WO2020119592A1 - Novel three-ring fused structure compound, preparation method therefor and use thereof - Google Patents

Novel three-ring fused structure compound, preparation method therefor and use thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
haloalkyl
ring
alkenyl
Prior art date
Application number
PCT/CN2019/123563
Other languages
French (fr)
Chinese (zh)
Inventor
张龙
宋国伟
Original Assignee
信达生物制药(苏州)有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 信达生物制药(苏州)有限公司 filed Critical 信达生物制药(苏州)有限公司
Priority to CN201980082000.1A priority Critical patent/CN113195492B/en
Publication of WO2020119592A1 publication Critical patent/WO2020119592A1/en

Links

Images

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to the field of medicinal chemistry. Disclosed are a three-ring fused structure compound, a preparation method therefor and use thereof. The compound of the present invention can be used as a selective inhibitor of PI3K-γ, and has a variety of pharmacological activities such as anti-tumor, anti-neurodegenerative diseases (such as Alzheimer's disease), anti-inflammation, anti-virus, anti-multiple sclerosis, and immune regulation.

Description

一种新颖的三并环结构化合物及其制备方法和用途A novel compound with triple ring structure, its preparation method and use
相关申请的引用Citation of related applications
本发明要求2018年12月12日在中国提交的，名称为“一种新颖的三并环结构化合物及其制备方法和用途”、申请号为201811517957.8的发明专利申请的优先权，并通过引用方式将其全部内容并入本文。The present invention claims the priority of the invention patent application filed in China on December 12, 2018, titled "A Novel Compound with a Tricyclic Structure and its Preparation Method and Use", and the application number is 201811517957.8, and is cited by reference. All of its contents are incorporated into this article.
技术领域Technical field
本发明属于药物化学领域，涉及一种新颖的三并环结构化合物，该类化合物具有强效的PI3K-γ抑制作用和良好的选择性，可以作为高效的PI3K-γ选择性抑制剂。此外，本发明还涉及该类化合物的制备方法，包含其的药物组合物，及其医药用途，特别是在制备用于预防和/或治疗至少部分由PI3K-γ介导的疾病的药物中的用途。The invention belongs to the field of medicinal chemistry, and relates to a novel compound with triple ring structure. The compound has strong PI3K-γ inhibitory effect and good selectivity, and can be used as an efficient PI3K-γ selective inhibitor. In addition, 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-γ use.
背景技术Background technique
磷酸肌醇3-激酶(PI3K)是一大类酶，其主要功能是磷酸肌醇的肌醇环的磷酸化。根据结构相似性、调节亚基的类型和各种磷酸肌醇底物的特异性，PI3K被分成三类(I、II和III)(Marone R，et al.，Biochim.Biophys.Acta，2008；1784：159-185)，其中针对I类PI3K的研究最为广泛。该类型的所有成员都由一个催化子单元和一个相关的监管部分组成，用于催化磷脂酰肌醇4，5-二磷酸(PIP2)的磷酸化，从而产生信号分子磷脂酰肌醇3，4，5-三磷酸(PIP3)。除此之外，还有一些证据表明，该类型可以作为蛋白激酶，尽管底物的确切性质和生理意义仍在探索中(Backer JM.，et al.，Nat.Cell.Biol.，2005；7：773-774)。该类型进一步分为两个亚组(IA和IB)。IA类成员PI3K-α、PI3K-β、和PI3K-γ三种亚型由涉及酪氨酸磷酸化的细胞信号转导事件激活。PI3K-α和PI3K-β被广泛表达，并在细胞生长、分裂和存活中发挥作用(Thomas M，et al.，Curr.Opin.Pharmacol.，2008；8：267-274)。这两种激酶在许多生物学和生理功能中发挥作用，在缺乏PI3K-α或PI3K-β的小鼠中观察到的胚胎致死性被增强。由于它们在体内平衡中的作用，PI3K-α和PI3K-β的临床评价受限于肿瘤学领域，并且一些化合物也处于临床开发的不同阶段。PI3K-δ亚型的情况则有所不同，它主要在造血细胞中表达，并可能在炎症和自身免疫疾病、血液性疾病如白血病、淋巴瘤等中发挥重要作用，因此已经成为治疗血癌的热门靶点。Phosphoinositide 3-kinase (PI3K) 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). In addition, there is some evidence that 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). The three subtypes of class IA members PI3K-α, PI3K-β, and PI3K-γ are activated by cellular signal transduction events involving tyrosine phosphorylation. PI3K-α and PI3K-β 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-α or PI3K-β is enhanced. Due to their role in homeostasis, the clinical evaluation of PI3K-α and PI3K-β is limited to the field of oncology, and some compounds are also at different stages of clinical development. The situation of the PI3K-δ 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.
PI3K-γ亚型主要在免疫细胞中表达，并且在正常的上皮细胞和结缔组织细胞中具有有限的表达。PI3K-γ敲除小鼠的研究结果表明，PI3K-γ对于细胞活化和一些趋化因子的迁移是重要的(Sasaki T.，et al.，Science，2000；287：1040-1046；Hirsch E.，et al.，Science，2000；287：1049-1053)。PI3K-γ信号转导对骨髓细胞功能特别重要，它在G蛋白偶联受体(GPCRs)(如趋化因子受体)和RAS的下游。此外，在这些细胞中，PI3K-γ可被激活以响应组织缺氧。PI3K-γ在独特的髓样细胞中发挥关键作用，其构成了免疫抑制性肿瘤微环境的关键组成部分，这在PI3K-γ缺失和激酶死亡敲入研究得到验证。例如，小鼠同基因肿瘤在移植到PI3K-γ基因失活的免疫活性小鼠体内时生长缓慢(Schmid M.C.，et al.，Cancer Cell，2011；19：715-727；Joshi S.，et al.，Mol.Cancer Res.，2014；12：1520-1531)。这种生长延缓是由于肿瘤相关骨髓的消除，而这些细胞可促进肿瘤生长的免疫抑制性肿瘤微环境业已周知(Gunderson A.J.，et al.，Cancer Discovery，2016；6：270-285)。此外，肿瘤相关的骨髓细胞被假设为在放疗或化疗后支持肿瘤再生，并能够转移扩散(De Palma M.，et al.，J.Med.Chem.，2012；55：8559-8581)。这些临床前研究突出了PI3K-γ在髓样细胞生物学中的关键作用，并提示肿瘤相关髓样细胞中的PI3K-γ抑制可能有效地预防各种环境中的肿瘤生长。特别是近来研究发现，很多肿瘤中巨噬细胞存在PI3K-γ高表达现象，介导了巨噬细胞的M2极化，引起免疫耐受以及肿瘤耐药或复发，因此PI3K-γ已经成为新一代免疫调节靶点。The PI3K-γ subtype is mainly expressed in immune cells and has limited expression in normal epithelial cells and connective tissue cells. PI3K-γ knockout mice research results show that PI3K-γ 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-γ 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. In addition, in these cells, PI3K-γ can be activated in response to tissue hypoxia. PI3K-γ plays a key role in unique myeloid cells, which constitute a key component of the immunosuppressive tumor microenvironment, which has been validated in PI3K-γ deletion and kinase death knock-in studies. For example, mouse isogenic tumors grow slowly when transplanted into immunocompetent mice with PI3K-γ 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. J., et al., Cancer Discovery, 2016; 6:270-285). In addition, tumor-associated bone marrow cells are assumed to support tumor regeneration after radiotherapy or chemotherapy, and to be able to metastasize and spread (De Palma M., et al., J. Med. Chem., 2012; 55: 8559-8581). These preclinical studies highlight the key role of PI3K-γ in myeloid cell biology and suggest that PI3K-γ inhibition in tumor-associated myeloid cells may effectively prevent tumor growth in various environments. In particular, recent studies have found that macrophages in many tumors have high expression of PI3K-γ, which mediates the M2 polarization of macrophages, causing immune tolerance and tumor resistance or recurrence. Therefore, PI3K-γ has become a new generation Immune regulation target.
尽管在过去近十年的时间里已经报道了部分PI3K-γ抑制剂，但多数属于pan-PI3K抑制剂，存在选择性差、活性低、毒性较大等问题。前期的研究也发现，pan-PI3K的毒性很大程度上由PI3K-α和PI3K-β的抑制引起，且PI3K-δ和PI3K-γ亚型在介导免疫反应方面，尤其是效应T细胞反应方面是相反的。因此，开发出高选择性PI3K-γ抑制剂将具有巨大的理论和临床价值。Although some PI3K-γ 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-α and PI3K-β, and PI3K-δ and PI3K-γ subtypes mediate immune responses, especially effector T cell responses The aspect is the opposite. Therefore, the development of highly selective PI3K-γ inhibitors will have great theoretical and clinical value.
发明内容Summary of the invention
发明要解决的问题Problems to be solved by the invention
本发明旨在提供一系列对于PI3K-γ活性具有抑制作用的新颖的三并环化合物，该类三并环化合物对其它PI3K亚型没有抑制作用或仅有微弱的抑制作用，显示了良好的选择性。此外，本发明还提供了该系列化合物的制备方法，包含该系列化合物的药物组合物，以及该系列化合物的医药用途。The present invention aims to provide a series of novel tricyclic compounds that have an inhibitory effect on PI3K-γ activity. Such tricyclic compounds have no inhibitory effect on other PI3K subtypes or only a weak inhibitory effect, showing a good choice Sex. In addition, 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.
用于解决问题的方案Solutions for solving problems
第一方面，本发明提供了一种具有式I结构的化合物：In a first aspect, the present invention provides a compound having the structure of formula I:
Figure PCTCN2019123563-appb-000001
Figure PCTCN2019123563-appb-000001
或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，其中：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, solvate, hydrate, isotopic label or prodrug thereof, wherein
A为四至十元环状结构，优选五至六元环状结构，所述环状结构为饱和或不饱和的脂肪环或者芳香环，且所述环状结构任选地含有0至多个杂原子；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 0为-C(＝R 2)-、-S(＝R 2) n-或-P(＝R 2)(R 0)-； X 0 is -C(=R 2 )-, -S(=R 2 ) n -or -P(=R 2 )(R 0 )-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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 8为-CH 2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2)-、-NH-或-NR 7-； X 8 is -CH 2 -, -CHR 7 -, -C(R 7 ) 2 -, -C(=R 2 )-, -NH- or -NR 7 -;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、杂芳基烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且R 0中的氢任选地被氘或卤素取代； 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 alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro Ring or bridge ring; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
R 1和R 4各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1和R 4中的氢任选地被0至多个基团取代，每一个所述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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 R″ are each independently hydrogen, 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, phosphoryl or alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring or spiro ring Or a bridged ring; and the heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkynyl groups;
每一个R 2各自独立地为NH、NR 7、N-OH、S或O； Each R 2 is independently NH, NR 7 , N-OH, S or O;
R 3为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 3中的氢任选地被0至多个基团取代，每一个所述基团各自独立地为氘、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、杂环烷基、芳基、杂芳基、芳基烷基、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、 杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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′ 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 groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro Ring or bridge ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkynyl groups ;
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
第二方面，本发明提供了上述具有式I结构的化合物，其包括：In a second aspect, the present invention provides the above compound having the structure of Formula I, which includes:
(1)(S)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(1)(S)-2-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]pyrimidine-3-carboxamide;
(2)(R)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(2)(R)-2-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]pyrimidine-3-carboxamide;
(3)(S)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(3) (S)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2,4 , 5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(4)(R)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(4) (R)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2,4 , 5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(5)(S)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(5) (S)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2,4 ,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(6)(R)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(6) (R)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2,4 ,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(7)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(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] Pyrimidine-3-carboxamide;
(8)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(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] Pyrimidine-3-carboxamide;
(9)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(9)(S)-2-((N-ethylsulfamoyl)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]pyrimidine -3-formamide;
(10)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(10)(R)-2-((N-ethylsulfamoyl)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]pyrimidine -3-formamide;
(11)(S)-2-氨基-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(11)(S)-2-Amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de] Isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(12)(R)-2-氨基-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(12) (R)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de] Isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(13)(S)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(13)(S)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinoline- 3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(14)(R)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(14)(R)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinoline- 3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(15)(S)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(15)(S)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinoline- 3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(16)(R)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N- 甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(16)(R)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinoline- 3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(17)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(17)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5 -Tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(18)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(18)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5 -Tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(19)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(19) (S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4, 5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(20)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(20) (R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4, 5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(21)(S)-2-氨基-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(21)(S)-2-amino-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2 , 4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(22)(R)-2-氨基-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(22)(R)-2-amino-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2 , 4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(23)(S)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(23)(S)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5 ,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(24)(R)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(24) (R)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5 ,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(25)(S)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(25)(S)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5 ,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(26)(R)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(26)(R)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5 ,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(27)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(27)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a] Pyrimidine-3-carboxamide;
(28)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(28)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a] Pyrimidine-3-carboxamide;
(29)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(29)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-formamide;
(30)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(30)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-formamide;
(31)(S)-2-氨基-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(31)(S)-2-Amino-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de] Isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(32)(R)-2-氨基-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(32)(R)-2-amino-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de] Isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(33)(S)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(33)(S)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline- 3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(34)(R)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(34)(R)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline- 3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(35)(S)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(35)(S)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline- 3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(36)(R)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(36)(R)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline- 3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(37)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(37) (S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5, 6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(38)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(38)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5, 6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(39)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异 喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(39)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6 -Tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(40)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(40)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6 -Tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(41)(S)-2-氨基-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(41)(S)-2-amino-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2 ,4-dihydro-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(42)(R)-2-氨基-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(42)(R)-2-amino-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2 ,4-dihydro-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(43)(S)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(43)(S)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4-di Hydrogen-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(44)(R)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(44) (R)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4-di Hydrogen-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(45)(S)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(45)(S)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4-di Hydrogen-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine- 3-formamide;
(46)(R)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(46)(R)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4-di Hydrogen-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine- 3-formamide;
(47)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(47)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-formamide;
(48)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(48)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-formamide;
(49)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(49)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-formamide;
(50)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(7-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(50)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(7-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-formamide;
(51)(S)-2-氨基-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(51)(S)-2-amino-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]iso Quinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(52)(R)-2-氨基-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(52)(R)-2-amino-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]iso Quinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(53)(S)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(53)(S)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinoline-3 -Yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(54)(R)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(54)(R)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinoline-3 -Yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(55)(S)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(55)(S)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinoline-3 -Yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(56)(R)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(56)(R)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro-1H-cyclobutadieno[de]isoquinoline-3 -Yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(57)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(57) (S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro -1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(58)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(58)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro -1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(59)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(59)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro- 1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(60)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(7-乙炔基-1-氧代-2-苯基-2，4-二氢-1H-环丁二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(60)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(7-ethynyl-1-oxo-2-phenyl-2,4-dihydro- 1H-cyclobutadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(61)(S)-2-氨基-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(61)(S)-2-amino-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl-2 , 3,7,8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(62)(R)-2-氨基-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚 三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(62)(R)-2-amino-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl-2 , 3,7,8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(63)(S)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(63)(S)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl-2,3,7 , 8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3 -Formamide;
(64)(R)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(64)(R)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl-2,3,7 , 8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3 -Formamide;
(65)(S)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(65)(S)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl-2,3,7 , 8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5 -a] pyrimidine-3-carboxamide;
(66)(R)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(66)(R)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl-2,3,7 , 8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5 -a] pyrimidine-3-carboxamide;
(67)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(67)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl) -3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1, 5-a]pyrimidine-3-carboxamide;
(68)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(68)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl) -3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1, 5-a]pyrimidine-3-carboxamide;
(69)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(69)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5 -a] pyrimidine-3-carboxamide;
(70)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(70)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(4-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5 -a] pyrimidine-3-carboxamide;
(71)(S)-2-氨基-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(71)(S)-2-amino-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocycloheptatriene And [de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(72)(R)-2-氨基-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(72)(R)-2-amino-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocycloheptatriene And [de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(73)(S)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(73)(S)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de] Isoquinolin-1-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(74)(R)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(74)(R)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de] Isoquinolin-1-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(75)(S)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(75)(S)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de] Isoquinolin-1-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(76)(R)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(76)(R)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8,9,10-hexahydrocyclohepta[de] Isoquinolin-1-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(77)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(77)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7, 8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(78)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(78)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7, 8,9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(79)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(79)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8 , 9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(80)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(4-乙炔基-3-氧代-2-苯基-2，3，7，8，9，10-六氢环庚三烯并[de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(80)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(4-ethynyl-3-oxo-2-phenyl-2,3,7,8 , 9,10-hexahydrocyclohepta[de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(81)(S)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(81)(S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1 , 2-dihydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(82)(R)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(82)(R)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1 , 2-dihydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(83)(S)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(83)(S)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-di Hydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(84)(R)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(84)(R)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-di Hydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(85)(S)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹 啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(85)(S)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-di Hydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidin-3-methyl Amide
(86)(R)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(86)(R)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2-di Hydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidin-3-methyl Amide
(87)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(87)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide
(88)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(88)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide
(89)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(89)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-methyl Amide
(90)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(90)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-methyl Amide
(91)(S)-2-氨基-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(91)(S)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinoline- 3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(92)(R)-2-氨基-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(92)(R)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinoline- 3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(93)(S)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(93)(S)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl) Ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(94)(R)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(94)(R)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl) Ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(95)(S)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(95)(S)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl) Ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(96)(R)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(96)(R)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydrocyclopenta[de]isoquinolin-3-yl) Ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(97)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(97)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydro ring Pentadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(98)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(98)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydro ring Pentadieno[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(99)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(99)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydro Cyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(100)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2-二氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(100)(R)-2-((N-Cyclopropylsulfamoyl)amino)-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2-dihydro Cyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(101)(S)-2-氨基-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(101)(S)-2-amino-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl-4 , 5-dihydro-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(102)(R)-2-氨基-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(102)(R)-2-amino-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl-4 , 5-dihydro-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(103)(S)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(103)(S)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl-4,5-di Hydrogen-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-methyl Amide
(104)(R)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(104)(R)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl-4,5-di Hydrogen-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-methyl Amide
(105)(S)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(105)(S)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl-4,5-di Hydrogen-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methyl)amino)pyrazolo[1,5-a]pyrimidine- 3-formamide;
(106)(R)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(106)(R)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl-4,5-di Hydrogen-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methyl)amino)pyrazolo[1,5-a]pyrimidine- 3-formamide;
(107)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(107)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl) -5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5- a] pyrimidine-3-carboxamide;
(108)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基 -4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(108)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl) -5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5- a] pyrimidine-3-carboxamide;
(109)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(109)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide;
(110)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(110)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide;
(111)(S)-2-氨基-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(111)(S)-2-amino-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2- de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(112)(R)-2-氨基-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(112)(R)-2-amino-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2- de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(113)(S)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(113)(S)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquine Lin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(114)(R)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(114)(R)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquine Lin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(115)(S)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(115)(S)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquine Lin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(116)(R)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(116)(R)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro-2H-furo[4,3,2-de]isoquine Lin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(117)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(117)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro- 2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(118)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(118)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro- 2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(119)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(119)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro -2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(120)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-5-氧代-4-苯基-4，5-二氢-2H-呋喃并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(120)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-5-oxo-4-phenyl-4,5-dihydro -2H-furo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(121)(S)-2-氨基-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(121)(S)-2-amino-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4 -Phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide
(122)(R)-2-氨基-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(122)(R)-2-amino-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4 -Phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3- Formamide
(123)(S)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(123)(S)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl- 1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide;
(124)(R)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(124)(R)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl- 1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a ] Pyrimidine-3-carboxamide;
