓶中，向里加1,4-二氧六环溶剂，再加入DIPEA(0.55mL， 3当量)，100℃下反应16小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得24a和24b的混合物。
Figure PCTCN2022096880-appb-000065
步骤2：称量24a和24b的混合物(493mg，1当量)、PdCl 2(PPh 3) 2(67mg，0.1当量)、CuI(38mg，0.2当量)于单口瓶中，向里加四氢呋喃溶剂，再加入乙酸丙炔酯(0.19mL，2当量)、DIPEA(0.63mL，4当量)，氮气保护，80℃下加热反应5小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物24c和24d。化合物24c的分析数据： 1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.66(s,1H),5.36(t,J＝4.9Hz,1H),4.98(s,2H),3.63–3.54(m,6H),3.24–3.14(m,4H),2.14(s,3H),1.49(s,9H),1.31(t,J＝7.2Hz,3H)；化合物24d的分析数据： 1H NMR(400MHz,CDCl 3)δ7.80(s,1H),7.70(s,1H),4.98(s,2H),3.65–3.59(m,4H),3.58–3.52(m,2H),3.27–3.21(m,4H),2.15(s,3H),1.49(s,9H),1.31(t,J＝7.2Hz,3H).
Figure PCTCN2022096880-appb-000066
步骤3：称量化合物24c(64mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(97μL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(23mg，1.5当量)，TBTU(84mg，2当量)，DIPEA(0.11mL 5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物24e。化合物24e的分析数据： 1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.67(s,1H),5.37–5.34(m,1H),4.98(s,2H),4.66(dd,J＝7.4,5.3Hz,1H),3.98–3.73(m,6H),3.58(dt,J＝12.7,6.4Hz,2H),3.30(t,J＝5.0Hz,2H),3.27–3.21(m,2H),2.15(s,3H),2.12–1.98(m,4H),1.32(t,J＝7.2Hz,3H).
Figure PCTCN2022096880-appb-000067
步骤4：称量化合物24e(62mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(11mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S24。化合物S24的分析数据： 1H NMR(400MHz,CD 3OD)δ7.73(d,J＝3.7Hz,1H),7.58(d,J＝3.1Hz,1H),4.78(dd,J＝7.7,6.0Hz,1H),4.46(s,2H),3.96(dd,J＝14.7,6.8Hz,1H),3.87(dd,J＝14.6,6.6Hz,3H),3.82–3.75(m,2H),3.57(q,J＝7.1Hz,2H),3.30–3.20(m,4H),2.24–2.17(m,1H),2.13–2.05(m,1H),2.00–1.92(m,2H),(t,J＝7.1Hz,3H).
制备实施例25 化合物S25的制备
Figure PCTCN2022096880-appb-000068
步骤1：称量化合物24d(60mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(91μL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(21mg，1.5当量)，TBTU(79mg，2当量)，DIPEA(0.10mL 5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物25a。化合物25a的分析数据： 1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.70(s,1H),5.19(t,J＝5.6Hz,1H),4.98(s,2H),4.66(dd,J＝7.1,5.6Hz,1H),3.98–3.78(m,6H),3.57(dt,J＝14.3,7.0Hz,2H),3.34(br,2H),3.28(br,2H),2.15(s,3H),2.11–1.91(m,4H),1.32(t,J＝7.2Hz,3H).
Figure PCTCN2022096880-appb-000069
步骤2：称量化合物25a(52mg，1当量)于单口瓶中，加入四氢呋喃和水(2：1)作溶剂，然后再向里加氢氧化锂一水合物(9mg，2当量)，室温下反应4小时。反应结束后，向反应液中加水和二氯甲烷萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S25。化合物S25的分析数据：
1H NMR(400MHz,CD 3OD)δ7.68(s,1H),7.63(d,J＝2.4Hz,1H),4.78(dd,J＝7.6,6.1Hz,1H),4.47(s,2H),3.95(dd,J＝14.6,6.9Hz,1H),3.87(dd,J＝14.4,6.6Hz,3H),3.81–3.74(m,2H),3.56(q,J＝7.1Hz,2H),3.35(br,4H),2.26–2.17(m,1H),2.12–2.05(m,1H),2.00–1.92(m,2H),1.29(t,J＝7.1Hz,3H).
