WO2020119592A1 - Nouveau composé de structure à trois cycles condensés, son procédé de préparation et utilisation associée - Google Patents

Nouveau composé de structure à trois cycles condensés, son procédé de préparation et utilisation associée Download PDF

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WO2020119592A1
WO2020119592A1 PCT/CN2019/123563 CN2019123563W WO2020119592A1 WO 2020119592 A1 WO2020119592 A1 WO 2020119592A1 CN 2019123563 W CN2019123563 W CN 2019123563W WO 2020119592 A1 WO2020119592 A1 WO 2020119592A1
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alkyl
haloalkyl
ring
alkenyl
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张龙
宋国伟
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信达生物制药(苏州)有限公司
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a novel compound with triple ring structure.
  • the compound has strong PI3K- ⁇ inhibitory effect and good selectivity, and can be used as an efficient PI3K- ⁇ selective inhibitor.
  • the present invention also relates to methods for preparing such compounds, pharmaceutical compositions containing them, and their medical uses, especially in the preparation of drugs for the prevention and/or treatment of diseases mediated at least in part by PI3K- ⁇ use.
  • Phosphoinositide 3-kinase is a large class of enzymes whose main function is the phosphorylation of the inositol ring of phosphoinositide. According to structural similarity, types of regulatory subunits and specificity of various phosphoinositide substrates, PI3K is divided into three categories (I, II and III) (Marone R, et al., Biochim. Biophys. Acta, 2008; 1784:159-185), of which the most extensive research is on class I PI3K.
  • All members of this type are composed of a catalytic subunit and a related regulatory part, which are used to catalyze the phosphorylation of phosphatidylinositol 4,5-diphosphate (PIP2) to produce the signal molecule phosphatidylinositol 3,4 , 5-triphosphate (PIP3).
  • PIP2 phosphatidylinositol 4,5-diphosphate
  • PIP3 phosphatidylinositol 3,4 , 5-triphosphate
  • this type can be used as a protein kinase, although the exact nature and physiological significance of the substrate is still being explored (Backer JM., et.al., Nat. Cell. Biol., 2005; 7; : 773-774). This type is further divided into two subgroups (IA and IB).
  • PI3K- ⁇ The three subtypes of class IA members PI3K- ⁇ , PI3K- ⁇ , and PI3K- ⁇ are activated by cellular signal transduction events involving tyrosine phosphorylation.
  • PI3K- ⁇ and PI3K- ⁇ are widely expressed and play a role in cell growth, division and survival (Thomas M, et al., Curr. Opin. Pharmacol., 2008; 8:267-274). These two kinases play a role in many biological and physiological functions, and the embryonic lethality observed in mice lacking PI3K- ⁇ or PI3K- ⁇ is enhanced.
  • PI3K- ⁇ and PI3K- ⁇ Due to their role in homeostasis, the clinical evaluation of PI3K- ⁇ and PI3K- ⁇ is limited to the field of oncology, and some compounds are also at different stages of clinical development.
  • the situation of the PI3K- ⁇ subtype is different. It is mainly expressed in hematopoietic cells and may play an important role in inflammation and autoimmune diseases, blood diseases such as leukemia, lymphoma, etc., so it has become a popular treatment for blood cancer Target.
  • the PI3K- ⁇ subtype is mainly expressed in immune cells and has limited expression in normal epithelial cells and connective tissue cells.
  • PI3K- ⁇ knockout mice research results show that PI3K- ⁇ is important for cell activation and migration of some chemokines (Sasaki T., et.al., Science, 2000; 287: 1040-1046; Hirsch E. , Et al., Science, 2000; 287: 1049-1053).
  • PI3K- ⁇ signal transduction is particularly important for bone marrow cell function, which is downstream of G protein coupled receptors (GPCRs) (such as chemokine receptors) and RAS.
  • GPCRs G protein coupled receptors
  • PI3K- ⁇ can be activated in response to tissue hypoxia.
  • PI3K- ⁇ plays a key role in unique myeloid cells, which constitute a key component of the immunosuppressive tumor microenvironment, which has been validated in PI3K- ⁇ deletion and kinase death knock-in studies.
  • mouse isogenic tumors grow slowly when transplanted into immunocompetent mice with PI3K- ⁇ gene inactivation (Schmid MC, et al., Cancer Cell, 2011; 19:715-727; Joshi S., et al ., Mol. Cancer Res., 2014; 12:1520-1531). This growth retardation is due to the elimination of tumor-related bone marrow, and the immunosuppressive tumor microenvironment that these cells can promote tumor growth is well known (Gunderson A.
  • pan-PI3K inhibitors Although some PI3K- ⁇ inhibitors have been reported in the past ten years, most of them are pan-PI3K inhibitors, which have problems such as poor selectivity, low activity, and high toxicity. Earlier studies also found that the toxicity of pan-PI3K is largely caused by the inhibition of PI3K- ⁇ and PI3K- ⁇ , and PI3K- ⁇ and PI3K- ⁇ subtypes mediate immune responses, especially effector T cell responses The aspect is the opposite. Therefore, the development of highly selective PI3K- ⁇ inhibitors will have great theoretical and clinical value.
  • the present invention aims to provide a series of novel tricyclic compounds that have an inhibitory effect on PI3K- ⁇ activity. Such tricyclic compounds have no inhibitory effect on other PI3K subtypes or only a weak inhibitory effect, showing a good choice Sex.
  • the present invention also provides a preparation method of the series of compounds, a pharmaceutical composition containing the series of compounds, and medical uses of the series of compounds.
