WO2023071218A1 - 一类吡唑并嘧啶衍生物及制备方法和应用 - Google Patents

一类吡唑并嘧啶衍生物及制备方法和应用 Download PDF

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WO2023071218A1
WO2023071218A1 PCT/CN2022/098519 CN2022098519W WO2023071218A1 WO 2023071218 A1 WO2023071218 A1 WO 2023071218A1 CN 2022098519 W CN2022098519 W CN 2022098519W WO 2023071218 A1 WO2023071218 A1 WO 2023071218A1
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methyl
pyrazol
pyrazolo
pyrimidine
diamine
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PCT/CN2022/098519
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English (en)
French (fr)
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赵冬梅
孙印
程卯生
吴天啸
孙宇
王林
王靖凯
薛艳丽
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沈阳药科大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • 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
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and relates to a class of novel pyrazolopyrimidine derivatives, a preparation method thereof and an application as a therapeutic agent, especially as a PLK4 inhibitor.
  • Polo-like kinase 4 (PLK4), as a key protein in centrosome replication in cells, plays an important role in centrosome duplication and mitosis. Many studies have shown that overexpression of PLK4 can lead to centrosome amplification and induce cancer. At present, the design of PLK4 small-molecule ATP-competitive inhibitors has become an important means of treating tumors induced by centrosome misduplication, and PLK4 inhibitors can achieve precise treatment of tumors containing TRIM37 gene amplification. This research has been conducted in breast cancer , confirmed in glioblastoma.
  • Polo-like kinase 4 one of the members of the Polo-like protein kinase family, is a highly evolutionarily conserved serine/threonine protein kinase with five isoforms, namely PLK1-5.
  • PLK4 is mainly expressed in actively dividing tissues and cells. A series of biological studies have shown that PLK4 is closely related to centrosome duplication in the cell cycle, and tumor cells have the characteristics of unlimited proliferation. Therefore, PLK4 plays an irreplaceable role in various biological functions such as proliferation, migration, invasion, and apoptosis of tumor cells.
  • PLK4 is abnormally expressed in most human tumors, such as liver cancer, gastric cancer, lung cancer, breast cancer, melanoma, and hematological malignancies.
  • PLK4 inhibitors reported so far only have two types of core structures.
  • the representative inhibitor of one type of structure, LCR-263 has nanomolar kinase activity and high selectivity for PLK4, but it has not yet entered preclinical research; the representative inhibitor of another type of structure, CFI-400945, has entered the second phase of clinical trials.
  • Phase study but it lacks selectivity for TRKA, Aurora A/B. Therefore, it is of great scientific value and research significance to find new PLK4 inhibitors with high efficiency, high selectivity and good in vivo properties.
  • the object of the present invention is to provide a novel pyrazolopyrimidine derivative, its preparation method and its use as a therapeutic agent, especially as a PLK4 inhibitor.
  • a pyrazolopyrimidine derivative is a compound represented by general formula (I), and its geometric isomers, enantiomers or pharmaceutically acceptable salts thereof; represented by general formula (I)
  • the compounds are as follows:
  • R 1 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, unsubstituted or aryl substituted by 1-4 same or different R a , unsubstituted or C3-C7 cycloalkyl substituted by 1-2 of the following groups, C3-C7 aliphatic ring containing 1-2 heteroatoms; the following groups are C1-C4 alkyl or amino; the ring, containing The heteroatom aliphatic ring can also contain 1-2 carbonyl groups, and the heteroatom in the heteroatom-containing aliphatic ring is condensed with aromatic amide and aromatic sulfonamide;
  • R is selected from hydrogen, halogen, cyano, formamide, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, C3-C6 aliphatic ring containing heteroatoms;
  • R is selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, C1-C4 alkoxy, unsubstituted or aryl substituted by 1-4 R a which may be the same or different;
  • Ring C is selected from aryl groups that are unsubstituted or substituted by 1-4 R a that may be the same or different;
  • R a is selected from halogen, C1-C4 alkyl or C1-C4 haloalkyl
  • B is selected from a C5-C7 aliphatic ring or NHRc containing up to 2 heteroatoms
  • Rc is selected from unsubstituted or substituted by 1-4 R b which may be the same or different: aryl, arylmethyl, arylethyl, C5-C7 aliphatic ring containing 1-2 heteroatoms or C5- C7 aliphatic heterocyclic phenylmethyl;
  • R b is selected from halogen, cyano, methylsulfoneethylamino, C1-C4 alkoxy, C1-C4 alkylamino, C3-C7 cycloalkyl, C4-C7 aliphatic ring containing up to 2 heteroatoms, NR d R e ;
  • R d is selected from C1-C4 alkoxy C1-C4 alkyl, C1-C6 hydroxyalkyl, C4-C7 aliphatic ring containing 1-2 heteroatoms;
  • R e is selected from hydrogen, C1-C4 alkyl
  • the heteroatom is nitrogen, oxygen or sulfur;
  • the aryl is phenyl, pyridyl, pyrimidinyl;
  • R d is selected from a C4-C7 aliphatic ring containing 1-2 heteroatoms and the heteroatom is S
  • the sulfur atom can be further oxidized to sulfoxide or sulfone.
  • Rc is selected from C5-C7 aliphatic heterocyclic phenylmethyl, and the heteroatom is N, the nitrogen atom can be further substituted by C1-C4 alkyl.
  • the derivative is a compound represented by general formula (I), and its geometric isomers, enantiomers or pharmaceutically acceptable salts thereof;
  • R is selected from hydrogen, methyl, isopropyl, trifluoroethyl, hydroxytert-butyl, cyclohexyl, unsubstituted or aryl substituted by 1-4 R which may be the same or different, containing 1 - C3-C7 aliphatic ring with 2 heteroatoms; the heteroatom-containing aliphatic ring may also contain 1-2 carbonyl groups, and the heteroatoms in the heteroatom-containing alicyclic ring are condensed with aromatic amide and aromatic sulfonamide;
  • R is selected from hydrogen, halogen or formamide
  • the A ring part is selected from
  • R is selected from hydrogen, halogen, methyl, ethyl, cyclopropyl, tert-butyl, unsubstituted or aryl substituted by 1-4 R which may be the same or different;
  • Ring C is selected from unsubstituted or aryl groups substituted by 1-4 R a which may be the same or different;
  • R a is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl;
  • B is selected from piperazinyl or NHRc
  • Rc is selected from unsubstituted or substituted by 1-4 R b which may be the same or different: phenyl, pyridyl, pyrimidinyl, C5-C7 alicyclic ring containing 1-2 heteroatoms, C5-C7 aliphatic heterocyclic ring phenylmethyl;
  • R b is selected from halogen, cyano, methylsulfone ethylamino, methoxy, morpholinyl, thiomorpholinyl, C1-C4 alkyl, C1-C4 alkylamino, NR d R e ;
  • R d is selected from C1-C6 hydroxyalkyl, C1-C4 alkoxy C1-C4 alkyl, C4-C7 aliphatic ring containing 1-2 heteroatoms;
  • R e is selected from hydrogen, C1-C4 alkyl
  • heteroatoms are nitrogen, oxygen or sulfur;
  • R d is selected from a C4-C7 aliphatic ring containing 1-2 heteroatoms
  • the sulfur atom when the heteroatom is S, the sulfur atom can be further oxidized to sulfoxide or sulfone;
  • Rc is selected from C5-C7 aliphatic heterocyclic phenylmethyl, and the heteroatom is N, the nitrogen atom can be further substituted by C1-C4 alkyl.
  • the compound represented by the general formula (I) of the derivative and its geometric isomers, enantiomers or pharmaceutically acceptable salts thereof;
  • R is selected from hydrogen, methyl, isopropyl, trifluoroethyl, hydroxy-tert-butyl, cyclohexyl, p-fluorophenyl, 4-tetrahydropyran, 2-tetrahydropyran, 4-hexa Hydropyridine;
  • R is selected from hydrogen, halogen or formamide
  • the A ring part is selected from
  • R is selected from hydrogen, halogen, methyl, ethyl, cyclopropyl, tert-butyl, unsubstituted or phenyl substituted by 1-4 R which may be the same or different;
  • the C ring is selected from unsubstituted or substituted phenyl groups with 1-4 R a which may be the same or different;
  • R a is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl;
  • B is selected from piperazinyl
  • R b which may be the same or different: 4-hexahydropyridylamino, 3-tetrahydropyrrolylamino, aniline, benzylamino, 1-(2,4-difluorophenyl ) ethylamino, 2-phenylethylamino;
  • R b is selected from halogen, cyano, methylsulfone ethylamino, methoxy, morpholinyl, thiomorpholinyl, C1-C4 alkyl, C1-C4 alkylamino, NR d R e
  • R d is selected from C1-C6 hydroxyalkyl, C1-C4 alkoxy C1-C4 alkyl, C4-C7 aliphatic ring containing 1-2 heteroatoms;
  • R e is selected from hydrogen, methyl
  • heteroatoms are nitrogen, oxygen or sulfur;
  • R d is selected from a C4-C7 aliphatic ring containing 1-2 heteroatoms and the heteroatom is S, the sulfur atom can be further oxidized into a sulfone.
  • the compound represented by the general formula (I) of the derivative and its geometric isomers, enantiomers or pharmaceutically acceptable salts thereof;
  • R is selected from hydrogen, methyl, isopropyl, trifluoroethyl, hydroxy-tert-butyl, cyclohexyl, p-fluorophenyl, 4-tetrahydropyran, 2-tetrahydropyran, 4-hexa Hydropyridine;
  • R 2 is selected from hydrogen, bromine
  • the A ring part is selected from
  • R is selected from hydrogen, halogen, methyl, ethyl, cyclopropyl, tert-butyl, phenyl, p-fluorophenyl;
  • C ring is selected from phenyl, 3-chlorophenyl
  • B is selected from piperazinyl, Unsubstituted or substituted by 1-4 R b which may be the same or different: 4-hexahydropyridylamino, 3-tetrahydropyrrolylamino, aniline, benzylamino, 1-(2,4-difluorophenyl ) ethylamino, 2-phenylethylamino,
  • R b is selected from chlorine, bromine, difluoro, trifluoro, cyano, methylsulfoneethylamino, methoxyl, morpholinyl, thiomorpholinyl, C1-C4 alkyl, C1-C4 alkylamino, NR d R e ;
  • R d is selected from C1-C6 hydroxyalkyl, C1-C4 alkoxy C1-C4 alkyl, C4-C7 aliphatic ring containing 1-2 heteroatoms;
  • R e is selected from hydrogen, methyl
  • heteroatoms are nitrogen, oxygen or sulfur;
  • R d is selected from a C4-C7 aliphatic ring containing 1-2 heteroatoms and the heteroatom is S, the sulfur atom can be further oxidized into a sulfone.