制备实施例26 化合物S26的制备
Figure PCTCN2022096880-appb-000070
步骤1：称量1g和1h的混合物(519mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入三氟醋酸(TFA，0.74mL，10当量)，室温下反应3小时。反应完全后，旋干反应液。然后向里加二氯甲烷作溶剂，依次加入(R)-四氢呋喃甲酸(174mg，1.5当量)，TBTU(642mg，2当量)，DIPEA(0.83mL，5当量)，室温反应3小时。反应完全后，用二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得26a和26b的混合物。
Figure PCTCN2022096880-appb-000071
步骤2：称量26a和26b的混合物(460mg，1当量)、氨基甲酸叔丁酯(138mg，1.3当量)、Pd 2(dba) 3(83mg，0.1当量)、Xantphos(110mg，0.2当量)、碳酸铯(598mg，2当量)于单口瓶中，向里加1，4-二氧六环作溶剂，氮气保护，100℃下加热反应6小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物26c和26d。化合物26c的分析数据： 1H NMR(400MHz,CDCl 3)δ8.63(d,J＝5.9Hz,1H),8.59(d,J＝4.3Hz,1H),7.72(d,J＝5.2Hz,1H),7.08(s,1H),4.81–4.75(m,0.6H),4.73–4.62(m,3H),4.27–4.20(m,0.4H),4.05–3.86(m,2H),3.16–3.03(m,2H),2.93(s,2H),2.82(s,1H),2.29–2.18(m,1H),2.15–2.03(m,2H),1.99–1.89(m,2H),1.84–1.77(m,3H),1.58(s,9H).化合物26d的分析数据： 1H NMR(400MHz,CDCl 3)δ8.47(d,J＝7.5 Hz,1H),8.45(d,J＝4.2Hz,1H),7.85(d,J＝5.1Hz,1H),7.22(d,J＝5.3Hz,1H),4.80–4.59(m,3.5H),4.27–4.17(m,0.5H),4.03–3.85(m,2H),3.12–3.01(m,2H),2.89(s,2H),2.78(s,1H),2.44–2.37(m,0.5H),2.26–2.16(m,1H),2.13–2.00(m,2.5H),1.97–1.87(m,3H),1.81–1.75(m,1H),1.56(s,9H).
Figure PCTCN2022096880-appb-000072
步骤3：称量化合物26d(52mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入三氟醋酸(TFA，79μL，10当量)，室温下反应5小时。反应完全后，旋干反应液。饱和碳酸氢钠溶液中和，二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S26。化合物S26的分析数据： 1H NMR(400MHz,CD 3OD)δ8.35(d,J＝2.8Hz,1H),7.65(d,J＝2.3Hz,1H),6.89(s,1H),4.86–4.81(m,0.5H),4.73–4.59(m,3H),4.22–4.13(m,0.5H),4.00–3.82(m,2H),3.05(q,J＝13.0Hz,2H),2.91(s,1.7H),2.78(s,1.3H),2.27–2.17(m,1H),2.14–1.68(m,7H).
制备实施例27 化合物S27的制备
Figure PCTCN2022096880-appb-000073
称量化合物26c(147mg，1当量)于单口瓶中，向里加二氯甲烷溶剂，再加入TFA(0.22mL，10当量)，室温下反应5小时。反应完全后，旋干反应液。饱和碳酸氢钠溶液中和，二氯甲烷和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S27。化合物S27的分析数据： 1H NMR(400MHz,CD 3OD)δ8.55(s,1H),7.59(s,1H),7.15(s,1H),4.86–4.81(m,0.5H),4.71(dd,J＝6.9,4.2Hz,0.5H),4.59(d,J＝11.3Hz,2H),4.15(t,J＝10.6Hz,0.5H),3.99–3.82(m,2H),3.03(dd,J＝23.2,10.3Hz,2H),2.91(s,1.7H),2.78(s,1.3H),2.29–2.17(m,1H),2.14–2.06(m,0.5H),2.02–1.89(m,3.5H),1.87–1.76(m,2H),1.74–1.66(m,1H).