  • the present invention provides a compound having the structure of formula I:
  • optical isomer or a mixture of both or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic label or prodrug thereof, wherein
  • A is a 4- to 10-membered ring structure, preferably a 5- to 6-membered ring structure, the ring structure is a saturated or unsaturated aliphatic ring or aromatic ring, and the ring structure optionally contains 0 to more heteroatoms ;
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged ring , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, aminoacyl, substituted acyl, hydroxyl, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, Alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged ring, aryl, arylalkyl, heteroaryl, halogen , Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, or
  • R 1 and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclyl, spirocyclic, heterospirocyclic, bridged, Heterobridge ring group, aryl group or heteroaryl group; and the hydrogen in R 1 and R 4 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy , Haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxyl, Nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, alkylureido, amino or -NR′R′′, where: R′ and
  • Each R 2 is independently NH, NR 7 , N-OH, S or O;
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Group or heteroaryl; and the hydrogen in R 3 is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, Haloalkyl, alkoxy, heterocyclyl, spirocyclic, heterospirocyclic, bridged, heterobridged, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cyano, hydroxyl , Nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, alkylureido, amino, or -NR′R′′, wherein: R
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the present invention provides the above compound having the structure of Formula I, which includes:
  • the present invention provides a method for preparing the above compound having the structure of Formula I, the specific steps are as follows:
  • groups X 0 , X 1 , X 2 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , substituents R 0 , R 1 , R 3 , R 4 , R 5 and R 6 , and ring A are as defined above for the compound having the structure of formula I.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound having the structure of Formula I, or an optical isomer or a mixture of the two, or a cis-trans isomer or a mixture of the two, or Its pharmaceutically acceptable salts, solvates, hydrates, isotope labels or prodrugs.
  • the present invention provides the above-mentioned compound having the structure of Formula I, or its optical isomer or a mixture of both, or its cis-trans isomer or a mixture of both, or a pharmaceutically acceptable salt thereof, Solvates, hydrates, isotope labels or prodrugs, or the above pharmaceutical compositions, are used as PI3K- ⁇ inhibitors.
  • the present invention provides the above-mentioned compound having the structure of formula I, or its optical isomer or a mixture of both, or its cis-trans isomer or a mixture of both, or a pharmaceutically acceptable salt thereof,
  • solvates, hydrates, isotope labels or prodrugs, or the aforementioned pharmaceutical compositions, as PI3K- ⁇ inhibitors are used.
  • the present application provides the above-mentioned compound having the structure of formula I, or an optical isomer or a mixture of both, or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt thereof, Solvates, hydrates, isotope labels or prodrugs, or the above pharmaceutical compositions, are prepared for the prevention and/or treatment of diseases that are at least partially mediated by PI3K- ⁇ or benefit from PI3K- ⁇ signaling pathway inhibition Use in medicine.
  • the present invention provides a method for preventing and/or treating diseases at least partially mediated by PI3K- ⁇ or benefiting from PI3K- ⁇ signaling pathway inhibition, which includes the steps of: treating a therapeutically effective amount
  • the above-mentioned compound having the structure of formula I, or its optical isomer or a mixture of both, or its cis-trans isomer or a mixture of both, or a pharmaceutically acceptable salt, solvate, hydrate Isotope markers or prodrugs, or the aforementioned pharmaceutical compositions, are administered to patients in need thereof.
  • the present invention provides a pharmaceutical combination comprising the above compound having the structure of Formula I, or an optical isomer or a mixture of both, or a cis-trans isomer or a mixture of both, or A pharmaceutically acceptable salt, solvate, hydrate, isotopic label or prodrug thereof, or the above pharmaceutical composition, and at least one additional cancer therapeutic agent.
  • the present invention provides a method for preventing and/or treating cancer, which comprises the steps of: adding a therapeutically effective amount of the above-mentioned compound having the structure of formula I, or an optical isomer thereof or a mixture of both , Or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic label or prodrug thereof, or the above pharmaceutical composition, and at least one additional cancer
  • the therapeutic agent preferably anti-PD-1/PD-L1 monoclonal antibody, is administered to patients in need thereof.
  • novel tri-cyclic compound of formula I provided by the present invention can be used as a highly effective PI3K inhibitor with anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammatory and anti-atherosclerosis , Anti-infection and other pharmacological activities.
  • the synthesis method is gentle, the operation is simple and easy, and it is easy to derivatize, which is suitable for industrial scale-up production.
  • Figure 1 shows the tumor inhibition curve of the test compound in the mouse CT26 model.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound having the structure of Formula I that is substantially non-toxic to an organism.
  • Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by the reaction of the compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases, such salts are also known as acid addition salts or Alkali addition salt.
  • Common inorganic acids include (but not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.
  • common organic acids include (but not limited to) trifluoroacetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid , Lactic acid, pyruvic acid, oxalic acid, formic acid, acetic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • common inorganic bases include (but not limited to) sodium hydroxide, potassium hydroxide, calcium hydroxide , Barium hydroxide, etc.
  • common organic bases include (but are not limited to) diethylamine, triethylamine, ethambutol, etc.
  • solvate refers to a substance formed by combining a compound of the present invention or a pharmaceutically acceptable salt thereof with at least one solvent molecule through non-covalent intermolecular forces.
  • solvate includes "hydrate”. Common solvates include (but are not limited to) hydrates, ethanolates, acetones and the like.
  • hydrate refers to a substance formed by the non-covalent intermolecular force of a compound of the present invention or a pharmaceutically acceptable salt thereof and water. Common hydrates include (but are not limited to) hemihydrate, monohydrate, dihydrate, trihydrate and the like.
  • isomer refers to compounds that have the same number of atoms and atom types and therefore the same molecular weight, but differ in the spatial arrangement or configuration of the atoms.
  • stereoisomer refers to isomers produced by atoms in a molecule due to different spatial arrangements, and includes two major categories: “configuration isomers” and “conformation isomers”.
  • configuration isomer refers to isomers produced by atoms in a molecule due to different spatial arrangements, and includes two major categories of “cis-trans isomers” and “optical isomers”.
  • cis-trans isomer refers to isomers that are generated by atoms (or groups) located on both sides of a double bond or ring system due to different positions relative to the reference plane.
  • the atom (or group) is located on the opposite side of the double bond or ring system, where "double bond” generally refers to a carbon-carbon double bond, also Contains carbon-nitrogen double bonds and nitrogen-nitrogen double bonds.
  • optical isomer refers to a vertical asymmetric plane due to having at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), which enables stable polarization rotation of plane polarized light Constructor.
  • the present invention also includes these stereoisomers and mixtures thereof.
  • the compounds of the present invention and their salts include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers and mixtures of diastereomers. Generally, these compounds can be prepared as racemic mixtures. However, if required, such compounds can be prepared or separated to obtain pure stereoisomers, that is, single enantiomers or diastereomers, or enrichment of single stereoisomers (purity ⁇ 98%, ⁇ 95%, ⁇ 93%, ⁇ 90%, ⁇ 88%, ⁇ 85% or ⁇ 80%).