  • the derivative is:
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Alkyl straight-chain or branched-chain alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
  • Cycloalkyl substituted or unsubstituted cyclic alkyl, eg cyclopropyl, cyclopentyl or cyclohexyl. Substituents such as methyl, halogen, etc.
  • Haloalkyl Straight chain or branched chain alkyl, the hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, dichloromethyl, Fluoromethyl, trifluoromethyl, etc.
  • Hydroxyalkyl Straight chain or branched alkyl, the hydrogen atoms on these alkyl groups may be partially substituted by hydroxyl groups, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, alkyl, on these alkyl groups Hydrogen atoms may be partially substituted by hydroxyl groups, for example, hydroxymethyl, hydroxyethyl, hydroxybutyl, 1,2-dihydroxypropyl, hydroxypropyl-2-yl, and the like.
  • Alkoxy straight-chain or branched-chain alkyl
  • the hydrogen atoms of the hydroxyl group can be replaced by these straight-chain or branched-chain alkyl groups, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy Base etc.
  • Alkylamino straight-chain or branched-chain alkyl
  • the hydrogen atoms of the amino group can be substituted by these straight-chain or branched-chain alkyl groups, for example, methylamino, ethylamino, propylamino, isopropylamino, etc.
  • Aliphatic heterocyclic phenylmethyl refers to an aliphatic cyclophenylmethyl group containing one or more heteroatoms selected from N, O, and S, such as
  • the Vilsmeier-Haack reaction occurs at low temperature, followed by the chlorination of phosphorus oxychloride at high temperature to obtain intermediate 2, and the low temperature reaction temperature is -78 ⁇ 0°C, preferably -40°C, high-temperature reaction temperature is 100-140°C, preferably 120°C; intermediate 2 is obtained by interlocking with hydrazine hydrate under low-temperature alkaline conditions, and the reaction solvent can be methanol, ethanol, Isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethylsulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, preferably ethanol, The reaction temperature is -78 ⁇ 0°C, preferably -78°C.
  • the base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate, etc., preferably Triethylamine; intermediate 3 is protected by THP under acidic conditions to obtain intermediate 4, and the reaction solvent can be dimethyl sulfoxide, tetrahydrofuran, dichloromethane, 1,4-dioxane, N,N-dimethyl Formamide or a mixed solvent of the two, preferably a mixed solvent of tetrahydrofuran and dichloromethane, the reaction temperature is 0-78°C, preferably 25°C, the acid in the reaction can be a saturated ethyl acetate solution of hydrogen chloride, an ethanol solution of hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, aqueous solution of hydrogen chloride, p-toluenesulfonic acid, benzenesulfonic acid, etc.
  • intermediate 9 was obtained by Buchwald-hartwig coupling reaction, and intermediate 9 was further reduced under borane tetrahydrofuran to obtain intermediate 10; intermediate 2 and hydrazine rings with different substituents were Intermediate 11, followed by a two-step substitution reaction to obtain the target compound 13.
  • the target compound with a similar structure can also be prepared according to the above general formula.
  • the intermediate 9 is obtained by Buchwald-hartwig coupling reaction with polyhalogen-substituted benzonitrile as the starting material
  • the reaction temperature is 80-150°C, preferably 100-120°C
  • the reaction solvent can be dimethyl sulfoxide , toluene, N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, etc., preferably toluene
  • the catalyst can be palladium acetate, Pd(dba) 2 , tetratriphenyl Phosphopalladium, PdCl 2 (dppf) 2 , etc., preferably palladium acetate
  • the ligand can be triphenylphosphine, Xphos, Xtanphos, BINAP, etc., preferably BINAP
  • the base can be potassium acetate, potassium carbonate, sodium carbonate, sodium bicarbonate, Sodium hydride
  • Intermediate 3 was halogenated to obtain intermediate 14, which was reacted with tetrahydropyran-4-ol by Mitsunobu to obtain intermediate 15, and intermediate 15 underwent two more substitution reactions to obtain the target compound 17.
  • the target compound with a similar structure can also be prepared according to the above general formula.
  • the intermediate 3 is halogenated to obtain the intermediate 14, and the reaction solvent can be acetonitrile, dichloromethane, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N-dimethylmethane Amide, preferably acetonitrile, the reaction temperature is 40-100°C, preferably 75°C; intermediate 14 reacts with tetrahydropyran-4-ol to obtain intermediate 15, and the reaction solvent can be dimethyl sulfoxide, toluene, N , N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, etc., preferably tetrahydrofuran, the reaction temperature is 0-50 ° C, preferably 25 ° C; intermediate 15 under alkaline conditions , to obtain intermediate 16 through substitution reaction, the reaction solvent can be methanol, ethanol, isopropanol, n-propanol,
  • the reaction solvent can be methanol, ethanol, isopropanol, n-propanol, tert-butanol, sec-butanol, n-butanol, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, N,N -Dimethylformamide, preferably isopropanol
  • the reaction temperature is 100-160°C, preferably 135°C
  • the base in the reaction can be triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate , sodium carbonate, sodium bicarbonate, etc., preferably triethylamine;
  • pyrazolopyrimidine derivatives the compound represented by the general formula I, and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs in the preparation of prevention or treatment of PLK4 kinase
  • the expression or activity related to the application of the drug in the disease The expression or activity related to the application of the drug in the disease.
  • a pharmaceutical composition comprising the compound represented by general formula I and its geometric isomers or pharmaceutically acceptable salts, hydrates, solvates or prodrugs as active ingredients and pharmaceutically acceptable excipients.
  • composition in the preparation of medicines for preventing or treating diseases related to the expression or activity of PLK4 kinase.
  • the present invention focuses on tumors caused by centrosome abnormalities, designs compounds with the structure shown in general formula I, and finds that the compounds with such structures exhibit better PLK4 inhibitory activity, and are used to treat other diseases related to abnormal expression of PLK4.
  • the compound with the structure shown in the general formula I of the present invention is not limited to its specific isomers, and all exhibit good inhibitory activity on PLK4, and are used to treat other diseases related to abnormal expression of PLK4.
  • the examples are intended to illustrate, not limit, the scope of the invention.
  • the proton nuclear magnetic resonance spectrum of the compound was determined by Bruker ARX-400; the reagents used were analytically or chemically pure.
  • Embodiment 15 adopts following route to prepare:
  • Dissolve intermediate 12 (0.08g, 0.24mmol) in 1.5mL of isopropanol, then add p-chlorobenzylamine (0.041g, 0.29mmol) and 0.10mL of triethylamine, then heat to 135°C under sealed tube to react 15h.
  • step b the (tetrahydro-2H-pyran-4-yl)hydrazine hydrochloride raw material in step b was replaced by tert-butyl 4-hydrazinopiperidine-1-carboxylate in equal proportions, and In step e, the piperazine raw material is replaced by 2,4-difluorobenzylamine in equal proportions to obtain Example 22.
  • HRMS(ESI,m/z) calcd for C 21 H 23 ClN 8 O[M+H] + ,439.1762; found 439.1779.
  • Example 22 replace the 5-methyl-1H-pyrazol-3-amine raw material in step d with 5-phenyl-1H-pyrazol-3-amine in equal proportions to obtain Example 31.
  • HRMS(ESI,m/z) calcd for C 26 H 25 F 2 N 9 [M+H] + ,502.2279; found 502.2303.
  • Example 22 replace the 5-methyl-1H-pyrazol-3-amine raw material in step d with 5-cyclopropyl-1H-pyrazol-3-amine in equal proportions to obtain Example 32 .
  • Example 16 replace the 5-methyl-1H-pyrazol-3-amine raw material in step d with 5-phenyl-1H-pyrazol-3-amine in equal proportions to obtain Example 36.
  • HRMS(ESI,m/z) calcd for C 26 H 24 F 2 N 8 O[M+H] + ,503.2119; found 503.2139 .
  • Example 16 replace the 5-methyl-1H-pyrazol-3-amine raw material in step d with 5-ethyl-1H-pyrazol-3-amine in equal proportions to obtain Example 40.
  • HRMS(ESI,m/z) calcd for C 22 H 24 F 2 N 8 O[M +H] + ,455.2119; found 455.2132.
  • Example 16 Referring to the method for preparing Example 16, the 5-methyl-1H-pyrazol-3-amine raw material in step d was replaced by 1H-indazol-3-amine in equal proportions to obtain Example 41.
  • Embodiment 44 adopts following route to prepare:
  • Example 44 Referring to the method for preparing Example 44, the 5-bromo-2,4-difluorobenzonitrile raw material in step g was replaced by 3-bromo-4-chlorobenzonitrile in equal proportions to obtain Example 46.
  • Example 50 With reference to the method for preparing Example 49, the morpholine raw material in step g was replaced by thiomorpholine in equal proportions to obtain Example 50.
  • HRMS(ESI,m/z) calcd for C 25 H 30 FN 9 OS
  • Example 46 the 2-(methylsulfonyl)ethylamine raw material in step g was replaced by tetrahydro-2H-pyran-4-amine in equal proportions to obtain Example 51.
  • Example 52 Referring to the method for preparing Example 51, the 3-bromo-4-chlorobenzonitrile raw material in step g was replaced with 3-bromo-4-fluorobenzonitrile in equal proportions to obtain Example 52.
  • Example 52 replace the tetrahydro-2H-pyran-4-amine raw material in step g with tetrahydropyran-3-amine in equal proportions to obtain Example 53.