制备实施例28 化合物S28的制备
Figure PCTCN2022096880-appb-000074
称量26a和26b的混合物(200mg，1当量)、1H-吡唑-3-硼酸(78mg，1.5当量)、Pd(PPh 3) 4(92mg，0.2当量)、碳酸钠(130mg，3当量)于单口瓶中，向里加1，4-二氧六环(10mL)和水(0.6mL)作溶剂，氮气保护，100℃下加热反应3小时。反应完全后，用乙酸乙酯和水萃取，有机相用饱和食盐水洗，无水硫酸钠干燥后拌样上柱，得化合物S28和化合物S29。化合物S28的分析数据： 1H NMR(400MHz,CD 3OD)δ8.70(s,1H),7.88(br,2H),7.76(br,1H),6.78(s,1H),4.86–4.81(m,0.5H),4.79–4.60(m,3H),4.23–4.17(m,0.5H),3.99–3.80(m,2H),3.08(t,J＝10.9Hz,2H),2.90(s,1.7H),2.77(s,1.3H),2.26–2.06(m,1.5H),2.01–1.69(m,6.5H).
制备实施例29 化合物S29的制备
化合物S29的合成方法参见化合物S28，化合物S29的分析数据： 1H NMR(400MHz,CD 3OD)δ8.72(s,1H),8.04(br,1H),7.72(s,2H),6.73(s,1H),4.85–4.61(m,3.5H),4.22(br,0.5H),4.00–3.82(m,2H),3.10(t,J＝12.5Hz,2H),2.92(s,1.7H),2.78(s,1.3H),2.25–2.07(m,1.5H),2.02–1.74(m,6.5H).
制备实施例30 化合物S30的制备
化合物S30的合成方法参见化合物S28，化合物S30的分析数据： 1H NMR(400MHz,CD 3OD)δ8.66(t,J＝7.8Hz,1H),8.07(br,2H),7.85(t,J＝6.9Hz,1H),7.74(t,J＝7.0Hz,1H),4.85(t,J＝6.8Hz,0.5H),4.80–4.69(m,2.5H),4.64(dd,J＝11.9,7.9Hz,0.5H),4.21(br,0.5H),4.01–3.81(m,2H),3.08(t,J＝12.8Hz,2H),2.91(d,J＝2.7Hz,1.7H),2.78(d,J＝1.7Hz,1.3H),2.29–2.07(m,1.5H),2.04–1.71(m,6.5H).
制备实施例31：化合物S31的制备
化合物S31的合成方法参见化合物S28，化合物S31的分析数据： 1H NMR(400MHz,CD 3OD)δ8.73(d,J＝3.0Hz,1H),8.03(br,2H),7.92(d,J＝2.4Hz,1H),7.74(d,J＝2.0Hz,1H),4.85–4.60(m,4H),4.27–4.20(m,0.5H),3.98–3.86(m,2H),3.18–3.07(m,2H),2.93(s,1.7H),2.79(s,1.3H),2.28–2.12(m,2H),2.06–1.82(m,6H).
制备实施例32 化合物S32的制备
化合物S32的合成方法参见化合物S28，化合物S32的分析数据： 1H NMR(400MHz,CD 3OD)δ8.71(d,J＝2.5Hz,1H),7.88(d,J＝2.7Hz,1H),7.84(d,J＝3.0Hz,1H),6.52(s,1H),4.87–4.83(m,1H),4.81–4.69(m,3H),4.69–4.62(m,0.5H),4.27–4.17(m,0.5H),3.99–3.83(m,2H),3.16–3.03(m,2H),2.91(s,1.7H),2.78(s,1.3H),2.37(s,3H),2.28–2.17(m,1H),2.14–2.06(m,0.5H),2.02–1.75(m,6.5H).