  • the single stereoisomer of the compound is prepared from the optically active starting material containing the desired chiral center, or is prepared by preparing a mixture of enantiomer products and then separating or resolving The obtained, for example, is converted into a mixture of diastereomers before separation or recrystallization, chromatographic treatment, use of chiral resolution reagents, or direct separation of enantiomers on a chiral chromatography column.
  • Starting compounds with specific stereochemistry can be either commercially available or can be prepared according to the methods described below and then resolved by methods well known in the art.
  • the term "enantiomer” refers to a pair of stereoisomers that have mirror images that cannot overlap with each other.
  • racemic mixture or “racemate” refers to a mixture containing equal parts of a single enantiomer (ie, an equimolar mixture of two R and S enantiomers).
  • non-racemic mixture refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the invention are within the scope of the invention.
  • tautomer refers to structural isomers with different energies that can be interconverted by a low energy barrier. If tautomerism is possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers include (but are not limited to) interconversion through proton migration, such as keto-enol isomerization, imine-enamine isomerization , Amide-imino alcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • isotopic label refers to a compound formed by replacing a specific atom in a structure with its isotopic atom.
  • the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as 2 H(D), 3 H(T), 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.
  • prodrug refers to a derivative compound that can directly or indirectly provide the compound of the present invention after being applied to a patient.
  • Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compounds of the present invention when administered to a patient (eg, are more easily absorbed into blood), or promote delivery of the parent compound to the site of action (eg, lymphatic system) compound of.
  • site of action eg, lymphatic system
  • all prodrug forms of the compounds of the invention are within the scope of the invention, and various prodrug forms are well known in the art.
  • X and Y are each independently hydrogen, halogen, hydroxy, cyano, alkyl, or aryl, then when X is hydrogen, Y may be either hydrogen, or halogen, hydroxy, cyano, alkyl, or Aryl; in the same way, when Y is hydrogen, X can be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl.
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I) located in main group VII of the periodic table.
  • the hypophosphorous group can connect the structural core of the compound of formula I of the present invention in an unsubstituted form, and can also replace the hydrogen atom therein with other substituents.
  • alkyl refers to a monovalent straight or branched chain alkane group, which is composed of carbon atoms and hydrogen atoms, does not contain unsaturation, and is connected to the parent core through a single bond, preferably C 1 -C 6 alkyl groups, more preferably C 1 -C 4 alkyl groups; common alkyl groups include (but are not limited to) methyl (-CH 3 ), ethyl (-CH 2 CH 3 ), n-propyl (-CH 2 CH 2 CH 3 ), isopropyl (-CH(CH 3 ) 2 ), n-butyl (-CH 2 CH 2 CH 2 CH 3 ), sec-butyl (-CH(CH 3 )CH 2 CH 3 ), iso Butyl (-CH 2 CH(CH 3 ) 2 ), tert-butyl (-C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), neopentyl (-
  • alkynyl refers to a monovalent straight-chain or branched-chain alkyne group, which is composed of only carbon atoms and hydrogen atoms, contains at least one triple bond, and is connected to the parent nucleus through a single bond, preferably C 2- C 6 alkynyl; common alkynyl groups include (but are not limited to) ethynyl (-C ⁇ CH), 1-propyn-1-yl (ie propynyl) (-C ⁇ C-CH 3 ), 1- Butyn-1-yl (ie butynyl) Pentyn-1-yl 1,3-butadiyn-1-yl (-C ⁇ CC ⁇ CH), 1,4-pentadiyn-1-yl Wait.
  • alkoxy refers to a monovalent linear or branched group consisting of only carbon, hydrogen and oxygen atoms, may contain unsaturation, and is connected by a single bond to an oxygen atom To the core, preferably C 1 -C 4 alkoxy; common alkoxy groups include (but are not limited to) methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy ( -OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 ) CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentyloxy (-OCH 2 CH 2 CH 2 CH 3 ), neopentyloxy (-OCH 2 C(CH 3 ) 3 ), etc
  • alkylamido refers to a monovalent straight or branched chain group, which is composed only of carbon atoms, hydrogen atoms, oxygen atoms, and nitrogen atoms, and does not contain unsaturation other than the carbonyl group in its own structure.
  • cycloalkyl refers to a monovalent, monocyclic, non-aromatic ring system consisting only of carbon and hydrogen atoms, containing no unsaturation, and connected to the parent core through a single bond; common naphthenes
  • the group includes cycloalkyl having 3 to 10 ring atoms, including (but not limited to) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heterocyclic group refers to a monovalent, monocyclic, non-aromatic ring system composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, containing no unsaturation, and through a single bond Connected to the parent core; common heterocyclic groups include three to eighteen membered non-aromatic monocyclic rings with at least one ring heteroatom selected from nitrogen, oxygen, phosphorus and sulfur, including (but not limited to) oxirane , Oxetane-3-yl, azetidine-3-yl, tetrahydrofuran-2-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, tetrahydro-2H-pyran-2 -Yl, tetrahydro-2H-pyran-4-yl, piperidin-2-yl, piperidin-4-yl, etc.
  • spiro ring group refers to a monovalent non-aromatic ring system in which two single rings share a carbon atom, which is composed only of carbon atoms and hydrogen atoms, does not contain unsaturation, and is connected to the parent through a single bond Core; according to the number of spiro atoms, it can be divided into monospiro compounds, dispiro compounds, trispiro compounds, etc.; common spirocyclic groups include (but not limited to) spiro[2.4]heptane-1-yl, spiro[3.5 ] Nonane-2-yl, spiro[4.5]decane-2-yl, dispiro[5.2.5.2]hexadecyl-3-yl, etc.
  • heterospirocyclic group refers to a monovalent non-aromatic ring system in which two monocyclic rings share one carbon atom, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, and does not contain unsaturated Degree, and is connected to the parent nucleus through a single bond;
  • common heterospirocyclic groups include (but are not limited to) 6-oxaspiro[3.3]heptane-2-yl, 7-methyl-7-azaspiro[ 3.5] Nonane-2-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2-yl, 9-methyl-9-phosphaspiro[5.5]undecane-3 -Base etc.
  • bridged ring group refers to a monovalent non-aromatic ring system in which any two single rings share two carbon atoms that are not directly connected, which is composed only of carbon atoms and hydrogen atoms, does not contain unsaturation, and passes A single bond connects to the parent nucleus; according to the number of constituent rings, it can be divided into bicyclic compounds, tricyclic compounds, tetracyclic compounds, etc.; common bridged ring groups include (but are not limited to) decalin-1-yl, di Cyclo[3.2.1]octan-1-yl, tricyclo[2.2.1.0 2.6 ]heptan-1-yl, 1-adamantyl, etc.