(125)(S)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(125)(S)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl- 1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo [1,5-a]pyrimidine-3-carboxamide;
(126)(R)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(126)(R)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-5-oxo-4-phenyl- 1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo [1,5-a]pyrimidine-3-carboxamide;
(127)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(127)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazole And [1,5-a]pyrimidine-3-carboxamide;
(128)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(128)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazole And [1,5-a]pyrimidine-3-carboxamide;
(129)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(129)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl )Ethynyl)-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo [1,5-a]pyrimidine-3-carboxamide;
(130)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(130)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl )Ethynyl)-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo [1,5-a]pyrimidine-3-carboxamide;
(131)(S)-2-氨基-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3- 基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(131)(S)-2-amino-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[ 4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(132)(R)-2-氨基-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(132)(R)-2-amino-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[ 4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(133)(S)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(133) (S)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3, 2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(134)(R)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(134) (R)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3, 2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(135)(S)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(135) (S)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3, 2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(136)(R)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(136) (R)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3, 2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(137)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(137)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1, 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(138)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(138)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1, 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(139)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(139)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1 , 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(140)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-5-氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(140)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-5-oxo-4-phenyl-1 , 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(141)(S)-2-氨基-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(141)(S)-2-amino-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-diox 4--4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-formamide;
(142)(R)-2-氨基-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(142)(R)-2-amino-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-diox 4--4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine -3-formamide;
(143)(S)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(143) (S)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4- Phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1, 5-a]pyrimidine-3-carboxamide;
(144)(R)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(144) (R)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4- Phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1, 5-a]pyrimidine-3-carboxamide;
(145)(S)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(145)(S)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4- Phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(146)(R)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(146) (R)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4- Phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(147)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(147) (S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl ) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(148)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(148)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl ) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(149)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(149)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl )Ethynyl)-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(150)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(1-甲基-6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(150)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(1-methyl-6-((1-methyl-1H-pyrazol-4-yl )Ethynyl)-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(151)(S)-2-氨基-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(151)(S)-2-Amino-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydro Pyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(152)(R)-2-氨基-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(152)(R)-2-amino-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydro Pyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(153)(S)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(153)(S)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4 , 3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(154)(R)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基) 乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(154)(R)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4 , 3,2-de]isoquinolin-3-yl) ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(155)(S)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(155)(S)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4 , 3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(156)(R)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(156)(R)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4 , 3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(157)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(157)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl -1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(158)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(158)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-phenyl -1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(159)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(159)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-benzene Yl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(160)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-1-甲基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(160)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-1-methyl-2,5-dioxo-4-benzene Yl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(161)(S)-2-氨基-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(161)(S)-2-amino-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4-benzene Yl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(162)(R)-2-氨基-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(162)(R)-2-amino-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4-benzene Yl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(163)(S)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(163) (S)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4-phenyl-1, 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(164)(R)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(164)(R)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4-phenyl-1, 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(165)(S)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(165) (S)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4-phenyl-1, 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(166)(R)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(166) (R)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2,5-dioxo-4-phenyl-1, 2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(167)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(167)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl) -2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(168)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(168)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl) -2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(169)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(169)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(170)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-((1-甲基-1H-吡唑-4-基)乙炔基)-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(170)(R)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(171)(S)-2-氨基-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(171)(S)-2-amino-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4, 3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(172)(R)-2-氨基-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(172)(R)-2-amino-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4, 3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(173)(S)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(173) (S)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2- de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(174)(R)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(174) (R)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2- de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(175)(S)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(175)(S)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2- de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(176)(R)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(176) (R)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2,4,5-tetrahydropyrrolo[4,3,2- de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(177)(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并 [4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(177)(S)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2, 4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(178)(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(178) (R)-2-((N-ethylsulfamoyl)amino)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2, 4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(179)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(179)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2 , 4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(180)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(6-乙炔基-2，5-二氧代-4-苯基-1，2，4，5-四氢吡咯并[4，3，2-de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(180)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(6-ethynyl-2,5-dioxo-4-phenyl-1,2 , 4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(181)2-氨基-N-((S)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(181) 2-amino-N-((S)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo- 2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl ) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(182)2-氨基-N-((R)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(182) 2-amino-N-((R)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo- 2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl ) Pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(183)N-((S)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(183) N-((S)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl -2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2- (Sulfamoylamino) pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(184)N-((R)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(184)N-((R)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl -2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2- (Sulfamoylamino) pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(185)N-((S)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(185)N-((S)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl -2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2- ((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(186)N-((R)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(186)N-((R)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazol-4-yl)ethynyl)-3-oxo-2-phenyl -2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2- ((N-methylsulfamoyl)amino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(187)2-((N-环丙基氨磺酰基)氨基)-N-((S)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(187) 2-((N-cyclopropylsulfamoyl)amino)-N-((S)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazole-4 -Yl)ethynyl)-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3- de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(188)2-((N-环丙基氨磺酰基)氨基)-N-((R)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(188)2-((N-cyclopropylsulfamoyl)amino)-N-((R)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazole-4 -Yl)ethynyl)-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3- de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(189)2-((N-乙基氨磺酰基)氨基)-N-((S)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(189)2-((N-ethylsulfamoyl)amino)-N-((S)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de ]Isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(190)2-((N-乙基氨磺酰基)氨基)-N-((R)-1-((6bR，7aS)-4-((1-甲基-1H-吡唑-4-基)乙炔基)-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(190)2-((N-ethylsulfamoyl)amino)-N-((R)-1-((6bR,7aS)-4-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de ]Isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(191)2-氨基-N-((S)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(191) 2-amino-N-((S)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H -Cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(192)2-氨基-N-((S)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(192)2-amino-N-((S)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H -Cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(193)N-((S)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(193) N-((S)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropane [4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(194)N-((R)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(194) N-((R)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropane [4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(195)N-((S)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(195) N-((S)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropane [4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(196)N-((R)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(196) N-((R)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2,6b,7,7a-tetrahydro-3H-cyclopropane [4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(197)2-((N-环丙基氨磺酰基)氨基)-N-((S)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四 氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(197) 2-((N-cyclopropylsulfamoyl)amino)-N-((S)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl- 2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(198)2-((N-环丙基氨磺酰基)氨基)-N-((R)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(198) 2-((N-cyclopropylsulfamoyl)amino)-N-((R)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl- 2,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(199)2-((N-乙基氨磺酰基)氨基)-N-((S)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(199)2-((N-ethylsulfamoyl)amino)-N-((S)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2 ,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(200)2-((N-乙基氨磺酰基)氨基)-N-((R)-1-((6bR，7aS)-4-乙炔基-3-氧代-2-苯基-2，6b，7，7a-四氢-3H-环丙烷并[4，5]环戊二烯并[1，2，3-de]异喹啉-1-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(200)2-((N-ethylsulfamoyl)amino)-N-((R)-1-((6bR,7aS)-4-ethynyl-3-oxo-2-phenyl-2 ,6b,7,7a-tetrahydro-3H-cyclopropa[4,5]cyclopenta[1,2,3-de]isoquinolin-1-yl)ethyl)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(201)2-氨基-N-((1S)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环氧苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(201) 2-amino-N-((1S)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2 , 4,5,6-tetrahydro-1H-4,6-epoxybenzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(202)2-氨基-N-((1R)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环氧苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(202) 2-amino-N-((1R)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2 , 4,5,6-tetrahydro-1H-4,6-epoxybenzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide ;
(203)N-((1S)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环氧苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(203) N-((1S)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5 ,6-tetrahydro-1H-4,6-epoxybenzo[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(204)N-((1R)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环氧苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(204) N-((1R)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5 ,6-tetrahydro-1H-4,6-epoxybenzo[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine -3-formamide;
(205)2-((N-环丙基氨磺酰基)氨基)-N-((1S)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环氧苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(205) 2-((N-cyclopropylsulfamoyl)amino)-N-((1S)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-4,6-epoxybenzo[de]isoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(206)2-((N-环丙基氨磺酰基)氨基)-N-((1R)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环氧苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(206) 2-((N-cyclopropylsulfamoyl)amino)-N-((1R)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl) -1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-4,6-epoxybenzo[de]isoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(207)2-氨基-N-((S)-1-((4R，6S)-10-甲基-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环亚氨基苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(207) 2-amino-N-((S)-1-((4R,6S)-10-methyl-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-4,6-cycloiminobenzo[de]isoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(208)2-氨基-N-((R)-1-((4R，6S)-10-甲基-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环亚氨基苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(208) 2-amino-N-((R)-1-((4R,6S)-10-methyl-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-4,6-cycloiminobenzo[de]isoquinolin-3-yl)ethyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide;
(209)N-((1S)-1-(10-甲基-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环亚氨基苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(209)N-((1S)-1-(10-methyl-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl- 2,4,5,6-tetrahydro-1H-4,6-cycloiminobenzo[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(210)N-((1R)-1-(10-甲基-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环亚氨基苯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(210)N-((1R)-1-(10-methyl-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl- 2,4,5,6-tetrahydro-1H-4,6-cycloiminobenzo[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(211)2-((N-环丙基氨磺酰基)氨基)-N-((1S)-1-(10-甲基-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环亚氨基苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(211) 2-((N-cyclopropylsulfamoyl)amino)-N-((1S)-1-(10-methyl-9-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-4,6-cycloiminobenzo[de]isoquinolin-3-yl)ethyl Group) pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(212)2-((N-环丙基氨磺酰基)氨基)-N-((1R)-1-(10-甲基-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-4，6-环亚氨基苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(212)2-((N-cyclopropylsulfamoyl)amino)-N-((1R)-1-(10-methyl-9-((1-methyl-1H-pyrazole-4- Yl)ethynyl)-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-4,6-cycloiminobenzo[de]isoquinolin-3-yl)ethyl Group) pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(213)(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(213)(S)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(2-(3-fluorophenyl)-9-((1-methyl-1H- Pyrazol-4-yl)ethynyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(214)(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(214)(R)-2-((N-cyclopropylsulfamoyl)amino)-N-(1-(2-(3-fluorophenyl)-9-((1-methyl-1H- Pyrazol-4-yl)ethynyl)-1-oxo-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1 , 5-a]pyrimidine-3-carboxamide;
(215)(S)-2-氨基-N-(1-(2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(215)(S)-2-amino-N-(1-(2-(3-fluorophenyl)-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1 -Oxo-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(216)(S)-2-氨基-N-(1-(9-((1-(甲基-d3)-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺；(216)(S)-2-amino-N-(1-(9-((1-(methyl-d3)-1H-pyrazol-4-yl)ethynyl)-1-oxo-2- Phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;
(217)(S)-2-氨基-N-(1-(1-氧代-2-苯基-8-((1-(2，2，2-三氟乙基)-1H-吡唑-4-基)乙炔基)-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺。(217)(S)-2-amino-N-(1-(1-oxo-2-phenyl-8-((1-(2,2,2-trifluoroethyl)-1H-pyrazole -4-yl)ethynyl)-1,2,4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine- 3-Formamide.
第三方面，本发明提供了上述具有式I结构的化合物的制备方法，具体步骤如下所示：In a third aspect, the present invention provides a method for preparing the above compound having the structure of Formula I, the specific steps are as follows:
Figure PCTCN2019123563-appb-000002
Figure PCTCN2019123563-appb-000002
S-1：化合物I-1发生关环，得到化合物I-2；S-1: The ring closure of compound I-1 gives compound I-2;
S-2：化合物I-2与化合物I-3反应，得到式I化合物；S-2: Compound I-2 reacts with compound I-3 to obtain the compound of formula I;
其中：基团X 0、X 1、X 2、X 7、X 8、X 9、X 10、X 11、X 12、X 13和X 14，取代基R 0、R 1、R 3、R 4、R 5和R 6，以及环A，如上述具有式I结构的化合物中所限定。 Among them: 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.
第四方面，本发明提供了一种药物组合物，其包含上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药。In a fourth aspect, the present invention provides 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.
第五方面，本发明提供了上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，其用作PI3K-γ抑制剂。In a fifth aspect, 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-γ inhibitors.
第六方面，本发明提供了上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，用作PI3K-γ抑制剂的用途。In a sixth aspect, 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, The use of solvates, hydrates, isotope labels or prodrugs, or the aforementioned pharmaceutical compositions, as PI3K-γ inhibitors.
第七方面，本申请提供了上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，在制备用于预防和/或治疗至少部分由PI3K-γ介导或者从PI3K-γ信号通路抑制中获益的疾病的药物中的用途。In a seventh aspect, 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-γ or benefit from PI3K-γ signaling pathway inhibition Use in medicine.
第八方面，本发明提供了一种用于预防和/或治疗至少部分由PI3K-γ介导或者从PI3K-γ信号通路抑制中获益的疾病的方法，其包括下列步骤：将治疗有效量的上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，施用于对其有需求的患者。In an eighth aspect, the present invention provides a method for preventing and/or treating diseases at least partially mediated by PI3K-γ or benefiting from PI3K-γ 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.
第九方面，本发明提供了一种药物联合形式，其包含上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，以及至少一种额外的癌症治疗剂。In a ninth aspect, 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.
第十方面，本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的上述具有式I结构的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，以及至少一种额外的癌症治疗剂，优选抗PD-1/PD-L1单抗，施用于对其有需求的患者。According to a tenth aspect, 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.
发明的效果Effect of invention
本发明提供的结构新颖的式I结构三并环化合物，其可以作为高效的PI3K抑制剂，具有抗肿瘤、抗神经退行性疾病(如阿尔茨海默病)、抗炎、抗动脉粥样硬化、抗感染等多种药理活性。合成方法温和，操作简单易行，易于衍生化，适合工业放大量生产。The 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.
附图说明BRIEF DESCRIPTION
图1示出了测试化合物在小鼠CT26模型中的肿瘤抑制曲线。Figure 1 shows the tumor inhibition curve of the test compound in the mouse CT26 model.
具体实施方式detailed description
在进一步描述本发明之前，应当理解，本发明不限于本文中所述的特定实施方案；还应该理解，本文中所使用的术语仅用于描述而非限制特定实施方案。Before further describing the present invention, it should be understood that the present invention is not limited to the specific embodiments described herein; it should also be understood that the terminology used herein is for describing rather than limiting specific embodiments.
[术语定义][Definition of Terms]
除非另有说明，下列术语的含义如下。Unless otherwise stated, the following terms have the following meanings.
“药学上可接受的盐”是指对生物体基本上无毒性的具有式I结构的化合物的盐。药学上可接受的盐通常包括(但不限于)本发明的化合物与药学上可接受的无机/有机酸或无机/有机碱反应而形成的盐，此类盐又被称为酸加成盐或碱加成盐。常见的无机酸包括(但不限于)盐酸、氢溴酸、硫酸、磷酸等，常见的有机酸包括(但不限于)三氟乙酸、柠檬酸、马来酸、富马酸、琥珀酸、酒石酸、乳酸、丙酮酸、草酸、甲酸、乙酸、苯甲酸、甲磺酸、苯磺酸、对甲苯磺酸等，常见的无机碱包括(但不限于)氢氧化钠、氢氧化钾、氢氧化钙、氢氧化钡等，常见的有机碱包括(但不限于)二乙胺、三乙胺、乙胺丁醇等。"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.
术语“溶剂化物”是指由本发明的化合物或其药学上可接受的盐与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。术语“溶剂化物”包括“水合物”。常见的溶剂化物包括(但不限于)水合物、乙醇合物、丙酮合物等。The term "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. The term "solvate" includes "hydrate". Common solvates include (but are not limited to) hydrates, ethanolates, acetones and the like.
术语“水合物”是指由本发明的化合物或其药学上可接受的盐与水通过非共价分子间作用力结合而形成的物质。常见的水合物包括(但不限于)半水合物、一水合物、二水合物、三水合物等。The term "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.
术语“异构体”是指具有相同原子数和原子类型因而具有相同分子量，但原子的空间排列或构型不同的化合物。The term "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.
术语“立体异构体”是指由分子中的原子因空间排列方式不同而产生的异构体，包括“构型异构体”和“构象异构体”两大类。术语“构型异构体”是指分子中的原子因不同空间排列而产生的异构体，包括“顺反异构体”和“光学异构体”两大类。术语“顺反异构体”是指位于双键或环系两侧的原子(或基团)因相对于参考平面的位置不同而产生的异构体，在顺式异构体中原子(或基团)位于双键或环系的同侧，在反式异构体中原子(或基团)位于双键或环系的异侧，其中的“双键”一般指碳碳双键，也包含碳氮双键和氮氮双键。术语“光学异构体”是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面，从而能够使平面偏振光旋转的稳定异构体。由于本发明化合物中存在可能导致立体异构的不对称中心以及其他化学结构，因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物及其盐包括不对称碳原子，因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常，这些化合物能够以外消旋混合物的形式制备。然而，如果需要的话，可以将这类化合物制备或分离后得到纯的立体异构体，即单一对映异构体或非对映异构体，或者单一立体异构体富集化(纯度≥98％、≥95％、≥93％、≥90％、≥88％、≥85％或≥80％)的混合物。如下文中所述，化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的，或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的，例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂，或者在手性色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到，也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。术语“对映异构体”是指彼此具有不能重叠的镜像的一对立体异构体。术语“非对映异构体”或“非对映体”是指彼此不构成镜像的光学异构体。术语“外消旋混合物”或“外消旋物”是指含有等份的单一对映异构体的混合物(即两种R和S对映体的等摩尔量混合物)。术语“非外消旋混合物”是指含有不等份的单一对映异构体的混合物。除非另外指出，本发明的化合物的所有立体异构体形式都在本发明的范围之内。The term "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". The term "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". The term "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. In the cis isomer (or Group) located on the same side of the double bond or ring system, in the trans isomer 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. The term "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. Because of the presence of asymmetric centers and other chemical structures in the compounds of the present invention that may cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since 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%). As described below, 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. The term "diastereomer" or "diastereomer" refers to optical isomers that do not form mirror images of each other. The term "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). The term "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.
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化，如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化等。除非另外指出，本发明的化合物的所有互变异构体形式都在本发明的范围之内。The term "tautomer" (or "tautomeric form") 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. For example, proton tautomers (or proton transfer 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.
术语“同位素标记物”是指将结构中的特定原子替换为其同位素原子而形成的化合物。除非另外 指出，本发明的化合物中包括H、C、N、O、F、P、S、Cl的各种同位素，如 2H(D)、 3H(T)、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S、 36S和 37Cl。 The term "isotopic label" refers to a compound formed by replacing a specific atom in a structure with its isotopic atom. Unless otherwise indicated, 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.
术语“前药”是指在适用于患者后能够直接或间接地提供本发明的化合物的衍生化合物。特别优选的衍生化合物或前药是在施用于患者时可以提高本发明的化合物的生物利用度的化合物(例如，更易吸收入血)，或者促进母体化合物向作用位点(例如，淋巴系统)递送的化合物。除非另外指出，本发明的化合物的所有前药形式都在本发明的范围之内，且各种前药形式是本领域熟知的。The term "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. Unless otherwise indicated, 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.
术语“各自独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或环系)可以在特定情形下具有相同或不同的含义。例如，X和Y各自独立地为氢、卤素、羟基、氰基、烷基或芳基，则当X为氢时，Y既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基；同理，当Y为氢时，X既可以为氢，也可以为卤素、羟基、氰基、烷基或芳基。The term "independently" means that at least two groups (or ring systems) having the same or similar value range in the structure may have the same or different meanings under certain circumstances. For example, 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.
术语“卤素”是指位于元素周期表第VII主族的氟(F)、氯(Cl)、溴(Br)和碘(I)。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I) located in main group VII of the periodic table.
术语“次磷酰基”是指一价的基团，其由次磷酸失去羟基后形成，并且通过一个与磷原子相连的单键连接至母核(-P(＝O)H 2)。次磷酰基既能够以未取代的形式连接本发明的式I化合物的结构母核，也能够将其中的氢原子替换为其他取代基。常见的取代的次磷酰基包括(但不限于)二烷基次磷酰基(-P(＝O)(Alk) 2，如二甲基次磷酰基)、二芳基次磷酰基(-P(＝O)(Ar) 2，如二苯基次磷酰基)、烷基芳基次磷酰基(-P(＝O)(Alk)(Ar)，如甲基苯基次磷酰基)、二烷氧基次磷酰基(-P(＝O)(OAlk) 2，如二甲氧基次磷酰基)等。 The term "phosphinyl" refers to a monovalent group that is formed by the loss of the hydroxyl group of hypophosphorous acid and is connected to the parent nucleus (-P(=O)H 2 ) through a single bond to a phosphorus atom. 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. Common substituted phosphinyl groups include, but are not limited to, dialkylphosphinyl groups (-P(=O)(Alk) 2 , such as dimethylphosphinyl group), diarylphosphinyl groups (-P( ＝O)(Ar) 2 , such as diphenylphosphinyl), alkylarylphosphinyl (-P(＝O)(Alk)(Ar), such as methylphenylphosphinyl), dioxane Oxyphosphinyl (-P(=O)(OAlk) 2 , such as dimethoxyphosphinyl) and the like.
术语“磷酰基”是指一价的基团，其由磷酸失去羟基后形成，并且通过一个与磷原子相连的单键连接至母核(-P(＝O)(OH) 2)。 The term "phosphoryl" refers to a monovalent group, which is formed after phosphoric acid loses a hydroxyl group, and is connected to the parent nucleus (-P(=O)(OH) 2 ) through a single bond connected to a phosphorus atom.
术语“烷基”是指一价的直链或支链的烷烃基团，其由碳原子和氢原子构成，不含有不饱和度，并且通过一个单键连接至母核，优选C 1-C 6烷基，更优选C 1-C 4烷基；常见的烷基包括(但不限于)甲基(-CH 3)、乙基(-CH 2CH 3)、正丙基(-CH 2CH 2CH 3)、异丙基(-CH(CH 3) 2)、正丁基(-CH 2CH 2CH 2CH 3)、仲丁基(-CH(CH 3)CH 2CH 3)、异丁基(-CH 2CH(CH 3) 2)、叔丁基(-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、新戊基(-CH 2C(CH 3) 3)等。 The term "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 2 CH 3 ), neopentyl (-CH 2 C(CH 3 ) 3 ) etc.
术语“烯基”是指一价的直链或支链的烯烃基团，其仅由碳原子和氢原子构成，含有至少一个双键，并且通过一个单键连接至母核，优选C 2-C 6烯基；常见的烯基包括(但不限于)乙烯基(-CH＝CH 2)、1-丙烯-1-基(-CH＝CH-CH 3)、1-丁烯-1-基(-CH＝CH-CH 2-CH 3)、1-戊烯-1-基(-CH＝CH-CH 2-CH 2-CH 3)、1，3-丁二烯-1-基(-CH＝CH-CH＝CH 2)、1，4-戊二烯-1-基(-CH＝CH-CH 2-CH＝CH 2)等。 The term "alkenyl" refers to a monovalent straight-chain or branched-chain olefin group consisting only of carbon and hydrogen atoms, containing at least one double bond, and connected to the parent core through a single bond, preferably C 2- C 6 alkenyl; common alkenyl groups include (but are not limited to) vinyl (-CH=CH 2 ), 1-propen-1-yl (-CH=CH-CH 3 ), 1-buten-1-yl (-CH=CH-CH 2 -CH 3 ), 1-penten-1-yl (-CH=CH-CH 2 -CH 2 -CH 3 ), 1,3-butadien-1-yl (- CH=CH-CH=CH 2 ), 1,4-pentadien-1-yl (-CH=CH-CH 2 -CH=CH 2 ), etc.
术语“炔基”是指一价的直链或支链的炔烃基团，其仅由碳原子和氢原子构成，含有至少一个三键，并且通过一个单键连接至母核，优选C 2-C 6炔基；常见的炔基包括(但不限于)乙炔基(-C≡CH)、1-丙炔-1-基(即丙炔基)(-C≡C-CH 3)、1-丁炔-1-基(即丁炔基)
Figure PCTCN2019123563-appb-000003
戊炔-1-基
Figure PCTCN2019123563-appb-000004
1，3-丁二炔-1-基(-C≡C-C≡CH)、1，4-戊二炔-1-基
Figure PCTCN2019123563-appb-000005
等。 The term "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)
Figure PCTCN2019123563-appb-000003
Pentyn-1-yl
Figure PCTCN2019123563-appb-000004
1,3-butadiyn-1-yl (-C≡CC≡CH), 1,4-pentadiyn-1-yl
Figure PCTCN2019123563-appb-000005
Wait.
术语“烷氧基”是指一价的直链或支链的基团，其仅由碳原子、氢原子和氧原子构成，可以含有不饱和度，并且通过一个与氧原子相连的单键连接至母核，优选C 1-C 4烷氧基；常见的烷氧基包括(但不限于)甲氧基(-OCH 3)、乙氧基(-OCH 2CH 3)、正丙氧基(-OCH 2CH 2CH 3)、异丙氧基(-OCH(CH 3) 2)、正丁氧基(-OCH 2CH 2CH 2CH 3)、仲丁氧基(-OCH(CH 3)CH 2CH 3)、异丁氧基(-OCH 2CH(CH 3) 2)、叔丁氧基(-OC(CH 3) 3)、正戊氧基(-OCH 2CH 2CH 2CH 2CH 3)、新戊氧基(-OCH 2C(CH 3) 3)等。 The term "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 2 CH 3 ), neopentyloxy (-OCH 2 C(CH 3 ) 3 ), etc.
术语“烷基酰基”是指一价的直链或支链的基团，其仅由碳原子、氢原子和氧原子构成，除自身结构中的羰基以外不含有不饱和度，并且通过一个与羰基相连的单键连接至母核，优选C 1-C 4烷基酰基；常见的烷基酰基包括(但不限于)甲酰基(-C(＝O)H)、乙酰基(-C(＝O)CH 3)、正丙酰基(-C(＝O)CH 2CH 3)、正丁酰基(-C(＝O)CH 2CH 2CH 3)、异丁酰基(-C(＝O)CH(CH 3) 2)、正戊酰基(-C(＝O)CH 2CH 2CH 2CH 3)、新戊酰基(-C(＝O)C(CH 3) 3)等。 The term "alkylacyl" refers to a monovalent linear or branched group, which is composed only of carbon atoms, hydrogen atoms, and oxygen atoms. It does not contain unsaturation other than the carbonyl group in its own structure, and is passed through a The single bond connected by the carbonyl group is connected to the parent nucleus, preferably a C 1 -C 4 alkyl acyl group; common alkyl acyl groups include (but are not limited to) formyl (-C(=O)H), acetyl (-C(= O)CH 3 ), n-propionyl (-C(=O)CH 2 CH 3 ), n-butyryl (-C(=O)CH 2 CH 2 CH 3 ), isobutyryl (-C(=O) CH(CH 3 ) 2 ), n-valeryl (-C(=O)CH 2 CH 2 CH 2 CH 3 ), pivaloyl (-C(=O)C(CH 3 ) 3 ), etc.