  • Example 54 Referring to the method for preparing Example 53, the tetrahydro-2H-pyran-4-amine raw material in step g was replaced by oxetane-3-amine in equal proportions to obtain Example 54.
  • Example 51 Referring to the method for preparing Example 51, the tetrahydro-2H-pyran-4-amine raw material in step g was replaced by oxetane-3-amine in equal proportions to obtain Example 55.
  • Example 52 replace the tetrahydro-2H-pyran-4-amine raw material in step g with ethanolamine in equal proportions to obtain Example 56.
  • HRMS(ESI,m/z) calcd for C 23 H 27 N 9 O 2 [M+H
  • Embodiment 60 adopts following route to prepare:
  • Dissolve intermediate 16 (0.08g, 0.19mmol) in 1.5mL of isopropanol, then add 2,4-difluorobenzylamine (0.028mL, 0.24mmol) and 0.053mL of triethylamine, then heat under sealed tube Reaction at 135°C for 15h.
  • Example 61 Study on in vitro enzyme inhibitory activity of some products of the present invention
  • Kinase Binding Assay kit including Kinase Tracer 236, Eu ⁇ Anti ⁇ GST Antibody, kinase buffer solution (1X Kinase Buffer A)), 384 shallow well plate, recombinant human PLK4 protein (aa 1-836, containing a GST tag).
  • the compound samples prepared in the above examples were formulated into a 20 mM solution with DMSO, and then diluted with a kinase buffer solution (1X Kinase Buffer A) to 200 ⁇ M, 40 ⁇ M, 10 ⁇ M, 1.6 ⁇ M, 0.32 ⁇ M, 0.064 ⁇ M, 0.0128 ⁇ M, 0.00256 ⁇ M, 0.000512, 0.0001024 ⁇ M; add the compound sample (4 ⁇ L) to the 384-well plate, and then add 8 ⁇ L of the kinase buffer solution containing recombinant human PLK4 kinase (concentration: 50ng/ ⁇ L) and Eu-Anti-GST Antibody , 4 ⁇ L of kinase buffer solution containing Tracer 236, incubate at room temperature for 60 minutes, and read the plate.
  • a kinase buffer solution (1X Kinase Buffer A)
  • IC50 % DF of kinase activity with added compound is plotted on the Y-axis and log concentration of the compound is plotted on the X-axis. IC50 values were obtained by fitting the data to a sigmoidal stoichiometric response curve (Table 1).
  • Example IC 50 (nM) Example IC 50 (nM) Example 2 453.9 Example 3 483.9 Example 4 206.0
  • Example 5 87.1 Example 6 5.5
  • Example 7 23.3 Example 8 0.3
  • Example 9 1.1
  • Example 10 0.1
  • Example 11 Example 12
  • Example 12 78.4
  • Example 13 10.5
  • Example 14 6.5
  • Example 15 Example 16
  • Example 17 3.8
  • Example 18 2.7
  • 47.9 Example 20 7.9
  • Example 22 0.7
  • Example 23 26.1
  • Example 24 2.1 Example 25 20.2
  • Example 26 27.6 Example 27 3.7
  • Example 28 1.1 Example 29 241.3
  • Example 30 117.9 Example 32 3.6
  • Example 35 Example 37 1.8
  • Example 39 282.1
  • Example 40 0.7
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Abstract

本发明属药物合成领域，涉及一类新型吡唑并嘧啶衍生物与其类似物，及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。如通式(I)的化合物及其几何异构体或其药学上可接受的盐和它们的制备方法。优选的化合物具有作为蛋白激酶抑制剂，特别是PLK4激酶抑制剂的活性。

Description

一类吡唑并嘧啶衍生物及制备方法和应用 技术领域
本发明属药物合成领域，涉及一类新型吡唑并嘧啶衍生物及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。
背景技术
恶性肿瘤是目前全世界的主要死亡原因之一。针对恶性肿瘤的化学药物正在经历由早期的非选择性药物到如今拥有特定靶点的小分子药物转变。随着精准医疗概念的提出，靶向肿瘤细胞中异常表达的蛋白激酶，应是未来抗肿瘤领域的主要研究方向。近年来，以控制中心体扩增为途径达到抑制肿瘤细胞增殖目的的治疗手段已成为肿瘤化疗的新兴方案。
Polo样激酶4(PLK4)作为细胞内中心体复制的关键蛋白，在中心体复制和有丝分裂过程中发挥重要功能。已有不少研究表明PLK4过表达会导致中心体扩增而诱发癌症。目前，设计PLK4小分子ATP竞争性抑制剂已成为治疗中心体错误复制诱发的肿瘤的重要手段，且PLK4抑制剂能实现对含有TRIM37基因扩增的肿瘤的精准治疗，这一研究已在乳腺癌、胶质母细胞瘤中得以证实。
Polo样激酶4为Polo样蛋白激酶家族的成员之一，是一种进化上高度保守的丝氨酸/苏氨酸蛋白激酶，其共有5种亚型，即PLK1-5。PLK4主要在分裂活跃组织和细胞中表达，一系列的生物学研究表明，PLK4与细胞周期中中心体复制密切相关，而肿瘤细胞又具有无限增殖的特点。因此，PLK4在肿瘤细胞的增殖，迁移，侵袭，凋亡等多种生物学功能中，发挥着不可替代的作用。大量研究发现，PLK4在人类大部分肿瘤中均存在异常表达，如肝癌、胃癌、肺癌、乳腺癌、黑色素瘤和恶性血液病等。目前，尚未有PLK4抑制剂上市，迄今已报道的PLK4抑制剂仅有两类母核结构。其中一类结构的代表性抑制剂LCR-263对PLK4具有纳摩尔激酶活性且具有高选择性，但其至今未进入临床前研究；另一类结构的代表性抑制剂CFI-400945已进入临床二期研究，但其对TRKA、Aurora A/B缺乏选择性。因此，找到高效、高选择性且具有良好体内性质的新型PLK4抑制剂具有重大科学价值和研究意义。
发明内容
本发明的目的在于提供一种新型吡唑并嘧啶衍生物及其制备方法和作为治疗剂特别是作为PLK4抑制剂的用途。
为实现上述目的，本发明采用技术方案为：
一种吡唑并嘧啶衍生物，衍生物为通式(I)所示的化合物，及其几何异构体,对映异构体或其药学上可接受的盐；通式(I)所示化合物如下：
Figure PCTCN2022098519-appb-000001
其中，R 1选自氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟烷基、未取代或被1-4个可相同或不同的R a取代的芳基、未取代或被1-2个下述基团取代的C3-C7环烷基、含1-2个杂原子的C3-C7脂肪环；下述基团为C1-C4烷基或氨基；所述环、含杂原子脂肪环中还可含1-2个羰基，所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合；
R 2选自氢、卤素、氰基、甲酰胺、C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、含杂原子的C3-C6脂肪环；
A选自：
Figure PCTCN2022098519-appb-000002
R 3选自氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C4烷氧基，未取代或被1-4个可相同或不同的R a取代的芳基；
C环选自未取代或被1-4个可相同或不同的R a取代的芳基；
R a选自卤素、C1-C4烷基或C1-C4卤代烷基；
B选自含最多2个杂原子的C5-C7脂肪环或NHRc；
Rc选自未取代或被1-4个可相同或不同的R b取代的：芳基、芳基甲基、芳基乙基、含1-2个杂原子的C5-C7脂肪环或C5-C7脂肪杂环并苯基甲基；
R b选卤素，氰基，甲砜乙基氨基，C1-C4烷氧基，C1-C4烷氨基，C3-C7环烷基，含最多2个杂原子的C4-C7脂肪环，NR dR e；
R d选自C1-C4烷氧基C1-C4烷基、C1-C6羟烷基、含1-2个杂原子的C4-C7脂肪环；
R e选自氢、C1-C4烷基；
上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；芳基为苯基，吡啶基，嘧啶基；
当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜。
当Rc选自C5-C7脂肪杂环并苯基甲基，且杂原子为N时，氮原子其还可进一步被C1-C4烷基取代。
优选，所述衍生物通式(I)所示的化合物，及其几何异构体，对映异构体或其药学上可接受的盐；
其中，R 1选自氢，甲基，异丙基，三氟乙基，羟叔丁基，环己基，未取代或被1-4个可相同或不同的R a取代的芳基，含1-2个杂原子的C3-C7脂肪环；所述含杂原子脂肪环中还可含1-2个羰基，所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合；
R 2选自氢，卤素或甲酰胺；
A环部分选自
Figure PCTCN2022098519-appb-000003
R 3选自氢，卤素，甲基，乙基，环丙基，叔丁基，未取代或被1-4个可相同或不同的R a取代的芳基；
C环选自未取代或被1-4个可相同或不同的R a取代的芳基；
R a选自卤素，C1-C4烷基，C1-C4卤代烷基；
B选自哌嗪基或NHRc；
Rc选自未取代或被1-4个可相同或不同的R b取代的：苯基，吡啶基，嘧啶基，含1-2个杂原子的C5-C7脂肪环，C5-C7脂肪杂环并苯基甲基；
R b选自卤素，氰基，甲砜乙基氨基，甲氧基，吗啉基，硫代吗啉基，C1-C4烷基、C1-C4烷氨基，NR dR e；
R d选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环；
R e选自氢、C1-C4烷基；
上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；
当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜；
当Rc选自C5-C7脂肪杂环并苯基甲基，且杂原子为N时，氮原子其还可进一步被C1-C4烷基取代。
进一步优选，所述衍生物通式(I)所示的化合物，及其几何异构体，对映异构体或其药学上可接受的盐；
其中，R 1选自氢，甲基，异丙基，三氟乙基，羟叔丁基，环己基，对氟苯基，4-四氢吡喃，2-四氢吡喃，4-六氢吡啶；
R 2选自氢，卤素或甲酰胺；
A环部分选自
Figure PCTCN2022098519-appb-000004
R 3选自氢，卤素，甲基，乙基，环丙基，叔丁基，未取代或被1-4个可相同或不同的R a取代的苯基；
C环选自未取代或被1-4个可相同或不同的R a取代的苯基；
R a选自卤素，C1-C4烷基，C1-C4卤代烷基；
B选自哌嗪基，
Figure PCTCN2022098519-appb-000005
未取代或被1-4个可相同或不同的R b取代的：4-六氢吡啶氨基，3-四氢吡咯氨基，苯氨基，苯甲氨基，1-(2，4-二氟苯基)乙氨基，2-苯基乙氨基；
R b选自卤素，氰基，甲砜乙基氨基，甲氧基，吗啉基，硫代吗啉基，C1-C4烷基，C1-C4烷氨基，NR dR e
R d选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环；
R e选自氢、甲基；
上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；
当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
在进一步优选，所述衍生物通式(I)所示的化合物，及其几何异构体，对映异构体或其药学上可接受的盐；
其中，R 1选自氢，甲基，异丙基，三氟乙基，羟叔丁基，环己基，对氟苯基，4-四氢吡喃，2-四氢吡喃，4-六氢吡啶；
R 2选自氢，溴；
A环部分选自
Figure PCTCN2022098519-appb-000006