  • heterobridge ring group refers to a monovalent non-aromatic ring system in which any two monocycles share two carbon atoms that are not directly connected, and are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus Composition, does not contain unsaturation, and is connected to the parent nucleus through a single bond;
  • common heterocyclic ring groups include (but are not limited to) 1,4-diazabicyclo[2.2.2]octan-2-yl , 2,8-diazabicyclo[4.3.0]nonane-8-yl and so on.
  • aryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system, which consists of only carbon atoms and hydrogen atoms, and is connected to the parent core through a single bond; common aromatic
  • the group includes aryl groups having 6 to 14 ring atoms, including (but not limited to) phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.
  • arylalkyl refers to a monovalent straight-chain or branched-chain alkane group, which is composed only of carbon atoms and hydrogen atoms, contains at least one aryl group, and is connected to the parent core through a single bond, preferably C 6- C 10 aryl-C 1 -C 6 alkyl, more preferably C 6 -C 10 aryl-C 1 -C 4 alkyl; common aryl alkyl groups include (but are not limited to) benzyl, ⁇ - Phenylethyl, ⁇ -phenethyl, naphthylmethyl, etc.
  • arylalkynyl refers to a monovalent straight-chain or branched-chain alkynyl group consisting only of carbon atoms and hydrogen atoms, containing at least one triple bond and at least one aryl group, and connected to it by a single bond Mother core, preferably C 6 -C 10 aryl-C 2 -C 6 alkynyl; common aryl alkynyl groups include (but are not limited to) phenylethynyl (-C ⁇ CPh), 3-phenyl-1-propane Alkyn-1-yl (-C ⁇ C-CH 2 Ph), 3,3-diphenyl-1-propyn-1-yl (-C ⁇ C-CHPh 2 ), 4-phenyl-1,3 -Butadiyn-1-yl (-C ⁇ CC ⁇ CPh), etc.
  • heteroaryl refers to a monovalent monocyclic or polycyclic (including fused form) aromatic ring system, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, and through a A single bond connects to the parent core; common heteroaryl groups include five to ten membered aromatic monocyclic or polycyclic rings with 1 to 4 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulfur, including (but not limited to) Benzopyrrolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, acridinyl, carbazolyl, pyrrolyl, furyl, thienyl, imidazolyl , Oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, indazolyl, indolizinyl, indolyl, quinolinyl
  • heteroarylalkyl refers to a monovalent straight or branched chain alkane group, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, and contains at least one heteroaryl group, and Connected to the parent nucleus through a single bond, preferably 5-10 membered heteroaryl-C 1 -C 6 alkyl, more preferably 5-10 membered heteroaryl-C 1 -C 4 alkyl; common heteroarylalkanes Groups include (but are not limited to) pyrrol-2-ylmethyl, furan-2-ylmethyl, thiophen-2-ylmethyl, 1H-pyrazol-3-ylmethyl, quinolin-4-ylmethyl Wait.
  • heteroarylalkenyl refers to a monovalent straight-chain or branched-chain olefin group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus, containing at least one double bond and at least one Heteroaryl, and is connected to the parent nucleus through a single bond, preferably 5-10 membered heteroaryl-C 2 -C 6 alkenyl; common heteroaryl alkenyl groups include (but are not limited to) 2-(pyrrole-2 -Yl)vinyl, 2-(furan-2-yl)vinyl, 2-(thiophen-2-yl)vinyl, 4-(1H-pyrazol-3-yl)-1,3-butadiene -1-yl and so on.
  • heteroarylalkynyl refers to a monovalent linear or branched alkyne group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus, containing at least one triple bond and at least one Heteroaryl, and is connected to the parent nucleus through a single bond, preferably 5-10 membered heteroaryl-C 2 -C 6 alkynyl; common heteroarylalkynyl groups include (but are not limited to) (pyrroli-2-yl )Ethynyl, (furan-2-yl)ethynyl, (thien-2-yl)ethynyl, (1H-pyrazol-3-yl)ethynyl, (1H-pyrazol-4-yl)ethynyl, (1-methyl-1H-pyrazol-4-yl)ethynyl and the like.
  • pentafluoro- ⁇ 6 -sulfanyl also known as “sulfur pentafluoride” refers to a monovalent group consisting of only sulfur atoms and fluorine atoms, and is connected to the parent core through a single bond (-SF 5 ).