术语“烷基酰氨基”是指一价的直链或支链的基团，其仅由碳原子、氢原子、氧原子和氮原子构成，除自身结构中的羰基以外不含有不饱和度，并且通过一个与氮原子相连的单键连接至母核，优选C 1-C 4烷基酰氨基；常见的烷基酰氨基包括(但不限于)甲酰氨基(-NHC(＝O)H)、乙酰氨基(- NHC(＝O)CH 3)、正丙酰氨基(-NHC(＝O)CH 2CH 3)、正丁酰氨基(-NHC(＝O)CH 2CH 2CH 3)、异丁酰氨基(-NHC(＝O)CH(CH 3) 2)、正戊酰氨基(-NHC(＝O)CH 2CH 2CH 2CH 3)、新戊酰氨基(-NHC(＝O)C(CH 3) 3)等。 The term "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. And is connected to the parent nucleus through a single bond connected to a nitrogen atom, preferably C 1 -C 4 alkylamido; common alkylamido includes (but is not limited to) formylamino (-NHC(=O)H) , Acetamido (- NHC(=O)CH 3 ), n-propionylamino (-NHC(=O)CH 2 CH 3 ), n-butyrylamino (-NHC(=O)CH 2 CH 2 CH 3 ), Isobutyrylamino (-NHC(=O)CH(CH 3 ) 2 ), n-valerylamino (-NHC(=O)CH 2 CH 2 CH 2 CH 3 ), pivaloylamino (-NHC(=O ) C(CH 3 ) 3 ) etc.
术语“烷基酰氧基”是指一价的直链或支链的基团，其仅由碳原子、氢原子和氧原子构成，除自身结构中的羰基以外不含有不饱和度，并且通过一个与氧原子相连的单键连接至母核，优选C 1-C 4烷基酰氧基；常见的烷基酰氧基包括(但不限于)甲酰氧基(-OC(＝O)H)、乙酰氧基(-OC(＝O)CH 3)、正丙酰氧基(-OC(＝O)CH 2CH 3)、正丁酰氧基(-OC(＝O)CH 2CH 2CH 3)、异丁酰氧基(-OC(＝O)CH(CH 3) 2)、正戊酰氧基(-OC(＝O)CH 2CH 2CH 2CH 3)、新戊酰氧基(-OC(＝O)C(CH 3) 3)等。 The term "alkylacyloxy" refers to a monovalent straight or branched chain group, which is composed only of carbon atoms, hydrogen atoms, and oxygen atoms, does not contain unsaturation other than the carbonyl group in its own structure, and passes A single bond to the oxygen atom is connected to the parent nucleus, preferably a C 1 -C 4 alkyl acyloxy group; common alkyl acyloxy groups include (but are not limited to) formyloxy (-OC(=O)H ), acetoxy (-OC(=O)CH 3 ), n-propionyloxy (-OC(=O)CH 2 CH 3 ), n-butyryloxy (-OC(=O)CH 2 CH 2 CH 3 ), isobutyryloxy (-OC(=O)CH(CH 3 ) 2 ), n-valeryloxy (-OC(=O)CH 2 CH 2 CH 2 CH 3 ), pivaloyloxy Radical (-OC(=O)C(CH 3 ) 3 ), etc.
术语“烷氧基羰基”是指一价的直链或支链的基团，其仅由碳原子、氢原子和氧原子构成，除自身结构中的羰基以外不含有不饱和度，并且通过一个与羰基相连的单键连接至母核，优选C 1-C 4烷氧基羰基；常见的烷氧基羰基包括(但不限于)甲氧羰基(-C(＝O)OCH 3)、乙氧羰基(-C(＝O)OCH 2CH 3)、正丙氧羰基(-C(＝O)OCH 2CH 2CH 3)、异丙氧羰基(-C(＝O)OCH(CH 3) 2)、正丁氧羰基(-C(＝O)OCH 2CH 2CH 2CH 3)、叔丁氧羰基(-C(＝O)OC(CH 3) 3)等。 The term "alkoxycarbonyl" refers to a monovalent straight or branched chain group, which is composed only of carbon atoms, hydrogen atoms, and oxygen atoms. It does not contain unsaturation other than the carbonyl group in its own structure, and passes a The single bond to the carbonyl group is connected to the parent core, preferably C 1 -C 4 alkoxycarbonyl; common alkoxycarbonyl groups include (but are not limited to) methoxycarbonyl (-C(=O)OCH 3 ), ethoxy Carbonyl (-C(=O)OCH 2 CH 3 ), n-propoxycarbonyl (-C(=O)OCH 2 CH 2 CH 3 ), isopropoxycarbonyl (-C(=O)OCH(CH 3 ) 2 ), n-butoxycarbonyl (-C(=O)OCH 2 CH 2 CH 2 CH 3 ), tert-butoxycarbonyl (-C(=O)OC(CH 3 ) 3 ), etc.
术语“环烷基”是指一价的单环的非芳香族环系，其仅由碳原子和氢原子构成，不含有不饱和度，并且通过一个单键连接至母核；常见的环烷基包括具有3至10个环原子的环烷基，包括(但不限于)环丙基、环丁基、环戊基、环己基等。The term "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.
术语“杂环基”是指一价的单环的非芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，不含有不饱和度，并且通过一个单键连接至母核；常见的杂环基包括具有至少一个选自氮、氧、磷和硫的环杂原子的三至十八元非芳香族单环，包括(但不限于)环氧乙烷基、氧杂环丁烷-3-基、氮杂环丁烷-3-基、四氢呋喃-2-基、吡咯烷-1-基、吡咯烷-2-基、四氢-2H-吡喃-2-基、四氢-2H-吡喃-4-基、哌啶-2-基、哌啶-4-基等。The term "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.
术语“螺环基”是指两个单环共用一个碳原子的一价的非芳香族环系，其仅由碳原子和氢原子构成，不含有不饱和度，并且通过一个单键连接至母核；按照螺原子的个数，可以分为单螺化合物、二螺化合物、三螺化合物等；常见的螺环基包括(但不限于)螺[2.4]庚烷-1-基、螺[3.5]壬烷-2-基、螺[4.5]癸烷-2-基、二螺[5.2.5.2]十六烷-3-基等。The term "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.
术语“杂螺环基”是指两个单环共用一个碳原子的一价的非芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，不含有不饱和度，并且通过一个单键连接至母核；常见的杂螺环基包括(但不限于)6-氧杂螺[3.3]庚烷-2-基、7-甲基-7-氮杂螺[3.5]壬烷-2-基、7-甲基-2，7-二氮杂螺[3.5]壬烷-2-基、9-甲基-9-膦杂螺[5.5]十一烷-3-基等。The term "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.
术语“桥环基”是指任意两个单环共用不直接相连的两个碳原子的一价的非芳香族环系，其仅由碳原子和氢原子构成，不含有不饱和度，并且通过一个单键连接至母核；按照组成环的数目，可以分为二环化合物、三环化合物、四环化合物等；常见的桥环基包括(但不限于)十氢萘-1-基、二环[3.2.1]辛烷-1-基、三环[2.2.1.0 2.6]庚烷-1-基、1-金刚烷基等。 The term "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.
术语“杂桥环基”是指任意两个单环共用不直接相连的两个碳原子的一价的非芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，不含有不饱和度，并且通过一个单键连接至母核；常见的杂桥环基包括(但不限于)1，4-二氮杂二环[2.2.2]辛烷-2-基、2，8-二氮杂二环[4.3.0]壬烷-8-基等。The term "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.
术语“芳基”是指一价的单环或多环(包含稠合形式)的芳香族环系，其仅有碳原子和氢原子构成，并且通过一个单键连接至母核；常见的芳基包括具有6至14个环原子的芳基，包括(但不限于)苯基、萘基、蒽基、菲基、苊基、薁基、芴基、茚基、芘基等。The term "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.
术语“芳基烷基”是指一价的直链或支链的烷烃基团，其仅由碳原子和氢原子构成，含有至少一个芳基，并且通过一个单键连接至母核，优选C 6-C 10芳基-C 1-C 6烷基，更优选C 6-C 10芳基-C 1-C 4烷基；常见的芳基烷基包括(但不限于)苄基、β-苯乙基、α-苯乙基、萘甲基等。 The term "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, β- Phenylethyl, α-phenethyl, naphthylmethyl, etc.
术语“芳基烯基”是指一价的直链或支链的烯烃基团，其仅由碳原子和氢原子构成，含有至少一个双键及至少一个芳基，并且通过一个单键连接至母核，优选C 6-C 10芳基-C 2-C 6烯基；常见的芳基烯基包括(但不限于)1-苯乙烯基(-CPh＝CH 2)、2-苯乙烯基(-CH＝CHPh)、3-苯基-1-丙烯-1-基(-CH＝CH-CH 2Ph)、2-苯基-1-丙烯-1-基(-CH＝CPh-CH 3)、4-苯基-1，3-丁二烯-1-基(-CH＝CH-CH＝CHPh)、4，4-二 苯基-1，3-丁二烯-1-基(-CH＝CH-CH＝CPh 2)等。 The term "arylalkenyl" refers to a monovalent straight-chain or branched-chain olefin group consisting only of carbon atoms and hydrogen atoms, containing at least one double bond and at least one aryl group, and connected to the same through a single bond Mother core, preferably C 6 -C 10 aryl-C 2 -C 6 alkenyl; common aryl alkenyl groups include (but are not limited to) 1-styryl (-CPh=CH 2 ), 2-styryl (-CH=CHPh), 3-phenyl-1-propen-1-yl (-CH=CH-CH 2 Ph), 2-phenyl-1-propen-1-yl (-CH=CPh-CH 3 ), 4-phenyl-1,3-butadien-1-yl (-CH=CH-CH=CHPh), 4,4-diphenyl-1,3-butadien-1-yl (- CH=CH-CH=CPh 2 ) etc.
术语“芳基炔基”是指一价的直链或支链的炔烃基团，其仅由碳原子和氢原子构成，含有至少一个三键及至少一个芳基，并且通过一个单键连接至母核，优选C 6-C 10芳基-C 2-C 6炔基；常见的芳基炔基包括(但不限于)苯乙炔基(-C≡CPh)、3-苯基-1-丙炔-1-基(-C≡C-CH 2Ph)、3，3-二苯基-1-丙炔-1-基(-C≡C-CHPh 2)、4-苯基-1，3-丁二炔-1-基(-C≡C-C≡CPh)等。 The term "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.
术语“杂芳基”是指一价的单环或多环(包含稠合形式)的芳香族环系，其由碳原子及选自氮、氧、硫和磷的杂原子构成，并且通过一个单键连接至母核；常见的杂芳基包括具有1至4个选自氮、氧、磷和硫的环杂原子的五至十元芳香族单环或多环，包括(但不限于)苯并吡咯基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并噻唑基、吖啶基、咔唑基、吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、噻唑基、吡唑基、异噁唑基、异噻唑基、吲唑基、吲嗪基、吲哚基、喹啉基、异喹啉基、吩嗪基、吩噁嗪基、吩噻嗪基、蝶啶基、嘌呤基、吡嗪基、嘧啶基、哒嗪基、吡啶基、三唑基、四唑基等。The term "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, isoquinolinyl, phenazinyl, phenoxazinyl , Phenothiazine, pteridyl, purinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyridyl, triazolyl, tetrazolyl, etc.
术语“杂芳基烷基”是指一价的直链或支链的烷烃基团，其由碳原子及选自氮、氧、硫和磷的杂原子构成，含有至少一个杂芳基，并且通过一个单键连接至母核，优选5-10元杂芳基-C 1-C 6烷基，更优选5-10元杂芳基-C 1-C 4烷基；常见的杂芳基烷基包括(但不限于)吡咯-2-基甲基、呋喃-2-基甲基、噻吩-2-基甲基、1H-吡唑-3-基甲基、喹啉-4-基甲基等。 The term "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.
术语“杂芳基烯基”是指一价的直链或支链的烯烃基团，其由碳原子及选自氮、氧、硫和磷的杂原子构成，含有至少一个双键及至少一个杂芳基，并且通过一个单键连接至母核，优选5-10元杂芳基-C 2-C 6烯基；常见的杂芳基烯基包括(但不限于)2-(吡咯-2-基)乙烯基、2-(呋喃-2-基)乙烯基、2-(噻吩-2-基)乙烯基、4-(1H-吡唑-3-基)-1，3-丁二烯-1-基等。 The term "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.
术语“杂芳基炔基”是指一价的直链或支链的炔烃基团，其由碳原子及选自氮、氧、硫和磷的杂原子构成，含有至少一个三键及至少一个杂芳基，并且通过一个单键连接至母核，优选5-10元杂芳基-C 2-C 6炔基；常见的杂芳基炔基包括(但不限于)(吡咯-2-基)乙炔基、(呋喃-2-基)乙炔基、(噻吩-2-基)乙炔基、(1H-吡唑-3-基)乙炔基、(1H-吡唑-4-基)乙炔基、(1-甲基-1H-吡唑-4-基)乙炔基等。 The term "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.
术语“脲基”是指一价的基团，其由尿素失去一个氢原子后形成，并且通过一个单键连接至母核(-NHC(＝O)NH 2)。术语“烷基脲基”是指一价的基团，其由烷基取代脲基中的氢原子(取代位点通常为另一个氨基中的氮原子上)后形成，并且通过一个单键连接至母核(-NHC(＝O)NHAlk或-NHC(＝O)NAlk 2)。 The term "ureido" refers to a monovalent group that is formed by the loss of a hydrogen atom from urea and is connected to the parent nucleus (-NHC(=O)NH 2 ) through a single bond. The term "alkylureido" refers to a monovalent group, which is formed by the substitution of an alkyl group with a hydrogen atom in the ureido group (the substitution site is usually on a nitrogen atom in another amino group) and is connected by a single bond To the mother core (-NHC(=O)NHAlk or -NHC(=O)NAlk 2 ).
术语“五氟-λ 6-硫烷基”(又称“五氟化硫基”)是指一价的基团，其仅由硫原子和氟原子构成，并且通过一个单键连接至母核(-SF 5)。 The term “pentafluoro-λ 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 ).
[通式化合物][Formula compound]
本发明提供了一种式I化合物：The present invention provides a compound of formula I:
Figure PCTCN2019123563-appb-000006
Figure PCTCN2019123563-appb-000006
或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，其中：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, solvate, hydrate, isotopic label or prodrug thereof, wherein
A为四至十元环状结构，优选五至六元环状结构，该环状结构为饱和或不饱和的脂肪环或者芳香环，且该环状结构任选地含有0至多个杂原子；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 0为-C(＝R 2)-、-S(＝R 2) n-或-P(＝R 2)(R 0)-； X 0 is -C(=R 2 )-, -S(=R 2 ) n -or -P(=R 2 )(R 0 )-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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 8为-CH 2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2)-、-NH-或-NR 7-； X 8 is -CH 2 -, -CHR 7 -, -C(R 7 ) 2 -, -C(=R 2 )-, -NH- or -NR 7 -;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、杂芳基烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且R 0中的氢任选地被氘或卤素取代； 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 alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro Ring or bridge ring; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
R 1和R 4各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1和R 4中的氢任选地被0至多个基团取代，每一个所述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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 R″ are each independently hydrogen, 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, phosphoryl or alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring or spiro ring Or a bridged ring; and the heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkynyl groups;
每一个R 2各自独立地为NH、NR 7、N-OH、S或O； Each R 2 is independently NH, NR 7 , N-OH, S or O;
R 3为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 3中的氢任选地被0至多个基团取代，每一个所述基团各自独立地为氘、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、杂环烷基、芳基、杂芳基、芳基烷基、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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′ 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 alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro Ring or bridge ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkynyl groups ;
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，上述式I化合物为式IA化合物：In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IA:
Figure PCTCN2019123563-appb-000007
Figure PCTCN2019123563-appb-000007
其中：among them:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkyne Radical substitution
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，上述式I化合物为式IB化合物：In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IB:
Figure PCTCN2019123563-appb-000008
Figure PCTCN2019123563-appb-000008
其中：among them:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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和X 4各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3和X 4一起形成双键或三键； 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;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkyne Radical substitution
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，上述式I化合物为式IC化合物：In some preferred embodiments of the present invention, the compound of formula I above is a compound of formula IC:
Figure PCTCN2019123563-appb-000009
Figure PCTCN2019123563-appb-000009
其中：among them:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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和X 5各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4和X 5任意两者之间形成双键或三键； 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;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkyne Radical substitution
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，上述式I化合物为式ID化合物：In some preferred embodiments of the present invention, the compound of formula I above is a compound of formula ID:
Figure PCTCN2019123563-appb-000010
Figure PCTCN2019123563-appb-000010
其中：among them:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkyne Radical substitution
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，上述式I化合物为式IE化合物：In some preferred embodiments of the invention, the compound of formula I above is a compound of formula IE:
Figure PCTCN2019123563-appb-000011
Figure PCTCN2019123563-appb-000011
其中：among them:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkyne Radical substitution
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，在上述式I或式IA-IE化合物中：In some preferred embodiments of the invention, in the compound of formula I or formula IA-IE above:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-；优选-C(＝O)-或-C(＝S)-；最优选-C(＝O)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-; preferably -C(=O)- or- C(=S)-; most preferably -C(=O)-;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；优选氢、氘、卤素、烷基、卤代烷基、氨基或 -NR′R″； 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 ring; preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, amino or -NR'R";
R 1为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选芳基或杂芳基；最优选苯基；且R 1中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选烷基、卤代烷基或烷氧基；且R 4中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤素、羟基或氨基； 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;
每一个R 5各自独立地为NH、NR 7、N-OH、S或O；优选NH、S或O；最优选O； Each R 5 is independently NH, NR 7 , N-OH, S or O; preferably NH, S or O; most preferably O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7；优选氨基、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或酰胺基，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基或硝基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 ; preferably amino, -(CH 2 ) m NHSO 2 NH 2 , -NR'R",- NR 7 SO 2 NR′R″, —(CH 2 ) m SO 2 NR′R″, —(CH 2 ) m S(═O)NR′R″ or amide group, wherein: R′ and R″ are each independent Ground is hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl , Heteroaryl, halogen, cyano, hydroxy or nitro, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基；优选氢、氘、烷基、卤代烷基或氘代烷基； 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为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式I或式IA-IE化合物中：In some more preferred embodiments of the invention, in the compounds of formula I or IA-IE above:
X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-；优选-C(＝O)-或-C(＝S)-；最优选-C(＝O)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-; preferably -C(=O)- or- C(=S)-; most preferably -C(=O)-;
X 1、X 2和X 7各自独立地为CH、CR 7或N；优选CH或CR 7；最优选CH； X 1 , X 2 and X 7 are each independently CH, CR 7 or N; preferably CH or CR 7 ; most preferably CH;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；优选氢、氘、卤素、烷基、卤代烷基、氨基或-NR′R″； 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 ring; preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, amino or -NR'R";
R 1为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选芳基或杂芳基；最优选苯基；且R 1中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基或杂环基；优选烷基、卤代烷 基或烷氧基；且R 4中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤素、羟基或氨基； 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;
每一个R 5各自独立地为NH、NR 7、N-OH、S或O；优选NH、S或O；最优选O； Each R 5 is independently NH, NR 7 , N-OH, S or O; preferably NH, S or O; most preferably O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7；优选氨基、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或酰胺基，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基或硝基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 ; preferably amino, -(CH 2 ) m NHSO 2 NH 2 , -NR'R",- NR 7 SO 2 NR′R″, —(CH 2 ) m SO 2 NR′R″, —(CH 2 ) m S(═O)NR′R″ or amide group, wherein: R′ and R″ are each independent Ground is hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl , Heteroaryl, halogen, cyano, hydroxy or nitro, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基；优选氢、氘、烷基、卤代烷基或氘代烷基； 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为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式IA化合物中：In some more preferred embodiments of the invention, in the compound of formula IA above:
X 0为-C(＝O)-或-C(＝S)-； X 0 is -C(=O)- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且R 0中的氢任选地被氘或卤素取代； 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为芳基，优选苯基；且上述芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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 the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为NH、S或O； Each R 5 is independently NH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
R 8为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述 基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式IB化合物中：In some more preferred embodiments of the invention, in the compound of formula IB above:
X 0为-C(＝O)-或-C(＝S)-； X 0 is -C(=O)- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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和X 4各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3和X 4一起形成双键或三键； 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;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且R 0中的氢任选地被氘或卤素取代； 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为芳基或杂芳基，优选苯基或吡啶基；且上述芳基或杂芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为NH、S或O； Each R 5 is independently NH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
R 8为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式IC化合物中：In some more preferred embodiments of the invention, in the compound of formula IC above:
X 0为-C(＝O)-或-C(＝S)-； X 0 is -C(=O)- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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和X 5各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4和X 5任意两者之间形成双键或三键； 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;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且R 0中的氢任选地被氘或卤素取代； 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为芳基或杂芳基，优选苯基或吡啶基；且上述芳基或杂芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为NH、S或O； Each R 5 is independently NH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
R 8为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些优选的实施方案中，在上述式ID或式IE化合物中：In some preferred embodiments of the invention, in the compound of formula ID or formula IE above:
X 0为-C(＝O)-或-C(＝S)-； X 0 is -C(=O)- or -C(=S)-;
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0取代基中的氢任选地被氘或卤素取代； 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为芳基或杂芳基，优选苯基或吡啶基；且上述芳基或杂芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为NH、S或O； Each R 5 is independently NH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
R 8为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式IA-IE化合物中：In some more preferred embodiments of the invention, in the compounds of formula IA-IE above:
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基或环烷基；且R 0取代基中的氢任选地被氘或卤素取代； 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为芳基或杂芳基，优选苯基或吡啶基；且上述芳基或杂芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基。 Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl.
R 8为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式IA-IE化合物中：In some more preferred embodiments of the invention, in the compounds of formula IA-IE above:
X 1、X 2和X 7各自独立地为CH或CR 7；优选CH； 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和X 14各自独立地为CH、CR 7或N；优选CH或N； 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;
X 3、X 4、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基或环烷基；且R 0取代基中的氢任选地被氘或卤素取代； 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为芳基或杂芳基，优选苯基或吡啶基；且上述芳基或杂芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为S或O； Each R 5 is independently S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基。 Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl.
R 8为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
在本发明的一些更优选的实施方案中，在上述式IA-IE化合物中：In some more preferred embodiments of the invention, in the compounds of formula IA-IE above:
X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基或环烷基；且R 0取代基中的氢任选地被氘或卤素取代； 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为芳基或杂芳基，优选苯基或吡啶基；且上述芳基或杂芳基任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
R 4为氢、烷基、环烷基、卤素、卤代烷基、烷氧基或杂环基； R 4 is hydrogen, alkyl, cycloalkyl, halogen, haloalkyl, alkoxy or heterocyclic group;
每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
R 8为氢或吡唑基；且吡唑基中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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 a single ring, spiro ring or bridge ring;
每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
[制备方法][Preparation]
本发明提供了上述式I化合物的制备方法，具体步骤如下所示：The present invention provides a preparation method of the compound of formula I, the specific steps are as follows:
Figure PCTCN2019123563-appb-000012
Figure PCTCN2019123563-appb-000012
S-1：化合物I-1发生关环(优选在格式试剂和金属有机化合物存在的条件下，更优选在异丙基氯化镁和正丁基锂存在的条件下)，得到化合物I-2；S-1: Compound I-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 I-2;
S-2：化合物I-2与化合物I-3反应(优选通过取代反应)，得到式I化合物；S-2: Compound I-2 reacts with Compound I-3 (preferably through substitution reaction) to obtain the compound of Formula I;
其中：基团X 0、X 1、X 2、X 7、X 8、X 9、X 10、X 11、X 12、X 13和X 14，取代基R 0、R 1、R 3、R 4、R 5和R 6，以及环A，如上述式I化合物中所限定。 Among them: 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.
在本发明的一些更优选的实施方案中，上述制备方法包括：In some more preferred embodiments of the present invention, the above preparation method includes:
1)式IA化合物的制备方法，具体步骤如下所示：1) The preparation method of the compound of formula IA, the specific steps are as follows:
Figure PCTCN2019123563-appb-000013
Figure PCTCN2019123563-appb-000013
S-1：化合物IA-1发生关环(优选在格式试剂和金属有机化合物存在的条件下，更优选在异丙基氯化镁和正丁基锂存在的条件下)，得到化合物IA-2；S-1: ring closure of compound IA-1 (preferably in the presence of a reagent and a metal organic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium), to obtain compound IA-2;
S-2：化合物IA-2与化合物IA-3反应(优选通过偶联反应或取代反应)，得到化合物IA-4；S-2: Compound IA-2 reacts with compound IA-3 (preferably through coupling reaction or substitution reaction) to obtain compound IA-4;
S-3：化合物I-4与化合物IA-5反应(优选通过取代反应)，得到式IA化合物；S-3: Compound I-4 reacts with compound IA-5 (preferably through substitution reaction) to obtain compound of formula IA;
其中：X为离去基团，优选三氟甲磺酸酯基、硼酸酯基、氯、溴或碘；基团X 0、X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14，以及取代基R 0、R 1、R 4、R 5、R 6、R 7和R 8，如上述式IA化合物中所限定； Wherein: 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;
2)式IB化合物的制备方法，具体步骤如下所示：2) The preparation method of the compound of formula IB, the specific steps are as follows:
Figure PCTCN2019123563-appb-000014
Figure PCTCN2019123563-appb-000014
S-1：化合物IB-1发生关环(优选在格式试剂和金属有机化合物存在的条件下，更优选在异丙基氯化镁和正丁基锂存在的条件下)，得到化合物IB-2；S-1: ring closure of compound IB-1 (preferably in the presence of a reagent and a metal organic compound, more preferably in the presence of isopropyl magnesium chloride and n-butyl lithium), to obtain compound IB-2;
S-2：化合物IB-2与IB-3在催化剂的作用下反应(优选通过偶联反应或取代反应)，得到化合物IB-4；S-2: Compounds IB-2 and IB-3 react under the action of a catalyst (preferably through a coupling reaction or a substitution reaction) to obtain compound IB-4;
S-3：化合物IB-4与化合物IB-5反应(优选通过取代反应)，得到式IB化合物；S-3: Compound IB-4 reacts with compound IB-5 (preferably through substitution reaction) to obtain the compound of formula IB;
其中：X为离去基团，优选三氟甲磺酸酯基、硼酸酯基、氯、溴或碘；基团X 0、X 1、X 2、X 3、X 4、X 7、X 9、X 10、X 11、X 12、X 13和X 14，以及取代基R 0、R 1、R 4、R 5、R 6、R 7和R 8，如上述式IB化合物中所限定； Wherein: 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;
3)式IC化合物的制备方法，具体步骤如下所示：3) The preparation method of the compound of formula IC, the specific steps are as follows:
Figure PCTCN2019123563-appb-000015
Figure PCTCN2019123563-appb-000015
S-1：化合物IC-1发生关环(优选在格式试剂和金属有机化合物存在的条件下，更优选在异丙基氯化镁和正丁基锂存在的条件下)，得到化合物IC-2；S-1: The compound IC-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 IC-2;
S-2：化合物IC-2与IC-3在催化剂的作用下反应(优选通过取代反应)，得到化合物IC-4；S-2: Compounds IC-2 and IC-3 react under the action of a catalyst (preferably through substitution reaction) to obtain compound IC-4;
S-3：化合物IC-4与化合物IC-5反应，得到式IC化合物；S-3: Compound IC-4 reacts with compound IC-5 to obtain a compound of formula IC;
其中：X为离去基团，优选三氟甲磺酸酯基、硼酸酯基、氯、溴或碘；基团X 0、X 1、X 2、X 3、X 4、X 5、X 7、X 9、X 10、X 11、X 12、X 13和X 14，以及取代基R 0、R 1、R 4、R 5、R 6、R 7和R 8，如上述式IC化合物中所限定； Wherein: 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
4)式ID化合物的制备方法，具体步骤如下所示：4) The preparation method of the compound of formula ID, the specific steps are as follows:
Figure PCTCN2019123563-appb-000016
Figure PCTCN2019123563-appb-000016
S-1：化合物ID-1发生关环(优选在格式试剂和金属有机化合物存在的条件下，更优选在异丙基氯化镁和正丁基锂存在的条件下)，得到化合物ID-2；S-1: ring closure of compound ID-1 (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 ID-2;
S-2：化合物ID-2与ID-3在催化剂作用下反应(优选通过偶联反应或取代反应)，得到化合物ID-4；S-2: Compound ID-2 and ID-3 react under the action of a catalyst (preferably through a coupling reaction or a substitution reaction) to obtain compound ID-4;
S-3：化合物ID-4与化合物ID-5反应(优选通过取代反应)，得到式ID化合物；S-3: Compound ID-4 reacts with Compound ID-5 (preferably through substitution reaction) to obtain the compound of formula ID;
其中：X为离去基团，优选三氟甲磺酸酯基、硼酸酯基、氯、溴或碘；基团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和X 14，以及取代基R 0、R 1、R 4、R 5、R 6、R 7和R 8，如上述式ID化合物中所限定； Wherein: 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;
5)式IE化合物的制备方法，具体步骤如下所示：5) The preparation method of the compound of formula IE, the specific steps are as follows:
Figure PCTCN2019123563-appb-000017
Figure PCTCN2019123563-appb-000017
S-1：化合物IE-1发生关环(优选在格式试剂和金属有机化合物存在的条件下，更优选在异丙基氯化镁和正丁基锂存在的条件下)，得到化合物IE-2；S-1: 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;
S-2：化合物IE-2与IE-3在催化剂的作用下反应(优选通过偶联反应或取代反应)，得到化合物IE-4；S-2: Compound IE-2 and IE-3 react under the action of a catalyst (preferably through a coupling reaction or a substitution reaction) to obtain compound IE-4;
S-3：化合物IE-4与化合物IE-5反应(优选通过取代反应)，得到式IE化合物；S-3: Compound IE-4 reacts with compound IE-5 (preferably through substitution reaction) to obtain the compound of formula IE;
其中：X为离去基团，优选三氟甲磺酸酯基、硼酸酯基、氯、溴或碘；基团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和X 14，以及取代基R 0、R 1、R 4、R 5、R 6、R 7和R 8，如上述式IE化合物中所限定。 Wherein: 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.
在本发明的一些实施方案中，上述制备方法中的偶联反应包括(但不限于)铃木反应(Suzuki Reaction)、赫克反应(Heck Reaction)、斯蒂尔反应(Stille Reaction)、菌头偶联反应(Sogonoshira Coupling)、熊田偶联反应(Kumada Coupling)反应、根岸偶联反应(Negishi Coupling)、桧山偶联反应(Hiyama Coupling)等。可以理解的是，本领域技术人员已熟知上述偶联反应的实验条件。In some embodiments of the present invention, 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.
当上述式I化合物具有特定构型时，本发明还提供了相应的制备方法，以便得到具有特定构型的化合物。这些具有特定构型的化合物及其制备方法同样属于本发明的一部分。When the above formula I compound has a specific configuration, 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.
[药物组合物][Pharmaceutical composition]
术语“药物组合物”是指可以用作药物的组合物，其包含药物活性成分(API)以及可选的一种或多种药学上可接受载体。术语“药学上可接受的载体”是指与药物活性成分相容并且对受试者无害的药用辅料，包括(但不限于)稀释剂(或称填充剂)、粘合剂、崩解剂、润滑剂、润湿剂、增稠剂、助流 剂、矫味剂、矫嗅剂、防腐剂、抗氧化剂、pH调节剂、溶剂、助溶剂、表面活性剂等。The term "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. The term "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.
本发明提供了一种药物组合物，其包含上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药。The present invention provides 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.
在本发明的一些实施方案中，上述药物组合物还包含药学上可接受的载体。In some embodiments of the invention, the aforementioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier.
[医药用途][Medical use]
无论是上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，还是上述药物组合物，都可以用作PI3K-γ抑制剂。因此，本发明提供了上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，用作PI3K-γ抑制剂的用途。Whether it is the compound of formula I above, or its optical isomer or a mixture of both, or its cis-trans isomer or a mixture of both, or its pharmaceutically acceptable salt, solvate, hydrate, isotope label The drug or prodrug, or the above pharmaceutical composition, can be used as a PI3K-γ inhibitor. Therefore, 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-γ inhibitors.
另外，本申请还提供了上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，在制备用于预防和/或治疗至少部分由PI3K-γ介导或者从PI3K-γ信号通路抑制中获益的疾病的药物中的用途。In addition, 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-γ or benefiting from inhibition of PI3K-γ signaling pathway use.
术语“至少部分由PI3K-γ介导的疾病”是指发病机理中至少包含一部分与PI3K-γ有关的因素的疾病，这些疾病包括(但不限于)癌症(例如宫颈癌)、神经退行性疾病(例如阿尔茨海默病)、病毒感染(例如AIDS)、细菌感染(例如链球菌感染)、眼部疾病(例如白内障)、自身免疫性疾病(例如类风湿性关节炎)、抑郁症、焦虑症以及心理障碍。The term "disease mediated at least in part by PI3K-γ" refers to diseases whose pathogenesis contains at least a part of factors related to PI3K-γ, 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.
[治疗方法][treatment method]
本发明提供了一种用于预防和/或治疗至少部分由PI3K-γ介导或者从PI3K-γ信号通路抑制中获益的疾病的方法，其包括下列步骤：将治疗有效量的上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，施用于对其有需求的患者。The present invention provides a method for preventing and/or treating diseases at least partially mediated by PI3K-γ or benefiting from inhibition of PI3K-γ 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.
术语“治疗有效量”是指能够诱发细胞、组织、器官或生物体(例如患者)产生生物或医学反应的药物活性成分的剂量。The term "therapeutically 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).
术语“施用”是指将药物活性成分(比如本发明的化合物)或包含药物活性成分的药物组合物(例如本发明的药物组合物)应用于患者或其细胞、组织、器官、生物流体等部位，以便使药物活性成分或药物组合物与患者或其细胞、组织、器官、生物流体等部位接触的过程。常见的施用方式包括(但不限于)口服施用、皮下施用、肌内施用、腹膜下施用、眼部施用、鼻部施用、舌下施用、直肠施用、阴道施用等。The term "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. 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.
术语“对其有需求”是指医生或其他护理人员对患者需要或者将要从预防和/或治疗过程中获益的判断，该判断的得出基于医生或其他护理人员在其专长领域中的各种因素。The term "needs 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.
术语“患者”(或称受试者)是指人类或非人类的动物(例如哺乳动物)。The term "patient" (or subject) refers to a human or non-human animal (eg, mammal).
[联合用药][Combination]
本发明提供了一种药物联合形式，其包含上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，以及至少一种额外的癌症治疗剂。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.
术语“癌症”是指以失控的或失调的细胞增殖、减少的细胞分化、不适宜的侵入周围组织的能力和/或在异位建立新生长的能力为特征的细胞障碍。常见的癌症包括(但不限于)脑癌、肝癌、胆囊癌、支气管癌、肺癌、膀胱癌、卵巢癌、宫颈癌、睾丸癌、唇癌、舌癌、下咽癌、喉癌、食管癌、胃癌、肠癌(例如结肠癌、直肠癌)、甲状腺癌、唾液腺癌、胰腺癌、乳腺癌、前列腺癌、血癌(或称白血病)、淋巴癌(或称淋巴瘤)、骨癌和皮肤癌。The term "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.
术语“癌症治疗剂”是指能够有效控制和/或对抗癌症的药物组合物或药物制剂。常见的癌症治疗剂包括(但不限于)抗嘌呤药(例如喷司他丁等)、抗嘧啶药(例如氟尿嘧啶)、抗叶酸药(例如甲氨蝶呤)、DNA多聚酶抑制剂(如阿糖胞苷)、烷化剂(如环磷酰胺)、铂类配合物(例如顺铂)、破坏DNA的抗生素(例如丝裂霉素)、拓扑异构酶抑制剂(例如喜树碱)、嵌入DNA干扰核酸合成药(例如表柔 比星)、阻止原料供应药(例如门冬酰胺酶)、干扰微管蛋白形成药(例如紫杉醇)、干扰核糖体功能药(例如三尖杉酯碱)、细胞因子(例如IL-1)、胸腺肽、肿瘤细胞增殖病毒(如腺病毒ONYX-015)、抗PD-1/PD-L1单抗等。The term "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.
另外，本发明提供了一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的上述式I化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者上述药物组合物，以及至少一种额外的癌症治疗剂(优选抗PD-1/PD-L1单抗)，施用于对其有需求的患者。与单独使用相比，上述式I化合物与抗PD-1/PD-L1单抗联合使用能够显著提高肿瘤抑制率。In addition, 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. Compared with the use alone, the combination of the above formula I compound and anti-PD-1/PD-L1 monoclonal antibody can significantly improve the tumor suppression rate.
以下将结合具体的实施例来进一步阐述本发明。应当理解，这些实施例仅用于说明本发明，而并不旨在限制本发明的范围。如果下列实施例中的实验方法未注明具体条件，则通常按照常规条件或生产厂商所建议的条件。除非另外说明，下列实施例中出现的百分比和份数均以重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention. If the experimental methods in the following examples do not indicate specific conditions, they generally follow conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, the percentages and parts appearing in the following examples are all calculated by weight.
中间体制备例1：5-氯-2，3-二氢-1H-茚-4-甲酸甲酯(中间体A)的合成。Intermediate Preparation Example 1: Synthesis of 5-chloro-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (Intermediate A).
Figure PCTCN2019123563-appb-000018
Figure PCTCN2019123563-appb-000018
S1：2-溴-1-(溴甲基)-3-氯苯(中间体A-2)的合成：S1: Synthesis of 2-bromo-1-(bromomethyl)-3-chlorobenzene (intermediate A-2):
Figure PCTCN2019123563-appb-000019
Figure PCTCN2019123563-appb-000019
在搅拌条件下，向化合物A-1(23g，0.11mol)的CCl 4(400mL)溶液中，加入NBS(23.4g，0.13mol)。将所得混合物在回流条件下搅拌过夜。混合物浓缩，并将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚＝1∶100，V/V)，得到粗产物A-2(34g，65％纯度，收率约为70％)。 Under stirring, to a solution of compound A-1 (23 g, 0.11 mol) in CCl 4 (400 mL), NBS (23.4 g, 0.13 mol) was added. The resulting mixture was stirred overnight under reflux conditions. The mixture was concentrated, and the residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether = 1:100, V/V) to obtain crude product A-2 (34 g, 65% purity, yield about 70) %).
S2：3-(2-溴-3-氯苯基)丙酸(中间体A-3)的合成：S2: Synthesis of 3-(2-bromo-3-chlorophenyl)propionic acid (intermediate A-3):
Figure PCTCN2019123563-appb-000020
Figure PCTCN2019123563-appb-000020
向乙醇钠(7.8g，0.12mol)的200mL干燥乙醇溶液中，加入丙二酸二乙酯(14g，0.09mol)，然后在氩气气氛下添加化合物A-2(25g，0.09mol)。将所得混合物加热至回流，过夜。除去溶剂后，将残余物用EtOH(200mL)/H 2O(50mL)重新溶解，向混合物中加入KOH(20g，0.36mol)。使反应混合物继续回流2天。然后将反应混合物浓缩，将残余物用水稀释，用1M HCl酸化至pH＝6，用乙酸乙酯萃取两次。浓缩有机层，并用硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚＝1∶100至1∶10，V/V)，得到化合物A-3(9.5g，30％产率)。LC-MS：m/z 261[M-1] -。 To a 200 mL dry ethanol solution of sodium ethoxide (7.8 g, 0.12 mol), diethyl malonate (14 g, 0.09 mol) was added, and then compound A-2 (25 g, 0.09 mol) was added under an argon atmosphere. The resulting mixture was heated to reflux overnight. After removing the solvent, the residue was redissolved with EtOH (200 mL)/H 2 O (50 mL), and KOH (20 g, 0.36 mol) was added to the mixture. The reaction mixture was continued to reflux for 2 days. The reaction mixture was then concentrated, the residue was diluted with water, acidified with 1M HCl to pH=6, and extracted twice with ethyl acetate. The organic layer was concentrated and purified with a silica gel column (eluent: ethyl acetate: petroleum ether = 1:100 to 1:10, V/V) to obtain compound A-3 (9.5 g, 30% yield). LC-MS: m/z 261[M-1] - .