R 3选自氢，卤素，甲基，乙基，环丙基，叔丁基，苯基，对氟苯基；
C环选自苯基，3-氯苯基；
B选自哌嗪基，
Figure PCTCN2022098519-appb-000007
未取代或被1-4个可相同或不同的R b取代的：4-六氢吡啶氨基，3-四氢吡咯氨基，苯氨基，苯甲氨基，1-(2，4-二氟苯基)乙氨基，2-苯基乙氨基，
R b选自氯，溴，双氟，三氟，氰基，甲砜乙基氨基，甲氧基，吗啉基，硫代吗啉基，C1-C4烷基，C1-C4烷氨基，NR dR e；
R d选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环；
R e选自氢、甲基；
上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；
当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
更进一步优选，所述衍生物为：
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1H-吡唑[3,4-d]嘧啶-4-胺；
N 4-(5-甲基-1H-吡唑-3-基)-N 6-(吡咯烷-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 4-(5-甲基-1H-吡唑-3-基)-N 6-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 4-(5-甲基-1H-吡唑-3-基)-N 6-苯基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 4-(5-甲基-1H-吡唑-3-基)-N 6-苯乙基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(3-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(3-溴苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-溴苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(3,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 4-(5-甲基-1H-吡唑-3-基)-N 6-(2,4,6-三氟苄基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
4-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苄腈；
N 6-(4-甲氧基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2，4-,二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
1-{6-[(4-氯苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇；
1-{6-[(2,4-二氟苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇；
1-环己基-N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
1-环己基-N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-[(3,5-二氟吡啶-2-基)甲基]-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-1-甲基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-1-甲基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-1-异丙基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-1-异丙基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-1-(4-氟苯基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-(2,2,2,-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-苯基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-环丙基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-叔丁基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-[5-(4-氟苯基)-1H-吡唑-3-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-[5-甲基噻唑-2-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-苯基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-环丙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-叔丁基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-[5-(4-氟苯基)-1H-吡唑-3-基]-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-乙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟苄基)-N 4-(5-氯-1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(3,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氯-3-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
4-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢-2H-噻喃-1,1-二氧化物；
3-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢噻吩-1,1-二氧化物；
N 6-(4-氟-3-吗啉代苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-(4-氟-3-硫代吗啉代苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-{4-氯-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-{4-氟-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-{4-氟-3-[(四氢吡喃-3-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
2-{[2-氟-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇；
2-{[2-氯-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇；
N 6-[(3，4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 4-(5-甲基-1H-吡唑-3-基)-N 6-((4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 6-{4-氟-3-[(2-甲氧基乙基)甲氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-N 6-((2,3,4,5-四氢苯并[b][1,4]氧杂氮杂-7-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
3-溴-N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺。
上面给出的通式I化合物的定义中，汇集所用术语一般定义如下：
卤素：指氟、氯、溴或碘。烷基：直链或支链烷基，例如甲基、乙基、丙基、异丙基、正丁基或叔丁基。环烷基：取代或未取代的环状烷基，例如环丙基、环戊基或环己基。取代基如甲基、卤素等。卤代烷基：直链或支链烷基，在这些烷基上的氢原子可部分或全部被卤原子所取代，例如，氯甲基、二氯甲基、三氯甲基、氟甲基、二氟甲基、三氟甲基等。羟烷基：直链或支链烷基，在这些烷基上的氢原子可部分被羟基所取代，例如，羟甲基、羟乙基、羟丙基、烷基，在这些烷基上的氢原子可部分被羟基所取代，例如，羟甲基、羟乙基、羟丁基、1,2-二羟基丙基、羟丙基-2-基等。烷氧基：直链或支链烷基，羟基的氢原子可被这些直链或支链烷基所取代，例如，甲基氧基，乙基氧基，丙基氧基，异丙基氧基等。烷氨基：直链或支链烷基，氨基的氢原子可被这些直链或支链烷基所取代，例如，甲基氨基，乙基氨基，丙基氨基，异丙基氨基等。含1-2个杂原子的脂肪环，如N、O、S的环状烷基，如四氢呋喃基，哌啶基，哌嗪基。脂肪杂环并苯基甲基：指含有一个或多个选自N、O、S杂原子的脂肪环并苯基甲基，如
Figure PCTCN2022098519-appb-000008
上述通式I所示衍生物的制备方法，所述通式I所示衍生物得到制备反应如下：
1)当R 1为哌啶基，4-六氢吡啶氨基，3-四氢吡咯氨基，苯氨基，有R b取代的苯甲氨基时，通式I所示衍生物结构如通式7所示，具体为：
Figure PCTCN2022098519-appb-000009
以巴比妥酸为起始原料，发生Vilsmeier-Haack反应和三氯氧磷氯代得到中间体2，中间体2在低温碱性条件下，与水合肼扣环得到中间体3，再在酸性条件下，THP保护得到中间体4，中间体4在碱性条件下，经过取代反应得到中间体5，再在高温碱性条件下，发生取代反应得到中间体6，最后酸性条件下脱除THP保护基得到目标化合物7。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说，进一步的说，以巴比妥酸为起始原料，在低温下发生Vilsmeier-Haack反应，紧接着在高温下发生三氯氧磷氯代得到中间体2，低温反应温度为-78～0℃，优选-40℃，高温反应温度为100～140℃，优选120℃；中间体2在低温碱性条件下，与水合肼扣环得到中间体3，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为-78～0℃，优选-78℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；中间体3在酸性条件下，THP保护得到中间体4，反应溶剂可为二甲基亚砜，四氢呋喃，二氯甲烷，1,4-二氧六环，N,N-二甲基甲酰胺或者其中两者混合溶剂，优选四氢呋喃与二氯甲烷混合溶剂，反应温度为0～78℃，优选25℃，反应中的酸可为氯化氢的乙酸乙酯饱和溶液，氯化氢的乙醇溶液，氯化氢的1,4-二氧六环溶液，氯化氢的水溶液，对甲苯磺酸，苯磺酸等，优选对甲苯磺酸；中间体4在碱性条件下，经过取代反应得到中间体5，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选N,N-二甲基甲酰胺，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为40～80℃，优选65℃；中间体5在高温碱性条件下，发生取代反应得到中间体6，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选异丙醇，反应温度为100～160℃，优选135℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；中间体6在酸性条件下脱除THP保护基得到目标化合物7，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，乙酸乙酯，优选乙酸乙酯，反应温度为0～70℃，优选25℃，反应中的酸可为氯化氢的乙酸乙酯饱和溶液，氯化氢的乙醇溶液，氯化氢的1,4-二氧六环溶液，氯化氢的甲醇溶液，氯化氢的水溶液，对甲苯磺酸，苯磺酸等，优选氯化氢的乙酸乙酯饱和溶液。
2)X、Y为卤素取代，R 3为氢或甲基取代时，通式(I)所示衍生物结构如通式13所示，具体为：
Figure PCTCN2022098519-appb-000010
以多卤素取代苯腈为起始原料，发生Buchwald-hartwig偶联反应得到中间体9，中间体9进一步在硼烷四氢呋喃下还原得到中间体10；中间体2与不同取代基的肼扣环得到中间体11,接着再通过两步取代反应即可得到目标化合物13。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说，以多卤素取代苯腈为起始原料，发生Buchwald-hartwig偶联反应得到中间体9，反应温度为80～150℃，优选100～120℃，反应溶剂可为二甲基亚砜，甲苯，N,N-二甲基甲酰胺，N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃等，优选甲苯，催化剂可为乙酸钯，Pd(dba) 2,四三苯基磷钯，PdCl 2(dppf) 2等，优选乙酸钯，配体可为三苯基磷，Xphos，Xtanphos，BINAP等，优选BINAP，碱可为乙酸钾，碳酸钾，碳酸钠，碳酸氢钠，氢化钠，叔丁醇钾，叔丁醇钠，碳酸铯，甲醇钠，乙醇钠等，优选叔丁醇钠；中间体9进一步在硼烷四氢呋喃下还原得到中间体10，反应温度为0～100℃，优选70℃；中间体2在低温碱性条件下，与不同取代基的肼扣环得到中间体11，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙醇，反应温度为-78～0℃，优选-78℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；中间体11在碱性条件下，经过取代反应得到中间体12，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选N,N-二甲基甲酰胺，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为40～80℃，优选65℃；中间体12在高温碱性条件下，发生取代反应得到中间体13，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选异丙醇，反应温度为100～160℃，优选135℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选三乙胺；