  • the present invention provides a compound of formula I:
  • optical isomer or a mixture of both or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt, solvate, hydrate, isotopic label or prodrug thereof, wherein
  • A is a 4- to 10-membered ring structure, preferably a 5- to 6-membered ring structure, the ring structure is a saturated or unsaturated aliphatic ring or aromatic ring, and the ring structure optionally contains 0 to more heteroatoms;
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged ring , Aryl, arylalkyl, heteroaryl, heteroarylalkyl, aminoacyl, substituted acyl, hydroxyl, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, Alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged ring, aryl, arylalkyl, heteroaryl, halogen , Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, or
  • R 1 and R 4 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclyl, spirocyclic, heterospirocyclic, bridged, Heterobridge ring group, aryl group or heteroaryl group; and the hydrogen in R 1 and R 4 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy , Haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxyl, Nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, alkylureido, amino or -NR′R′′, where: R′ and
  • Each R 2 is independently NH, NR 7 , N-OH, S or O;
  • R 3 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Group or heteroaryl; and the hydrogen in R 3 is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, Haloalkyl, alkoxy, heterocyclyl, spirocyclic, heterospirocyclic, bridged, heterobridged, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cyano, hydroxyl , Nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, alkylureido, amino, or -NR′R′′, wherein: R
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the compound of formula I above is a compound of formula IA:
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, hydroxy, amino, cycloalkyl, heterocyclyl, spirocyclic , Bridged ring, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 , R 4 and R 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridge Cyclic group, heterobridged cyclic group, aryl group or heteroaryl group; and the hydrogen in R 1 , R 4 and R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl Group, alkoxy group, haloalkyl group, heterocycloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group, heteroaryl group, halogen, Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl,
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the compound of formula I above is a compound of formula IB:
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • X 3 and X 4 are each independently CH, CR 7 , CH 2 , O, C ⁇ O, S, NH, NR 7 or N; or X 3 and X 4 together form a double bond or a triple bond;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, hydroxy, amino, cycloalkyl, heterocyclyl, spirocyclic , Bridged ring, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 , R 4 and R 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridge Cyclic group, heterobridged cyclic group, aryl group or heteroaryl group; and the hydrogen in R 1 , R 4 and R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl Group, alkoxy group, haloalkyl group, heterocycloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group, heteroaryl group, halogen, Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl,
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the compound of formula I above is a compound of formula IC:
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • X 3 , X 4 and X 5 are each independently CH, CR 7 , CH 2 , O, C ⁇ O, S, NH, NR 7 or N; or formed between any two of X 3 , X 4 and X 5 Double or triple bond;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, hydroxy, amino, cycloalkyl, heterocyclyl, spirocyclic , Bridged ring, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 , R 4 and R 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridge Cyclic group, heterobridged cyclic group, aryl group or heteroaryl group; and the hydrogen in R 1 , R 4 and R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl Group, alkoxy group, haloalkyl group, heterocycloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group, heteroaryl group, halogen, Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl,
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the compound of formula I above is a compound of formula ID:
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, hydroxy, amino, cycloalkyl, heterocyclyl, spirocyclic , Bridged ring, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 , R 4 and R 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridge Cyclic group, heterobridged cyclic group, aryl group or heteroaryl group; and the hydrogen in R 1 , R 4 and R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl Group, alkoxy group, haloalkyl group, heterocycloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group, heteroaryl group, halogen, Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl,
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the compound of formula I above is a compound of formula IE:
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, hydroxy, amino, cycloalkyl, heterocyclyl, spirocyclic , Bridged ring, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 , R 4 and R 8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridge Cyclic group, heterobridged cyclic group, aryl group or heteroaryl group; and the hydrogen in R 1 , R 4 and R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl Group, alkoxy group, haloalkyl group, heterocycloalkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group, heteroaryl group, halogen, Cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl,
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, aminoacyl, substituted acyl, hydroxyl, amino, or- NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro Cyclic, bridging, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxyl, nitro, phosphate, sulfonyl, sulfonylamino, hypophosphorous, phosphoryl, or alkylurea Group, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably aryl or heteroaryl; most preferably phenyl; and the hydrogen in R 1 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl,
  • R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Group or heteroaryl; preferably alkyl, haloalkyl or alkoxy; and the hydrogen in R 4 is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, alkoxy Group, halogen, hydroxyl or amino;
  • Each R 5 is independently NH, NR 7 , N-OH, S or O; preferably NH, S or O; most preferably O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl; preferably hydrogen, deuterium, alkyl, haloalkyl or deuterated alkyl;
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 and X 7 are each independently CH, CR 7 or N; preferably CH or CR 7 ; most preferably CH;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, aminoacyl, substituted acyl, hydroxyl, amino, or- NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro Cyclic, bridging, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxyl, nitro, phosphate, sulfonyl, sulfonylamino, hypophosphorous, phosphoryl, or alkylurea Group, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably aryl or heteroaryl; most preferably phenyl; and the hydrogen in R 1 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl,
  • R 4 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group; preferably alkyl, haloalkyl or alkoxy; and the hydrogen in R 4 is optional Is substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, halogen, hydroxyl or amino;
  • Each R 5 is independently NH, NR 7 , N-OH, S or O; preferably NH, S or O; most preferably O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl; preferably hydrogen, deuterium, alkyl, haloalkyl or deuterated alkyl;
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, hydroxy, amino, or -NR′R′′, wherein: R′ and R′′ are each independently Hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro ring, bridged ring, aryl, arylalkyl, hetero Aryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, or alkylurea groups, or R'and R" are formed together with the nitrogen atom to which they are attached Single ring, spiro ring or bridge ring; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 is an aryl group, preferably a phenyl group; and the above aryl group is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl , Alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl , Alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxyl, nitro, phosphate, sulfonate Acyl, sulfonamido, phosphinyl, phosphoryl or alkylureido groups, or R′ and R′′ together with
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently NH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • X 3 and X 4 are each independently CH, CR 7 , CH 2 , O, C ⁇ O, S, NH, NR 7 or N; or X 3 and X 4 together form a double bond or a triple bond;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, hydroxy, amino, or -NR′R′′, wherein: R′ and R′′ are each independently Hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro ring, bridged ring, aryl, arylalkyl, hetero Aryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, or alkylurea groups, or R'and R" are formed together with the nitrogen atom to which they are attached Single ring, spiro ring or bridge ring; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 is aryl or heteroaryl, preferably phenyl or pyridyl; and the above aryl or heteroaryl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently NH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • X 3 , X 4 and X 5 are each independently CH, CR 7 , CH 2 , O, C ⁇ O, S, NH, NR 7 or N; or formed between any two of X 3 , X 4 and X 5 Double or triple bond;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, hydroxy, amino, or -NR′R′′, wherein: R′ and R′′ are each independently Hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spiro ring, bridged ring, aryl, arylalkyl, hetero Aryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl, or alkylurea groups, or R'and R" are formed together with the nitrogen atom to which they are attached Single ring, spiro ring or bridge ring; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
  • R 1 is aryl or heteroaryl, preferably phenyl or pyridyl; and the above aryl or heteroaryl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently NH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, hydroxy, amino, cycloalkyl, heterocyclyl, spirocyclic , Bridged ring, aryl, arylalkyl, heteroaryl or heteroarylalkyl; and the hydrogen in the R 0 substituent is optionally substituted by deuterium or halogen;
  • R 1 is aryl or heteroaryl, preferably phenyl or pyridyl; and the above aryl or heteroaryl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently NH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, or cycloalkyl; and the hydrogen in the R 0 substituent is optionally Replaced by deuterium or halogen;
  • R 1 is aryl or heteroaryl, preferably phenyl or pyridyl; and the above aryl or heteroaryl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl.
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 and X 7 are each independently CH or CR 7 ; preferably CH;
  • X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N; preferably CH or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, or cycloalkyl; and the hydrogen in the R 0 substituent is optionally substituted with deuterium or halogen;
  • R 1 is aryl or heteroaryl, preferably phenyl or pyridyl; and the above aryl or heteroaryl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl.