制备实施例33 化合物S33的制备
化合物S33的合成方法参见化合物S28，化合物S33的分析数据： 1H NMR(400MHz,CD 3OD)δ8.70(s,1H),7.99(s,1H),7.69(s,1H),6.48(s,1H),4.87–4.59(m,3.5H),4.21(br,0.5H),4.03–3.80(m,2H),3.09(t,J＝11.1Hz,2H),2.91(s,1.7H),2.78(s,1.3H),2.36(s,3H),2.27–2.08(m,1.5H),2.02–1.73(m,6.5H).
制备实施例34 化合物S34的制备
化合物S34的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为(2R)-1,4-二氧六环-2-甲酸，化合物S34的分析数据： 1H NMR(400MHz,CD 3OD)δ8.69(d,J＝5.5Hz,1H),7.80(d,J＝2.6Hz,1H),7.71(d,J＝3.0Hz,1H),4.76(d,J＝13.3Hz,2H),4.64–4.56(m,0.6H),4.49(s,2H),4.53(dd,J＝9.4,2.8Hz,0.4H),4.40(dd,J＝9.4,2.8Hz,0.6H),4.23–4.16(m,0.4H),3.90–3.71(m,4H),3.70–3.59(m,2H),3.18–3.03(m,2H),2.95(s,1.7H),2.76(s,1.3H),1.99–1.78(m,3H),1.73(d,J＝10.3Hz,1H).
制备实施例35 化合物S35的制备
化合物S35的合成方法参见化合物S1，将(R)-四氢呋喃甲酸替换为(2S)-1,4-二氧六环-2-甲酸，化合物S35的分析数据： 1H NMR(400MHz,CD 3OD)δ8.70(d,J＝5.5Hz,1H),7.83(d,J＝2.6Hz,1H),7.71(d,J＝3.0Hz,1H),4.76(d,J＝13.3Hz,2H),4.64–4.56(m,0.6H),4.49(s,2H),4.53(dd,J＝9.4,2.8Hz,0.4H),4.40(dd,J＝9.4,2.8Hz,0.6H),4.23–4.16(m,0.4H),3.90–3.71(m,4H),3.70–3.59(m,2H),3.18–3.03(m,2H),2.95(s,1.7H),2.76(s,1.3H),1.99–1.78(m,3H),1.72(d,J＝10.3Hz,1H).
二、生物活性测试实施例
实施例1.化合物对PGK1酶抑制活性测试
每一个反应加入20μL 50mM磷酸二氢钾,pH 7.0,4μL 50mM GAP,6μL 10mM βNAD,4μL 10mM二磷酸腺苷,10μL 100mM硫酸镁,20μL 1M Glycine,4μL 0.25μg/μL GAPDH,32μL去离子水，共计100ul底物混合体系。将PGK1蛋白稀释0.1ng/μL，每个反应中加入100uL PGK1蛋白稀释液混合。37℃条件反应30min。
将ATP检测液用ATP检测稀释液按1：10稀释。在96孔白板中，每孔加入 100uL稀释后的检测液，室温反应5min(去除本底ATP影响)，加入酶活反应溶液100uL，至少反应2s，在化学发光检测仪中读取荧光值。
设置化合物浓度梯度，在上述反应过程中，200uL反应体系内加入不同浓度的化合物，设置至少3个复孔，读出荧光值后，与对照组比较，计算出相对酶活，用GraphPad Prism绘制拟合曲线，计算IC 50值。
表2.化合物对PGK1酶抑制活性
Figure PCTCN2022096880-appb-000075
实施例2.化合物对SNU739细胞增殖抑制活性测试
实验步骤：
1)培养相应的目的细胞系，用血球板计数板进行细胞计数铺96孔板，1000个细胞/孔，待细胞贴壁。
2)细胞贴壁后，设置化合物浓度梯度，配置含有不同浓度化合物的10％血清培养液，加入96孔板中，每个浓度至少3个复孔。
3)72小时后，配置CCK8检测液，1:10稀释，每孔100uL，抽掉原有培养液，加入检测液，在37℃和5％CO 2的条件下培养2小时，用多模式微孔板检测仪(酶标仪)在波长450nm检测OD值
4)与对照组比较，计算出相对细胞数量，用GraphPad Prism绘制拟合曲线，计算IC 50值。