3)且Z为卤素时，通式(I)所示衍生物结构如通式17所示，具体为：
Figure PCTCN2022098519-appb-000011
中间体3经过卤代得到中间体14，中间体14与四氢吡喃-4-醇发生光延反应得到中间体15，中间体15再发生两步取代反应即可得到目标化合物17。根据上述通式方法亦可制备具有类似结构的目标化合物。
进一步的说，中间体3经过卤代得到中间体14，反应溶剂可为乙腈，二氯甲烷，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选乙腈，反应温度为40～100℃，优选75℃；中间体14与四氢吡喃-4-醇发生光延反应得到中间体15，反应溶剂可为二甲基亚砜，甲苯，N,N-二甲基甲酰胺，N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃等，优选四氢呋喃，反应温度为0～50℃，优选25℃；中间体15在碱性条件下，经过取代反应得到中间体16，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选N,N-二甲基甲酰胺，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸氢钠等，优选N,N-二异丙基乙胺，反应温度为40～80℃，优选65℃；中间体16在高温碱性条件下，发生取代反应得到中间体17，反应溶剂可为甲醇，乙醇，异丙醇，正丙醇，叔丁醇，仲丁醇，正丁醇，二甲基亚砜，四氢呋喃，1,4-二氧六环，N,N-二甲基甲酰胺，优选异丙醇，反应温度为100～160℃，优选135℃，反应中的碱可为三乙胺，N,N-二异丙基乙胺，碳酸铯，碳酸钾，碳酸钠，碳酸 氢钠等，优选三乙胺；
吡唑并嘧啶衍生物的应用，所述通式I所示的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
所述通式I所示的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或抗肿瘤药物中的应用。
一种药用组合物，包含通式I所示的化合物及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
所述组合物在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
所述组合物在制备预防或抗肿瘤药物中的应用。
本发明所具有的优点：
本发明着眼于中心体异常引发的肿瘤，设计具有通式I所示结构的化合物，并发现具有此类结构的化合物表现出较好的PLK4抑制活性，用以治疗PLK4表达异常相关的其它疾病。
本发明通式I所示结构的化合物，不限定于其具体同分异构体，且对PLK4均表现出较好抑制活性，用以治疗PLK4表达异常相关的其它疾病。
具体实施方式
实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-400测定；所用试剂均为分析纯或化学纯。
具体实施例结构如下：
实施例1的制备路线如下所示：
Figure PCTCN2022098519-appb-000012
具体合成步骤如下：
2,4,6-三氯嘧啶-5-甲醛(2)的合成
向50mL干燥的反应瓶加入三氯氧磷9.2mL，置于-40℃低温下，后滴加干燥的N,N-二甲基甲酰胺1.2mL，再分批加入巴比妥酸(2.00g,15.60mmol)，加毕，移至120℃回流反应15h。TLC监测(PE:EA＝4:1)原料反应完全，待反应冷却至室温，将反应液缓慢倒入冰水中，有黄色固体析出，抽滤得棕黄色固体，乙酸乙酯萃取滤液三次，浓缩，合并经柱层析纯化(PE:EA＝40:1)得白色固体，产率82％。
4,6-二氯-1H-吡唑并[3,4-d]嘧啶(3)的合成
将80％水合肼0.027mL溶于10.0mL乙醇中，置于-78℃低温下，再缓慢滴入中间体2(0.65g,3.10mmol)的乙醇溶液10.0mL，再加入三乙胺0.650mL，继续-78℃反应30min，随后移至室温反应1h。TLC监测(PE:EA＝4:1)原料反应完全，旋除溶剂，柱层析纯化(PE:EA＝4:1)，得白色固体，收率71％。
4,6-二氯-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶(4)的合成
将中间体3(0.5g,2.65mmol)，对甲苯磺酸(0.23g,1.32mmo1)溶于THF(10mL)和DCM(30mL)的混合液中，再加入3,4-二氢吡喃(0.67g,7.96mmol)，室温搅拌10h，TLC检测(PE:EA＝4:1)，原料反应完全，旋干溶剂，经柱层析(PE:EA＝40:1)得白色固体，产率78％。6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(5)的合成
将中间体4(0.65g,2.39mmol)溶于5mL DMF中，再依次5-甲基-1H-吡唑-3-胺(0.24g,2.39mmol)、N,N-二异丙基乙胺(0.555mL,3.11mmol)、碘化钾(0.48g,2.87mmol)，后65℃反应1h。TLC检测(DCM:MeOH＝15:1)，原料反应完全，待反应冷却至室温，加入水50mL，析出白色沉淀，抽滤，得到白色固体，产率92％。
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(6)的合成
将中间体5(0.10g,0.30mmol)溶于1.5mL异丙醇中，再加入哌嗪(0.065g,0.75mmol)、三乙胺0.11mL，后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH＝10:1)原料反应完毕，待反应冷却至室温，旋干溶剂，经柱层析(DCM:MeOH＝40:1)得白色固体，产率53％。
N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(实施例1)的制备
将中间体6(0.05g,0.13mmol),溶于1mL氯化氢的乙酸乙酯饱和溶液，室温搅拌4h。TLC监测(DCM:MeOH＝8:1)反应完全，减压过滤，用乙酸乙酯洗涤滤饼三次，将滤饼溶于20mL水，乙酸乙酯萃取(10mL×3),弃去有机层。水层在冰浴条件下用10％的氢氧化钠溶液调pH>10,乙酸乙酯萃取(10mL×3),饱和食盐水洗涤(10mL×3)，无水硫酸钠干燥。减压过滤除去硫酸钠，旋除乙酸乙酯，得白色固体，收率69％。 1H NMR(600MHz,DMSO-d 6)δ11.35(s,1H),9.60(s,2H),8.47(s,1H),6.40(s,1H),4.07(s,4H),3.25(s,4H),2.30(s,3H).HRMS(ESI,m/z)calcd for C 13H 17N 9[M+H] +,300.1685；found 300.1660.
实施例2
N 4-(5-甲基-1H-吡唑-3-基)-N 6-(吡咯烷-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺的制备
Figure PCTCN2022098519-appb-000013
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为吡咯烷-3-胺，即得实施例2. 1H NMR(600MHz,DMSO-d 6)δ12.54–11.82(m,1H),9.82(s,1H),9.68–8.45(m,3H),6.53(s,1H),4.62(s,2H),3.51(dt,J＝11.9,6.0Hz,1H),3.40(s,1H),3.32–3.23(m,2H),2.38–2.28(m,4H),2.07(s,1H).HRMS(ESI,m/z)calcd for C 13H 17N 9[M+H] +,300.1685；found 300.1682.
实施例3
N 4-(5-甲基-1H-吡唑-3-基)-N 6-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例3)的制备：
Figure PCTCN2022098519-appb-000014
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为哌啶-4-胺，即得实施例3. 1H NMR(600MHz,DMSO-d 6)δ12.75(s,1H),12.11–11.79(m,1H),9.09(s,2H),9.02–8.84(m,1H),6.82–6.41(m,1H),4.02(s,1H),3.76–3.73(m,1H),3.36(s,2H),3.01(m,2H),2.30(s,3H),2.13(d,J＝38.1Hz,2H),1.84(s,2H).HRMS(ESI,m/z)calcd for C 14H 19N 9[M+H] +,314.1842；found 314.1844.
实施例4
N 4-(5-甲基-1H-吡唑-3-基)-N 6-苯基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例4)的制备
Figure PCTCN2022098519-appb-000015
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为苯胺，即得实施例4. 1H NMR(600MHz,DMSO-d 6)δ11.70(s,1H),10.33(s,1H),8.48(s,1H),7.77(s,2H),7.45(s,3H),7.18(m,1H),6.36(s,1H),2.32(s,3H).HRMS(ESI,m/z)calcd for C 15H 14N 8[M+H] +,307.1420；found 307.1422.
实施例5
N 4-(5-甲基-1H-吡唑-3-基)-N 6-苯乙基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例5)的制备
Figure PCTCN2022098519-appb-000016
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为苯乙胺，即得实施例5. 1H NMR(600MHz,DMSO-d 6)δ13.02–12.55(m,1H),12.10–11.48(m,1H),8.72(s,1H),8.24(s,1H),7.38(dt,J＝22.5,7.7Hz,5H),6.66(s,1H),3.84–3.82(m,2H),3.01(t,J＝7.2Hz,2H),2.34(m,3H).HRMS(ESI,m/z)calcd for C 17H 18N 8[M+H] +,335.1733；found 335.1739.
实施例6
N 6-(3-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例6)的制备
Figure PCTCN2022098519-appb-000017
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为3-氯苄胺，即得实施例6. 1H NMR(600MHz,DMSO-d 6)δ13.74–12.21(m,1H),11.83(s,1H),9.76–8.81(s,1H),8.67(s,1H),7.55–7.31(m,5H),6.65–6.14(m,1H),4.72(s,2H),2.26(m,3H).HRMS(ESI,m/z)calcd for C 16H 15ClN 8[M+H] +,355.1186；found 355.1190.
实施例7
N 6-(3-溴苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例7)的制备
Figure PCTCN2022098519-appb-000018
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为3-溴苄胺，即得实施例7. 1H NMR(600MHz,DMSO-d 6)δ13.84–12.37(m,1H),11.83(s,1H),9.86–8.81(m,1H),8.68(s,1H),7.67–7.29(m,5H),6.61–6.17(m,1H),4.71(s,2H),2.32–
2.18(m,3H).HRMS(ESI,m/z)calcd for C 16H 15BrN 8[M+H] +,399.0681；found 399.0685.
实施例8
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例8)的制备
Figure PCTCN2022098519-appb-000019
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为4-氯苄胺，即得实施例8. 1H NMR(600MHz,DMSO-d 6)δ13.49–12.35(m,1H),11.83(s,1H),9.82–8.77(m,1H),8.68(s,1H),7.43(d,J＝5.7Hz,5H),6.62–6.13(m,1H),4.70(s,2H),2.28(m,3H).HRMS(ESI,m/z)calcd for C 16H 15ClN 8[M+H] +,355.1186；found 355.1194.
实施例9
N 6-(4-溴苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例9)的制备
Figure PCTCN2022098519-appb-000020
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为4-溴苄胺，即得实施例9. 1H NMR(600MHz,DMSO-d 6)δ12.54–12.37(m,1H),11.81(s,1H),9.80–8.72(m,1H),8.67(s,1H),7.56(d,J＝7.3Hz,2H),7.34(s,2H),6.11(s,1H),4.68(s,2H),2.32–2.16(m,3H).HRMS(ESI,m/z)calcd for C 16H 15BrN 8[M+H] +,399.0681；found 399.0704.