  • R 8 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, halogen, haloalkyl, alkoxy, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, heterobridged ring, aromatic Radical or heteroaryl; preferably hydrogen, alkyl, cycloalkyl, haloalkyl, heterocyclyl, aryl or heteroaryl; most preferably hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl Group; and the hydrogen in R 8 is optionally substituted by 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalky
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N;
  • Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, or cycloalkyl; and the hydrogen in the R 0 substituent is optionally Replaced by deuterium or halogen;
  • R 1 is aryl or heteroaryl, preferably phenyl or pyridyl; and the above aryl or heteroaryl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, Alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′
  • R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
  • Each R 5 is independently NH, NR 7 , N-OH, S or O;
  • Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
  • R 8 is hydrogen or pyrazolyl; and the hydrogen in the pyrazolyl is optionally substituted with 0 to more groups, each of which is independently deuterium, alkyl, alkoxy, haloalkyl, heterocycle Alkyl, alkenyl, alkynyl, cycloalkyl, halogen, amino or -NR′R′′, wherein: R′ and R′′ are each independently hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycle Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate groups , Sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido, or R′ and R′′ together with the nitrogen atom to which they are attached form
  • Each m is independently 0, 1, 2 or 3;
  • n is independently 0, 1, or 2.
  • the present invention provides a preparation method of the compound of formula I, the specific steps are as follows:
  • groups X 0 , X 1 , X 2 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , substituents R 0 , R 1 , R 3 , R 4 , R 5 and R 6 , and ring A are as defined above for compounds of formula I.
  • the above preparation method includes:
  • X is a leaving group, preferably triflate group, borate group, chlorine, bromine or iodine; groups X 0 , X 1 , X 2 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , and the substituents R 0 , R 1 , R 4 , R 5 , R 6 , R 7 and R 8 as defined in the compound of the above formula IA;
  • X is a leaving group, preferably triflate group, borate group, chlorine, bromine or iodine; groups X 0 , X 1 , X 2 , X 3 , X 4 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , and the substituents R 0 , R 1 , R 4 , R 5 , R 6 , R 7 and R 8 as defined in the above compound of formula IB;
  • X is a leaving group, preferably triflate group, borate group, chlorine, bromine or iodine; groups X 0 , X 1 , X 2 , X 3 , X 4 , X 5 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , as well as the substituents R 0 , R 1 , R 4 , R 5 , R 6 , R 7 and R 8 , as in the compounds of formula IC above Restricted
  • X is a leaving group, preferably triflate group, borate group, chlorine, bromine or iodine; groups X 0 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , and the substituents R 0 , R 1 , R 4 , R 5 , R 6 , R 7 and R 8 as in the above formula As defined in the ID compound;
  • Compound IE-1 undergoes ring closure (preferably in the presence of a format reagent and a metal organic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium) to obtain compound IE-2;
  • X is a leaving group, preferably triflate group, borate group, chlorine, bromine or iodine; groups X 0 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 9 , X 10 , X 11 , X 12 , X 13 and X 14 , and the substituents R 0 , R 1 , R 4 , R 5 , R 6 , R 7 and R 8 as in the above formula As defined in the IE compound.
  • the coupling reaction in the above preparation method includes (but is not limited to) Suzuki Reaction (Suzuki Reaction), Heck Reaction (Heck Reaction), Stille Reaction (Stille Reaction), Bacteria Sogonoshira Coupling, Kumada Coupling reaction, Negishi Coupling, Hiyama Coupling, etc. It is understandable that those skilled in the art are already familiar with the experimental conditions of the above coupling reaction.
  • the present invention also provides a corresponding preparation method in order to obtain a compound with a specific configuration.
  • These compounds with specific configurations and methods for their preparation are also part of the present invention.
  • pharmaceutical composition refers to a composition that can be used as a medicament, which contains a pharmaceutically active ingredient (API) and optionally one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier refers to pharmaceutical excipients that are compatible with the pharmaceutically active ingredient and are not harmful to the subject, including (but not limited to) diluents (or fillers), binders, disintegrating Agents, lubricants, wetting agents, thickeners, glidants, flavoring agents, odorants, preservatives, antioxidants, pH adjusters, solvents, cosolvents, surfactants, etc.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound of formula I, or its optical isomer or mixture of both, or its cis-trans isomer or mixture of both, or a pharmaceutically acceptable salt thereof , Solvates, hydrates, isotope labels or prodrugs.
  • the aforementioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
  • the present invention provides the above compound of formula I, or its optical isomer or a mixture of the two, or its cis-trans isomer or the mixture of the two, or a pharmaceutically acceptable salt, solvate, hydrate Substances, isotope labels or prodrugs, or the above-mentioned pharmaceutical compositions, as PI3K- ⁇ inhibitors.
  • the present application also provides the above compound of formula I, or its optical isomer or a mixture of the two, or its cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt, solvate, Hydrates, isotope labels or prodrugs, or the above pharmaceutical compositions, in the preparation of a medicament for the prevention and/or treatment of diseases at least partially mediated by PI3K- ⁇ or benefiting from inhibition of PI3K- ⁇ signaling pathway use.
  • disease mediated at least in part by PI3K- ⁇ refers to diseases whose pathogenesis contains at least a part of factors related to PI3K- ⁇ , including (but not limited to) cancer (eg cervical cancer), neurodegenerative diseases (E.g. Alzheimer's disease), viral infections (e.g. AIDS), bacterial infections (e.g. streptococcal infections), eye diseases (e.g. cataracts), autoimmune diseases (e.g. rheumatoid arthritis), depression, anxiety Symptoms and psychological disorders.
  • cancer eg cervical cancer
  • neurodegenerative diseases E.g. Alzheimer's disease
  • viral infections e.g. AIDS
  • bacterial infections e.g. streptococcal infections
  • eye diseases e.g. cataracts
  • autoimmune diseases e.g. rheumatoid arthritis
  • depression anxiety Symptoms and psychological disorders.
  • the present invention provides a method for preventing and/or treating diseases at least partially mediated by PI3K- ⁇ or benefiting from inhibition of PI3K- ⁇ signaling pathway, which includes the steps of: treating a therapeutically effective amount of the above formula I Compounds, or optical isomers or mixtures of the two, or cis-trans isomers or mixtures of the two, or pharmaceutically acceptable salts, solvates, hydrates, isotope labels or prodrugs, Or the above pharmaceutical composition is administered to patients in need thereof.