表3.化合物对人肝癌细胞SNU739或HepG2增殖抑制活性
Figure PCTCN2022096880-appb-000076
Figure PCTCN2022096880-appb-000077
ND：未测试，没有数据。
由此可见，本发明提供了一类作为PGK1抑制剂的喹喔啉衍生物新型，其中部分优选化合物对PGK1具有很强的抑制活性，在人肝癌SNU739或HepG2细胞上显示出较强的增殖抑制活性。与现有PGK1抑制剂相比具有显著优势。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药；
    Figure PCTCN2022096880-appb-100001
    其中，
    X选自下组：N或CH；
    A选自下组：不存在(化学键)、取代或未取代的C1-C3亚烷基、
    Figure PCTCN2022096880-appb-100002
    R a选自下组：H、取代或未取代的C1-C3烷基；
    R 1和R 2各自独立地选自下组：H、取代或未取代的C1-C6烷基(较佳地，C1-C3烷基)、卤素(较佳地，为Cl)、氰基、N(R c) 2、
    Figure PCTCN2022096880-appb-100003
    未取代或被一个或多个R s1所取代的C6-C10芳环、未取代或被一个或多个R s1所取代的5-10元杂芳环；
    R s1各自独立地选自下组：卤素、取代或未取代的C1-C3烷基、氰基；
    R b选自下组：H、未取代或被一个或多个R s2所取代的C1-C6烷基(较佳地，C1-C3烷基)、
    Figure PCTCN2022096880-appb-100004
    R c各自独立地选自下组：H、取代或未取代的C1-C3烷基；
    R s2各自独立地选自下组：羟基、取代或未取代的C1-C3烷氧基、卤素、取代或未取代的C1-C3烷基、氰基；
    R 3选自下组：H、取代或未取代的C1-C6烷基(较佳地，C1-C3烷基)、N(R d) 2；
    R d各自独立地选自下组：H、取代或未取代的C1-C3烷基；
    R 4选自下组：未取代或被一个或多个R s3所取代的C1-C6(较佳地，C1-C3烷基)、未取代或被一个或多个R s3所取代的C4-C10环烷基、未取代或被一个或多个R s3所取代的4-10元杂环烷基、未取代或被一个或多个R s3所取代的C6-C10芳基、未取代或被一个或多个R s3所取代的5-10元杂芳基；
    R s3各自独立地选自下组：羟基、取代或未取代的C1-C3烷基、卤素、取代或未取代的C1-C3烷基酰基、取代或未取代的C1-C3烷氧基、取代或未取代的C1-C3卤代烷基、取代或未取代的C1-C3羟基烷基；
    除非特别说明，所述的取代是指基团中一个或多个氢任选地被选自下组的取代基取代：羟基、卤素、C1-C3烷基、C1-C3卤代烷基、氨基(-NH 2)、-N(C1-C3烷基) 2、-NH(C1-C3烷基)、氰基。
  2. 如权利要求1所述的式I化合物，其特征在于，X为CH；和/或，A为
    Figure PCTCN2022096880-appb-100005
    其中，R a选自下组：H、C1-C3烷基。
  3. 如权利要求1所述的式I化合物，其特征在于，R 1和R 2之一为卤素，另一个为
    Figure PCTCN2022096880-appb-100006
  4. 如权利要求1所述的式I化合物，其特征在于，R 1为卤素且R 2为
    Figure PCTCN2022096880-appb-100007
    R b为未取代或被一个或多个R s2所取代的C1-C6烷基，且R s2各自独立地选自下组：羟基、取代或未取代的C1-C3烷氧基。
  5. 如权利要求1所述的式I化合物，其特征在于，R 3为H或C1-C6烷基。
  6. 如权利要求1所述的式I化合物，其特征在于，R 4选自下组：未取代或被一个或多个R s3所取代的C1-C6烷基、未取代或被一个或多个R s3所取代的C4-C6环烷基、未取代或被一个或多个R s3所取代的5-6元杂环烷基、未取代或被一个或多个R s3所取代的苯基、未取代或被一个或多个R s3所取代的5-6元杂芳基。