实施例10
N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例10)的制备
Figure PCTCN2022098519-appb-000021
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例10. 1H NMR(600MHz,DMSO-d 6)δ13.45–12.16(m,1H),11.74(s,1H),9.36–8.61(m,1H),8.59–8.42(m,1H),7.38(m,1H),7.23(t,J＝8.9Hz,1H),6.99(s,1H),6.54–6.07(m,1H),4.63(s,2H),2.23–2.08(m,3H).HRMS(ESI,m/z)calcd for C 16H 15F 2N 8[M+H] +,357.1388；found 357.1402.
实施例11
N 6-(3,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例11)的制备
Figure PCTCN2022098519-appb-000022
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为3,4-二氟苄胺，即得实施例11. 1H NMR(600MHz,DMSO-d 6)δ13.60–12.32(m,1H),11.82(s,1H),9.77–8.75(m,1H),8.68(s,1H),7.53–7.38(m,2H),7.23(s,1H),6.61(s,1H),6.14(s,1H),4.69(s,2H),2.24(m,3H).HRMS(ESI,m/z)calcd for C 16H 15F 2N 8[M+H] +,357.1388；found357.1406.
实施例2
N 4-(5-甲基-1H-吡唑-3-基)-N 6-(2,4,6-三氟苄基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例12)的制备
Figure PCTCN2022098519-appb-000023
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为2,4,6-三氟苄胺，即得实施例12. 1H NMR(600MHz,DMSO-d 6)δ13.65–12.29(m,1H),11.89(s,1H),8.68(s,2H),7.28(t,J＝8.4Hz,2H),6.57(s,1H),4.78(s,2H),2.29(s,3H).HRMS(ESI,m/z)calcd for C 16H 13F 3N 8[M+H] +,375.1294；found 375.1313.
实施例13
4-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苄腈(实施例13)的制备
Figure PCTCN2022098519-appb-000024
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为4-氰基苄胺，即得实施例13. 1H NMR(600MHz,DMSO-d 6)δ12.59(s,1H),11.98(s,1H),10.10(s,1H),8.04(s,1H),7.78(d,J＝8.2Hz,2H),7.52(d,J＝8.0Hz,2H),7.40(d,J＝7.6Hz,1H),6.06–5.66(m,1H),4.60(d,J＝5.3Hz,2H),2.20(s,3H).HRMS(ESI,m/z)calcd for C 17H 15N 9[M+H] +,346.1529；found 346.1530.
实施例14
N 6-(4-甲氧基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例14)的制备
Figure PCTCN2022098519-appb-000025
参考制备实施例1的方法，将e步骤中哌嗪原料等比例替换为4-甲氧基苄胺，即得实施例14. 1H NMR(600MHz,DMSO-d 6)δ13.33–12.54(m,1H),11.84(s,1H),9.80–8.79(m,1H),8.68(s,1H),7.33(d,J＝35.0Hz,3H),6.93(d,J＝5.6Hz,
2H),6.63–6.32(m,1H),4.64(s,2H),3.74(s,3H),2.26(m,3H).HRMS(ESI,m/z)calcd for C 17H 18N 8O[M+H] +,351.1682；found 351.1684.
实施例15采用如下路线进行制备：
Figure PCTCN2022098519-appb-000026
4,6-二氯-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶(11)的合成
将(四氢-2H-吡喃-4-基)肼盐酸盐(1.00g,6.58mmol)溶于15.0mL乙醇中，置于-78℃低温下，再缓慢滴入中间体2(1.38g,6.58mmol)的乙醇溶液15.0mL，再加入三乙胺4.58mL，继续-78℃反应30min，随后移至室温反应1h。TLC监测(PE:EA＝4:1)原料反应完全，旋除溶剂，柱层析纯化(PE:EA＝10:1)，得白色固体，收率85％。
6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(12)的合成
将中间体11(0.50g,1.84mmol)溶于5mL DMF中，再依次5-甲基-1H-吡唑-3-胺(0.18g,1.84mmol)、N,N-二异丙基乙胺(0.425mL,2.40mmol)、碘化钾(0.37g,2.21mmol)，后65℃反应1h。TLC检测(DCM:MeOH＝15:1)，原料反应完全，待反应冷却至室温，加入水50mL，析出白色沉淀，抽滤，得到白色固体，产率88％。
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例15)的制备
将中间体12(0.08g,0.24mmol)溶于1.5mL异丙醇中，再加入对氯苄胺(0.041g,0.29mmol)、三乙胺0.10mL，后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH＝10:1)原料反应完毕，待反应冷却至室温，旋干溶剂，经柱层析(DCM:MeOH＝40:1)得白色固体，产率46％。 1H NMR(600MHz,DMSO-d 6)δ12.67–11.89(m,1H),10.67–9.93(m,1H),8.07(s,1H),7.53–7.31(m,5H),4.61(s,1H),4.51(s,2H),3.97(d,J＝8.9Hz,2H),3.48(t,J＝11.5Hz,2H),2.15(m,3H),2.12–2.06(m,2H),1.76(s,2H).HRMS(ESI,m/z)calcd for C 21H 23ClN 8O[M+H] +,439.1762；found 439.1774.
实施例16
N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例16)的制备
Figure PCTCN2022098519-appb-000027
参考制备实施例15的方法，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例16. 1H NMR(600MHz,DMSO-d 6)δ12.66–11.86(m,1H),10.72–9.91(m,1H),8.08(s,1H),7.47(s,2H),7.21(s,1H),7.01(t,J＝7.4Hz,1H),4.63(s,1H),4.52(s,2H),3.98(d,J＝7.8Hz,2H),3.49(t,J＝11.6Hz,2H),2.18(s,3H),2.09(d,J＝9.3Hz,2H),1.76(s,2H).HRMS(ESI,m/z)calcd for C 21H 22F 2N 8O[M+H] +,441.1963；found 441.1970.
实施例17
1-{6-[(4-氯苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇(实施例17)的制备
Figure PCTCN2022098519-appb-000028
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为1-肼-2-甲基丙烷-2-醇，即得实施例17. 1H NMR(600MHz,DMSO-d 6)δ12.63–11.98(m,1H),10.65–10.09(m,1H),8.09(s,1H),7.50(s,1H),7.35(s,4H),4.80(s,1H),4.50(s,2H),4.04(s,2H),2.22(d,J＝25.1Hz,3H),1.03(s,6H).HRMS(ESI,m/z)calcd for C 20H 23ClN 8O[M+H] +,427.1762；found 427.1777.
实施例18
1-{6-[(2,4-二氟苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇(实施例18)的制备
Figure PCTCN2022098519-appb-000029
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为1-肼-2-甲基丙烷-2-醇，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例18. 1H NMR(600MHz,DMSO-d 6)δ12.66–11.94(m,1H),10.66–10.00(m,1H),8.09(s,1H),7.47(s,2H),7.20(s,1H),7.00(d,J＝7.0Hz,1H),4.75(s,1H),4.52(s,2H),4.04(s,2H),2.20(s,3H),1.02(s,6H).HRMS(ESI,m/z)calcd for C 20H 22F 2N 8O[M+H] +,429.1963；found 429.1972.
实施例19
1-环己基-N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例19)的制备
Figure PCTCN2022098519-appb-000030
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为环己基肼，即得实施例19. 1H NMR(600MHz,DMSO-d 6)δ12.68–11.83(m,1H),10.67–9.87(m,1H),8.21–7.74(m,1H),7.40(m,5H),4.50(s,2H),4.36(s,1H),2.17(s,3H),1.82(d,J＝9.8Hz,6H),1.67(d,J＝12.4Hz,1H),1.49–1.25(m,3H).HRMS(ESI,m/z)calcd for C 22H 25ClN 8[M+H] +,437.1969；found 437.1977.
实施例20
1-环己基-N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例20)的制备
Figure PCTCN2022098519-appb-000031
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为环己基肼，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例20. 1H NMR(600MHz,DMSO-d 6)δ11.98(s,1H),10.68–9.95(m,1H),8.05(s,1H),7.45(s,2H),7.20(s,1H),7.01(d,J＝7.3Hz,1H),4.51(s,2H),4.37(s,1H),2.18(s,3H),1.83(d,J＝10.6Hz,6H),1.68(d,J＝12.2Hz,1H),1.50–1.33(m,3H).HRMS(ESI,m/z)calcd for C 22H 24F 2N 8[M+H] +,439.2170；found 439.2177.
实施例21
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例21)的制备
Figure PCTCN2022098519-appb-000032
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为4-肼基哌啶-1-羧酸叔丁酯，即得实施例21. 1H NMR(600MHz,DMSO-d 6)δ12.60(s,1H),9.33(s,1H),9.09(s,1H),8.51(s,1H),7.51(m,3H),7.41(d,J＝8.3Hz,2H),6.25(s,1H),4.82(s,1H),4.63(s,2H),4.02(d,J＝5.7Hz,1H),3.39(d,J＝3.4Hz,2H),3.13(s,2H),2.40–2.23(m,5H),2.09–1.96(m,2H).HRMS(ESI,m/z)calcd for C 21H 24ClN 9[M+H] +,438.1921；found 438.1931.
实施例22
N 6-(2，4-,二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例22)的制备
Figure PCTCN2022098519-appb-000033
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为4-肼基哌啶-1-羧酸叔丁酯，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例22. 1H NMR(600MHz,DMSO-d 6)δ11.87(s,1H),9.04(s,1H),8.79(s,1H),8.25(s,1H),7.61(s,1H),7.26(t,J＝8.8Hz,1H),7.06(s,1H),6.30(s,1H),4.80(t,J＝10.9Hz,1H),4.61(s,2H),3.42(d,J＝11.8Hz,2H),3.16(d,J＝6.4Hz,2H),2.33–2.21(m,5H),2.04(d,J＝12.7Hz,2H).HRMS(ESI,m/z)calcd for C 21H 24ClN 9[M+H] +,438.1921；found438.1931.