  • terapéuticaally effective amount refers to a dose of a pharmaceutical active ingredient that can induce a biological or medical response in a cell, tissue, organ, or organism (eg, patient).
  • administering refers to applying a pharmaceutical active ingredient (such as a compound of the present invention) or a pharmaceutical composition containing the pharmaceutical active ingredient (such as a pharmaceutical composition of the present invention) to a patient or its cells, tissues, organs, biological fluids, etc.
  • a pharmaceutical active ingredient such as a compound of the present invention
  • a pharmaceutical composition containing the pharmaceutical active ingredient such as a pharmaceutical composition of the present invention
  • the process of contacting the patient's or its cells, tissues, organs, biological fluids, etc. with the active pharmaceutical ingredient or pharmaceutical composition Common modes of administration include, but are not limited to, oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration, and the like.
  • needles for it refers to the judgment of the doctor or other caregiver on the patient's needs or the benefit from the prevention and/or treatment process, which is based on the doctor or other caregiver's various areas of expertise Kinds of factors.
  • patient refers to a human or non-human animal (eg, mammal).
  • the present invention provides a pharmaceutical combination comprising the compound of formula I above, or its optical isomer or a mixture of the two, or its cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt thereof , Solvates, hydrates, isotope labels or prodrugs, or the above pharmaceutical compositions, and at least one additional cancer treatment agent.
  • cancer refers to a cellular disorder characterized by uncontrolled or unregulated cell proliferation, reduced cell differentiation, unsuitable ability to invade surrounding tissues, and/or the ability to establish new growth in ectopic.
  • Common cancers include (but are not limited to) brain cancer, liver cancer, gallbladder cancer, bronchial cancer, lung cancer, bladder cancer, ovarian cancer, cervical cancer, testicular cancer, lip cancer, tongue cancer, hypopharyngeal cancer, laryngeal cancer, esophageal cancer, Gastric cancer, intestinal cancer (eg colon cancer, rectal cancer), thyroid cancer, salivary adenocarcinoma, pancreatic cancer, breast cancer, prostate cancer, blood cancer (or leukemia), lymphoma (or lymphoma), bone cancer and skin cancer.
  • cancer therapeutic agent refers to a pharmaceutical composition or pharmaceutical preparation capable of effectively controlling and/or fighting cancer.
  • Common cancer treatment agents include (but are not limited to) antipurine drugs (such as pentostatin, etc.), antipyrimidine drugs (such as fluorouracil), antifolate drugs (such as methotrexate), DNA polymerase inhibitors (such as arabinose) Cytidine), alkylating agents (e.g. cyclophosphamide), platinum complexes (e.g. cisplatin), DNA-damaging antibiotics (e.g. mitomycin), topoisomerase inhibitors (e.g.
  • camptothecin intercalation DNA-interfering nucleic acid synthesis drugs (e.g., epirubicin), drugs that prevent the supply of raw materials (e.g., asparaginase), drugs that interfere with tubulin formation (e.g., paclitaxel), drugs that interfere with ribosomal function (e.g., cephalosporin), Cytokines (such as IL-1), thymosin, tumor cell proliferation virus (such as adenovirus ONYX-015), anti-PD-1/PD-L1 monoclonal antibody, etc.
  • intercalation DNA-interfering nucleic acid synthesis drugs e.g., epirubicin
  • drugs that prevent the supply of raw materials e.g., asparaginase
  • drugs that interfere with tubulin formation e.g., paclitaxel
  • drugs that interfere with ribosomal function e.g., cephalosporin
  • Cytokines such as IL-1
  • the present invention provides a method for preventing and/or treating cancer, which comprises the steps of: adding a therapeutically effective amount of the compound of formula I, or its optical isomer or a mixture of the two, or its cis-trans Isomers or mixtures of the two, or pharmaceutically acceptable salts, solvates, hydrates, isotope labels or prodrugs, or the above pharmaceutical compositions, and at least one additional cancer therapeutic agent (preferably anti- PD-1/PD-L1 monoclonal antibody), administered to patients in need of it.
  • the combination of the above formula I compound and anti-PD-1/PD-L1 monoclonal antibody can significantly improve the tumor suppression rate.
  • step S2 The product of step S2 was redissolved with n-BuOH (1 L) and stirred at 110°C for 2 days. After cooling, the solid was filtered and dried to obtain compound M-4 (45 g, 66% yield).
  • Example 7 (S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl )-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a ] Synthesis of pyrimidine-3-carboxamide (compound 7).
  • Example 8 (R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl )-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a ] Synthesis of pyrimidine-3-carboxamide (Compound 8).
  • Example 16 The following compounds can be synthesized according to Example 1 and Example 11, using the corresponding intermediate A, intermediate B, intermediate C, intermediate D, intermediate E, intermediate F, intermediate G, Intermediate H, Intermediate I, Intermediate J, Intermediate K, Intermediate L, Intermediate M and Intermediate N were replaced to obtain the compounds shown in the following table:
  • Example 17 The following compounds can be synthesized according to Example 1 and Example 11, using the corresponding chiral enantiomers and intermediate A, intermediate B, intermediate C, intermediate D, intermediate E, intermediate F, Intermediate G, Intermediate H, Intermediate I, Intermediate J, Intermediate K, Intermediate L, Intermediate M and Intermediate N were replaced to obtain the compounds shown in the following table:
  • Example 18 The following compounds can be synthesized according to Example 3 and replaced with the corresponding starting materials to obtain the compounds shown in the following table:
  • Example 19 The following compounds can be synthesized according to Example 4 and replaced with the corresponding starting materials to obtain the compounds shown in the following table:
  • Example 20 The following examples can be carried out with reference to the synthesis of Example 5 and replaced with the corresponding starting materials to obtain the compounds shown in the following table:
  • Example 21 The following examples can be carried out with reference to the synthesis of Example 6, using different intermediates for substitution to obtain the compounds shown in the following table:
  • Example 22 PI3K inhibition test in vitro.
  • IC 50 was determined values human PI3K (Millipore) class I ⁇ , ⁇ , ⁇ and ⁇ 4 subtypes using Promega ADP-Glo TM Max detection kit.