S3：4-溴-5-氯-2，3-二氢-1H-茚-1-酮(中间体A-4)的合成：S3: Synthesis of 4-bromo-5-chloro-2,3-dihydro-1H-inden-1-one (intermediate A-4):
Figure PCTCN2019123563-appb-000021
Figure PCTCN2019123563-appb-000021
将化合物A-3(9.5g，0.036mol)和SOCl 2(50mL)的混合物加热至回流4小时。然后在减压下 除去SOCl 2。将残余物用CH 2Cl 2(100mL)溶解并冷却至0℃。然后向混合物中添加AlCl 3(9.5g，0.072mmol)。将所得混合物缓慢加热，并在室温下搅拌过夜。将反应混合物用1M HCl淬灭，用CH 2Cl 2萃取。将有机层洗涤并干燥。浓缩后，将其用硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚＝1∶100至1∶10，V/V)，得到化合物A-4(5.5g，62％产率)。LC-MS：m/z 245[M+1] +。 A mixture of compound A-3 (9.5 g, 0.036 mol) and SOCl 2 (50 mL) was heated to reflux for 4 hours. Then SOCl 2 was removed under reduced pressure. The residue was dissolved with CH 2 Cl 2 (100 mL) and cooled to 0°C. Then AlCl 3 (9.5 g, 0.072 mmol) was added to the mixture. The resulting mixture was slowly heated and stirred at room temperature overnight. The reaction mixture was quenched with 1M HCl and extracted with CH 2 Cl 2 . The organic layer was washed and dried. After concentration, it was purified with a silica gel column (eluent: ethyl acetate: petroleum ether = 1:100 to 1:10, V/V) to obtain compound A-4 (5.5 g, 62% yield). LC-MS: m/z 245[M+1] + .
S4：4-溴-5-氯-2，3-二氢-1H-茚-1-醇(中间体A-5)的合成：S4: Synthesis of 4-bromo-5-chloro-2,3-dihydro-1H-inden-1-ol (intermediate A-5):
Figure PCTCN2019123563-appb-000022
Figure PCTCN2019123563-appb-000022
向化合物A-4(5.5g，0.023mol)的EtOH(50mL)溶液中添加NaBH 4(0.95g，0.025mol)。将所得混合物在0℃下搅拌2小时。反应完成后，将反应混合物在减压下浓缩，并将残余物用NH 4Cl(100mL)水溶液溶解。用乙酸乙酯(200mL×2)萃取。将有机层干燥并浓缩，得到化合物A-5(5.0g，90％产率)。LC-MS：m/z 247[M+1] +。 To a solution of compound A-4 (5.5 g, 0.023 mol) in EtOH (50 mL) was added NaBH 4 (0.95 g, 0.025 mol). The resulting mixture was stirred at 0°C for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved with an aqueous solution of NH 4 Cl (100 mL). Extract with ethyl acetate (200 mL x 2). The organic layer was dried and concentrated to obtain compound A-5 (5.0 g, 90% yield). LC-MS: m/z 247[M+1] + .
S5：4-溴-5-氯-2，3-二氢-1H-茚(中间体A-6)的合成：S5: Synthesis of 4-bromo-5-chloro-2,3-dihydro-1H-indene (intermediate A-6):
Figure PCTCN2019123563-appb-000023
Figure PCTCN2019123563-appb-000023
向化合物A-5(5.5g，0.022mol)的CH 2Cl 2(200mL)溶液中加入TFA(25g，0.22mol)和Et 3SiH(25.5g，0.22mol)。向反应混合物中充入氮气两次，然后加热至回流并搅拌过夜。然后将反应混合物过滤，将滤液浓缩并通过柱色谱法纯化(洗脱液：乙酸乙酯∶石油醚＝1∶100至1∶10，V/V)，得到粗产物A-6(5g，50％纯度)。 To a solution of compound A-5 (5.5 g, 0.022 mol) in CH 2 Cl 2 (200 mL) was added TFA (25 g, 0.22 mol) and Et 3 SiH (25.5 g, 0.22 mol). The reaction mixture was filled with nitrogen twice, then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:100 to 1:10, V/V) to obtain crude product A-6 (5g, 50 %purity).
S6：5-氯-2，3-二氢-1H-茚-4-甲酸甲酯(中间体1-1)的合成：S6: Synthesis of 5-chloro-2,3-dihydro-1H-indene-4-carboxylic acid methyl ester (intermediate 1-1):
Figure PCTCN2019123563-appb-000024
Figure PCTCN2019123563-appb-000024
向化合物A-6(1.5g，6.7mmol)的CH 3OH(50mL)溶液中加入TEA(1.3g，13mmol)和PdCl 2(dppf) 2(489mg，0.67mol)。添加后，将所得混合物在50℃的CO气球下搅拌过夜。将溶液浓缩，并通过柱色谱法纯化(洗脱液：乙酸乙酯∶石油醚＝1∶100至1∶10，V/V)，得到中间体A(500mg，70％纯度)。LC-MS：m/z 211[M+1] +。 To a solution of compound A-6 (1.5 g, 6.7 mmol) in CH 3 OH (50 mL) was added TEA (1.3 g, 13 mmol) and PdCl 2 (dppf) 2 (489 mg, 0.67 mol). After the addition, the resulting mixture was stirred under a CO balloon at 50°C overnight. The solution was concentrated, and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:100 to 1:10, V/V) to obtain Intermediate A (500 mg, 70% purity). LC-MS: m/z 211[M+1] + .
中间体制备例2：2-甲氧基-5，6，7，8-四氢萘-1-甲酸(中间体B)的合成。Intermediate Preparation Example 2: Synthesis of 2-methoxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (intermediate B).
Figure PCTCN2019123563-appb-000025
Figure PCTCN2019123563-appb-000025
S1：1-溴-5，6，7，8-四氢萘-2-酚(中间体B-2)的合成：S1: Synthesis of 1-bromo-5,6,7,8-tetrahydronaphthalene-2-phenol (intermediate B-2):
Figure PCTCN2019123563-appb-000026
Figure PCTCN2019123563-appb-000026
向化合物B-1(14.8g，100mmol)的DMF(100mL)溶液中加入NBS(21.4g，120mmol)。将所得混合物在室温搅拌过夜。然后将其倒入NaHCO 3水溶液中。用乙酸乙酯(500mL×2)萃取。合并的有机层用水洗涤，干燥并浓缩，得到化合物B-2(20g，90％产率)。LC-MS：m/z 227[M+1] +。 To a solution of compound B-1 (14.8 g, 100 mmol) in DMF (100 mL) was added NBS (21.4 g, 120 mmol). The resulting mixture was stirred at room temperature overnight. It was then poured into aqueous NaHCO 3 solution. Extract with ethyl acetate (500 mL×2). The combined organic layer was washed with water, dried and concentrated to give compound B-2 (20 g, 90% yield). LC-MS: m/z 227[M+1] + .
S2：5-溴-6-甲氧基-1，2，3，4-四氢萘(中间体B-3)的合成：S2: Synthesis of 5-bromo-6-methoxy-1,2,3,4-tetrahydronaphthalene (intermediate B-3):
Figure PCTCN2019123563-appb-000027
Figure PCTCN2019123563-appb-000027
向化合物B-2(20g，88.5mmol)的丙酮(500mL)溶液中加入MeI(11.2mL，177mmol)和K 2CO 3(24.4g，177mmol)。将所得混合物在40℃下搅拌过夜。冷却和过滤后，将滤液浓缩并通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-20％，V/V)，得到化合物B-3(20g，94％产率)，为白色油状物。LC-MS：m/z 241[M+1] +。 To a solution of compound B-2 (20 g, 88.5 mmol) in acetone (500 mL) was added MeI (11.2 mL, 177 mmol) and K 2 CO 3 (24.4 g, 177 mmol). The resulting mixture was stirred at 40°C overnight. After cooling and filtering, the filtrate was concentrated and purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate%=0-20%, V/V) to give compound B-3 (20g, 94% Yield) as a white oil. LC-MS: m/z 241[M+1] + .
S3：2-甲氧基-5，6，7，8-四氢萘-1-甲酸乙酯(中间体B-4)的合成：S3: Synthesis of ethyl 2-methoxy-5,6,7,8-tetrahydronaphthalene-1-carboxylate (intermediate B-4):
Figure PCTCN2019123563-appb-000028
Figure PCTCN2019123563-appb-000028
采用干冰-乙醇对化合物B-3(9g，37.5mmol)的THF(100mL)溶液进行冷却，缓慢滴加BuLi(18mL，45mmol)。加完后，在该温度下再搅拌1小时。然后向混合物中添加ClCO 2Et(3.75mL，45mmol)，并搅拌30分钟。之后，将反应混合物用饱和NH 4Cl水溶液淬灭。用乙酸乙酯(200mL×2)萃取，洗涤并干燥。浓缩有机相，并通过硅胶柱纯化(洗脱液：石油醚/乙酸乙酯＝20∶1)，得到化合物B-4(7.0g，79％产率)，为白色油状物。LC-MS：m/z 235[M+1] +。 A solution of compound B-3 (9 g, 37.5 mmol) in THF (100 mL) was cooled with dry ice-ethanol, and BuLi (18 mL, 45 mmol) was slowly added dropwise. After the addition is complete, stir at this temperature for another hour. Then ClCO 2 Et (3.75 mL, 45 mmol) was added to the mixture and stirred for 30 minutes. After that, the reaction mixture was quenched with saturated aqueous NH 4 Cl solution. Extract with ethyl acetate (200 mL×2), wash and dry. The organic phase was concentrated and purified through a silica gel column (eluent: petroleum ether/ethyl acetate = 20:1) to obtain compound B-4 (7.0 g, 79% yield) as a white oil. LC-MS: m/z 235[M+1] + .
S4：2-甲氧基-5，6，7，8-四氢萘-1-甲酸(中间体B)的合成：S4: Synthesis of 2-methoxy-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid (intermediate B):
Figure PCTCN2019123563-appb-000029
Figure PCTCN2019123563-appb-000029
向化合物B-4(7g，32mmol)的THF(100mL)/H 2O(100mL)溶液中加入LiOH·H 2O(13g，0.32mol)。将所得混合物加热至回流并搅拌过夜。除去有机溶剂后，用乙酸乙酯(100mL)萃取。将水层用1MHCl酸化至pH＝6。用乙酸乙酯(200mL×2)萃取，洗涤并干燥。浓缩有机层，得到中间体B(5.9g，89％产率)，为白色油状物。LC-MS：m/z 207[M+1] +。 To a solution of compound B-4 (7 g, 32 mmol) in THF (100 mL)/H 2 O (100 mL) was added LiOH·H 2 O (13 g, 0.32 mol). The resulting mixture was heated to reflux and stirred overnight. After removing the organic solvent, it was extracted with ethyl acetate (100 mL). The aqueous layer was acidified with 1M HCl to pH=6. Extract with ethyl acetate (200 mL×2), wash and dry. The organic layer was concentrated to give Intermediate B (5.9 g, 89% yield) as a white oil. LC-MS: m/z 207[M+1] + .
中间体制备例3：中间体C至中间体H的合成。Intermediate Preparation Example 3: Synthesis of Intermediate C to Intermediate H.
根据中间体制备例1描述的中间体A的合成路线，采用相应的物料，得到如下表所示的中间体化合物。According to the synthesis route of Intermediate A described in Intermediate Preparation Example 1, using the corresponding materials, the intermediate compounds shown in the following table are obtained.
Figure PCTCN2019123563-appb-000030
Figure PCTCN2019123563-appb-000030
Figure PCTCN2019123563-appb-000031
Figure PCTCN2019123563-appb-000031
中间体制备例4：中间体I至中间体L的合成。Intermediate Preparation Example 4: Synthesis of Intermediate I to Intermediate L.
根据中间体制备例2描述的中间体B的合成路线，采用相应的物料，得到如下表所示的中间体化合物。According to the synthesis route of Intermediate B described in Intermediate Preparation Example 2, using the corresponding materials, the intermediate compounds shown in the following table are obtained.
Figure PCTCN2019123563-appb-000032
Figure PCTCN2019123563-appb-000032
中间体制备例5：2，5-二氧代吡咯烷-1-基2-氨基吡唑并[1，5-a]嘧啶-3-甲酸酯(中间体M)的合成。Intermediate Preparation Example 5: Synthesis of 2,5-dioxopyrrolidin-1-yl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate (Intermediate M).
Figure PCTCN2019123563-appb-000033
Figure PCTCN2019123563-appb-000033
S1：2-氰基-2-(1，3-二氧杂环戊-2-亚基)乙酸乙酯(中间体M-2)的合成：S1: Synthesis of ethyl 2-cyano-2-(1,3-dioxol-2-ylidene) (intermediate M-2):
Figure PCTCN2019123563-appb-000034
Figure PCTCN2019123563-appb-000034
在15℃下，向NaOH(28.3g，0.71mol)在CH 3CN(1L)中的悬浮液中缓慢加入化合物M-1(40g，0.75mol)。添加后，继续搅拌2小时。然后在15-30℃下加入氯甲酸2-氯乙酯(50.6g，0.35mol)的CH 3CN(100mL)溶液。添加完成后，将溶液回流2小时。将反应混合物冷却至室温，并通过过滤除去产生的NaCl。浓缩溶液，残余物用冷却的MeOH洗涤。干燥后，得到所需的粗产物M-2(45g，35％产率)。LC-MS：m/z 184[M+1] +。 At 15° C., to a suspension of NaOH (28.3 g, 0.71 mol) in CH 3 CN (1L), compound M-1 (40 g, 0.75 mol) was slowly added. After the addition, stirring was continued for 2 hours. Then a solution of 2-chloroethyl chloroformate (50.6 g, 0.35 mol) in CH 3 CN (100 mL) was added at 15-30°C. After the addition is complete, the solution is refluxed for 2 hours. The reaction mixture was cooled to room temperature, and the generated NaCl was removed by filtration. The solution was concentrated and the residue was washed with cooled MeOH. After drying, the desired crude product M-2 (45 g, 35% yield) was obtained. LC-MS: m/z 184[M+1] + .
S2：(Z)-3-氨基-2-氰基-3-肼基丙烯酸乙酯(中间体M-3)的合成：S2: Synthesis of (Z)-3-amino-2-cyano-3-hydrazinoethyl acrylate (intermediate M-3):
Figure PCTCN2019123563-appb-000035
Figure PCTCN2019123563-appb-000035
在室温下，向化合物M-2(75g，0.04mol)在i-PrOH(1L)中的溶液中加入NH 3·H 2O(38mL)，搅拌1.5小时。然后向混合物中加入NH 2NH 2·H 2O(38mL)，并在70℃下搅拌2小时。浓缩，直接进入下一步反应。 At room temperature, to a solution of compound M-2 (75 g, 0.04 mol) in i-PrOH (1 L) was added NH 3 .H 2 O (38 mL) and stirred for 1.5 hours. Then NH 2 NH 2 .H 2 O (38 mL) was added to the mixture, and stirred at 70° C. for 2 hours. Concentrate and proceed directly to the next reaction.
S3：3，5-二氨基-1H-吡唑-4-甲酸乙酯(中间体M-4)的合成：S3: Synthesis of 3,5-diamino-1H-pyrazole-4-carboxylic acid ethyl ester (intermediate M-4):
Figure PCTCN2019123563-appb-000036
Figure PCTCN2019123563-appb-000036
将S2步骤的产物用n-BuOH(1L)重新溶解，并在110℃下搅拌2天。冷却后，将固体过滤并干燥，得到化合物M-4(45g，66％产率)。LC-MS：m/z 171[M+1] +。 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). LC-MS: m/z 171[M+1] + .
S4：2-氨基吡唑并[1，5-a]嘧啶-3-甲酸乙酯(中间体M-5)的合成：S4: Synthesis of ethyl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate (intermediate M-5):
Figure PCTCN2019123563-appb-000037
Figure PCTCN2019123563-appb-000037
向化合物M-4(48g，0.28mol)在CH 3COOH(400mL)中的溶液中加入1，1，3，3-四甲氧基丙烷(46g，0.28mol)。将反应混合物在回流条件下搅拌过夜，然后真空浓缩。残余物用丙酮洗涤，得到化合物M-5，为浅黄色固体(46g，82％产率)。LC-MS：m/z 207[M+1] +。 To a solution of compound M-4 (48 g, 0.28 mol) in CH 3 COOH (400 mL) was added 1,1,3,3-tetramethoxypropane (46 g, 0.28 mol). The reaction mixture was stirred at reflux overnight, then concentrated in vacuo. The residue was washed with acetone to obtain compound M-5 as a pale yellow solid (46 g, 82% yield). LC-MS: m/z 207[M+1] + .
S4：2-氨基吡唑并[1，5-a]嘧啶-3-甲酸(中间体M-6)的合成：S4: Synthesis of 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (intermediate M-6):
Figure PCTCN2019123563-appb-000038
Figure PCTCN2019123563-appb-000038
向化合物M-5(46g，0.22mol)在MeOH(150mL)/水(300mL)中的混合物中加入LiOH·H 2O(41.3g，0.98mol)。将反应混合物在60℃下搅拌2小时。然后将其用1MHCl酸化至pH＝5，将固体过滤并干燥，得到化合物M-6(40g，99％产率)。LC-MS：m/z 179[M+1] +。 To a mixture of compound M-5 (46 g, 0.22 mol) in MeOH (150 mL)/water (300 mL) was added LiOH·H 2 O (41.3 g, 0.98 mol). The reaction mixture was stirred at 60°C for 2 hours. It was then acidified with 1M HCl to pH=5, and the solid was filtered and dried to give compound M-6 (40 g, 99% yield). LC-MS: m/z 179[M+1] + .
S5：2，5-二氧代吡咯烷-1-基2-氨基吡唑并[1，5-a]嘧啶-3-甲酸酯(中间体M)的合成：S5: Synthesis of 2,5-dioxopyrrolidin-1-yl 2-aminopyrazolo[1,5-a]pyrimidine-3-carboxylate (intermediate M):
Figure PCTCN2019123563-appb-000039
Figure PCTCN2019123563-appb-000039
向化合物M-6(10g，56.2mmol)与DMF(300mL)的混合物中加入N-羟基琥珀酰亚胺(8.4g，73mmol)和EDCI(14g，73mmol)。将反应混合物在室温搅拌48小时。然后在1小时内向反应混合物中加入水(300mL)，将固体过滤并干燥，得到中间体M(12.5g，80％产率)。LC-MS：m/z 276[M+1] +。 To a mixture of compound M-6 (10 g, 56.2 mmol) and DMF (300 mL) was added N-hydroxysuccinimide (8.4 g, 73 mmol) and EDCI (14 g, 73 mmol). The reaction mixture was stirred at room temperature for 48 hours. Then water (300 mL) was added to the reaction mixture within 1 hour, and the solid was filtered and dried to obtain intermediate M (12.5 g, 80% yield). LC-MS: m/z 276[M+1] + .
中间体制备例6：(S)-3-(1-(叔丁氧羰基氨基)乙基)-1-氧代-2-苯基-1，2，4，5-四氢环戊并[de]异喹啉-8-基三氟甲磺酸酯(中间体N)的合成。Intermediate Preparation Example 6: (S)-3-(1-(tert-butoxycarbonylamino)ethyl)-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[ de] Isoquinolin-8-yl trifluoromethanesulfonate (intermediate N) synthesis.
Figure PCTCN2019123563-appb-000040
Figure PCTCN2019123563-appb-000040
S1：4-溴-5-甲氧基-2，3-二氢-1H-茚-1-酮(化合物N-2)的合成：S1: Synthesis of 4-bromo-5-methoxy-2,3-dihydro-1H-inden-1-one (compound N-2):
Figure PCTCN2019123563-appb-000041
Figure PCTCN2019123563-appb-000041
向化合物N-1(50g，0.3mol)的水(600mL)溶液中加入NBS(55.7g，0.31mol)。将所得混合物在室温搅拌过夜。然后将其倒入NaHCO 3水溶液中。用乙酸乙酯(500mL×2)萃取。合并的有机层用水洗涤，干燥并浓缩，得到化合物N-2(62g，84％产率)。LC-MS：m/z 241[M+1] +。 To a solution of compound N-1 (50 g, 0.3 mol) in water (600 mL) was added NBS (55.7 g, 0.31 mol). The resulting mixture was stirred at room temperature overnight. It was then poured into aqueous NaHCO 3 solution. Extract with ethyl acetate (500 mL×2). The combined organic layer was washed with water, dried and concentrated to give compound N-2 (62 g, 84% yield). LC-MS: m/z 241[M+1] + .
S2：4-溴-5-甲氧基-2，3-二氢-1H-茚(化合物N-3)的合成：S2: Synthesis of 4-bromo-5-methoxy-2,3-dihydro-1H-indene (compound N-3):
Figure PCTCN2019123563-appb-000042
Figure PCTCN2019123563-appb-000042
向化合物N-2(55g，0.23mol)的TFA(200mL)溶液中加入Et 3SiH(100mL)。将所得混合物加热至回流过夜。除去溶剂后，将残余物用饱和NaHCO 3水溶液碱化。用乙酸乙酯(200mL×2)萃取。合并的有机层用水洗涤，干燥并浓缩。将残余物用硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚＝0∶100至1∶100，V/V)，得到化合物N-3(36g，70％产率)。LC-MS：m/z 227[M+1] +。 To a solution of compound N-2 (55 g, 0.23 mol) in TFA (200 mL) was added Et 3 SiH (100 mL). The resulting mixture was heated to reflux overnight. After removing the solvent, the residue was basified with saturated aqueous NaHCO 3 solution. Extract with ethyl acetate (200 mL x 2). The combined organic layer was washed with water, dried and concentrated. The residue was purified with a silica gel column (eluent: ethyl acetate: petroleum ether = 0:100 to 1:100, V/V) to obtain compound N-3 (36 g, 70% yield). LC-MS: m/z 227[M+1] + .
S3：5-甲氧基-2，3-二氢-1H-茚-4-腈(化合物N-4)的合成：S3: Synthesis of 5-methoxy-2,3-dihydro-1H-indene-4-carbonitrile (Compound N-4):
Figure PCTCN2019123563-appb-000043
Figure PCTCN2019123563-appb-000043
在化合物N-3(35g，0.15mol)和NMP(600mL)的混合物中加入CuCN(69g，0.78mol)。将 所得混合物加热至150℃过夜。然后将其倒入水中，用乙酸乙酯(500mL×2)萃取。合并的有机层用水洗涤，干燥并浓缩。将残余物用硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚＝1∶100至1∶20，V/V)，得到化合物N-4(4.1g，15％产率)。LC-MS：m/z 174[M+1] +。 CuCN (69 g, 0.78 mol) was added to a mixture of compound N-3 (35 g, 0.15 mol) and NMP (600 mL). The resulting mixture was heated to 150°C overnight. Then it was poured into water and extracted with ethyl acetate (500 mL×2). The combined organic layer was washed with water, dried and concentrated. The residue was purified with a silica gel column (eluent: ethyl acetate: petroleum ether = 1:100 to 1:20, V/V) to obtain compound N-4 (4.1 g, 15% yield). LC-MS: m/z 174[M+1] + .
S4：5-甲氧基-2，3-二氢-1H-茚-4-甲酰胺(化合物N-5)的合成：S4: Synthesis of 5-methoxy-2,3-dihydro-1H-indene-4-carboxamide (Compound N-5):
Figure PCTCN2019123563-appb-000044
Figure PCTCN2019123563-appb-000044
向化合物N-4(4.1g，23.7mmol)和K 2CO 3(9.8g，71.1mmol)的DMSO(100mL)溶液中加入30％H 2O 2(15mL)。将所得混合物在室温搅拌2小时。反应完成后，然后将其倒入水中，用乙酸乙酯(200mL×2)萃取。合并的有机层用水洗涤，干燥并浓缩，得到化合物N-5(4.0g，88％产率)。LC-MS：m/z 192[M+1] +。 To a solution of compound N-4 (4.1 g, 23.7 mmol) and K 2 CO 3 (9.8 g, 71.1 mmol) in DMSO (100 mL) was added 30% H 2 O 2 (15 mL). The resulting mixture was stirred at room temperature for 2 hours. After the reaction was completed, it was then poured into water and extracted with ethyl acetate (200 mL×2). The combined organic layer was washed with water, dried and concentrated to give compound N-5 (4.0 g, 88% yield). LC-MS: m/z 192[M+1] + .
S5：5-甲氧基-2，3-二氢-1H-茚-4-甲酸(化合物N-6)的合成：S5: Synthesis of 5-methoxy-2,3-dihydro-1H-indene-4-carboxylic acid (compound N-6):
Figure PCTCN2019123563-appb-000045
Figure PCTCN2019123563-appb-000045
向化合物N-5(4.0g，0.21mol)的CH 2Cl 2(100mL)溶液中，加入亚硝酰基硫酸(10mL)的水(20mL)溶液。将反应混合物搅拌4小时。反应完成后，然后将其倒入水中，用乙酸乙酯(200mL×2)萃取。合并的有机层用水洗涤，干燥并浓缩，得到化合物N-6(4.0g，99％产率)。LC-MS：m/z 193[M+1] +。 To a solution of compound N-5 (4.0 g, 0.21 mol) in CH 2 Cl 2 (100 mL), a solution of nitrosyl sulfuric acid (10 mL) in water (20 mL) was added. The reaction mixture was stirred for 4 hours. After the reaction was completed, it was then poured into water and extracted with ethyl acetate (200 mL×2). The combined organic layer was washed with water, dried and concentrated to give compound N-6 (4.0 g, 99% yield). LC-MS: m/z 193[M+1] + .
S6：5-甲氧基-N-苯基-2，3-二氢-1H-茚-4-甲酰胺(化合物N-7)的合成：S6: Synthesis of 5-methoxy-N-phenyl-2,3-dihydro-1H-indene-4-carboxamide (compound N-7):
Figure PCTCN2019123563-appb-000046
Figure PCTCN2019123563-appb-000046
向冰水冷却的化合物N-6(4.0g，20mmol)和DMF(1mL)的CH 2Cl 2(100mL)溶液中，滴加草酰氯(2.1mL，25mmol)。添加后，将其在室温搅拌4小时。将混合物真空浓缩，得到粗制的酰氯，其直接用于下一步。 To a solution of compound N-6 (4.0 g, 20 mmol) and DMF (1 mL) in CH 2 Cl 2 (100 mL) cooled in ice water, oxalyl chloride (2.1 mL, 25 mmol) was added dropwise. After the addition, it was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give the crude acid chloride, which was used directly in the next step.
向冰水冷却的化合物苯胺(2.0g，22mmol)和三乙胺(4.1g，40mmol)的CH 2Cl 2(100mL)溶液中，加入酰氯(上步制备得到)的CH 2Cl 2(10mL)溶液。将所得混合物在室温搅拌过夜，然后加入CH 2Cl 2(100mL)和水(100mL)。分离有机层并用盐水洗涤，经Na 2SO 4干燥并过滤。将滤液真空浓缩。将产物悬浮在石油醚(100mL)中，并在室温下搅拌过夜。通过过滤收集沉淀物，用石油醚(50mL)冲洗，并在真空中进一步干燥，得到呈黄色固体的化合物N-7(4.3g，80％产率)。LC-MS：m/z 268[M+1] +。 To a solution of ice water-cooled compounds aniline (2.0 g, 22 mmol) and triethylamine (4.1 g, 40 mmol) in CH 2 Cl 2 (100 mL), add acid chloride (prepared in the previous step) in CH 2 Cl 2 (10 mL) Solution. The resulting mixture was stirred at room temperature overnight, and then CH 2 Cl 2 (100 mL) and water (100 mL) were added. The organic layer was separated and washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (100 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (50 mL), and further dried in vacuo to give compound N-7 (4.3 g, 80% yield) as a yellow solid. LC-MS: m/z 268[M+1] + .
S7：(2S)-1-(6-甲氧基-7-(苯基氨基甲酰基)-2，3-二氢-1H-茚-1-基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(化合物N-8)的合成：S7: (2S)-1-(6-methoxy-7-(phenylcarbamoyl)-2,3-dihydro-1H-inden-1-yl)-1-oxopropane-2-yl ) Synthesis of tert-butyl carbamate (compound N-8):
Figure PCTCN2019123563-appb-000047
Figure PCTCN2019123563-appb-000047
将化合物N-7(4.3g，16mmol)和HMPA(3.0mL，17.6mmol)在无水四氢呋喃(100mL)中的溶液冷却至-78℃，然后将正丁基锂的己烷溶液(2.5M，19.2mL)在30分钟内向其中缓慢加入。将反应混合物在相同温度下搅拌30分钟。A solution of compound N-7 (4.3 g, 16 mmol) and HMPA (3.0 mL, 17.6 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to -78°C, and then a hexane solution of n-butyl lithium (2.5 M, 19.2 mL) was slowly added thereto within 30 minutes. The reaction mixture was stirred at the same temperature for 30 minutes.
在另一个烧瓶中，将(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(4.83g，20.8mmol)在无水四氢呋喃(100mL)中的溶液冷却至-78℃，缓慢加入异丙基氯化镁的四氢呋喃溶液(24mL，24mmol)。将反应混合物在相同温度下搅拌30分钟，然后添加至上述反应混合物中。加入后，将其缓慢加热并在-20℃下搅拌4小时。用水(200mL)淬灭反应混合物，然后用乙酸乙酯(400mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。化合物N-8(6.2g粗品)无需进一步纯化即可用于随后的反应中。LC-MS：m/z 439[M+1] +。 In another flask, put (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (4.83 g, 20.8 mmol) in anhydrous The solution in tetrahydrofuran (100 mL) was cooled to -78°C, and a solution of isopropylmagnesium chloride in tetrahydrofuran (24 mL, 24 mmol) was slowly added. The reaction mixture was stirred at the same temperature for 30 minutes and then added to the above reaction mixture. After the addition, it was slowly heated and stirred at -20°C for 4 hours. The reaction mixture was quenched with water (200 mL), and then extracted with ethyl acetate (400 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. Compound N-8 (6.2 g crude) was used in the subsequent reaction without further purification. LC-MS: m/z 439[M+1] + .
S8：(S)-3-(1-氨基乙基)-8-甲氧基-2-苯基-4，5-二氢环戊二烯并[de]异喹啉-1(2H)-酮(化合物N-9)：S8: (S)-3-(1-aminoethyl)-8-methoxy-2-phenyl-4,5-dihydrocyclopenta[de]isoquinoline-1(2H)- Ketone (compound N-9):
Figure PCTCN2019123563-appb-000048
Figure PCTCN2019123563-appb-000048
向化合物N-8(6.2g，14mmol)在MeOH(200mL)中的溶液中加入浓HCl(100毫升)。将所得混合物加热至回流并搅拌10小时。反应完成后，将反应混合物在减压下浓缩，并将残余物用水(100mL)溶解，用乙酸乙酯(100mL×2)萃取。然后将水层用K 2CO 3碱化，用DCM(200mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：MeOH∶CH 2Cl 2，MeOH％＝0-5％，V/V)，得到化合物N-9(2.1g，46％产率)。LC-MS：m/z 321[M+1] +。 To a solution of compound N-8 (6.2 g, 14 mmol) in MeOH (200 mL) was added concentrated HCl (100 mL). The resulting mixture was heated to reflux and stirred for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved with water (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueous layer was then basified with K 2 CO 3 and extracted with DCM (200 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: MeOH:CH 2 Cl 2 , MeOH%=0-5%, V/V) to obtain compound N-9 (2.1 g, 46% yield). LC-MS: m/z 321[M+1] + .
S9：(S)-1-(8-羟基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基氨基甲酸叔丁基酯(化合物N-10)的合成：S9: (S)-1-(8-hydroxy-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethane Synthesis of tert-butyl carbamate (compound N-10):
Figure PCTCN2019123563-appb-000049
Figure PCTCN2019123563-appb-000049
向干冰-乙醇冷却的化合物N-9(1.2g，3.75mmol)的无水CH 2Cl 2(100mL)溶液中，加入BBr 3的CH 2Cl 2溶液(1.0M，7.5mL)。加入后，将其缓慢加热并在室温下搅拌2小时。然后将其用NaHCO 3水溶液淬灭。用DCM(200mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物溶于EtOH(20mL)和饱和NaHCO 3的混合物中。将所得混合物在室温搅拌过夜。然后将其用DCM(100mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。在减压下，将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-25％，V/V)，得到化合物N-10(1.55g，99％产率)。LC-MS：m/z 407[M+1] +。 To a dry ice-ethanol cooled compound N-9 (1.2 g, 3.75 mmol) solution in anhydrous CH 2 Cl 2 (100 mL) was added a solution of BBr 3 in CH 2 Cl 2 (1.0 M, 7.5 mL). After the addition, it was slowly heated and stirred at room temperature for 2 hours. It was then quenched with aqueous NaHCO 3 solution. Extract with DCM (200 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was dissolved in a mixture of EtOH (20 mL) and saturated NaHCO 3 . The resulting mixture was stirred at room temperature overnight. It was then extracted with DCM (100 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated. Under reduced pressure, the residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=0-25%, V/V) to obtain compound N-10 (1.55 g, 99% Yield). LC-MS: m/z 407[M+1] + .
S10：(S)-3-(1-(叔丁氧羰基氨基)乙基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-8-基三氟甲磺酸酯(中间体N)的合成：S10: (S)-3-(1-(tert-butoxycarbonylamino)ethyl)-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de] Synthesis of isoquinolin-8-yl trifluoromethanesulfonate (intermediate N):
Figure PCTCN2019123563-appb-000050
Figure PCTCN2019123563-appb-000050
向干冰-乙醇冷却的化合物N-10(1.75g，4.31mmol)的THF(100mL)溶液中加入HMDSLi的THF溶液(1.0M，10.8mL)。将所得混合物搅拌30分钟。然后向混合物中加入Tf 2NPh(2.3g，6.47mmol)。加入后，将其缓慢加热并在室温下搅拌过夜。然后将其用NH 4Cl水溶液淬灭。用乙酸乙酯(200mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-25％，V/V)，得到中间体N(1.7g，73％产率)。LC-MS：m/z 539[M+1] +。 To a dry ice-ethanol cooled compound N-10 (1.75 g, 4.31 mmol) in THF (100 mL) was added HMDSLi in THF (1.0 M, 10.8 mL). The resulting mixture was stirred for 30 minutes. Then Tf 2 NPh (2.3 g, 6.47 mmol) was added to the mixture. After the addition, it was slowly heated and stirred at room temperature overnight. It was then quenched with aqueous NH 4 Cl. Extract with ethyl acetate (200 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=0-25%, V/V) to obtain intermediate N (1.7 g, 73% yield). LC-MS: m/z 539[M+1] + .
实施例1：(S)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物1)的合成。Example 1: (S)-2-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]pyrimidine-3-carboxamide (Compound 1) synthesis.
Figure PCTCN2019123563-appb-000051
Figure PCTCN2019123563-appb-000051
S1：向中间体A(500mg，2.4mmol)和中间体1-2(300mg，2.86mmol)的CH 3CN(20mL)溶液中加入K 3PO 4(506mg，2.4mmol)、X-Phos(0.23g，0.48mmol)和Pd 2(dba) 3(0.23g，0.24mmol)。向反应混合物中加入N 2，然后加热至回流并搅拌过夜。然后过滤反应混合物，浓缩滤液并通过柱色谱法纯化(洗脱液：CH 2Cl 2/MeOH＝100∶1至10∶1，V/V)，得到中间体1-3(200mg，产率30％)。LC-MS：m/z 281.1[M+1] +。 S1: To a solution of Intermediate A (500 mg, 2.4 mmol) and Intermediate 1-2 (300 mg, 2.86 mmol) in CH 3 CN (20 mL) was added K 3 PO 4 (506 mg, 2.4 mmol), X-Phos (0.23 g, 0.48 mmol) and Pd 2 (dba) 3 (0.23 g, 0.24 mmol). N 2 was added to the reaction mixture, then heated to reflux and stirred overnight. The reaction mixture was then filtered, the filtrate was concentrated and purified by column chromatography (eluent: CH 2 Cl 2 /MeOH=100:1 to 10:1, V/V) to obtain intermediate 1-3 (200 mg, yield 30 %). LC-MS: m/z 281.1 [M+1] + .
S2：向中间体1-3(200mg，0.71mol)的THF/H 2O(10mL/10mL)溶液中加入LiOH·H 2O(145mg，3.55mol)，过夜。反应液加入1M HCl溶液，调节PH为6。采用乙酸乙酯萃取3次(20mL×3)，得到目标中间体酸(180mg)。在室温下，向中间体酸在CH 2Cl 2(10mL)中的搅拌溶液中滴加草酰氯(0.5mL)，并将得到的混合物在室温下搅拌2小时，然后将混合物真空浓缩，得到粗品，将其直接用于下一步骤。向冰水冷却的粗品和三乙胺(202mg，2mmol)的CH 2Cl 2溶液中加入苯胺(94mg，1mmol)的CH 2Cl 2(5mL)溶液。将得到的混合物在室温下搅拌过夜，然后加入水(10mL)。分离有机层并用盐水洗涤，用Na 2SO 4干燥并过滤。将滤液真空浓缩。将产物悬浮在石油醚中并在室温下搅拌过夜。过滤收集沉淀物，用石油醚冲洗，并进一步真空干燥，得到中间体1-4(150mg，产率60％)，为黄色固体。LC-MS：m/z 342.1[M+1] +。 S2: To a solution of intermediate 1-3 (200 mg, 0.71 mol) in THF/H 2 O (10 mL/10 mL) was added LiOH·H 2 O (145 mg, 3.55 mol) overnight. 1M HCl solution was added to the reaction solution to adjust the pH to 6. Extract 3 times with ethyl acetate (20 mL×3) to obtain the target intermediate acid (180 mg). At room temperature, oxalyl chloride (0.5 mL) was added dropwise to a stirred solution of intermediate acid in CH 2 Cl 2 (10 mL), and the resulting mixture was stirred at room temperature for 2 hours, and then the mixture was concentrated in vacuo to obtain a crude product. And use it directly in the next step. To a solution of crude ice-cooled water and triethylamine (202 mg, 2 mmol) in CH 2 Cl 2 was added a solution of aniline (94 mg, 1 mmol) in CH 2 Cl 2 (5 mL). The resulting mixture was stirred at room temperature overnight, and then water (10 mL) was added. The organic layer was separated and washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether, and further dried in vacuo to obtain Intermediate 1-4 (150 mg, yield 60%) as a yellow solid. LC-MS: m/z 342.1[M+1] + .
S3：将中间体1-4(150mg，0.44mmol)和HMPA(86mg，0.48mol)的无水四氢呋喃(10mL)溶液冷却至-78℃，然后在30分钟内向其中缓慢加入正丁基锂的己烷溶液(2.5M，0.53mL，1.32mmol)。将反应混合物在相同温度下搅拌30分钟。在另一个烧瓶中，冷却(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(111mg，0.48mol)的无水四氢呋喃溶液。在-78℃下缓慢加入异丙基氯化镁的四氢呋喃溶液(0.8mL，0.72mol)。将反应混合物在相同温度下搅拌30分钟，然后加入上述反应混合物中。在-78℃下搅拌1小时。将反应混合物用水(50mL)淬灭，然后用乙酸乙酯萃取。萃取液用Na 2SO 4干燥，然后减压浓缩，得到中间体1-5(200mg粗品)，不经进一步纯化，直接用于后续反应。LC-MS：m/z 513.2[M+1] +。 S3: Cool the solution of Intermediate 1-4 (150 mg, 0.44 mmol) and HMPA (86 mg, 0.48 mol) in anhydrous tetrahydrofuran (10 mL) to -78°C, then slowly add n-butyllithium to it within 30 minutes Alkane solution (2.5M, 0.53mL, 1.32mmol). The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, cool (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (111 mg, 0.48 mol) in anhydrous tetrahydrofuran Solution. A solution of isopropyl magnesium chloride in tetrahydrofuran (0.8 mL, 0.72 mol) was slowly added at -78°C. The reaction mixture was stirred at the same temperature for 30 minutes, and then added to the above reaction mixture. Stir at -78°C for 1 hour. The reaction mixture was quenched with water (50 mL) and then extracted with ethyl acetate. The extract was dried over Na 2 SO 4 and then concentrated under reduced pressure to obtain intermediate 1-5 (200 mg crude product), which was directly used in the subsequent reaction without further purification. LC-MS: m/z 513.2 [M+1] + .
S4：向中间体1-5(200mg粗品)的MeOH(10ml)溶液中加入浓HCl(5mL)。将得到的混合物在回流下搅拌2小时。反应完成后，将反应混合物减压浓缩，将残余物用水(20mL)溶解，用乙酸乙酯(20mL)萃取。然后将水层用K 2CO 3碱化并用乙酸乙酯(50mL)萃取。将合并的有机层用盐水洗涤并干燥。浓缩后，得到中间体1-6(30mg)。LC-MS：m/z 395.1[M+1] +。 S4: To a solution of intermediate 1-5 (200 mg crude) in MeOH (10 ml) was added concentrated HCl (5 mL). The resulting mixture was stirred at reflux for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, the residue was dissolved with water (20 mL), and extracted with ethyl acetate (20 mL). The aqueous layer was then basified with K 2 CO 3 and extracted with ethyl acetate (50 mL). The combined organic layer was washed with brine and dried. After concentration, intermediate 1-6 (30 mg) was obtained. LC-MS: m/z 395.1 [M+1] + .
S5：向中间体1-6(30mg，0.076mmol)和中间体1-7(25mg，0.091mmol)在CH 3CN(10mL)中的混合物中加入DIPEA(20mg，0.152mmol)。将混合物在回流下搅拌过夜。浓缩反应混合物，通过制备型HPLC纯化残余物，得到化合物1(5mg，产率12％)。LC-MS：m/z 555[M+1] +。 1H-NMR(400MHz，DMSO-d 6)δ8.91-8.92(d，J＝4.0Hz，1H)，8.54-8.55(d，J＝4.0Hz，1H)，7.98-7.99(d，J＝4.0Hz，1H)，7.46-7.52(m，6H)，7.42-7.44(d，J＝8.0Hz，1H)，7.01(m，1H)，6.87-6.89(d，J＝8.0Hz，1H)，6.45(S，2H)，4.48-4.51(m，1H)，3.77(S，3H)，3.24-3.26(m，2H)，3.07-3.10(d，J＝12.0Hz，1H)，1.32-1.34(d，J＝8.0Hz， 3H)。 S5: To a mixture of intermediate 1-6 (30 mg, 0.076 mmol) and intermediate 1-7 (25 mg, 0.091 mmol) in CH 3 CN (10 mL) was added DIPEA (20 mg, 0.152 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain compound 1 (5 mg, yield 12%). LC-MS: m/z 555[M+1] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.91-8.92 (d, J=4.0 Hz, 1H), 8.54-8.55 (d, J=4.0 Hz, 1H), 7.98-7.99 (d, J= 4.0Hz, 1H), 7.46-7.52(m, 6H), 7.42-7.44(d, J=8.0Hz, 1H), 7.01(m, 1H), 6.87-6.89(d, J=8.0Hz, 1H), 6.45 (S, 2H), 4.48-4.51 (m, 1H), 3.77 (S, 3H), 3.24-3.26 (m, 2H), 3.07-3.10 (d, J=12.0Hz, 1H), 1.32-1.34 ( d, J = 8.0 Hz, 3H).
实施例2：(R)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物2)的合成。Example 2: (R)-2-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]pyrimidine-3-carboxamide (Compound 2) synthesis.
Figure PCTCN2019123563-appb-000052
Figure PCTCN2019123563-appb-000052
参照实施例1，在S3中，将(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯替换为(R)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯，其余步骤按照实施例1中的具体方法实施，得到化合物2。LC-MS：m/z 555[M+1] +。 Referring to Example 1, in S3, (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester is replaced with (R)-( 1-(Methoxy(methyl)amino)-1-oxopropane-2-yl)carbamic acid tert-butyl ester, the rest of the steps are carried out according to the specific method in Example 1 to obtain compound 2. LC-MS: m/z 555[M+1] + .
实施例3：(S)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物3)的合成。Example 3: (S)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2, 4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 3) Synthesis.
Figure PCTCN2019123563-appb-000053
Figure PCTCN2019123563-appb-000053
向冰水冷却的叔丁醇(46mg，0.63mmol)的CH 2Cl 2(10mL)溶液中加入氯磺酰基异氰酸酯(89mg，0.63mmol)。将所得混合物搅拌10分钟。然后向混合物中加入化合物1(316mg，0.57mmol)和三乙胺(115mg，1.14mmol)的CH 2Cl 2(10mL)溶液。10分钟后，除去冰浴。然后将反应混合物在环境温度下搅拌3小时。浓缩反应溶液并再溶于二恶烷中，向溶液中加入10M HCl的二恶烷溶液(1mL)。30分钟后，浓缩反应混合物。通过制备型HPLC纯化残余物，得到化合物3(28mg，产率40％)。LC-MS：m/z 634.2[M+1] +。 To a solution of tert-butanol (46 mg, 0.63 mmol) in CH 2 Cl 2 (10 mL) cooled in ice water was added chlorosulfonyl isocyanate (89 mg, 0.63 mmol). The resulting mixture was stirred for 10 minutes. Then a solution of compound 1 (316 mg, 0.57 mmol) and triethylamine (115 mg, 1.14 mmol) in CH 2 Cl 2 (10 mL) was added to the mixture. After 10 minutes, the ice bath was removed. The reaction mixture was then stirred at ambient temperature for 3 hours. The reaction solution was concentrated and redissolved in dioxane, and 10M HCl in dioxane (1 mL) was added to the solution. After 30 minutes, the reaction mixture was concentrated. The residue was purified by preparative HPLC to obtain compound 3 (28 mg, yield 40%). LC-MS: m/z 634.2[M+1] + .
实施例4：(R)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-(氨磺酰基氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物4)的合成。Example 4: (R)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2, 4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-(sulfamoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis of (Compound 4).
Figure PCTCN2019123563-appb-000054