实施例23
N 6-[(3,5-二氟吡啶-2-基)甲基]-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例23)的制备
Figure PCTCN2022098519-appb-000034
参考制备实施例15的方法，将e步骤中哌嗪原料等比例替换为(3,5-二氟吡啶-2-基)甲胺，即得实施例23. 1H NMR(600MHz,DMSO-d 6)δ12.03(s,1H),10.14(s,1H),8.43–7.88(m,2H),6.89–6.10(m,1H),4.69–4.53(m,2H),3.97(dd,J＝11.1,3.5Hz,2H),3.63(q,J＝6.9Hz,2H),3.51–3.45(m,2H),2.22(d,J＝14.4Hz,3H),2.18–2.05(m,2H),1.81(dd,J＝12.6,2.3Hz,1H),1.71(s,1H).HRMS(ESI,m/z)calcd for C 20H 21F 2N 9O[M+H] +,442.1915；found 442.1943.
实施例24
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例24)的制备
Figure PCTCN2022098519-appb-000035
参考制备实施例8的方法，不对THP保护基进行脱除，即得
实施例24. 1H NMR(600MHz,DMSO-d 6)δ12.75–11.87(m,1H),10.84–9.86(m,1H),8.11(s,1H),7.56(s,1H),7.36(d,J＝5.7Hz,5H),5.62(d,J＝9.9Hz,1H),4.52(s,2H),3.94(d,J＝11.0Hz,1H),3.59(s,1H),2.38(dd,J＝22.2,9.6Hz,1H),2.18(s,3H),1.99(d,J＝11.4Hz,1H),1.76(d,J＝11.4Hz,1H),1.69(dd,J＝14.0,5.8Hz,1H),1.53(s,2H).HRMS(ESI,m/z)calcd for C 21H 23ClN 8O[M+H] +,439.1762；found 439.1779.
实施例25
N 6-(4-氯苄基)-1-甲基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例25)的制备
Figure PCTCN2022098519-appb-000036
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为甲基肼，即得实施例25. 1H NMR(600MHz,DMSO-d 6)δ12.53–11.77(m,1H),10.60–9.91(m,1H),7.97(s,1H),7.35(m,5H),4.46(d,J＝4.5Hz,2H),3.64(s,3H),2.11(s,3H).HRMS(ESI,m/z)calcd for C 17H 17ClN 8[M+H] +,369.1343；found 369.1350.
实施例26
N 6-(2,4-二氟苄基)-1-甲基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例26)的制备
Figure PCTCN2022098519-appb-000037
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为甲基肼，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例26. 1H NMR(600MHz,DMSO-d 6)δ12.59–11.89(m,1H),10.59–9.95(m,1H),7.99(s,1H),7.39(s,2H),7.14(s,1H),6.95(s,1H),4.48(s,2H),3.65(s,3H),2.11(s,3H).HRMS(ESI,m/z)calcd for C 17H 16F 2N 8[M+H] +,371.1544；found 371.1557.
实施例27
N 6-(4-氯苄基)-1-异丙基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例27)的制备
Figure PCTCN2022098519-appb-000038
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为异丙基肼，即得实施例27. 1H NMR(400MHz,DMSO-d 6)δ12.11(s,1H),10.19(s,1H),8.12(s,1H),7.57(s,1H),7.47(t,J＝6.4Hz,4H),4.91–4.87(m,1H),4.62(d,J＝5.7Hz,2H),2.29(s,3H),1.48(d,J＝6.7Hz,6H).HRMS(ESI,m/z)calcd forC 19H 21ClN 8[M+H] +,397.1656；found 397.1659.
实施例28
N 6-(2,4-二氟苄基)-1-异丙基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例28)的制备
Figure PCTCN2022098519-appb-000039
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为异丙基肼，将e步骤中哌嗪原料等比例替换为2,4-二氟苄胺，即得实施例28. 1H NMR(600MHz,DMSO-d 6)δ11.98(s,1H),10.13(s,1H),8.03(s,1H),7.46(m,2H),7.21(s,1H),7.01(s,1H),4.79(s,1H),4.52(s,2H),2.18(s,3H),1.37(d,J＝5.9Hz,6H).HRMS(ESI,m/z)calcd for C 19H 20F 2N 8[M+H] +,399.1857；found 399.1864.
实施例29
N 6-(4-氯苄基)-1-(4-氟苯基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例29)的制备
Figure PCTCN2022098519-appb-000040
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为对氟苯肼，即得实施例29. 1H NMR(600MHz,DMSO-d 6)δ12.59–11.89(m,1H),10.88–9.99(m,1H),8.36–8.00(m,3H),7.74(d,J＝73.0Hz,1H),7.39–7.23(m,6H),4.44(s,2H),2.15(t,J＝31.3Hz,3H).HRMS(ESI,m/z)calcd for C 22H 18ClFN 8[M+H] +,449.1405；found 449.1422.
实施例30
N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-(2,2,2,-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例30)的制备
Figure PCTCN2022098519-appb-000041
参考制备实施例15的方法，将b步骤中(四氢-2H-吡喃-4-基)肼盐酸盐原料等比例替换为三氟乙基肼，即得实施例30. 1H NMR(600MHz,DMSO-d 6)δ12.76–12.07(m,1H),10.96–10.08(m,1H),8.32(s,1H),7.78(s,1H),7.49(m,4H),5.11–5.04(m,2H),4.63(s,2H),2.33(s,3H).HRMS(ESI,m/z)calcd for C 18H 16ClF 3N 8[M+H] +,437.1217；found 437.1235.
实施例31
N 6-(2,4-二氟苄基)-N 4-(5-苯基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例31)的制备
Figure PCTCN2022098519-appb-000042
参考制备实施例22的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-苯基-1H-吡唑-3-胺，即得实施例31. 1H NMR(600MHz,DMSO-d 6)δ12.46–11.39(m,1H),9.44(dm,1H),9.18(s,1H),8.86–8.44(m,1H),7.85(m,2H),7.71–6.87(m,6H),5.03(t,J＝11.1Hz,1H),4.83(m,2H),3.45(d,J＝12.4Hz,2H),3.23(dd,J＝23.2,11.5Hz,2H),2.41–2.33(m,2H),2.14(d,J＝12.0Hz,2H).HRMS(ESI,m/z)calcd forC 26H 25F 2N 9[M+H] +,502.2279；found 502.2303.
实施例32
N 6-(2,4-二氟苄基)-N 4-(5-环丙基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例32)的制备
Figure PCTCN2022098519-appb-000043
参考制备实施例22的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-环丙基-1H-吡唑-3-胺，即得实施例32. 1H NMR(400MHz,DMSO-d 6)δ12.51(s,1H),9.37(d,J＝9.0Hz,1H),9.11(s,1H),8.55(s,1H),7.67(dt,J＝23.6,11.8Hz,1H),7.26(t,J＝9.4Hz,1H),7.06(t,J＝8.0Hz,1H),6.06(s,1H),4.82(s,1H),4.63(s,2H),4.04–3.99(m,1H),3.40(d,J＝11.5Hz,2H),3.15(d,J＝8.1Hz,2H),2.29(dd,J＝22.0,10.7Hz,2H),2.04(s,3H),1.07–0.93(m,2H),0.88–0.67(m,2H).HRMS(ESI,m/z)calcd forC 23H 25F 2N 9[M+H] +,466.2279；found 466.2252.
实施例33
N 6-(2,4-二氟苄基)-N 4-(5-叔丁基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例33)的制备
Figure PCTCN2022098519-appb-000044
参考制备实施例22的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-叔丁基-1H-吡唑-3-胺，即得实施例33. 1H NMR(600MHz,DMSO-d 6)δ13.25–11.32(m,1H),9.33(s,1H),9.07(s,1H),8.44(d,J＝61.8Hz,1H),7.69–7.40(m,1H),7.19(td,J＝10.5,2.5Hz,1H),7.00(t,J＝7.7Hz,1H),6.18(s,1H),4.78(s,1H),4.59(s,2H),4.01–3.90(m,1H),3.35(d,J＝11.0Hz,2H),3.06(s,2H),2.23(d,J＝11.6Hz,2H),2.00(s,2H),1.24(s,9H).HRMS(ESI,m/z)calcd for C 24H 29F 2N 9[M+H] +,482.2592；found 482.2615.
实施例34
N 6-(2,4-二氟苄基)-N 4-[5-(4-氟苯基)-1H-吡唑-3-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例34)的制备
Figure PCTCN2022098519-appb-000045
参考制备实施例22的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-(4-氟苯基)-1H-吡唑-3-胺，即得实施例34. 1H NMR(600MHz,DMSO-d 6)δ11.88–11.18(m,1H),9.24(m,1H),8.99(s,1H),8.46–8.23(m,1H),7.77(m,2H),7.55(s,1H),7.37–7.08(m,3H),7.05–6.91(m,1H),6.77(s,1H),4.92–4.81(m,1H),4.77(s,1H),4.57(s,2H),3.33(s,2H),3.08(t,J＝11.7Hz,2H),2.22(dd,J＝22.4,10.8Hz,2H),2.00(d,J＝11.7Hz,2H).HRMS(ESI,m/z)calcd for C 26H 24F 3N 9[M+H] +,520.2185；found 520.2202.
实施例35
N 6-(2,4-二氟苄基)-N 4-[5-甲基噻唑-2-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例35)的制备
Figure PCTCN2022098519-appb-000046
参考制备实施例22的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-甲基噻唑-2-胺，即得实施例35. 1H NMR(400MHz,DMSO-d 6)δ9.44(s,1H),9.18(s,1H),8.27(s,1H),7.24(s,2H),7.02(t,J＝7.6Hz,1H),4.92–4.52(m,3H),3.40(d,J＝10.9Hz,2H),3.11(s,2H),2.47–2.18(m,6H),2.08(s,2H).HRMS(ESI,m/z)calcd for C 21H 22F 2N 8S[M+H] +,457.1734；found 457.1751.
实施例36
N 6-(2,4-二氟苄基)-N 4-(5-苯基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例36)的制备
Figure PCTCN2022098519-appb-000047
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-苯基-1H-吡唑-3-胺，即得实施例36. 1H NMR(600MHz,DMSO-d 6)δ13.27–12.73(m,1H),11.44–10.17(m,1H),8.04(m,1H),7.89–7.32(m,7H),7.23(s,1H),7.03(s,1H),4.65(s,2H),4.56(s,1H),3.99(d,J＝9.2Hz,2H),3.52(dt,J＝22.7,9.3Hz,2H),2.11(d,J＝9.3Hz,2H),1.78(s,2H).HRMS(ESI,m/z)calcd for C 26H 24F 2N 8O[M+H] +,503.2119；found 503.2139.