  7. 如权利要求1所述的式I化合物，其特征在于，所述式I化合物为选自下表1中的化合物，
    表1
    Figure PCTCN2022096880-appb-100008
    Figure PCTCN2022096880-appb-100009
    Figure PCTCN2022096880-appb-100010
    或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药。
  8. 一种药物组合物，其特征在于，包括(i)治疗有效量的如权利要求1所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药，和(ii)任选的药学上可接受的载体、赋形剂或稀释剂。
  9. 一种如权利要求1所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药的制备方法，其特征在于，
    所述制备方法为方法一或方法二；
    其中，
    所述方法一包括步骤：
    Figure PCTCN2022096880-appb-100011
    v)使化合物ie脱除保护基，然后再与R 4COOH进行缩合反，从而得到化合物if；
    vi)任选地使化合物if脱去保护基，从而得到式I化合物；
    各式中，R 1'为R 1或被保护基团保护的R 1，R 2'为R 2或被保护基团保护的R 2；
    A、X、R 1、R 2、R 3和R 4如权利要求1中定义；
    所述方法二包括步骤：
    Figure PCTCN2022096880-appb-100012
    ii)在惰性溶剂中，在Pd催化下，使化合物iia-1或化合物iia-2或它们的混合物与R b-C≡CH或R 5-B(OH) 2进行偶联反应，从而得到式I化合物；
    其中，
    R 5为未取代或被一个或多个R s1所取代的C6-C10芳环或未取代或被一个或多个R s1所取代的5-10元杂芳环；
    式I化合物中，R 1和R 2之一为
    Figure PCTCN2022096880-appb-100013
    未取代或被一个或多个R s1所取代的C6-C10芳环或未取代或被一个或多个R s1所取代的5-10元杂芳环，且另一个如权利要求1中定义；
    A、X、R 3、R 4、R b和R s1如权利要求1中定义。
  10. 一种如权利要求1所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药，或者包含如权利要求1所述的式I化合物，或其药学上可接受的盐、对映异构体、非对映异构体、光学异构体、外消旋体、氘代衍生物、溶剂合物或水合物、代谢物或前药的药物组合物在制备(i)PGK1抑制剂和/或(ii)用于治疗或预防与PGK1相关疾病的药物中的用途。
  11. 如权利要求10所述的用途，其特征在于，所述与PGK1相关疾病包括：癌症、细胞异常增殖、形态变化、糖代谢异常、运动功能亢进、肿瘤生长、糖尿病、炎症、免疫性疾病，或其组合。
  12. 如权利要求11所述的用途，其特征在于，所述癌症包括：肝癌、胃癌、结直肠癌、乳腺癌、膀胱癌、胰腺癌、胰腺导管腺癌、神经母细胞瘤、***癌，或其组合。
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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 (en) * 2010-10-09 2012-04-12 Abbott Laboratories Phosphoglycerate kinase inhibitors
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 (en) * 2010-10-09 2012-04-12 Abbott Laboratories Phosphoglycerate kinase inhibitors
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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