Figure PCTCN2019123563-appb-000054
以化合物2为起始物料，参照实施例3的合成步骤，得到化合物4。LC-MS：m/z 634.1[M+1] +。 Using compound 2 as the starting material, and referring to the synthesis procedure of Example 3, compound 4 was obtained. LC-MS: m/z 634.1[M+1] + .
实施例5：(S)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物5)的合成。Example 5: (S)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2, 4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a] Synthesis of pyrimidine-3-carboxamide (Compound 5).
Figure PCTCN2019123563-appb-000055
Figure PCTCN2019123563-appb-000055
向化合物1(1000mg，1.89mmol)的吡啶(20mL)溶液中加入甲基氨磺酰氯(295mg，2.27mmol)。将反应混合物加热至60℃并搅拌过夜。然后浓缩反应混合物并通过制备型HPLC纯化，得到化合物5(60mg，产率5％)。LC-MS：m/z 648.1[M+1] +。 To a solution of compound 1 (1000 mg, 1.89 mmol) in pyridine (20 mL) was added methylsulfamoyl chloride (295 mg, 2.27 mmol). The reaction mixture was heated to 60°C and stirred overnight. The reaction mixture was then concentrated and purified by preparative HPLC to obtain compound 5 (60 mg, yield 5%). LC-MS: m/z 648.1 [M+1] + .
实施例6：(R)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)-2-((N-甲基氨磺酰基)氨基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物6)的合成。Example 6: (R)-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2, 4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)-2-((N-methylsulfamoyl)amino)pyrazolo[1,5-a] Synthesis of pyrimidine-3-carboxamide (Compound 6).
Figure PCTCN2019123563-appb-000056
Figure PCTCN2019123563-appb-000056
参照实施例5，以化合物2为起始物料，得到化合物6。LC-MS：m/z 648.1[M+1] +。 Referring to Example 5, using Compound 2 as a starting material, Compound 6 was obtained. LC-MS: m/z 648.1 [M+1] + .
实施例7：(S)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物7)的合成。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).
Figure PCTCN2019123563-appb-000057
Figure PCTCN2019123563-appb-000057
向化合物1(155mg，0.28mmol)的吡啶溶液(1mL)中加入环丙基氨磺酰氯(53mg，0.34mmol)。将反应混合物加热至60℃并搅拌过夜。然后浓缩反应混合物并通过制备型HPLC纯化，得到化合物7(20mg，产率11％)。LC-MS：m/z 674.2[M+1] +。 To the pyridine solution (1 mL) of compound 1 (155 mg, 0.28 mmol) was added cyclopropylsulfamoyl chloride (53 mg, 0.34 mmol). The reaction mixture was heated to 60°C and stirred overnight. The reaction mixture was then concentrated and purified by preparative HPLC to obtain compound 7 (20 mg, yield 11%). LC-MS: m/z 674.2 [M+1] + .
实施例8：(R)-2-((N-环丙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物8)的合成。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).
Figure PCTCN2019123563-appb-000058
Figure PCTCN2019123563-appb-000058
参照实施例7，以化合物2为起始物料，得到化合物8。LC-MS：m/z 674.2[M+1] +。 Referring to Example 7, using Compound 2 as a starting material, Compound 8 was obtained. LC-MS: m/z 674.2 [M+1] + .
实施例9：(S)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物9)的合成。Example 9: (S)-2-((N-ethylsulfamoyl)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 9).
Figure PCTCN2019123563-appb-000059
Figure PCTCN2019123563-appb-000059
向化合物1(155mg，0.28mmol)的吡啶溶液(1mL)中加入乙基氨磺酰氯(49mg，0.34mmol)。将反应混合物加热至60℃并搅拌过夜。然后浓缩反应混合物，并通过制备型HPLC纯化，得到化合物9(22mg，产率12％)。LC-MS：m/z 662.2[M+1] +。 To a pyridine solution (1 mL) of Compound 1 (155 mg, 0.28 mmol) was added ethylsulfamoyl chloride (49 mg, 0.34 mmol). The reaction mixture was heated to 60°C and stirred overnight. The reaction mixture was then concentrated and purified by preparative HPLC to obtain compound 9 (22 mg, yield 12%). LC-MS: m/z 662.2 [M+1] + .
实施例10：(R)-2-((N-乙基氨磺酰基)氨基)-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物10)的合成。Example 10: (R)-2-((N-ethylsulfamoyl)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 10).
Figure PCTCN2019123563-appb-000060
Figure PCTCN2019123563-appb-000060
参照实施例9，以化合物2为起始物料，得到化合物10。LC-MS：m/z 662.2[M+1] +。 Referring to Example 9, using Compound 2 as a starting material, Compound 10 was obtained. LC-MS: m/z 662.2 [M+1] + .
实施例11：(S)-2-氨基-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物21)的合成。Example 11: (S)-2-amino-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl- 2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 21) synthesis.
Figure PCTCN2019123563-appb-000061
Figure PCTCN2019123563-appb-000061
S1：2-甲氧基-N-苯基-5，6，7，8-四氢萘-1-甲酰胺(化合物21-1)的合成：S1: Synthesis of 2-methoxy-N-phenyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (Compound 21-1):
Figure PCTCN2019123563-appb-000062
Figure PCTCN2019123563-appb-000062
向冰水冷却的中间体B(5.3g，25.7mmol)和DMF(1mL)的CH 2Cl 2(100mL)溶液中，滴加草酰氯(3.3mL，38.6mmol)。添加后，将其在室温搅拌4小时。将混合物真空浓缩，得到粗制的酰氯，其直接用于下一步。 To a solution of Intermediate B (5.3 g, 25.7 mmol) and DMF (1 mL) in CH 2 Cl 2 (100 mL) cooled with ice water, oxalyl chloride (3.3 mL, 38.6 mmol) was added dropwise. After the addition, it was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give the crude acid chloride, which was used directly in the next step.
向冰水冷却的化合物苯胺(2.9g，30.8mol)和三乙胺(5.2g，51.4mmol)的CH 2Cl 2(100mL)溶液中，加入酰氯(上步制得)的CH 2Cl 2(10mL)溶液)。将所得混合物在室温搅拌过夜，然后加入CH 2Cl 2(10mL)和水(100mL)。分离有机层并用盐水洗涤，经Na 2SO 4干燥并过滤。将滤液真空浓缩。将产物悬浮在石油醚(100mL)中，并在室温下搅拌过夜。通过过滤收集沉淀物，用石油醚(50mL)冲洗，并在真空中进一步干燥，得到化合物21-1(6.2g，85％产率)，为黄色固体。LC-MS：m/z 282[M+1] +。 To an ice water cooled aniline compound (2.9g, 30.8mol) and triethylamine (5.2g, 51.4mmol) in CH 2 Cl 2 (100mL) was added the acid chloride (prepared on step) in CH 2 Cl 2 ( 10mL) solution). The resulting mixture was stirred at room temperature overnight, and then CH 2 Cl 2 (10 mL) and water (100 mL) were added. The organic layer was separated and washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (100 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (50 mL), and further dried in vacuo to give compound 21-1 (6.2 g, 85% yield) as a yellow solid. LC-MS: m/z 282[M+1] + .
S2：(2S)-1-(7-甲氧基-8-(苯基氨基甲酰基)-1，2，3，4-四氢萘-1-基)-1-氧代丙烷-2-基氨基甲酸叔丁酯(化合物21-2)的合成：S2: (2S)-1-(7-methoxy-8-(phenylcarbamoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1-oxopropane-2- Synthesis of tert-butyl carbamate (Compound 21-2):
Figure PCTCN2019123563-appb-000063
Figure PCTCN2019123563-appb-000063
将化合物21-1(2.8g，10mmol)和HMPA(2.2mL，13mmol)在无水四氢呋喃(100mL)中的溶液冷却至-78℃，然后在30分钟内向其中缓慢加入正丁基锂在己烷中的溶液(2.5M，12mL)。将反应混合物在相同温度下搅拌30分钟。在另一个烧瓶中，将(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(3.48g，15mol)在无水四氢呋喃(100mL)中的溶液冷却至-78℃，缓慢加入异丙 基氯化镁的四氢呋喃溶液(20mL，20mol)。将反应混合物在相同温度下搅拌30分钟，然后添加至上述反应混合物中。加入后，将其缓慢加热并在-20℃下搅拌4小时。用水(200mL)淬灭反应混合物，然后用乙酸乙酯(400mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。化合物21-2(3.4g粗品)无需进一步纯化即可用于随后的反应。LC-MS：m/z 453[M+1] +。 A solution of compound 21-1 (2.8 g, 10 mmol) and HMPA (2.2 mL, 13 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to -78°C, and then n-butyllithium was slowly added thereto in hexane over 30 minutes. Solution (2.5M, 12mL). The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, put (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (3.48 g, 15 mol) in anhydrous tetrahydrofuran The solution in (100 mL) was cooled to -78°C, and a solution of isopropyl magnesium chloride in tetrahydrofuran (20 mL, 20 mol) was slowly added. The reaction mixture was stirred at the same temperature for 30 minutes and then added to the above reaction mixture. After the addition, it was slowly heated and stirred at -20°C for 4 hours. The reaction mixture was quenched with water (200 mL), and then extracted with ethyl acetate (400 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. Compound 21-2 (3.4 g crude) was used in the subsequent reaction without further purification. LC-MS: m/z 453[M+1] + .
S3：(S)-3-(1-氨基乙基)-9-甲氧基-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物21-3)的合成：S3: (S)-3-(1-aminoethyl)-9-methoxy-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline-1 -Synthesis of ketone (Compound 21-3):
Figure PCTCN2019123563-appb-000064
Figure PCTCN2019123563-appb-000064
向化合物21-2(3.4g，7.5mmol)的MeOH(50mL)溶液中加入浓HCl(25毫升)。将所得混合物加热至回流并搅拌10小时。反应完成后，将反应混合物在减压下浓缩，并将残余物用水(100mL)溶解，用乙酸乙酯(100mL×2)萃取。然后将水层用K 2CO 3碱化，用DCM(200mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：MeOH∶CH 2Cl 2，MeOH％＝0-5％，V/V)，得到化合物21-3(1.2g，48％产率)。LC-MS：m/z 335[M+1] +。 To a solution of compound 21-2 (3.4 g, 7.5 mmol) in MeOH (50 mL) was added concentrated HCl (25 mL). The resulting mixture was heated to reflux and stirred for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved with water (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueous layer was then basified with K 2 CO 3 and extracted with DCM (200 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: MeOH:CH 2 Cl 2 , MeOH%=0-5%, V/V) to obtain compound 21-3 (1.2 g, 48% yield). LC-MS: m/z 335 [M+1] + .
S4：(S)-1-(9-羟基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物21-4)的合成：S4: (S)-1-(9-hydroxy-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethane Synthesis of tert-butyl carbamate (Compound 21-4):
Figure PCTCN2019123563-appb-000065
Figure PCTCN2019123563-appb-000065
向干冰-乙醇冷却的化合物21-3(500mg，1.5mmol)的无水CH 2Cl 2(20mL)溶液中，加入BBr 3的CH 2Cl 2溶液(1.6M，3mL)。加入后，将其缓慢加热并在室温下搅拌2小时。然后将其用NaHCO 3(10mL)水溶液淬灭。用DCM(200mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物溶于EtOH(10mL)和饱和NaHCO 3的混合物中。将所得混合物在室温搅拌过夜。然后将其用DCM(100mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-25％，V/V)，得到化合物21-4(210mg，27％产率)。LC-MS：m/z 421[M+1] +。 To a dry ice-ethanol cooled compound 21-3 (500 mg, 1.5 mmol) solution in anhydrous CH 2 Cl 2 (20 mL) was added a solution of BBr 3 in CH 2 Cl 2 (1.6 M, 3 mL). After the addition, it was slowly heated and stirred at room temperature for 2 hours. It was then quenched with aqueous NaHCO 3 (10 mL). Extract with DCM (200 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was dissolved in a mixture of EtOH (10 mL) and saturated NaHCO 3 . The resulting mixture was stirred at room temperature overnight. It was then extracted with DCM (100 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=0-25%, V/V) to obtain compound 21-4 (210 mg, 27% yield). LC-MS: m/z 421[M+1] + .
S5：(S)-3-(1-(叔丁氧基羰基氨基)乙基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-9-基三氟甲磺酸酯(化合物21-5)的合成：S5: (S)-3-(1-(tert-butoxycarbonylamino)ethyl)-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de ] Synthesis of isoquinolin-9-yl trifluoromethanesulfonate (compound 21-5):
Figure PCTCN2019123563-appb-000066
Figure PCTCN2019123563-appb-000066
向干冰-乙醇冷却的化合物21-4(210mg，0.5mmol)的THF(10mL)溶液中，加入HMDSLi的THF溶液(1.0M，1.25mL)。将所得混合物搅拌30分钟。然后向混合物中加入Tf 2NPh(214mg，0.6mmol)。加入后，将其缓慢加热并在室温下搅拌过夜。然后将其用NH 4Cl水溶液淬灭。用乙酸乙酯(100mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝10-25％，V/V)，得到化合物21-5(100mg，36％产率)。LC-MS：m/z 553[M+1] +。 To a solution of compound 21-4 (210 mg, 0.5 mmol) in THF (10 mL) cooled with dry ice-ethanol, a THF solution of HMDSLi (1.0 M, 1.25 mL) was added. The resulting mixture was stirred for 30 minutes. Then Tf 2 NPh (214 mg, 0.6 mmol) was added to the mixture. After the addition, it was slowly heated and stirred at room temperature overnight. It was then quenched with aqueous NH 4 Cl. Extract with ethyl acetate (100 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=10-25%, V/V) to obtain compound 21-5 (100 mg, 36% yield). LC-MS: m/z 553[M+1] + .
S6：(S)-1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物21-6)的合成：S6: (S)-1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2,4,5,6-tetra Synthesis of tert-butyl hydrogen-1H-benzo[de]isoquinolin-3-yl)ethylcarbamate (compound 21-6):
Figure PCTCN2019123563-appb-000067
Figure PCTCN2019123563-appb-000067
向化合物21-5(100mg，0.18mmol)和4-乙炔基-1-甲基-1H-吡唑(25mg，0.22mmol)在CH 3CN(10mL)中的溶液中加入K 3PO 4(50mg，0.22mmol)，Xphos(1.7mg，3.6μmol)和Pd 2(dba) 3(1.7mg，1.8μmol)。向反应混合物中充入氮气两次，然后通过微波加热至回流2小时。然后将反应混合物浓缩并通过柱色谱法纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝25-50％，V/V)，得到所需化合物21-6(30mg，33％产率)。LC-MS：m/z 509[M+1] +。 To a solution of compound 21-5 (100 mg, 0.18 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (25 mg, 0.22 mmol) in CH 3 CN (10 mL) was added K 3 PO 4 (50 mg , 0.22 mmol), Xphos (1.7 mg, 3.6 μmol) and Pd 2 (dba) 3 (1.7 mg, 1.8 μmol). The reaction mixture was filled with nitrogen twice, then heated to reflux by microwave for 2 hours. The reaction mixture was then concentrated and purified by column chromatography (eluent: ethyl acetate: petroleum ether, ethyl acetate %=25-50%, V/V) to obtain the desired compound 21-6 (30 mg, 33% Yield). LC-MS: m/z 509[M+1] + .
S7：(S)-3-(1-氨基乙基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物21-7)的合成：S7: (S)-3-(1-aminoethyl)-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenyl-2,4,5,6 -Synthesis of tetrahydro-1H-benzo[de]isoquinolin-1-one (Compound 21-7):
Figure PCTCN2019123563-appb-000068
Figure PCTCN2019123563-appb-000068
向冰水冷却的化合物21-6(30mg，0.06mmol)的CH 2Cl 2(5mL)溶液中加入TFA(2mL)。将所得混合物搅拌2小时。然后将其用NaHCO 3水溶液淬灭。用DCM(20mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩，得到化合物21-7(20mg，82％产率)。LC-MS：m/z 409[M+1] +。 To an ice-water-cooled compound 21-6 (30 mg, 0.06 mmol) in CH 2 Cl 2 (5 mL) solution was added TFA (2 mL). The resulting mixture was stirred for 2 hours. It was then quenched with aqueous NaHCO 3 solution. Extract with DCM (20 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated to give compound 21-7 (20 mg, 82% yield). LC-MS: m/z 409 [M+1] + .
S8：(S)-2-氨基-N-(1-(9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物21)的合成：S8: (S)-2-amino-N-(1-(9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-2, Synthesis of 4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 21):
Figure PCTCN2019123563-appb-000069
Figure PCTCN2019123563-appb-000069
向化合物21-7(20mg，0.049mmol)和中间体M(20mg，0.074mmol)在CH 3CN(5mL)中的溶液中，加入DIPEA(12.7mg，0.098mmol)。将混合物在回流下搅拌过夜。浓缩反应混合物，残余物通过制备型HPLC纯化，得到作为白色固体的化合物21(10mg，36％产率)。LC-MS：m/z 569[M+1] +。 1H-NMR(400MHz，DMSO-d 6)δ8.92(dd，J＝8.0Hz，4.0Hz，1H)，8.52(d，J＝4.0Hz，1H)，8.47(s，1H)，8.05(s，1H)，7.97(s，1H)，7.57-7.47(m，6H)，7.34-7.30(m，1H)，7.03-6.99(m，1H)，6.43(s，2H)，4.87-4.85(m，1H)，3.81(s，3H)，3.10-3.08(m，1H)，2.97-2.80(m，3H)，2.06-1.96(m，1H)，1.85-1.76(m，1H)，1.45(d，J＝8.0Hz，3H)。 To a solution of compound 21-7 (20 mg, 0.049 mmol) and intermediate M (20 mg, 0.074 mmol) in CH 3 CN (5 mL), DIPEA (12.7 mg, 0.098 mmol) was added. The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to obtain compound 21 (10 mg, 36% yield) as a white solid. LC-MS: m/z 569[M+1] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.92 (dd, J=8.0 Hz, 4.0 Hz, 1H), 8.52 (d, J=4.0 Hz, 1H), 8.47 (s, 1H), 8.05 ( s, 1H), 7.97 (s, 1H), 7.57-7.47 (m, 6H), 7.34-7.30 (m, 1H), 7.03-6.99 (m, 1H), 6.43 (s, 2H), 4.87-4.85 ( m, 1H), 3.81 (s, 3H), 3.10-3.08 (m, 1H), 2.97-2.80 (m, 3H), 2.06-1.96 (m, 1H), 1.85-1.76 (m, 1H), 1.45 ( d, J = 8.0 Hz, 3H).
实施例12：(S)-2-氨基-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物11)的合成。Example 12: (S)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de ] Synthesis of isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 11).
Figure PCTCN2019123563-appb-000070
Figure PCTCN2019123563-appb-000070
S1：(S)-1-(1-氧代-2-苯基-8-((三甲基硅烷基)乙炔基)-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物11-1)的合成：S1: (S)-1-(1-oxo-2-phenyl-8-((trimethylsilyl)ethynyl)-1,2,4,5-tetrahydrocyclopenta[de ] Isoquinolin-3-yl) ethyl carbamate tert-butyl ester (Compound 11-1) Synthesis:
Figure PCTCN2019123563-appb-000071
Figure PCTCN2019123563-appb-000071
向中间体N(1.0g，1.86mmol)和乙炔基三甲基硅烷(0.60mL，4.25mmol)的CH 3CN(20mL)溶液中加入K 3PO 4(1.33g，6.27mmol)，Xphos(20mg，0.05mmol)和Pd 2(dba) 3(20mg，0.025mmol)。向反应混合物中充入氮气两次，然后加热至回流并搅拌过夜。然后将反应混合物过滤，将滤液浓缩并通过柱色谱法纯化(洗脱液：CH 2Cl 2/MeOH＝100∶1，V/V)，得到所需化合物11-1(200mg，22％产率)。LC-MS：m/z 487[M+1] +。 To a solution of intermediate N (1.0 g, 1.86 mmol) and ethynyltrimethylsilane (0.60 mL, 4.25 mmol) in CH 3 CN (20 mL) was added K 3 PO 4 (1.33 g, 6.27 mmol), Xphos (20 mg , 0.05mmol) and Pd 2 (dba) 3 (20mg, 0.025mmol). The reaction mixture was filled with nitrogen twice, then heated to reflux and stirred overnight. The reaction mixture was then filtered, and the filtrate was concentrated and purified by column chromatography (eluent: CH 2 Cl 2 /MeOH=100:1, V/V) to obtain the desired compound 11-1 (200 mg, 22% yield) ). LC-MS: m/z 487[M+1] + .
S2：(S)-1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物11-2)的合成：S2: (S)-1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl) Synthesis of tert-butyl ethyl carbamate (Compound 11-2):
Figure PCTCN2019123563-appb-000072
Figure PCTCN2019123563-appb-000072
向化合物11-1(200mg，0.41mmol)的THF(10mL)溶液中加入TBAF的THF溶液(1M，0.6mL)。反应完成后，将反应混合物浓缩。然后将反应混合物过滤，将滤液浓缩并通过柱色谱法纯化(洗脱液：CH 2Cl 2/MeOH＝100∶1，V/V)，得到所需化合物11-2(140mg，82％产率)。LC-MS：m/z 415[M+1] +。 To a solution of compound 11-1 (200 mg, 0.41 mmol) in THF (10 mL) was added a THF solution of TBAF (1M, 0.6 mL). After the reaction was completed, the reaction mixture was concentrated. The reaction mixture was then filtered, and the filtrate was concentrated and purified by column chromatography (eluent: CH 2 Cl 2 /MeOH=100:1, V/V) to obtain the desired compound 11-2 (140 mg, 82% yield) ). LC-MS: m/z 415 [M+1] + .
S3：(S)-3-(1-氨基乙基)-8-乙炔基-2-苯基-4，5-二氢环戊二烯并[de]异喹啉-1(2H)-酮(化合物11-3)的合成：S3: (S)-3-(1-Aminoethyl)-8-ethynyl-2-phenyl-4,5-dihydrocyclopenta[de]isoquinolin-1(2H)-one Synthesis of (Compound 11-3):
Figure PCTCN2019123563-appb-000073
Figure PCTCN2019123563-appb-000073
向冰水冷却的化合物11-2(140mg，0.33mmol)的CH 2Cl 2(10mL)溶液中加入CF 3COOH(2mL)。将所得混合物在0℃下搅拌2小时。然后将其用饱和NaHCO 3水溶液淬灭，用CH 2Cl 2(20mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩，得到化合物11-3(108mg粗品，产率99％)。LC-MS：m/z 315 [M+1] +。 To a solution of Compound 11-2 (140 mg, 0.33 mmol) in CH 2 Cl 2 (10 mL) cooled with ice water was added CF 3 COOH (2 mL). The resulting mixture was stirred at 0°C for 2 hours. It was then quenched with saturated aqueous NaHCO 3 and extracted with CH 2 Cl 2 (20 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated to obtain compound 11-3 (108 mg crude, yield 99%). LC-MS: m/z 315 [M+1] + .
S4：(S)-2-氨基-N-(1-(8-乙炔基-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物11)的合成：S4: (S)-2-amino-N-(1-(8-ethynyl-1-oxo-2-phenyl-1,2,4,5-tetrahydrocyclopenta[de]iso Quinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 11):
Figure PCTCN2019123563-appb-000074
Figure PCTCN2019123563-appb-000074
向化合物11-3(108mg，0.34mmol)和中间体M(97.6mg，0.35mmol)在CH 3CN(20mL)中的混合物中加入DIPEA(0.2mL，7.4mmol)。将混合物在回流条件下搅拌过夜。浓缩反应混合物，残余物经制备型HPLC纯化，得到作为黄色固体的化合物11(50mg，30％产率)。LC-MS：m/z 475[M+1] +。 1H-NMR(400MHz，DMSO-d 6)δ8.93-8.91(dd，J＝6.7Hz，1.5Hz，1H)，8.56-8.54(dd，J＝4.5Hz，1.5Hz，1H)，8.01-8.00(d，J＝6.3Hz，1H)，7.68-7.45(m，6H)，7.36(d，J＝7.4Hz，1H)，7.03-7.01(d，J＝6.8Hz，1H)，6.45(s，2H)，4.53-4.50(m，1H)，4.21(s，1H)，3.33-3.11(m，4H)，1.36-1.35(d，J＝8.0Hz，3H)。 To a mixture of compound 11-3 (108 mg, 0.34 mmol) and intermediate M (97.6 mg, 0.35 mmol) in CH 3 CN (20 mL) was added DIPEA (0.2 mL, 7.4 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give Compound 11 (50 mg, 30% yield) as a yellow solid. LC-MS: m/z 475[M+1] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.93-8.91 (dd, J=6.7 Hz, 1.5 Hz, 1H), 8.56-8.54 (dd, J=4.5 Hz, 1.5 Hz, 1H), 8.01 8.00(d, J=6.3Hz, 1H), 7.68-7.45(m, 6H), 7.36(d, J=7.4Hz, 1H), 7.03-7.01(d, J=6.8Hz, 1H), 6.45(s , 2H), 4.53-4.50 (m, 1H), 4.21 (s, 1H), 3.33-3.11 (m, 4H), 1.36-1.35 (d, J = 8.0 Hz, 3H).
实施例13：(S)-2-氨基-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物31)的合成。Example 13: (S)-2-amino-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de ]Isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 31).
Figure PCTCN2019123563-appb-000075
Figure PCTCN2019123563-appb-000075
S1：2-甲氧基-N-苯基-5，6，7，8-四氢萘-1-甲酰胺(化合物31-1)的合成：S1: Synthesis of 2-methoxy-N-phenyl-5,6,7,8-tetrahydronaphthalene-1-carboxamide (compound 31-1):
Figure PCTCN2019123563-appb-000076
Figure PCTCN2019123563-appb-000076
向冰水冷却的中间体B(5.3g，25.7mmol)和DMF(1mL)的CH 2Cl 2(100mL)溶液中，滴加草酰氯(3.3mL，38.6mmol)。添加后，将其在室温搅拌4小时。将混合物真空浓缩，得到粗制的酰氯，其直接用于下一步。 To a solution of Intermediate B (5.3 g, 25.7 mmol) and DMF (1 mL) in CH 2 Cl 2 (100 mL) cooled with ice water, oxalyl chloride (3.3 mL, 38.6 mmol) was added dropwise. After the addition, it was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give the crude acid chloride, which was used directly in the next step.
向冰水冷却的化合物苯胺(2.9g，30.8mol)和三乙胺(5.2g，51.4mmol)的CH 2Cl 2(100mL) 溶液中，加入酰氯(上步制得)的CH 2Cl 2(10mL)溶液。将所得混合物在室温搅拌过夜，然后加入CH 2Cl 2(10mL)和水(100mL)。分离有机层并用盐水洗涤，经Na 2SO 4干燥并过滤。将滤液真空浓缩。将产物悬浮在石油醚(100mL)中，并在室温下搅拌过夜。通过过滤收集沉淀物，用石油醚(50mL)冲洗，并在真空中进一步干燥，得到化合物31-1(6.2g，85％产率)，为黄色固体。LC-MS：m/z 282[M+1] +。 To a solution of ice water-cooled compounds aniline (2.9 g, 30.8 mol) and triethylamine (5.2 g, 51.4 mmol) in CH 2 Cl 2 (100 mL), add acid chloride (prepared in the previous step) in CH 2 Cl 2 ( 10mL) solution. The resulting mixture was stirred at room temperature overnight, and then CH 2 Cl 2 (10 mL) and water (100 mL) were added. The organic layer was separated and washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (100 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (50 mL), and further dried in vacuo to give compound 31-1 (6.2 g, 85% yield) as a yellow solid. LC-MS: m/z 282[M+1] + .
S2：(2S)-1-(7-甲氧基-8-(苯基氨基甲酰基)-1，2，3，4-四氢萘-1-基)-1-氧代丙烷-2-基氨基甲酸叔丁酯(化合物31-2)的合成：S2: (2S)-1-(7-methoxy-8-(phenylcarbamoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-1-oxopropane-2- Synthesis of tert-butyl carbamate (Compound 31-2):
Figure PCTCN2019123563-appb-000077
Figure PCTCN2019123563-appb-000077
将化合物31-1(2.8g，10mmol)和HMPA(2.2mL，13mmol)在无水四氢呋喃(100mL)中的溶液冷却至-78℃，然后在30分钟内向其中缓慢加入正丁基锂的己烷溶液(2.5M，12mL)。将反应混合物在相同温度下搅拌30分钟。在另一个烧瓶中，将(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(3.48g，15mol)的无水四氢呋喃(100mL)溶液冷却至-78℃，缓慢加入异丙基氯化镁的四氢呋喃溶液(20mL，20mol)。将反应混合物在相同温度下搅拌30分钟，然后添加至上述反应混合物中。加入后，将其缓慢加热并在-20℃下搅拌4小时。用水(200mL)淬灭反应，然后用乙酸乙酯(400mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。化合物31-2(3.4g粗品)无需进一步纯化即可用于随后的反应。LC-MS：m/z 453[M+1] +。 A solution of compound 31-1 (2.8 g, 10 mmol) and HMPA (2.2 mL, 13 mmol) in anhydrous tetrahydrofuran (100 mL) was cooled to -78°C, and then n-butyllithium hexane was slowly added thereto within 30 minutes Solution (2.5M, 12mL). The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, put (S)-(1-(methoxy(methyl)amino)-1-oxopropane-2-yl)carbamic acid tert-butyl ester (3.48 g, 15 mol) in anhydrous tetrahydrofuran (100 mL) The solution was cooled to -78°C, and a solution of isopropyl magnesium chloride in tetrahydrofuran (20 mL, 20 mol) was slowly added. The reaction mixture was stirred at the same temperature for 30 minutes and then added to the above reaction mixture. After the addition, it was slowly heated and stirred at -20°C for 4 hours. The reaction was quenched with water (200 mL), and then extracted with ethyl acetate (400 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. Compound 31-2 (3.4 g crude) was used in the subsequent reaction without further purification. LC-MS: m/z 453[M+1] + .
S3：(S)-3-(1-氨基乙基)-9-甲氧基-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物31-3)的合成：S3: (S)-3-(1-aminoethyl)-9-methoxy-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline-1 -Synthesis of ketone (compound 31-3):
Figure PCTCN2019123563-appb-000078
Figure PCTCN2019123563-appb-000078
向化合物31-2(3.4g，7.5mmol)的MeOH(50mL)溶液中加入浓HCl(25毫升)。将所得混合物加热至回流并搅拌10小时。反应完成后，将反应混合物在减压下浓缩，并将残余物用水(100mL)溶解，用乙酸乙酯(100mL×2)萃取。然后将水层用K 2CO 3碱化，用DCM(200mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：MeOH∶CH 2Cl 2，MeOH％＝0-5％，V/V)，得到化合物31-3(1.2g，48％产率)。LC-MS：m/z 335[M+1] +。 To a solution of compound 31-2 (3.4 g, 7.5 mmol) in MeOH (50 mL) was added concentrated HCl (25 mL). The resulting mixture was heated to reflux and stirred for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved with water (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueous layer was then basified with K 2 CO 3 and extracted with DCM (200 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: MeOH:CH 2 Cl 2 , MeOH%=0-5%, V/V) to obtain compound 31-3 (1.2 g, 48% yield). LC-MS: m/z 335 [M+1] + .
S4：(S)-1-(9-羟基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物31-4)的合成：S4: (S)-1-(9-hydroxy-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethane Synthesis of tert-butyl carbamate (Compound 31-4):
Figure PCTCN2019123563-appb-000079
Figure PCTCN2019123563-appb-000079
向干冰-乙醇冷却的化合物31-3(500mg，1.5mmol)的无水CH 2Cl 2(20mL)溶液中，加入BBr3的CH 2Cl 2溶液(1.6M，3mL)。加入后，将其缓慢加热并在室温下搅拌2小时。然后将其用NaHCO 3(10mL)水溶液淬灭。用DCM(200mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物溶于EtOH(10mL)和饱和NaHCO 3的混合物中。将所得混合物在室温搅拌过夜。然后将其用DCM(100mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-25％，V/V)，得到化合物31-4(210mg，27％产率)。LC-MS：m/z 421[M+1] +。 To a dry ice-ethanol-cooled compound 31-3 (500 mg, 1.5 mmol) solution in anhydrous CH 2 Cl 2 (20 mL) was added BBr 3 in CH 2 Cl 2 solution (1.6 M, 3 mL). After the addition, it was slowly heated and stirred at room temperature for 2 hours. It was then quenched with aqueous NaHCO 3 (10 mL). Extract with DCM (200 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was dissolved in a mixture of EtOH (10 mL) and saturated NaHCO 3 . The resulting mixture was stirred at room temperature overnight. It was then extracted with DCM (100 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=0-25%, V/V) to obtain compound 31-4 (210 mg, 27% yield). LC-MS: m/z 421[M+1] + .
S5：(S)-3-(1-(叔丁氧基羰基氨基)乙基)-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-9基三氟 甲磺酸酯(化合物31-5)的合成：S5: (S)-3-(1-(tert-butoxycarbonylamino)ethyl)-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de ] Synthesis of isoquinolin-9yl trifluoromethanesulfonate (compound 31-5):
Figure PCTCN2019123563-appb-000080
Figure PCTCN2019123563-appb-000080
向干冰-乙醇冷却的化合物31-4(210mg，0.5mmol)的THF(10mL)溶液中加入HMDSLi的THF溶液(1.0M，1.25mL)。将所得混合物搅拌30分钟。然后向混合物中加入Tf 2NPh(214mg，0.6mmol)。加入后，将其缓慢加热并在室温下搅拌过夜。然后将其用NH 4Cl水溶液淬灭。用乙酸乙酯(100mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝10-25％，V/V)，得到化合物31-5(100mg，36％产率)。LC-MS：m/z 553[M+1] +。 To a solution of compound 31-4 (210 mg, 0.5 mmol) in dry ice-ethanol cooled in THF (10 mL) was added a solution of HMDSLi in THF (1.0 M, 1.25 mL). The resulting mixture was stirred for 30 minutes. Then Tf 2 NPh (214 mg, 0.6 mmol) was added to the mixture. After the addition, it was slowly heated and stirred at room temperature overnight. It was then quenched with aqueous NH 4 Cl. Extract with ethyl acetate (100 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=10-25%, V/V) to obtain compound 31-5 (100 mg, 36% yield). LC-MS: m/z 553[M+1] + .
S6：(S)-1-(1-氧代-2-苯基-9-((三甲基硅烷基)乙炔基)-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物31-6)的合成：S6: (S)-1-(1-oxo-2-phenyl-9-((trimethylsilyl)ethynyl)-2,4,5,6-tetrahydro-1H-benzo[de ] Synthesis of tert-butyl isoquinolin-3-yl)ethylcarbamate (compound 31-6):
Figure PCTCN2019123563-appb-000081
Figure PCTCN2019123563-appb-000081
向化合物31-5(1.5g，2.8mmol)和乙炔基三甲基硅烷(4.0mL，28mmol)的CH 3CN(20mL)溶液中加入K 3PO 4(0.712g，3.36mmol)，Xphos(27mg，0.056mmol)和Pd 2(dba) 3(25mg，0.028mmol)。向反应混合物中充入氮气两次，然后加热至回流并搅拌过夜。然后将反应混合物过滤，将滤液浓缩并通过柱色谱法纯化(洗脱液：乙酸乙酯∶石油醚＝1∶10至1∶3，V/V)，得到所需化合物31-6(1g，72％产率)。LC-MS：m/z 501[M+1] +。 To a solution of compound 31-5 (1.5 g, 2.8 mmol) and ethynyltrimethylsilane (4.0 mL, 28 mmol) in CH 3 CN (20 mL) was added K 3 PO 4 (0.712 g, 3.36 mmol), Xphos (27 mg , 0.056 mmol) and Pd 2 (dba) 3 (25 mg, 0.028 mmol). The reaction mixture was filled with nitrogen twice, then heated to reflux and stirred overnight. The reaction mixture was then filtered, and the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate: petroleum ether = 1:10 to 1:3, V/V) to obtain the desired compound 31-6 (1 g, 72% yield). LC-MS: m/z 501[M+1] + .
S7：(S)-1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物31-7)的合成：S7: (S)-1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl) Synthesis of tert-butyl ethylcarbamate (compound 31-7):
Figure PCTCN2019123563-appb-000082
Figure PCTCN2019123563-appb-000082
向化合物31-6(1000mg，2mmol)的THF(30mL)溶液中加入TBAF的THF溶液(1M，3mL)。反应完成后，将反应混合物浓缩。然后将反应混合物过滤，将滤液浓缩并通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚＝1∶10至1∶3，V/V)，得到所需化合物31-7(600mg，70％产率)。LC-MS：m/z 429[M+1] +。 To a solution of compound 31-6 (1000 mg, 2 mmol) in THF (30 mL) was added a THF solution of TBAF (1M, 3 mL). After the reaction was completed, the reaction mixture was concentrated. The reaction mixture was then filtered, and the filtrate was concentrated and purified through a silica gel column (eluent: ethyl acetate: petroleum ether = 1:10 to 1:3, V/V) to obtain the desired compound 31-7 (600 mg, 70 %Yield). LC-MS: m/z 429[M+1] + .
S8：(S)-3-(1-氨基乙基)-9-乙炔基-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物31-8)的合成：S8: (S)-3-(1-aminoethyl)-9-ethynyl-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline-1- Synthesis of ketone (compound 31-8):
Figure PCTCN2019123563-appb-000083
Figure PCTCN2019123563-appb-000083
向冰水冷却的化合物31-7(600mg，1.40mmol)的CH 2Cl 2(20mL)溶液中加入CF 3COOH(20mL)。将所得混合物在0℃下搅拌2小时。然后将其用NaHCO 3水溶液淬灭，用CH 2Cl 2(20mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物通过硅胶柱纯化(洗脱液：CH 2Cl 2/MeOH＝100∶1至10∶1，V/V)，得到所需化合物31-8(260mg，57％产率)。LC-MS：m/z 329[M+1] +。 To a solution of compound 31-7 (600 mg, 1.40 mmol) in CH 2 Cl 2 (20 mL) cooled with ice water was added CF 3 COOH (20 mL). The resulting mixture was stirred at 0°C for 2 hours. It was then quenched with aqueous NaHCO 3 and extracted with CH 2 Cl 2 (20 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified through a silica gel column (eluent: CH 2 Cl 2 /MeOH=100:1 to 10:1, V/V) to obtain the desired compound 31-8 (260 mg, 57% yield). LC-MS: m/z 329 [M+1] + .
S9：(S)-2-氨基-N-(1-(9-乙炔基-1-氧代-2-苯基-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并 [1，5-a]嘧啶-3-甲酰胺(化合物31)的合成：S9: (S)-2-amino-N-(1-(9-ethynyl-1-oxo-2-phenyl-2,4,5,6-tetrahydro-1H-benzo[de]iso Quinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 31):
Figure PCTCN2019123563-appb-000084
Figure PCTCN2019123563-appb-000084
向化合物31-8(260mg，0.80mmol)和中间体M(230mg，0.83mmol)的CH 3CN(20mL)溶液中加入DIPEA(206mg，1.60mmol)。将混合物在回流条件下搅拌过夜。浓缩反应混合物，残余物经制备型HPLC纯化，得到作为白色固体的化合物31(320mg，82％产率)。LC-MS：m/z 489[M+] +。 1H-NMR(400MHz，DMSO-d 6)δ8.89-8.91(dd，J＝6.7Hz，1.6Hz，1H)，8.50-8.52(dd，J＝4.5Hz，1.5Hz，1H)，8.02(brs，1H)，7.69-7.40(m，6H)，7.31(s，1H)，6.98-7.01(dd，J＝6.7Hz，4.5Hz，1H)，6.42(s，2H)，4.82(m，1H)，4.17(s，1H)，3.08-3.06(m，1H)，2.99-2.76(m，3H)，1.96-1.94(s，1H)，1.82-1.80(s，1H)，1.43-1.45(d，J＝7.2Hz，3H)。 To a solution of compound 31-8 (260 mg, 0.80 mmol) and intermediate M (230 mg, 0.83 mmol) in CH 3 CN (20 mL) was added DIPEA (206 mg, 1.60 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 31 (320 mg, 82% yield) as a white solid. LC-MS: m/z 489 [M+] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.89-8.91 (dd, J=6.7 Hz, 1.6 Hz, 1H), 8.50-8.52 (dd, J=4.5 Hz, 1.5 Hz, 1H), 8.02 ( brs, 1H), 7.69-7.40 (m, 6H), 7.31 (s, 1H), 6.98-7.01 (dd, J=6.7Hz, 4.5Hz, 1H), 6.42 (s, 2H), 4.82 (m, 1H ), 4.17 (s, 1H), 3.08-3.06 (m, 1H), 2.99-2.76 (m, 3H), 1.96-1.94 (s, 1H), 1.82-1.80 (s, 1H), 1.43-1.45 (d , J=7.2Hz, 3H).
实施例14：(S)-2-氨基-N-(1-(2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物215)的合成。Example 14: (S)-2-amino-N-(1-(2-(3-fluorophenyl)-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)- 1-oxo-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Synthesis of (Compound 215).
Figure PCTCN2019123563-appb-000085
Figure PCTCN2019123563-appb-000085
S1：N-(3-氟苯基)-2-甲氧基-5，6，7，8-四氢萘-1-甲酰胺(化合物215-1)的合成：S1: Synthesis of N-(3-fluorophenyl)-2-methoxy-5,6,7,8-tetrahydronaphthalene-1-carboxamide (Compound 215-1):
Figure PCTCN2019123563-appb-000086
Figure PCTCN2019123563-appb-000086
向冰水冷却的中间体B(5g，24.2mmol)和DMF(1mL)的CH 2Cl 2(100mL)溶液中，滴加草酰氯(2.25mL，26.7mmol)。添加后，将其在室温搅拌4小时。将混合物真空浓缩，得到粗制的酰氯，其直接用于下一步。 To a solution of Intermediate B (5 g, 24.2 mmol) and DMF (1 mL) in CH 2 Cl 2 (100 mL) cooled with ice water, oxalyl chloride (2.25 mL, 26.7 mmol) was added dropwise. After the addition, it was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo to give the crude acid chloride, which was used directly in the next step.
向冰水冷却的3-氟苯胺(2.9g，26.4mol)和三乙胺(7mL，54mmol)的CH 2Cl 2(100mL)溶液中，加入酰氯(上步制得)的CH 2Cl 2(10mL)溶液。将所得混合物在室温下搅拌过夜，然后加入CH 2Cl 2(10mL)和水(100mL)。分离有机层并用盐水洗涤，经Na 2SO 4干燥并过滤。将滤液真空浓缩。将产物悬浮在石油醚(100mL)中，并在室温下搅拌过夜。通过过滤收集沉淀物，用石油醚(50mL)冲洗，并进一步真空干燥，得到化合物215-1(6g粗品)，为白色固体。LC-MS：m/z 300.1[M+1] +。 To a solution of 3-fluoroaniline (2.9 g, 26.4 mol) and triethylamine (7 mL, 54 mmol) in CH 2 Cl 2 (100 mL) cooled in ice water, add acid chloride (prepared in the previous step) in CH 2 Cl 2 ( 10mL) solution. The resulting mixture was stirred at room temperature overnight, and then CH 2 Cl 2 (10 mL) and water (100 mL) were added. The organic layer was separated and washed with brine, dried over Na 2 SO 4 and filtered. The filtrate was concentrated in vacuo. The product was suspended in petroleum ether (100 mL) and stirred at room temperature overnight. The precipitate was collected by filtration, rinsed with petroleum ether (50 mL), and further dried in vacuo to give compound 215-1 (6 g of crude product) as a white solid. LC-MS: m/z 300.1 [M+1] + .
S2：(2S)-1-(8-(3-氟苯基氨基甲酰基)-7-甲氧基-1，2，3，4-四氢萘-1-基)-1-氧代丙烷-2-基氨基甲酸叔丁酯(化合物215-2)的合成：S2: (2S)-1-(8-(3-fluorophenylcarbamoyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-1-oxopropane Synthesis of tert-butyl-2-ylcarbamate (Compound 215-2):
Figure PCTCN2019123563-appb-000087
Figure PCTCN2019123563-appb-000087