  • the reaction was incubated at room temperature for 2 h, and then 25 ⁇ L of stop solution was added to stop the reaction (Promega kit). After incubation at room temperature for 40 min, 50 ⁇ L of detection mixture (Promega) was added, incubated at room temperature for 1 h, and the plate was read by an Envision plate reader. The data was converted to% inhibition and then plotted with% inhibition vs compound concentration and fitted to a four-parameter logistic equation to determine the IC 50 value. The results are shown in the table below.
  • the series of novel tricyclic compounds provided by the present invention can specifically produce a strong inhibitory effect on PI3K- ⁇ , and show a very high selectivity to other isozymes of the PI3Ks family Almost no inhibitory effect or only weak inhibitory effect, can be used as a highly effective PI3K- ⁇ selective inhibitor for prevention or treatment or adjuvant therapy at least partially mediated by PI3K- ⁇ or from PI3K- ⁇ signaling pathway inhibition Beneficial diseases such as tumors, neurodegenerative diseases (such as Alzheimer's disease), inflammation, atherosclerosis, infectious diseases, etc.
  • Example 23 PI3K enzyme activity inhibition test in vitro.
  • GSK2126458 (CAS No.: 1086062-66-9, this compound is used for internal control of experimental quality) was serially diluted 3 times from 10 ⁇ M in DMSO for a total of 10 concentrations.
  • PI3K ⁇ the stock solution concentration is 0.36 mg/mL, and the final concentration is 0.25 ⁇ g/mL. Therefore, 2.5 times is 0.625 ⁇ g/mL. Dilute 0.36mg/mL to 0.625 ⁇ g/mL using 1X analysis buffer;
  • the concentration of the stock solution is 0.1mg/mL, and the final concentration is 250ng/mL. Therefore, 2.5 times is 625ng/mL. Dilute 0.1 mg/mL to 625 ng/mL using IX analysis buffer.
  • the stock solution is 0.94mg/mL, and the final concentration is 1.5 ⁇ g/mL. Therefore, 2.5 times is 3.75 ⁇ g/mL. Dilute 0.94 mg/mL to 3.75 ⁇ g/mL using IX analysis buffer.
  • the raw material concentration is 0.1 mg/mL, and the final concentration is 250 ng/mL. Therefore, 2.5 times is 625ng/mL. Dilute 0.1 mg/mL to 625 ng/mL using IX analysis buffer.
  • PIP2 The final concentration of 3PS is 0.025 mg/mL; the final concentration of ATP is 25 ⁇ M.
  • the final concentration of the reference compound is 100, 33.33, 11.11, 3.70, 1.23, 0.41, 0.14, 0.05, 0.015, and 0.005 nM.
  • Final concentration of test compounds 3000, 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, and 0.15 ⁇ M for PI3K- ⁇ ; 30000, 10000, 3333.33, 1111.11, 370.37, 123.46 for PI3K ⁇ / ⁇ / ⁇ , 41.15, 13.72, 4.57 and 1.52 ⁇ M.
  • the final concentration of DMSO is 1%.
  • the IC50 was calculated by fitting the logarithm of% inhibition and compound concentration to non-linear regression (dose response-variable slope) using Graphpad 5.0.
  • the calculation formula is as follows:
  • a frozen CT26 cell (ATCC company, CRL-2638 TM ) was taken out from the -80°C refrigerator, quickly dissolved in a 37°C water bath, disinfected and transferred to a biological safety cabinet. Centrifuge, discard the supernatant, remix the pellet with complete medium, transfer to a culture bottle and add RPMI1640 complete medium (CIBICO company, article number: 22400-071), place in a CO 2 incubator to continue cultivation and passaging.
  • mice 100 BALB/c transgenic mice were obtained from Beijing Weitong Lihua Experimental Technology Co., Ltd., and the dorsal abdomen was shaved, and a 1.5 ⁇ 10 6 cell suspension 0.2 mL was implanted subcutaneously. After the mice were vaccinated, they were returned to their original cages to continue rearing.
  • Isotype h-IgG, Equitech-Bio, article number: SLH66-0001
  • anti-PD-1 monoclonal antibody the antibody can bind to mouse and human PD-1, which is compatible with the PD disclosed in CN108779177A -1
  • the sequence of "antibody C” is the same, Cinda Biomade), compound 21 and IPI-549 (CASNo.: 1693758-51-8, ie compound 4 disclosed in WO2015051244A1, positive control, Cinda made)
  • Use 5% 1-methyl-2-pyrrolidone in PEG400 mixed solvent to dissolve, the final concentrations are as follows: Isotype is 0.1mg/mL, anti-PD-1 monoclonal antibody is 0.1mg/mL, compound 21 is 2.0mg/mL, The compound IPI-549 was 2.0 mg/mL.
  • mice On the 7th day after inoculation, the mice were grouped according to the size of the tumor, and the mice with tumor volume in the range of 33.60 mm 3 to 87.18 mm 3 were selected and divided into 4 groups with 7 mice in each group. Each group was given the following test substances:
  • Tumor volume (V) W 2 ⁇ L/2;
  • W maximum long axis length
  • L maximum long axis length
  • the novel tricyclic ring compound provided by the present invention is used in combination with anti-PD-1 monoclonal antibody for administration, After 25 days of administration, the tumor inhibition rate can reach 66.3%, which is better than the combination of anti-PD-1 monoclonal antibody (43.0%) and the control compound IPI-549+anti-PD-1 combined use (50.5%). Therefore, the compounds of the present invention can be used as highly selective PI3K- ⁇ selective inhibitors for the prevention or treatment or adjuvant treatment of diseases that are at least partially mediated by PI3K- ⁇ or benefit from the inhibition of PI3K- ⁇ signaling pathway, such as Tumors, etc.

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Abstract

La présente invention concerne le domaine de la chimie médicinale. La présente invention concerne un composé de structure à trois cycles condensés, son procédé de préparation et une utilisation associée. Le composé selon la présente invention peut être utilisé en tant qu'inhibiteur sélectif de la PI3K-γ, et présente diverses activités pharmacologiques telles que des activités anti-tumorales, anti-maladies neurodégénératives (telles que la maladie d'Alzheimer), anti-inflammatoires, anti-virales, anti-sclérose en plaques et de régulation immunitaire.
PCT/CN2019/123563 2018-12-12 2019-12-06 Nouveau composé de structure à trois cycles condensés, son procédé de préparation et utilisation associée WO2020119592A1 (fr)

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