将化合物215-1(6g，20mmol)和HMPA(4.4mL，26mmol)在无水四氢呋喃(200mL)中的溶液冷却至-78℃，然后在30分钟内向其中缓慢加入正丁基锂在己烷中的溶液(1.6M，24mL)。将反应混合物在相同温度下搅拌30分钟。在另一个烧瓶中，将(S)-(1-(甲氧基(甲基)氨基)-1-氧代丙烷-2-基)氨基甲酸叔丁酯(6.96g，30mol)在无水四氢呋喃(200mL)中的溶液冷却至-78℃，缓慢加入异丙基氯化镁的四氢呋喃溶液(1.0M，40mL)。将反应混合物在相同温度下搅拌30分钟，然后添加至上述反应混合物中。加入后，将其缓慢加热并在-20℃下搅拌4小时。用水(100mL)淬灭反应，然后用乙酸乙酯(200mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。化合物215-2(7.0g粗品)无需进一步纯化即可用于随后的反应。LC-MS：m/z 471[M+1] +。 A solution of compound 215-1 (6g, 20mmol) and HMPA (4.4mL, 26mmol) in anhydrous tetrahydrofuran (200mL) was cooled to -78°C, and then n-butyllithium was slowly added thereto in hexane within 30 minutes Solution (1.6M, 24mL). The reaction mixture was stirred at the same temperature for 30 minutes. In another flask, put (S)-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamic acid tert-butyl ester (6.96 g, 30 mol) in anhydrous tetrahydrofuran The solution in (200 mL) was cooled to -78°C, and a solution of isopropyl magnesium chloride in tetrahydrofuran (1.0 M, 40 mL) was slowly added. The reaction mixture was stirred at the same temperature for 30 minutes and then added to the above reaction mixture. After the addition, it was slowly heated and stirred at -20°C for 4 hours. The reaction was quenched with water (100 mL), and then extracted with ethyl acetate (200 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. Compound 215-2 (7.0 g crude) was used in the subsequent reaction without further purification. LC-MS: m/z 471 [M+1] + .
S3：(S)-3-(1-氨基乙基)-2-(3-氟苯基)-9-甲氧基-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物215-3)的合成：S3: (S)-3-(1-aminoethyl)-2-(3-fluorophenyl)-9-methoxy-2,4,5,6-tetrahydro-1H-benzo[de] Synthesis of isoquinolin-1-one (compound 215-3):
Figure PCTCN2019123563-appb-000088
Figure PCTCN2019123563-appb-000088
向化合物215-2(7g，15mmol)的MeOH(200mL)溶液中加入浓HCl(100毫升)。将所得混合物加热至回流并搅拌10小时。反应完成后，将反应混合物在减压下浓缩，并将残余物用水(100mL)溶解，用乙酸乙酯(100mL×2)萃取。然后将水层用K 2CO 3碱化，用CH 2Cl 2(200mL×2)萃取。有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：MeOH∶CH 2Cl 2，MeOH％＝0-5％，V/V)，得到化合物215-3(1.5g，28％产率)。LC-MS：m/z 353[M+1] +。 To a solution of compound 215-2 (7 g, 15 mmol) in MeOH (200 mL) was added concentrated HCl (100 mL). The resulting mixture was heated to reflux and stirred for 10 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved with water (100 mL) and extracted with ethyl acetate (100 mL×2). The aqueous layer was then basified with K 2 CO 3 and extracted with CH 2 Cl 2 (200 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: MeOH:CH 2 Cl 2 , MeOH%=0-5%, V/V) to obtain compound 215-3 (1.5 g, 28% yield). LC-MS: m/z 353[M+1] + .
S4：(S)-3-(1-氨基乙基)-2-(3-氟苯基)-9-羟基-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物215-4)的合成：S4: (S)-3-(1-aminoethyl)-2-(3-fluorophenyl)-9-hydroxy-2,4,5,6-tetrahydro-1H-benzo[de]isoquine Synthesis of quinolin-1-one (compound 215-4):
Figure PCTCN2019123563-appb-000089
Figure PCTCN2019123563-appb-000089
向干冰-乙醇冷却的化合物215-3(1.5g，4mmol)的无水CH 2Cl 2(100mL)溶液中加入BBr 3的CH 2Cl 2溶液(1.0M，8mL)。加入后，将其缓慢加热并在室温下搅拌过夜。然后将其用饱和NaHCO 3水溶液淬灭，用CH 2Cl 2(200mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩，得到化合物215-4(1.3g 粗产物)。LC-MS：m/z 339[M+1] +。 To a dry ice-ethanol-cooled compound 215-3 (1.5 g, 4 mmol) solution in anhydrous CH 2 Cl 2 (100 mL) was added a solution of BBr 3 in CH 2 Cl 2 (1.0 M, 8 mL). After the addition, it was slowly heated and stirred at room temperature overnight. It was then quenched with saturated aqueous NaHCO 3 and extracted with CH 2 Cl 2 (200 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated to obtain compound 215-4 (1.3 g of crude product). LC-MS: m/z 339[M+1] + .
S5：(S)-1-(2-(3-氟苯基)-9-羟基-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物215-5)的合成：S5: (S)-1-(2-(3-fluorophenyl)-9-hydroxy-1-oxo-2,4,5,6-tetrahydro-1H-benzo[de]isoquinoline- Synthesis of tert-butyl 3-yl)ethylcarbamate (Compound 215-5):
Figure PCTCN2019123563-appb-000090
Figure PCTCN2019123563-appb-000090
向化合物215-4(1.3g，2.7mmol)和饱和NaHCO 3(10mL)的EtOH(20mL)溶液中加入Boc 2O(0.59g，2.7mmol)。将所得混合物在室温下搅拌过夜。然后用CH 2Cl 2(100mL×2)萃取，有机层经Na 2SO 4干燥，然后在减压下浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-10％，V/V)，得到化合物215-5(600mg，70％产率)。LC-MS：m/z 439[M+1] +。 To a solution of compound 215-4 (1.3 g, 2.7 mmol) and saturated NaHCO 3 (10 mL) in EtOH (20 mL) was added Boc 2 O (0.59 g, 2.7 mmol). The resulting mixture was stirred at room temperature overnight. It was then extracted with CH 2 Cl 2 (100 mL×2), and the organic layer was dried over Na 2 SO 4 and then concentrated under reduced pressure. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=0-10%, V/V) to obtain compound 215-5 (600 mg, 70% yield). LC-MS: m/z 439[M+1] + .
S6：(S)-3-(1-(叔丁氧基羰基氨基)乙基)-2-(3-氟苯基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-9-基三氟甲磺酸酯(化合物215-6)的合成：S6: (S)-3-(1-(tert-butoxycarbonylamino)ethyl)-2-(3-fluorophenyl)-1-oxo-2,4,5,6-tetrahydro-1H -Synthesis of benzo[de]isoquinolin-9-yl trifluoromethanesulfonate (compound 215-6):
Figure PCTCN2019123563-appb-000091
Figure PCTCN2019123563-appb-000091
向干冰-乙醇冷却的化合物215-5(600mg，1.37mmol)的THF(100mL)溶液中加入HMDSLi的THF溶液(1.0M，3.4mL)。将所得混合物搅拌30分钟。然后向混合物中加入PhNTf 2(586mg，1.64mmol)。添加后，将其缓慢加热并在室温下搅拌过夜。然后将其用NH 4Cl水溶液淬灭。用乙酸乙酯(100mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。将残余物通过硅胶柱纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝0-10％，V/V)，得到化合物215-6(400mg，51％收率)。LC-MS：m/z 571[M+1] +。 To a dry ice-ethanol cooled compound 215-5 (600 mg, 1.37 mmol) in THF (100 mL) was added a solution of HMDSLi in THF (1.0 M, 3.4 mL). The resulting mixture was stirred for 30 minutes. PhNTf 2 (586 mg, 1.64 mmol) was then added to the mixture. After the addition, it was slowly heated and stirred at room temperature overnight. It was then quenched with aqueous NH 4 Cl. Extract with ethyl acetate (100 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified through a silica gel column (eluent: ethyl acetate: petroleum ether, ethyl acetate %=0-10%, V/V) to obtain compound 215-6 (400 mg, 51% yield). LC-MS: m/z 571 [M+1] + .
S7：(S)-1-(2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物215-7)的合成：S7: (S)-1-(2-(3-fluorophenyl)-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2,4, Synthesis of tert-butyl 5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethylcarbamate (compound 215-7):
Figure PCTCN2019123563-appb-000092
Figure PCTCN2019123563-appb-000092
向化合物215-6(400mg，0.7mmol)和4-乙炔基-1-甲基-1H-吡唑(223mg，2.1mmol)的CH 3CN(10mL)溶液中加入K 3PO 4(170mg，0.84mmol)，Xphos(6.7mg，14μmol)和Pd 2(dba) 3(6.5mg，7μmol)。向反应混合物中充入氮气2次，然后加热至95℃过夜。然后浓缩反应混合物，并通过柱色谱法纯化(洗脱液：乙酸乙酯∶石油醚，乙酸乙酯％＝10-25％，V/V)，得到所需化合物215-7(200mg，54％产率)。LC-MS：m/z 527[M+1] +。 To a solution of compound 215-6 (400 mg, 0.7 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (223 mg, 2.1 mmol) in CH 3 CN (10 mL) was added K 3 PO 4 (170 mg, 0.84 mmol), Xphos (6.7 mg, 14 μmol) and Pd 2 (dba) 3 (6.5 mg, 7 μmol). The reaction mixture was filled with nitrogen twice, and then heated to 95°C overnight. The reaction mixture was then concentrated and purified by column chromatography (eluent: ethyl acetate: petroleum ether, ethyl acetate %=10-25%, V/V) to obtain the desired compound 215-7 (200 mg, 54% Yield). LC-MS: m/z 527[M+1] + .
S8：(S)-3-(1-氨基乙基)-2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-2，4，5，6-四氢-1H-苯并[de]异喹啉-1-酮(化合物215-8)的合成：S8: (S)-3-(1-aminoethyl)-2-(3-fluorophenyl)-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2, Synthesis of 4,5,6-tetrahydro-1H-benzo[de]isoquinolin-1-one (compound 215-8):
Figure PCTCN2019123563-appb-000093
Figure PCTCN2019123563-appb-000093
向冰水冷却的化合物215-7(200mg，0.38mmol)的CH 2Cl 2(10mL)溶液中，加入苯甲醚(0.5mL)和CF 3COOH(5mL)。将所得混合物搅拌2小时。然后将其用饱和NaHCO 3水溶液淬灭。用CH 2Cl 2(20mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩，得到化合物215-8(79mg，49％产率)。LC-MS：m/z 427[M+1] +。 To an ice-water-cooled compound 215-7 (200 mg, 0.38 mmol) in CH 2 Cl 2 (10 mL) solution, anisole (0.5 mL) and CF 3 COOH (5 mL) were added. The resulting mixture was stirred for 2 hours. It was then quenched with saturated aqueous NaHCO 3 solution. Extract with CH 2 Cl 2 (20 mL×2). The organic layer was dried over Na 2 SO 4 and then concentrated to give compound 215-8 (79 mg, 49% yield). LC-MS: m/z 427[M+1] + .
S9：(S)-2-氨基-N-(1-(2-(3-氟苯基)-9-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2，4，5，6-四氢-1H-苯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物215)的合成：S9: (S)-2-amino-N-(1-(2-(3-fluorophenyl)-9-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1- Oxo-2,4,5,6-tetrahydro-1H-benzo[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (compound 215) Synthesis:
Figure PCTCN2019123563-appb-000094
Figure PCTCN2019123563-appb-000094
向化合物215-8(79mg，0.186mmol)和中间体M(53.5mg，0.194mmol)的CH 3CN(5mL)溶液中加入DIPEA(0.2mL)。将混合物在回流条件下搅拌过夜。浓缩反应混合物，残余物通过制备型HPLC纯化，得到作为白色固体的化合物215(35mg，32％产率)。LC-MS：m/z 587[M+1] +。 1H-NMR(400MHz，DMSO-d 6)δ8.92-8.90(dd，J＝6.7Hz，1.4Hz，1H)，8.53-8.49(d，J＝8.0Hz，1H)，8.08(brs，1H)，7.97(s，1H)，7.68-7.17(m，7H)，7.01-6.99(dd，J＝6.7Hz，4.5Hz，1H)，6.44(s，2H)，4.92-4.85(m，1H)，3.81(s，3H)，3.15-3.06(m，1H)，2.99-2.83(m，3H)，2.00-1.95(m，1H)，1.86-1.72(m，1H)，1.48-1.46(d，J＝6.0Hz，3H)。 To a solution of compound 215-8 (79 mg, 0.186 mmol) and intermediate M (53.5 mg, 0.194 mmol) in CH 3 CN (5 mL) was added DIPEA (0.2 mL). The mixture was stirred at reflux overnight. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give compound 215 (35 mg, 32% yield) as a white solid. LC-MS: m/z 587[M+1] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.92-8.90 (dd, J=6.7 Hz, 1.4 Hz, 1H), 8.53-8.49 (d, J=8.0 Hz, 1H), 8.08 (brs, 1H ), 7.97 (s, 1H), 7.68-7.17 (m, 7H), 7.01-6.99 (dd, J=6.7Hz, 4.5Hz, 1H), 6.44 (s, 2H), 4.92-4.85 (m, 1H) , 3.81(s, 3H), 3.15-3.06(m, 1H), 2.99-2.83(m, 3H), 2.00-1.95(m, 1H), 1.86-1.72(m, 1H), 1.48-1.46(d, J = 6.0 Hz, 3H).
实施例15：(S)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物1)的合成(路线2)。Example 15: (S)-2-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]pyrimidine-3-carboxamide (Compound 1) Synthesis (Route 2).
Figure PCTCN2019123563-appb-000095
Figure PCTCN2019123563-appb-000095
S1：(S)-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基氨基甲酸叔丁酯(化合物1-1’)的合成：S1: (S)-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1,2,4,5- Synthesis of tert-butyl tetrahydrocyclopenta[de]isoquinolin-3-yl)ethylcarbamate (Compound 1-1'):
Figure PCTCN2019123563-appb-000096
Figure PCTCN2019123563-appb-000096
向中间体N(1.7g，3.2mmol)和4-乙炔基-1-甲基-1H-吡唑(0.4g，3.8mmol)的CH 3CN(10mL)溶液中加入K 3PO 4(0.8g，3.84mmol)，Xphos(30mg，0.064mmol)和Pd 2(dba) 3(29mg，0.032mol)。向反应混合物中充入氮气两次，然后通过微波加热至回流2小时。然后将反应混合物浓缩并通过柱色谱法纯化(洗脱液：MeOH∶CH 2Cl 2，MeOH％＝0-2.5％，V/V)，得到所需化合物1-1’(470mg，30％产率)。LC-MS：m/z 495[M+1] +。 To a solution of intermediate N (1.7 g, 3.2 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (0.4 g, 3.8 mmol) in CH 3 CN (10 mL) was added K 3 PO 4 (0.8 g , 3.84 mmol), Xphos (30 mg, 0.064 mmol) and Pd 2 (dba) 3 (29 mg, 0.032 mol). The reaction mixture was filled with nitrogen twice, then heated to reflux by microwave for 2 hours. The reaction mixture was then concentrated and purified by column chromatography (eluent: MeOH:CH 2 Cl 2 , MeOH%=0-2.5%, V/V) to obtain the desired compound 1-1′ (470 mg, 30% product) rate). LC-MS: m/z 495[M+1] + .
S2：(S)-3-(1-氨基乙基)-8-((1-甲基-1H-吡唑-4-基)乙炔基)-2-苯基-4，5-二氢环戊二烯并[de]异喹啉-1(2H)-酮(化合物1-2’)的合成：S2: (S)-3-(1-aminoethyl)-8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-2-phenyl-4,5-dihydro ring Synthesis of penta[de]isoquinoline-1(2H)-one (compound 1-2'):
Figure PCTCN2019123563-appb-000097
Figure PCTCN2019123563-appb-000097
向冰水冷却的化合物1-1’(420mg，0.85mmol)的CH 2Cl 2(10mL)溶液中，加入苯甲醚(1mL)和TFA(10mL)。将所得混合物搅拌2小时。然后将其用饱和NaHCO 3水溶液淬灭。用DCM(20mL×2)萃取。有机层经Na 2SO 4干燥，然后浓缩。残留物通过柱色谱法纯化(洗脱液：MeOH∶CH2Cl2，MeOH％＝0-5％，V/V)，得到所需化合物1-2’(290mg，86％产率)。LC-MS：m/z 395[M+1] +。 To an ice-water-cooled compound 1-1' (420 mg, 0.85 mmol) in CH 2 Cl 2 (10 mL) solution, anisole (1 mL) and TFA (10 mL) were added. The resulting mixture was stirred for 2 hours. It was then quenched with saturated aqueous NaHCO 3 solution. Extract with DCM (20 mL x 2). The organic layer was dried over Na 2 SO 4 and then concentrated. The residue was purified by column chromatography (eluent: MeOH:CH2Cl2, MeOH%=0-5%, V/V) to obtain the desired compound 1-2' (290 mg, 86% yield). LC-MS: m/z 395[M+1] + .
S3：(S)-2-氨基-N-(1-(8-((1-甲基-1H-吡唑-4-基)乙炔基)-1-氧代-2-苯基-1，2，4，5-四氢环戊二烯并[de]异喹啉-3-基)乙基)吡唑并[1，5-a]嘧啶-3-甲酰胺(化合物1)的合成：S3: (S)-2-amino-N-(1-(8-((1-methyl-1H-pyrazol-4-yl)ethynyl)-1-oxo-2-phenyl-1, Synthesis of 2,4,5-tetrahydrocyclopenta[de]isoquinolin-3-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Compound 1):
Figure PCTCN2019123563-appb-000098
Figure PCTCN2019123563-appb-000098
向化合物1-2’(290mg，0.74mmol)和中间体M(212mg，0.77mmol)的CH 3CN(50mL)溶液中加入DIPEA(150mg，0.81mmol)。将混合物在回流条件下搅拌过夜。浓缩反应混合物，残余物通过硅胶柱纯化(洗脱液：MeOH∶CH 2Cl 2，MeOH％＝0-5％，V/V)，得到化合物1(330mg，80％产率)，为白色固体。LC-MS：m/z 555[M+1] +。 1H-NMR(400MHz，DMSO-d 6)δ8.93-8.91(dd，J＝8.0Hz，4.0Hz，1H)，8.56-8.54(d，J＝4.0Hz，1H)，7.99-8.02(m，2H)，7.64-7.50(m，7H)，7.39(d，J＝8.0Hz，1H)，7.03-7.00(m，1H)，6.45(s，2H)，4.54-4.50(m，1H)，3.82(s，3H)，3.33-3.16(m，4H)，1.37-1.35(d，J＝8.0Hz，3H)。 To a solution of compound 1-2' (290 mg, 0.74 mmol) and intermediate M (212 mg, 0.77 mmol) in CH 3 CN (50 mL) was added DIPEA (150 mg, 0.81 mmol). The mixture was stirred at reflux overnight. The reaction mixture was concentrated, and the residue was purified through a silica gel column (eluent: MeOH:CH 2 Cl 2 , MeOH%=0-5%, V/V) to obtain Compound 1 (330 mg, 80% yield) as a white solid. . LC-MS: m/z 555[M+1] + . 1 H-NMR (400 MHz, DMSO-d 6 ) δ 8.93-8.91 (dd, J=8.0 Hz, 4.0 Hz, 1H), 8.56-8.54 (d, J=4.0 Hz, 1H), 7.99-8.02 (m , 2H), 7.64-7.50 (m, 7H), 7.39 (d, J = 8.0 Hz, 1H), 7.03-7.00 (m, 1H), 6.45 (s, 2H), 4.54-4.50 (m, 1H), 3.82 (s, 3H), 3.33-3.16 (m, 4H), 1.37-1.35 (d, J = 8.0 Hz, 3H).
实施例16：以下化合物可以参照实施例1和实施例11的合成进行，采用相应的中间体A、中间体B、中间体C、中间体D、中间体E、中间体F、中间体G、中间体H、中间体I、中间体J、中间体K、中 间体L、中间体M和中间体N进行替换，得到下表所示的化合物：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:
Figure PCTCN2019123563-appb-000099
Figure PCTCN2019123563-appb-000099
实施例17：以下化合物可以参照实施例1和实施例11的合成进行，采用相应的手性对映体和中间体A、中间体B、中间体C、中间体D、中间体E、中间体F、中间体G、中间体H、中间体I、中间体J、中间体K、中间体L、中间体M和中间体N进行替换，得到下表所示的化合物：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:
Figure PCTCN2019123563-appb-000100
Figure PCTCN2019123563-appb-000100
实施例18：以下化合物可以参照实施例3的合成进行，采用相应的起始物料进行替换，得到下表所示的化合物：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:
Figure PCTCN2019123563-appb-000101
Figure PCTCN2019123563-appb-000101
实施例19：以下化合物可以参照实施例4的合成进行，采用相应的起始物料进行替换，得到下表所示的化合物：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:
Figure PCTCN2019123563-appb-000102
Figure PCTCN2019123563-appb-000102
实施例20：以下实施例可以参照实施例5的合成进行，采用相应的起始物料进行替换，得到下表所示的化合物：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:
Figure PCTCN2019123563-appb-000103
Figure PCTCN2019123563-appb-000103
Figure PCTCN2019123563-appb-000104
Figure PCTCN2019123563-appb-000104
实施例21：以下实施例可以参照实施例6的合成进行，采用不同的中间体进行替换，得到下表所示的化合物：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:
Figure PCTCN2019123563-appb-000105
Figure PCTCN2019123563-appb-000105
实施例22：PI3K体外抑制试验。Example 22: PI3K inhibition test in vitro.
使用Promega ADP-Glo TM Max检测试剂盒测定人类PI3K(Millipore)的I类α、β、δ和γ4种亚型的IC 50值。在室温下，将本发明的化合物与20nM的PI3K-α、PI3K-δ或40nM的PI3K-β、PI3K-γ样品在反应缓冲液(15mM HEPES(4-羟乙基哌嗪乙磺酸，Sigma-Aldrich)pH＝7.4、20mM NaCl、1mM EGTA(3，6-二氧杂-1，8-辛二胺四乙酸，Sigma-Aldrich)、0.02％Tween 20、10mM MgCl 2、0.2mg/mL牛-γ-球蛋白)中孵育15min，然后加入ATP(Sigma-Aldrich)/diC8-PIP2(二辛酰基磷脂酰肌醇-4，5-双磷酸酯，Echelon)混合物，得到终浓度为3mM ATP和500μM diC8-PIP2的底物(用于I类PI3K)。将反应物在室温下温育2h，然后加入25μL终止液终止反应(Promega试剂盒)。在室温下孵育40min后，加入50μL检测混合物(Promega)，在室温下温育1h，Envision读板器读板。将数据转换为％抑制，然后以％抑制vs化合物浓度绘图，并拟合至四参数逻辑方程以确定IC 50值，结果见下表。 IC 50 was determined values human PI3K (Millipore) class I α, β, δ and γ4 subtypes using Promega ADP-Glo TM Max detection kit. At room temperature, mix the compound of the present invention with 20nM PI3K-α, PI3K-δ or 40nM PI3K-β, PI3K-γ samples in reaction buffer (15mM HEPES (4-hydroxyethylpiperazineethanesulfonic acid, Sigma -Aldrich) pH=7.4, 20 mM NaCl, 1 mM EGTA (3,6-dioxa-1,8-octanediaminetetraacetic acid, Sigma-Aldrich), 0.02% Tween 20 , 10 mM MgCl 2 , 0.2 mg/mL bovine -γ-globulin) for 15 minutes, then add ATP (Sigma-Aldrich)/diC8-PIP2 (dioctanoylphosphatidylinositol-4,5-bisphosphate, Echelon) mixture to obtain a final concentration of 3mM ATP and 500μM diC8-PIP2 substrate (for class I PI3K). The reaction was incubated at room temperature for 2 h, and then 25 μL of stop solution was added to stop the reaction (Promega kit). After incubation at room temperature for 40 min, 50 μL 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.
表1.本发明的化合物对PI3K的4种亚型的活性抑制效果Table 1. The inhibitory effect of the compounds of the present invention on the four subtypes of PI3K
Figure PCTCN2019123563-appb-000106
Figure PCTCN2019123563-appb-000106
Figure PCTCN2019123563-appb-000107
Figure PCTCN2019123563-appb-000107
注：A表示＜30nM；B表示＞30且＜300nM；C表示＞300nM且＜3000；D表示＞3000nM。Note: A means <30nM; B means>30 and <300nM; C means>300nM and <3000; D means>3000nM.
由表1中的结果可知，本发明提供的一系列结构新颖的三并环化合物能够特异性地对PI3K-γ产生强效抑制作用，且显示极高的选择性，对PI3Ks家族其它同工酶几乎无抑制作用或仅有微弱的抑制作用，可以作为高效的PI3K-γ选择性抑制剂，用于预防或治疗或辅助治疗至少部分由PI3K-γ介导的或者从PI3K-γ信号通路抑制中获益的疾病如肿瘤、神经退行性疾病(如阿尔茨海默病)、炎症、动脉粥样硬化、感染性疾病等。It can be seen from the results in Table 1 that the series of novel tricyclic compounds provided by the present invention can specifically produce a strong inhibitory effect on PI3K-γ, 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-γ selective inhibitor for prevention or treatment or adjuvant therapy at least partially mediated by PI3K-γ or from PI3K-γ signaling pathway inhibition Beneficial diseases such as tumors, neurodegenerative diseases (such as Alzheimer's disease), inflammation, atherosclerosis, infectious diseases, etc.
实施例23：PI3K酶活性体外抑制试验。Example 23: PI3K enzyme activity inhibition test in vitro.
1)试剂和耗材：1) Reagents and consumables:
Figure PCTCN2019123563-appb-000108
Figure PCTCN2019123563-appb-000108
2)化合物储备溶液：2) Compound stock solution:
按照标准方案将所有化合物配制为相应浓度的DMSO储备液(0.1mM至10mM)。All compounds were formulated into DMSO stock solutions (0.1 mM to 10 mM) at corresponding concentrations according to standard protocols.
3)化合物保存：3) Compound preservation:
DMSO中的所有化合物均在4℃的干燥器中短期储存。剩下的化合物可以在-20℃下长期保存。All compounds in DMSO are stored in a desiccator at 4°C for short periods. The remaining compounds can be stored for long periods at -20°C.
4)工作储备液的配制：4) Preparation of working stock solution:
A.GSK2126458(CAS No.：1086062-66-9，该化合物用于实验质量的内控)在DMSO中从10μM连续3倍稀释，共10个浓度。A. GSK2126458 (CAS No.: 1086062-66-9, this compound is used for internal control of experimental quality) was serially diluted 3 times from 10 μM in DMSO for a total of 10 concentrations.
B.将其他化合物从300μM(PI3K-γ测试起始浓度)/3mM(PI3K-α、β和δ测试的起始浓度)以DMSO稀释10个梯度，进行3倍系列稀释。共10个浓度和1个DMSO对照。B. Dilute other compounds from 300 μM (initial concentration of PI3K-γ test)/3 mM (initial concentration of PI3K-α, β, and δ test) with 10 gradients of DMSO and perform a 3-fold serial dilution. A total of 10 concentrations and 1 DMSO control.
C.以1％DMSO作为空白，100μMGSK2126458作为阳性控制。 C. Take 1% DMSO as a blank and 100 μMGSK2126458 as a positive control.
D.在平板振荡器上摇动平板5分钟。D. Shake the plate on the plate shaker for 5 minutes.
5)实验步骤：5) Experimental steps:
A.试剂制备：A. Reagent preparation:
1×实验缓冲液：1×Experiment buffer:
50mM HEPES pH＝7.5；3mM MgCl 2；1mM EGTA；0.03％CHAPS；100mM NaCl；2mM DTT(当使用时加入)。 50 mM HEPES pH=7.5; 3 mM MgCl 2 ; 1 mM EGTA; 0.03% CHAPS; 100 mM NaCl; 2 mM DTT (added when used).
2.5×脂质缓冲液：2.5×lipid buffer:
62.5mM HEPES pH＝7.5；1.25mM EGTA。62.5mM HEPES pH=7.5; 1.25mM EGTA.
2.5×PI3K工作溶液：2.5×PI3K working solution:
PI3Kα，储备液浓度为0.36mg/mL，最终浓度为0.25μg/mL。因此2.5倍为0.625μg/mL。使用1X分析缓冲液将0.36mg/mL稀释至0.625μg/mL；PI3Kα, the stock solution concentration is 0.36 mg/mL, and the final concentration is 0.25 μg/mL. Therefore, 2.5 times is 0.625 μg/mL. Dilute 0.36mg/mL to 0.625μg/mL using 1X analysis buffer;
PI3Kβ，储备液浓度为0.1mg/mL，最终浓度为250ng/mL。因此2.5倍为625ng/mL。使用1X分析缓冲液将0.1mg/mL稀释至625ng/mL。PI3Kβ, 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.
PI3Kγ，储备液为0.94mg/mL，终浓度为1.5μg/mL。因此2.5倍为3.75μg/mL。使用1X分析缓冲液将0.94mg/mL稀释至3.75μg/mL。PI3Kγ, the stock solution is 0.94mg/mL, and the final concentration is 1.5μg/mL. Therefore, 2.5 times is 3.75 μg/mL. Dilute 0.94 mg/mL to 3.75 μg/mL using IX analysis buffer.
PI3Kδ，原料浓度为0.1mg/mL，最终浓度为250ng/mL。因此2.5倍为625ng/mL。使用1X分析缓冲液将0.1mg/mL稀释至625ng/mL。PI3Kδ, 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.
2.5×基板工作液：2.5× substrate working fluid:
PIP2：3PS终浓度为0.025mg/mL；ATP终浓度为25μM。PIP2: The final concentration of 3PS is 0.025 mg/mL; the final concentration of ATP is 25 μM.
B.化合物筛选：B. Compound screening:
1)向384孔白色ProxiPlate中加入2μL 2.5×PI3Kα/β/γ/δ工作溶液。1) Add 2 μL 2.5×PI3Kα/β/γ/δ working solution to 384-well white ProxiPlate.
2)将1μl化合物添加到含384孔白色PI3Kα/β/γ/δ工作溶液的ProxiPlate中。2) Add 1 μl of compound to ProxiPlate containing 384-well white PI3K α/β/γ/δ working solution.
3)将化合物和PI3Kα/β/γ/δ工作溶液混合；在室温下孵育15分钟。3) Mix the compound and PI3Kα/β/γ/δ working solution; incubate at room temperature for 15 minutes.
4)在每个384孔中加入2μL 2.5×底物工作溶液以引发反应。因此参考化合物的最终浓度为100、33.33、11.11、3.70、1.23、0.41、0.14、0.05、0.015和0.005nM。测试化合物的最终浓度：对于PI3K-γ为3000、1000、333.33、111.11、37.04、12.35、4.12、1.37、0.46和0.15μM；对于PI3Kα/β/δ为30000、10000、3333.33、1111.11、370.37、123.46、41.15、13.72、4.57和1.52μM。DMSO的最终浓度为1％。4) Add 2 μL of 2.5× substrate working solution to each 384 well to initiate the reaction. Therefore 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 μM for PI3K-γ; 30000, 10000, 3333.33, 1111.11, 370.37, 123.46 for PI3Kα/β/δ , 41.15, 13.72, 4.57 and 1.52 μM. The final concentration of DMSO is 1%.
5)密封测定板。5) Seal the measuring plate.
6)在室温下孵育60分钟。6) Incubate at room temperature for 60 minutes.
7)向384孔白板的每个孔中添加5μL含10mM MgCl 2的ADP-Glo试剂缓冲液。在室温下孵育40分钟。 7) Add 5 μL of ADP-Glo reagent buffer containing 10 mM MgCl 2 to each well of the 384-well white plate. Incubate at room temperature for 40 minutes.
8)加入10μL激酶检测试剂。在室温下孵育40分钟。8) Add 10 μL kinase detection reagent. Incubate at room temperature for 40 minutes.
9)在Envision上阅读RLU(相对发光单位)的值。9) Read the value of RLU (Relative Luminescence Unit) on Envision.
C.数据分析：C. Data analysis:
1)检测每个孔的发光信号(RLU)。1) Detect the luminescence signal (RLU) of each well.
2)按照下面的公式计算％抑制：2) Calculate the% inhibition according to the following formula:
Figure PCTCN2019123563-appb-000109
Figure PCTCN2019123563-appb-000109
Figure PCTCN2019123563-appb-000110
整个板上阳性对照的平均RLU，
Figure PCTCN2019123563-appb-000111
整个板上阴性对照的平均RLU，RLU cmpd：测试化合物的RLU。
Figure PCTCN2019123563-appb-000110
The average RLU of the positive control on the entire plate,
Figure PCTCN2019123563-appb-000111
The average RLU of the negative control across the plate, RLU cmpd : RLU of the test compound.
3)计算测试化合物的IC50和绘图效果剂量曲线：3) Calculate the IC50 of the test compound and plot the effect dose curve:
通过使用Graphpad 5.0将抑制百分比％值和化合物浓度的对数拟合为非线性回归(剂量响应-可变斜率)来计算IC50，计算公式如下：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:
Y＝谷值+(峰值-谷值)/(1+10^((LogIC50-X)×HillSlope))；其中：Y=valley value+(peak value-valley value)/(1+10^((LogIC50-X)×HillSlope)); where:
X：化合物浓度的log值；Y：抑制％。X: log value of compound concentration; Y:% inhibition.
D.结果汇总：D. Summary of results:
表2.体外PI3K酶活性抑制IC50汇总Table 2. Summary of in vitro PI3K enzyme activity inhibition IC50
Figure PCTCN2019123563-appb-000112
Figure PCTCN2019123563-appb-000112
由表2中的结果可知，本发明提供的一系列结构新颖的三并环化合物能够特异性地对PI3K-γ产生强效抑制作用，且显示极高的选择性。对于阳性对照物IPI-549均显示了更高的PI3K-γ活性或者更高的PI3K-α选择性，可以作为高选择性的PI3K-γ选择性抑制剂，用于预防或治疗或辅助治疗至少部分由PI3K-γ介导的或者从PI3K-γ信号通路抑制中获益的疾病如肿瘤、神经退行性疾病(如阿尔茨海默病)、炎症、动脉粥样硬化、感染性疾病等。It can be seen from the results in Table 2 that a series of novel tricyclic compounds provided by the present invention can specifically produce a strong inhibitory effect on PI3K-γ, and show extremely high selectivity. For the positive control IPI-549, it shows higher PI3K-γ activity or higher PI3K-α selectivity, which can be used as a highly selective PI3K-γ selective inhibitor for prevention or treatment or adjuvant therapy. Diseases such as tumors, neurodegenerative diseases (such as Alzheimer's disease), inflammation, atherosclerosis, and infectious diseases that are partially mediated by PI3K-γ or benefit from PI3K-γ signaling pathway inhibition.
实验例24：PI3K细胞活性体外抑制试验。Experimental Example 24: PI3K cell activity inhibition test in vitro.
1)材料和设备：1) Materials and equipment:
Figure PCTCN2019123563-appb-000113
Figure PCTCN2019123563-appb-000113
2)实验步骤：2) Experimental steps:
A.Raji细胞测定：A. Raji cell assay:
a)准备第10代Raji细胞，并通过多滴在384孔板(6007680)中每孔添加6μL 60K细胞。在500RPM下离心30s，并在5％CO 2的37℃下孵育2小时。 a) Prepare the 10th generation of Raji cells and add 6 μL of 60K cells per well in a 384-well plate (6007680) by multiple drops. Centrifuge at 500 RPM for 30 s, and incubate at 37°C for 2 hours in 5% CO 2 .
b)然后，用Echo液体处理器加入30nL化合物，并在37℃，5％CO 2下孵育30分钟。 b) Then, add 30nL compound with Echo liquid processor and incubate at 37°C, 5% CO 2 for 30 minutes.
c)通过自动分液器每孔添加2μL IgM(4X，12μg/mL)。在500RPM下离心30s，并在5％CO 2的37℃下孵育10分钟。 c) Add 2 μL IgM (4X, 12 μg/mL) per well through an automatic dispenser. Centrifuge at 500 RPM for 30 s and incubate at 37° C. in 5% CO 2 for 10 minutes.
d)通过自动分液器加入2μL 5X裂解缓冲液。在平板振荡器上摇动10分钟。d) Add 2 μL of 5X lysis buffer through an automatic dispenser. Shake for 10 minutes on a plate shaker.
e)加入试剂盒中提供的5μL受体混合物。以1000RPM离心1分钟。e) Add 5 μL of the receptor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
f)加入试剂盒中提供的5μL供体混合物。以1000RPM离心1分钟。f) Add 5 μL of the donor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
g)然后在25℃下孵育2小时，使板保持黑暗。g) Then incubate at 25°C for 2 hours to keep the plate dark.
h)读取Envision上显示的AlphaLISA信号值。h) Read the AlphaLISA signal value displayed on Envision.
B.Raw264.7细胞测定：B. Raw264.7 cell assay:
a)准备第10代Raw264.7细胞，并通过多滴在384孔板(6007680)中每孔添加6μL 30K细胞。在500RPM下离心30s，并在5％CO 2的37℃下孵育2小时。 a) Prepare 10th-generation Raw264.7 cells and add 6 μL of 30K cells per well in a 384-well plate (6007680) by multiple drops. Centrifuge at 500 RPM for 30 s, and incubate at 37°C for 2 hours in 5% CO 2 .
b)然后，用Echo液体处理器添加30nL化合物，并在5％CO 2下于37℃孵育30分钟。 b) Then, add 30 nL of compound with Echo liquid processor and incubate at 37°C for 30 minutes under 5% CO 2 .
c)通过自动分液器每孔滴加2μL C5α(4X，320ng/mL)。在500RPM下离心30s，并在5％CO 2的37℃下孵育10分钟。 c) Add 2 μL of C5α (4X, 320 ng/mL) dropwise to each well through an automatic dispenser. Centrifuge at 500 RPM for 30 s and incubate at 37° C. in 5% CO 2 for 10 minutes.
d)通过自动分液器添加2μL 5X裂解缓冲液。在平板振荡器上摇动10分钟。d) Add 2 μL of 5X lysis buffer through an automatic dispenser. Shake for 10 minutes on a plate shaker.
e)加入试剂盒中提供的5μL受体混合物。以1000RPM离心1分钟。e) Add 5 μL of the receptor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
f)加入试剂盒中提供的5μL供体混合物。以1000RPM离心1分钟。f) Add 5 μL of the donor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
g)然后在25℃下孵育2小时，使板保持黑暗。g) Then incubate at 25°C for 2 hours to keep the plate dark.
h)读取Envision上显示的AlphaLISA信号值。h) Read the AlphaLISA signal value displayed on Envision.
C.C2C12细胞测定：C.C2C12 cell assay:
a)准备第8代C2C12细胞，并通过多滴在384孔板(6007680)中每孔添加6μL 30K细胞。在500RPM下离心30s，并在5％CO 2的37℃下孵育2小时。 a) Prepare 8th-generation C2C12 cells and add 6 μL of 30K cells per well in a 384-well plate (6007680) by multiple drops. Centrifuge at 500 RPM for 30 s, and incubate at 37°C for 2 hours in 5% CO 2 .
b)然后，用Echo液体处理器加入30nL化合物，在37℃，5％CO 2下孵育30分钟。 b) Then, add 30nL compound with Echo liquid processor and incubate at 37°C, 5% CO 2 for 30 minutes.
c)通过自动分液器每孔加入2μL IGF-1(4X，4800ng/ml)。在500RPM下离心30s，并在5％CO 2的37℃下孵育10分钟。 c) Add 2 μL IGF-1 (4X, 4800 ng/ml) per well through an automatic dispenser. Centrifuge at 500 RPM for 30 s and incubate at 37° C. in 5% CO 2 for 10 minutes.
d)通过自动分液器加入2μL 5X裂解缓冲液。在平板振荡器上摇动10分钟。d) Add 2 μL of 5X lysis buffer through an automatic dispenser. Shake for 10 minutes on a plate shaker.
e)加入试剂盒中提供的5μL受体混合物。以1000RPM离心1分钟。e) Add 5 μL of the receptor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
f)加入试剂盒中提供的5μL供体混合物。以1000RPM离心1分钟。f) Add 5 μL of the donor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
g)然后在25℃下孵育2小时，使板保持黑暗。g) Then incubate at 25°C for 2 hours to keep the plate dark.
h)读取Envision上显示的AlphaLISA信号值。h) Read the AlphaLISA signal value displayed on Envision.
D.PC-3细胞测定：D. PC-3 cell assay:
a)准备第9代PC-3细胞，并通过多滴在384孔板(6007680)中每孔添加6μL 60K细胞。在500RPM下离心30s，并在5％CO 2的37℃下孵育2小时。 a) Prepare 9th-generation PC-3 cells and add 6 μL of 60K cells per well in a 384-well plate (6007680) by multiple drops. Centrifuge at 500 RPM for 30 s, and incubate at 37°C for 2 hours in 5% CO 2 .
b)然后，用Echo液体处理器加入30nL化合物，在37℃，5％CO 2下孵育30分钟。 b) Then, add 30nL compound with Echo liquid processor and incubate at 37°C, 5% CO 2 for 30 minutes.
c)通过自动分液器每孔加入2μL LPA(4X，60μg/ml)。在500RPM下离心30s，并在5％CO 2的37℃下孵育10分钟。 c) Add 2 μL LPA (4X, 60 μg/ml) per well through an automatic dispenser. Centrifuge at 500 RPM for 30 s and incubate at 37° C. in 5% CO 2 for 10 minutes.
d)通过自动分液器加入2μL 5X裂解缓冲液。在平板振荡器上摇动10分钟。d) Add 2 μL of 5X lysis buffer through an automatic dispenser. Shake for 10 minutes on a plate shaker.
e)加入试剂盒中提供的5μL受体混合物。以1000RPM离心1分钟。e) Add 5 μL of the receptor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
f)加入试剂盒中提供的5μL供体混合物。以1000RPM离心1分钟。f) Add 5 μL of the donor mixture provided in the kit. Centrifuge at 1000 RPM for 1 minute.
g)然后在25℃下孵育2小时，使板保持黑暗。g) Then incubate at 25°C for 2 hours to keep the plate dark.
h)读取Envision上显示的AlphaLISA信号值。h) Read the AlphaLISA signal value displayed on Envision.
E.数据分析：E. Data analysis:
根据非线性回归方程拟合化合物IC50：Fit the compound IC50 according to the nonlinear regression equation:
Y＝谷值+(峰值-谷值)/(1+10^((Log IC50-X)×HillSlope))；其中：Y=valley value+(peak value-valley value)/(1+10^((Log IC50-X)×HillSlope)); where:
X：测试化合物浓度的对数；Y：抑制％。X: logarithm of test compound concentration; Y:% inhibition.
F.结果汇总：F. Summary of results:
表3.PI3K体外细胞活性抑制测试数据Table 3. PI3K cell activity inhibition test data in vitro
Figure PCTCN2019123563-appb-000114
Figure PCTCN2019123563-appb-000114
由表3中的结果可知，本发明提供的一系列结构新颖的三并环化合物能够特异性地对PI3K-γ产生强效抑制作用，且显示极高的选择性。对于阳性对照物IPI-549均显示了更高的PI3K-γ活性和更高的PI3K-α选择性，可以作为高选择性的PI3K-γ选择性抑制剂，用于预防或治疗或辅助治疗至少部分由PI3K-γ介导的或者从PI3K-γ信号通路抑制中获益的疾病如肿瘤、神经退行性疾病(如阿尔茨海默病)、炎症、动脉粥样硬化、感染性疾病等。From the results in Table 3, it can be seen that a series of novel tricyclic compounds provided by the present invention can specifically produce a strong inhibitory effect on PI3K-γ, and show extremely high selectivity. For the positive control IPI-549, it shows higher PI3K-γ activity and higher PI3K-α selectivity, and can be used as a highly selective PI3K-γ selective inhibitor for prevention or treatment or adjuvant therapy. Diseases such as tumors, neurodegenerative diseases (such as Alzheimer's disease), inflammation, atherosclerosis, and infectious diseases that are partially mediated by PI3K-γ or benefit from PI3K-γ signaling pathway inhibition.
实验例25：小鼠体内联合抗PD-1单抗的肿瘤抑制试验。Experimental Example 25: Tumor inhibition test with anti-PD-1 monoclonal antibody in mice.
1)细胞扩增：1) Cell expansion:
将一支冻存的CT26细胞(ATCC公司，CRL-2638 TM)从-80℃冰箱中取出，在37℃的水浴锅中迅速溶解，消毒后转入生物安全柜。离心，弃上清，沉淀采用完全培养基重混，转入培养瓶并添加RPMI1640完全培养基(CIBICO公司，货号：22400-071)，放置CO 2培养箱中继续培养并进行传代。 A frozen CT26 cell (ATCC company, CRL-2638 ™ ) 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.
2)接种细胞：2) Inoculate cells:
取100只BALB/c转基因小鼠，该小鼠采购自北京维通利华实验技术有限公司，背侧腹部剃毛，皮下种植1.5×10 6的细胞悬液0.2mL。小鼠接种完后放回原笼继续饲养。 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.
3)样品配制：3) Sample preparation:
称取Isotype(h-IgG，Equitech-Bio，货号：SLH66-0001)、抗PD-1单抗(该抗体与小鼠和人的PD-1均能结合，其与CN 108779177 A中公开的PD-1“抗体C”的序列相同，信达生物自制)、化合物21和IPI-549(CASNo.：1693758-51-8，即WO 2015051244 A1中公开的化合物4，阳性对照，信达自制)，使用5％的1-甲基-2-吡咯烷酮的PEG400混合溶剂溶解，终浓度分别如下：Isotype为0.1mg/mL，抗PD-1单抗为0.1mg/mL，化合物21为2.0mg/mL，化合物IPI-549为2.0mg/mL。Weigh 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.
4)给药：4) Administration:
小鼠接种后第7天，根据瘤体积大小分组，选取瘤体积在33.60mm 3至87.18mm 3范围内的小鼠，分为4组，每组7只。每组分别给予下表的受试物： 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:
Figure PCTCN2019123563-appb-000115
Figure PCTCN2019123563-appb-000115
5)肿瘤体积测试：5) Tumor volume test:
按照以下公式计算肿瘤的体积：Calculate the tumor volume according to the following formula:
肿瘤体积(V)＝W 2×L/2；其中： Tumor volume (V) = W 2 × L/2; where:
W：最大宽轴长；L：最大长轴长。W: maximum long axis length; L: maximum long axis length.
6)结果汇总：6) Summary of results:
表4.PI3K抑制剂与抗PD-1单克隆抗体联合使用对小鼠肿瘤抑制的数据Table 4. PI3K inhibitors combined with anti-PD-1 monoclonal antibodies are used to inhibit tumor growth in mice
Figure PCTCN2019123563-appb-000116
Figure PCTCN2019123563-appb-000116
由表4和图1中的结果可知，在BALB/c转基因小鼠CT-26肿瘤模型中，将本发明提供的结构新颖的三并环化合物与抗PD-1单抗联合使用进行给药，给药25天后的肿瘤抑制率可达66.3％，优于单独使用抗PD-1单抗(43.0％)和对照化合物IPI-549+抗PD-1的联合使用(50.5％)的抑瘤效果。因此，本发 明化合物可以作为高选择性的PI3K-γ选择性抑制剂，用于预防或治疗或辅助治疗至少部分由PI3K-γ介导的或者从PI3K-γ信号通路抑制中获益的疾病如肿瘤等。It can be seen from the results in Table 4 and FIG. 1 that in the BALB/c transgenic mouse CT-26 tumor model, 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-γ selective inhibitors for the prevention or treatment or adjuvant treatment of diseases that are at least partially mediated by PI3K-γ or benefit from the inhibition of PI3K-γ signaling pathway, such as Tumors, etc.

Claims (17)

  1. 一种具有式I结构的化合物：A compound with structure I:
    Figure PCTCN2019123563-appb-100001
    Figure PCTCN2019123563-appb-100001
    或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，其中：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, solvate, hydrate, isotopic label or prodrug thereof, wherein
    A为四至十元环状结构，所述环状结构为饱和或不饱和的脂肪环或者芳香环，且所述环状结构任选地含有0至多个杂原子；A is a four- to ten-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 0为-C(＝R 2)-、-S(＝R 2) n-或-P(＝R 2)(R 0)-； X 0 is -C(=R 2 )-, -S(=R 2 ) n -or -P(=R 2 )(R 0 )-;
    X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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 8为-CH 2-、-CHR 7-、-C(R 7) 2-、-C(＝R 2)-、-NH-或-NR 7-； X 8 is -CH 2 -, -CHR 7 -, -C(R 7 ) 2 -, -C(=R 2 )-, -NH- or -NR 7 -;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、杂芳基烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且R 0中的氢任选地被氘或卤素取代； 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 alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro Ring or bridge ring; and the hydrogen in R 0 is optionally substituted by deuterium or halogen;
    R 1和R 4各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1和R 4中的氢任选地被0至多个基团取代，每一个所述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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 R″ are each independently hydrogen, 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, phosphoryl or alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring or spiro ring Or a bridged ring; and the heterocyclic group, spirocyclic group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkynyl groups;
    每一个R 2各自独立地为NH、NR 7、N-OH、S或O； Each R 2 is independently NH, NR 7 , N-OH, S or O;
    R 3为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 3中的氢任选地被0至多个基团取代，每一个所述基团各自独立地为氘、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、杂环烷基、芳基、杂芳基、芳基烷基、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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′ 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 alkylureido groups, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro Ring or bridge ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl or alkynyl groups ;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环 基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  2. 根据权利要求1所述的具有式I结构的化合物，其特征在于：所述化合物为式IA化合物：The compound having the structure of formula I according to claim 1, wherein the compound is a compound of formula IA:
    Figure PCTCN2019123563-appb-100002
    Figure PCTCN2019123563-appb-100002
    其中：among them:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
    X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl Or alkynyl substitution;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  3. 根据权利要求1所述的具有式I结构的化合物，其特征在于：所述化合物为式IB化合物：The compound having the structure of formula I according to claim 1, wherein the compound is a compound of formula IB:
    Figure PCTCN2019123563-appb-100003
    Figure PCTCN2019123563-appb-100003
    其中：among them:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
    X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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和X 4各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3和X 4一起形成双键或三键； 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;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、羟基、氨基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； Each R 0 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, amino, heterocyclic, 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl Or alkynyl substitution;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  4. 根据权利要求1所述的具有式I结构的化合物，其特征在于：所述化合物为式IC化合物：The compound having the structure of formula I according to claim 1, wherein the compound is a compound of formula IC:
    Figure PCTCN2019123563-appb-100004
    Figure PCTCN2019123563-appb-100004
    其中：among them:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
    X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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和X 5各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4和X 5任意两者之间形成双键或三键； 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;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted by 0 to more alkyl, haloalkyl, alkenyl Or alkynyl substitution;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  5. 根据权利要求1所述的具有式I结构的化合物，其特征在于：所述化合物为式ID化合物：The compound having the structure of formula I according to claim 1, wherein the compound is a compound of formula ID:
    Figure PCTCN2019123563-appb-100005
    Figure PCTCN2019123563-appb-100005
    其中：among them:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
    X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl Or alkynyl substitution;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  6. 根据权利要求1所述的具有式I结构的化合物，其特征在于：所述化合物为式IE化合物：The compound having the structure of formula I according to claim 1, wherein the compound is a compound of formula IE:
    Figure PCTCN2019123563-appb-100006
    Figure PCTCN2019123563-appb-100006
    其中：among them:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-;
    X 1、X 2、X 7、X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N； 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、X 5和X 6各自独立地为CH、CR 7、CH 2、O、C＝O、S、NH、NR 7或N；或者X 3、X 4、X 5和X 6任意两者之间形成单键、双键或三键； X 3 , X 4 , X 5 and X 6 are each independently CH, CR 7 , CH 2 , O, C=O, S, NH, NR 7 or N; or X 3 , X 4 , X 5 and X 6 Form a single bond, double bond or triple bond between any two;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、羟基、氨基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基或杂芳基烷基；且R 0中的氢任选地被氘或卤素取代； 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和R 8各自独立地为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；且R 1、R 4和R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基、烷基脲基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；且所述杂环基、螺环基、桥环基、芳基、芳基烷基或杂芳基任选地被0至多个烷基、卤代烷基、烯基或炔基取代； 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, phosphoryl, alkylureido, 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 Monocyclic, spiro or bridged ring; and the heterocyclic group, spiro ring group, bridged ring group, aryl group, arylalkyl group or heteroaryl group is optionally substituted with 0 to more alkyl, haloalkyl, alkenyl Or alkynyl substitution;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O； Each R 5 is independently NH, NR 7 , N-OH, S or O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 , where: 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, sulfonyl, sulfonylamino, phosphinyl, phosphoryl or alkylureido groups, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基； Each R 7 is independently hydrogen, deuterium, halogen, alkyl, haloalkyl, alkoxy, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, bridged or Deuterated alkyl;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  7. 根据权利要求1至6中任一项所述的具有式I结构的化合物，其特征在于：The compound having the structure of formula I according to any one of claims 1 to 6, characterized in that:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-；优选-C(＝O)-或-C(＝S)-；最优选-C(＝O)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-; preferably -C(=O)- or- C(=S)-; most preferably -C(=O)-;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′ 和R″与其相连接的氮原子一起形成单环、螺环或桥环；优选氢、氘、卤素、烷基、卤代烷基、氨基或-NR′R″； 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 monocyclic ring, spiro ring or bridge ring; preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, amino or -NR'R";
    R 1为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选芳基或杂芳基；最优选苯基；且R 1中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    R 4为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选烷基、卤代烷基或烷氧基；且R 4中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤素、羟基或氨基； 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;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O；优选NH、S或O；最优选O； Each R 5 is independently NH, NR 7 , N-OH, S or O; preferably NH, S or O; most preferably O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7；优选氨基、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或酰胺基，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基或硝基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 ; preferably amino, -(CH 2 ) m NHSO 2 NH 2 , -NR'R",- NR 7 SO 2 NR′R″, —(CH 2 ) m SO 2 NR′R″, —(CH 2 ) m S(═O)NR′R″ or amide group, wherein: R′ and R″ are each independent Ground is hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl , Heteroaryl, halogen, cyano, hydroxy or nitro, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基；优选氢、氘、烷基、卤代烷基或氘代烷基； 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为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  8. 根据权利要求1至6中任一项所述的具有式I结构的化合物，其特征在于：The compound having the structure of formula I according to any one of claims 1 to 6, characterized in that:
    X 0为-C(＝O)-、-S(＝O) n-、-P(＝O)(R 0)-或-C(＝S)-；优选-C(＝O)-或-C(＝S)-；最优选-C(＝O)-； X 0 is -C(=O)-, -S(=O) n -, -P(=O)(R 0 )- or -C(=S)-; preferably -C(=O)- or- C(=S)-; most preferably -C(=O)-;
    X 1、X 2和X 7各自独立地为CH、CR 7或N；优选CH或CR 7；最优选CH； X 1 , X 2 and X 7 are each independently CH, CR 7 or N; preferably CH or CR 7 ; most preferably CH;
    X 9、X 10、X 11、X 12、X 13和X 14各自独立地为CH、CR 7或N；优选X 9、X 13和X 14为N，且X 10、X 11、X 12为CH； X 9 , X 10 , X 11 , X 12 , X 13 and X 14 are each independently CH, CR 7 or N; preferably X 9 , X 13 and X 14 are N, and X 10 , X 11 and X 12 are CH;
    每一个R 0各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂环烷基、烯基、炔基、环烷基、氨基酰基、取代酰基、羟基、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环；优选氢、氘、卤素、烷基、卤代烷基、氨基或-NR′R″； 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 ring; preferably hydrogen, deuterium, halogen, alkyl, haloalkyl, amino or -NR'R";
    R 1为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选芳基或杂芳基；最优选苯基；且R 1中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、 烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, arylalkyl, heteroaryl, halogen, cyano , Hydroxy, nitro, phosphate, sulfonyl, sulfonamido, phosphinyl, phosphoryl or alkylureido, or R′ and R″ together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    R 4为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基或杂环基；优选烷基、卤代烷基或烷氧基；且R 4中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤素、羟基或氨基； 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;
    每一个R 5各自独立地为NH、NR 7、N-OH、S或O；优选NH、S或O；最优选O； Each R 5 is independently NH, NR 7 , N-OH, S or O; preferably NH, S or O; most preferably O;
    R 6为氘、烷基、卤代烷基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、杂螺环基、桥环基、烷氧基、氨基、羟基、酰胺基、-(CH 2) mSF 5、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或-S(＝R 5) nR 7；优选氨基、-(CH 2) mNHSO 2NH 2、-NR′R″、-NR 7SO 2NR′R″、-(CH 2) mSO 2NR′R″、-(CH 2) mS(＝O)NR′R″或酰胺基，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基或硝基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； R 6 is deuterium, alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, spirocyclic, heterospirocyclic, bridged ring, alkoxy, amino, hydroxyl, Amide, -(CH 2 ) m SF 5 , -(CH 2 ) m NHSO 2 NH 2 , -NR′R″, -NR 7 SO 2 NR′R″, -(CH 2 ) m SO 2 NR′R ", -(CH 2 ) m S(=O)NR'R" or -S(=R 5 ) n R 7 ; preferably amino, -(CH 2 ) m NHSO 2 NH 2 , -NR'R",- NR 7 SO 2 NR′R″, —(CH 2 ) m SO 2 NR′R″, —(CH 2 ) m S(═O)NR′R″ or amide group, wherein: R′ and R″ are each independent Ground is hydrogen, deuterium, alkyl, alkoxy, haloalkyl, heterocycloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, spirocyclic, bridged, aryl, arylalkyl , Heteroaryl, halogen, cyano, hydroxy or nitro, or R'and R" together with the nitrogen atom to which they are attached form a single ring, spiro ring or bridge ring;
    每一个R 7各自独立地为氢、氘、卤素、烷基、卤代烷基、烷氧基、杂烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基或氘代烷基；优选氢、氘、烷基、卤代烷基或氘代烷基； 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为氢、烷基、烯基、炔基、环烷基、卤素、卤代烷基、烷氧基、杂环基、螺环基、杂螺环基、桥环基、杂桥环基、芳基或杂芳基；优选氢、烷基、环烷基、卤代烷基、杂环基、芳基或杂芳基；最优选氢、烷基、环烷基、杂环基、芳基或杂芳基；且R 8中的氢任选地被0至多个基团取代，每一个上述基团各自独立地为氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、卤素、氨基或-NR′R″，其中：R′和R″各自独立地为氢、氘、烷基、烷氧基、卤代烷基、杂环烷基、烯基、炔基、环烷基、杂环基、螺环基、桥环基、芳基、芳基烷基、杂芳基、卤素、氰基、羟基、硝基、磷酸酯基、磺酰基、磺酰氨基、次磷酰基、磷酰基或烷基脲基，或R′和R″与其相连接的氮原子一起形成单环、螺环或桥环； 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, haloalkyl, heterocycloalkyl, alkenyl, alkynyl , Cycloalkyl, heterocyclic, spirocyclic, bridged, aryl, arylalkyl, heteroaryl, halogen, cyano, hydroxy, nitro, phosphate, sulfonyl, sulfonamido, Hypophosphorous, phosphoryl or alkylureido, or R'and R" together with the nitrogen atom to which they are attached form a monocyclic ring, spiro ring or bridge ring;
    每一个m各自独立地为0、1、2或3；Each m is independently 0, 1, 2 or 3;
    每一个n各自独立地为0、1或2。Each n is independently 0, 1, or 2.
  9. 根据权利要求1所述的具有式I结构的化合物，其包括：The compound having the structure of formula I according to claim 1, comprising:
    Figure PCTCN2019123563-appb-100007
    Figure PCTCN2019123563-appb-100007
    Figure PCTCN2019123563-appb-100008
    Figure PCTCN2019123563-appb-100008
    Figure PCTCN2019123563-appb-100009
    Figure PCTCN2019123563-appb-100009
    Figure PCTCN2019123563-appb-100010
    Figure PCTCN2019123563-appb-100010
    Figure PCTCN2019123563-appb-100011
    Figure PCTCN2019123563-appb-100011
    Figure PCTCN2019123563-appb-100012
    Figure PCTCN2019123563-appb-100012
    Figure PCTCN2019123563-appb-100013
    Figure PCTCN2019123563-appb-100013
    Figure PCTCN2019123563-appb-100014
    Figure PCTCN2019123563-appb-100014
    Figure PCTCN2019123563-appb-100015
    Figure PCTCN2019123563-appb-100015
    Figure PCTCN2019123563-appb-100016
    Figure PCTCN2019123563-appb-100016
    Figure PCTCN2019123563-appb-100017
    Figure PCTCN2019123563-appb-100017
  10. 根据权利要求1所述的具有式I结构的化合物的制备方法，具体步骤如下所示：The method for preparing the compound having the structure of formula I according to claim 1, the specific steps are as follows:
    Figure PCTCN2019123563-appb-100018
    Figure PCTCN2019123563-appb-100018
    S-1：化合物I-1发生关环，得到化合物I-2；S-1: The ring closure of compound I-1 gives compound I-2;
    S-2：化合物I-2与化合物I-3反应，得到式I化合物；S-2: Compound I-2 reacts with compound I-3 to obtain the compound of formula I;
    其中：基团X 0、X 1、X 2、X 7、X 8、X 9、X 10、X 11、X 12、X 13和X 14，取代基R 0、R 1、R 3、R 4、R 5和R 6，以及环A，如权利要求1中所限定。 Among them: 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, as defined in claim 1.
  11. 一种药物组合物，其包含根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药。A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, or an optical isomer or a mixture of both, or a cis-trans isomer or a mixture of both, or Pharmaceutically acceptable salts, solvates, hydrates, isotope labels or prodrugs.
  12. 根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者根据权利要求11所述的药物组合物，其用作PI3K-γ抑制剂。The compound according to any one of claims 1 to 9, or an optical isomer or a mixture of the two, or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt or solvent thereof Compound, hydrate, isotope label or prodrug, or the pharmaceutical composition according to claim 11, which is used as a PI3K-γ inhibitor.
  13. 根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者根据权利要求11所述的药物组合物，用作PI3K-γ抑制剂的用途。The compound according to any one of claims 1 to 9, or an optical isomer or a mixture of the two, or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt or solvent thereof Use of the compound, hydrate, isotope label or prodrug, or the pharmaceutical composition according to claim 11, as a PI3K-γ inhibitor.
  14. 根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者根据权利要求11所述的药物组合物，在制备用于预防和/或治疗至少部分由P13K-γ介导或者从PI3K-γ信号通路抑制中获益的疾病的药物中的用途。The compound according to any one of claims 1 to 9, or an optical isomer or a mixture of the two, or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt or solvent thereof Compound, hydrate, isotope label or prodrug, or the pharmaceutical composition according to claim 11, when prepared for prevention and/or treatment is at least partially mediated by P13K-γ or inhibited from PI3K-γ signaling pathway Uses in medicines that benefit from diseases.
  15. 一种用于预防和/或治疗至少部分由PI3K-γ介导或者从PI3K-γ信号通路抑制中获益的疾病的方法，其包括下列步骤：将治疗有效量的根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者根据权利要求11所述的药物组合物，施用于对其有需求的患者。A method for preventing and/or treating diseases at least partially mediated by PI3K-γ or benefiting from inhibition of PI3K-γ signaling pathway, comprising the steps of: applying a therapeutically effective amount according to claims 1 to 9 The compound according to any one of the above, or an optical isomer or a mixture of the two, or a cis-trans isomer or a mixture of the two, or a pharmaceutically acceptable salt, solvate, hydrate, isotope The marker or prodrug, or the pharmaceutical composition according to claim 11, is administered to a patient in need thereof.
  16. 一种药物联合形式，其包含根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者根据权利要求11所述的药物组合物，以及至少一种额外的癌症治疗剂。A pharmaceutical combination comprising a compound according to any one of claims 1 to 9, 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, isotope label or prodrug, or the pharmaceutical composition according to claim 11, and at least one additional cancer therapeutic agent.
  17. 一种用于预防和/或治疗癌症的方法，其包括下列步骤：将治疗有效量的根据权利要求1至9中任一项所述的化合物，或其旋光异构体或二者的混合物，或其顺反异构体或二者的混合物，或其药学上可接受的盐、溶剂合物、水合物、同位素标记物或前药，或者根据权利要求11所述的药物组合物，以及至少一种额外的癌症治疗剂，优选抗PD-1/PD-L1单抗，施用于对其有需求的患者。A method for preventing and/or treating cancer, comprising the steps of: adding a therapeutically effective amount of a compound according to any one of claims 1 to 9, 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, solvate, hydrate, isotopic label or prodrug thereof, or the pharmaceutical composition according to claim 11, and at least An additional cancer treatment agent, preferably anti-PD-1/PD-L1 monoclonal antibody, is administered to patients in need thereof.
PCT/CN2019/123563 2018-12-12 2019-12-06 Novel three-ring fused structure compound, preparation method therefor and use thereof WO2020119592A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201980082000.1A CN113195492B (en) 2018-12-12 2019-12-06 Novel compound with three-fused ring structure, preparation method and application thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811517957.8 2018-12-12
CN201811517957 2018-12-12

Publications (1)

Publication Number Publication Date
WO2020119592A1 true WO2020119592A1 (en) 2020-06-18

Family

ID=71076727

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/123563 WO2020119592A1 (en) 2018-12-12 2019-12-06 Novel three-ring fused structure compound, preparation method therefor and use thereof

Country Status (2)

Country Link
CN (1) CN113195492B (en)
WO (1) WO2020119592A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024183806A1 (en) * 2023-03-08 2024-09-12 InventisBio Co., Ltd. Compounds, preparation methods and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104703979A (en) * 2012-04-10 2015-06-10 无限药品股份有限公司 Heterocyclic compounds and uses thereof
WO2017214269A1 (en) * 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof
CN105793255B (en) * 2013-10-04 2018-11-16 无限药品股份有限公司 Heterocyclic compound and application thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103965133B (en) * 2013-01-31 2018-11-30 华东理工大学 It is a kind of to contain N, S heterocyclic compound and its preparation and use with DHODH inhibitory activity
CN105884828A (en) * 2015-02-16 2016-08-24 上海迪诺医药科技有限公司 Polycyclic compound, pharmaceutical composition and application thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104703979A (en) * 2012-04-10 2015-06-10 无限药品股份有限公司 Heterocyclic compounds and uses thereof
CN105793255B (en) * 2013-10-04 2018-11-16 无限药品股份有限公司 Heterocyclic compound and application thereof
WO2017214269A1 (en) * 2016-06-08 2017-12-14 Infinity Pharmaceuticals, Inc. Heterocyclic compounds and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
EVANS, C. A. ET AL.: "Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor(IPI-549) as an Immuno-Oncology Clinical Candidate", ACS MEDICINAL CHEMISTRY LETTERS, vol. 7, no. 9, 22 July 2016 (2016-07-22), XP055311463, ISSN: 1948-5875, DOI: 20200113163714A *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024183806A1 (en) * 2023-03-08 2024-09-12 InventisBio Co., Ltd. Compounds, preparation methods and uses thereof

Also Published As

Publication number Publication date
CN113195492A (en) 2021-07-30
CN113195492B (en) 2022-07-08

Similar Documents

Publication Publication Date Title
WO2020094104A1 (en) Nitrogen-containing fused heterocyclic shp2 inhibitor compound, preparation method, and use
WO2020073945A1 (en) Bicyclic derivative inhibitor, preparation method therefor, and application thereof
WO2018166493A1 (en) Heteroaryl[4,3-c]pyrimidine-5-amine derivative, preparation method therefor, and medical uses thereof
AU2017284124B2 (en) Benzotriazole-derived α and β unsaturated amide compound used as TGF-βR1 inhibitor
WO2021143701A1 (en) Pyrimidine-4(3h)-ketone heterocyclic compound, preparation method therefor and use thereof in medicine and pharmacology
CN105658640A (en) Alkynyl alcohols and methods of use
WO2022253326A1 (en) Nlrp3 inflammasome inhibitor and application thereof
WO2021190417A1 (en) Novel aminopyrimidine egfr inhibitor
EP2697222A1 (en) Tri- and tetracyclic pyrazolo[3,4-b]pyridine compounds as antineoplastic agent
CA2700824A1 (en) Heterocyclic compounds as crth2 receptor antagonists
WO2021115457A9 (en) Pyrazolo[1,5-a]pyridine compound, preparation method therefor and use thereof
CN112292374B (en) Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof
WO2015192760A1 (en) Pyridino[1,2-a]pyrimidone analogue used as pi3k inhibitor
KR20240016938A (en) Phosphoinositide 3-kinase beta inhibitors and compositions and methods thereof
TW202233190A (en) IMIDAZO[1,5-A]PYRAZINE DERIVATIVES AS PI3Kdelta INHIBITORS
CN108779115B (en) Five-membered heteroaromatic ring bridged ring derivative, preparation method thereof and application thereof in medicine
AU2017373758A1 (en) Compounds and pharmaceutical compositions for modulating SGK activity, and methods thereof
WO2020119592A1 (en) Novel three-ring fused structure compound, preparation method therefor and use thereof
WO2018161871A1 (en) Imidazopyridine compound as p53-mdm2 inhibitor
WO2015120737A1 (en) Substituted pyridopyrimidine compounds, preparation methods therefor and uses thereof
WO2024046370A1 (en) Heterocyclic compounds as kras inhibitors, and preparation and therapeutic use thereof
CN110684048A (en) Novel phosphoinositide 3-kinase inhibitor and preparation method and application thereof
WO2022063050A1 (en) Pyrazole compound and preparation method therefor and use thereof
TW202214634A (en) Heterocyclic compound and derivative thereof
TWI707853B (en) 1,2-dihydro-1,6-naphthyridine derivatives, preparation method thereof, pharmaceutical composition and use in medicine

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19895105

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19895105

Country of ref document: EP

Kind code of ref document: A1