实施例37
N 6-(2,4-二氟苄基)-N 4-(5-环丙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例37)的制备
Figure PCTCN2022098519-appb-000048
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-环丙基-1H-吡唑-3-胺，即得实施例37. 1H NMR(400MHz,DMSO-d 6)δ11.97(s,1H),10.14(s,1H),7.98(s,1H),7.42(s,2H),7.13(t,J＝9.1Hz,1H),6.94(t,J＝8.4Hz,1H),4.56(t,J＝11.2Hz,1H),4.46(s,2H),3.91(d,J＝8.2Hz,2H),3.42(t,J＝11.4Hz,2H),2.02(dt,J＝11.9,8.2Hz,2H),1.93(dd,J＝15.5,7.8Hz,1H),1.69(d,J＝11.5Hz,2H),0.82(d,J＝8.0Hz,2H),0.62(s,2H).HRMS(ESI,m/z)calcd for C 23H 24F 2N 8O[M+H] +,467.2119；found467.2134.
实施例38
N 6-(2,4-二氟苄基)-N 4-(5-叔丁基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例38)的制备
Figure PCTCN2022098519-appb-000049
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-叔丁基-1H-吡唑-3-胺，即得实施例38. 1H NMR(600MHz,DMSO-d 6)δ11.96(s,1H),10.75–9.90(m,1H),8.00(m,1H),7.35(s,2H),7.11(t,J＝8.6Hz,1H),6.94(d,J＝6.5Hz,1H),4.56(s,3H),3.91(d,J＝8.9Hz,2H),3.41(t,J＝11.5Hz,2H),2.03(d,J＝9.7Hz,2H),1.70(s,2H),1.20(m,9H).HRMS(ESI,m/z)calcd for C 24H 28F 2N 8O[M+H] +,483.2432；found 483.2449.
实施例39
N 6-(2,4-二氟苄基)-N 4-[5-(4-氟苯基)-1H-吡唑-3-基]-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例39)的制备
Figure PCTCN2022098519-appb-000050
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-(4-氟苯基)-1H-吡唑-3-胺，即得实施例39. 1H NMR(600MHz,DMSO-d 6)δ13.24–12.64(m,1H),11.47–10.16(m,1H),8.50–7.78(m,3H),7.76–7.12(m,6H),7.03(s,1H),4.61(m,3H),3.99(d,J＝8.7Hz,2H),3.50(s,2H),2.12(d,J＝9.4Hz,2H),1.78(s,2H).HRMS(ESI,m/z)calcd for C 26H 23F 3N 8O[M+H] +,521.2025；found 521.2044.
实施例40
N 6-(2,4-二氟苄基)-N 4-(5-乙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例40)的制备
Figure PCTCN2022098519-appb-000051
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-乙基-1H-吡唑-3-胺，即得实施例40. 1H NMR(600MHz,DMSO-d 6)δ12.69–11.93(m,1H),10.74–9.85(m,1H),8.10(s,1H),7.61–7.31(m,2H),7.19(s,1H),7.00(s,1H),4.67–4.49(m,3H),3.98(d,J＝8.9Hz,2H),3.48(t,J＝11.5Hz,2H),2.54(s,2H),2.09(d,J＝9.7Hz,2H),1.76(s,2H),1.27–1.08(m,3H).HRMS(ESI,m/z)calcd for C 22H 24F 2N 8O[M+H] +,455.2119；found 455.2132.
实施例41
N 6-(2,4-二氟苄基)-N 4-(1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例41)的制备
Figure PCTCN2022098519-appb-000052
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3- 胺原料等比例替换为1H-吲唑-3-胺，即得实施例41. 1H NMR(600MHz,DMSO-d 6)δ12.79(s,1H),10.02(s,1H),7.66–7.41(m,3H),7.35(s,1H),7.27(s,1H),7.21–6.65(m,4H),4.62(s,1H),4.39(s,2H),3.98(d,J＝8.5Hz,2H),3.48(t,J＝11.6Hz,2H),2.08(d,J＝9.4Hz,2H),1.75(s,2H).HRMS(ESI,m/z)calcd for C 24H 22F 2N 8O[M+H] +,477.1963；found 477.1984.
实施例42
N 6-(2,4-二氟苄基)-N 4-(5-氯-1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例42)的制备
Figure PCTCN2022098519-appb-000053
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为5-氯-1H-吲唑-3-胺，即得实施例42. 1H NMR(400MHz,DMSO-d 6)δ12.89(s,1H),10.06(s,1H),7.60(s,2H),7.47(d,J＝8.9Hz,1H),7.29(dd,J＝6.8,2.1Hz,2H),7.21(s,1H),7.05–6.81(m,2H),4.57(d,J＝9.3Hz,1H),4.30(s,2H),3.93–3.89(m,2H),3.41(s,2H),2.02(d,J＝8.8Hz,2H),1.68(d,J＝11.3Hz,2H).HRMS(ESI,m/z)calcd forC 24H 21ClF 2N 8O[M+H] +,511.1573；found 511.1605.
实施例43
(S)-N 6-[1-(2,4-二氟苯基)乙基]-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例43)的制备
Figure PCTCN2022098519-appb-000054
参考制备实施例16的方法，将d步骤中5-甲基-1H-吡唑-3-胺原料等比例替换为(S)-1-(2,4-二氟苯基)乙基-1-胺，即得实施例43. 1H NMR(600MHz,DMSO-d 6)δ12.83–11.89(m,1H),10.85–9.80(m,1H),8.37–7.84(m,1H),7.49(s,2H),7.15(s,1H),7.00(t,J＝7.6Hz,1H),6.20(s,1H),5.51–5.18(m,1H),4.73–4.42(m,1H),3.99(s,2H),3.47(t,J＝11.5Hz,2H),2.23(s,3H),2.16–1.91(m,2H),1.79(s,2H),1.47(s,3H).HRMS(ESI,m/z)calcd for C 22H 24F 2N 8O[M+H] +,455.2119；found 455.2147.
实施例44采用如下路线进行制备：
Figure PCTCN2022098519-appb-000055
2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄腈(9)的合成
将原料8(0.25g,1.16mmol)，2-(甲基磺酰基)乙基-1-胺盐酸盐(0.18g,1.16mmol)和叔丁醇钠(0.22g,2.31mmol)溶于8mL无水甲苯，加入催化量的醋酸钯(0.03g,0.116mmol)和BINAP(0.07g,0.116mmol)，惰性气体置换，100℃反应10h。TLC监测，原料反应完全，旋除溶剂，经柱层析得白色固体，产率76％。
5-(氨甲基)-2,4-二氟-N-[2-(甲基磺酰基)乙基]苯胺(10)的合成
将中间体9(0.18g,0.69mmol)溶于1mL四氢呋喃中，再加入1mmol/L硼烷四氢呋喃溶液2mL，70℃反应4h。TLC监测，原料反应完全，待反应冷却至室温，置于冰浴中，缓慢加入2mmol/L盐酸溶液2mL，加毕，继续70℃加热1h，后将反应冷却至室温。加20mL乙酸乙酯，用水萃取三次，收集水层，用氨水调PH 8～9，再用乙酸乙酯萃取三次，收集有机层，用饱和食盐水洗，无水硫酸钠干燥，浓缩，得无色透明液体，产率78％。
N 6-(2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例44)的制备
将中间体12(0.17g,0.50mmol)溶于1.5mL异丙醇中，再加入中间体10(0.16g,0.61mmol)、三乙胺0.14mL，后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH＝10:1)原料反应完毕，待反应冷却至室温，旋干溶剂，经柱层析(DCM:MeOH＝40:1)得白色固体，产率53％。 1H NMR(600MHz,DMSO-d 6)δ12.81–11.91(m,1H),10.26(s,1H),8.07(s,1H),7.40(s,1H),7.10(t,J＝10.0Hz,1H),6.86(s,1H),5.42(s,1H),4.65(s,1H),4.51(s,2H),3.98(d,J＝8.7Hz,2H),3.58–3.37(m,6H),2.96(s,3H),2.19(s,3H),2.10(d,J＝9.0Hz,2H),1.78(d,J＝11.2Hz,2H).HRMS(ESI,m/z)calcd for C 24H 29F 2N 9O 3S[M+H] +,562.2160；found 562.2198.
实施例45
N 6-(3,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例45)的制备
Figure PCTCN2022098519-appb-000056
参考制备实施例44的方法，将g步骤中5-溴-2,4-二氟苯腈原料等比例替换为3-溴-4,5-二氟苯腈，即得实施例45. 1H NMR(600MHz,DMSO-d 6)δ12.66–11.88(m,1H),10.72–9.90(m,1H),8.07(s,1H),7.41(s,1H),6.64(s,2H),5.92(s,1H),4.64(s,1H),4.44(s,2H),3.97(d,J＝8.0Hz,2H),3.49(t,J＝11.7Hz,4H),3.37(s,2H),3.01(s,3H),2.19(s,3H),2.11(dt,J＝12.0,8.1Hz,2H),1.77(d,J＝11.5Hz,2H).HRMS(ESI,m/z)calcd for C 24H 29F 2N 9O 3S[M+H] +,562.2160；found 562.2194.
实施例46
N 6-(4-氯-3-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例46)的制备
Figure PCTCN2022098519-appb-000057
参考制备实施例44的方法，将g步骤中5-溴-2,4-二氟苯腈原料等比例替换为3-溴-4-氯苯腈，即得实施例46. 1H NMR(600MHz,DMSO-d 6)δ12.02(s,1H),10.23(s,1H),8.10(d,J＝37.3Hz,1H),7.43(s,1H),7.20(d,J＝7.8Hz,1H),6.80(s,1H),6.68(s,1H),5.52(s,1H),4.63(s,1H),4.49(s,2H),3.97(d,J＝8.7Hz,2H),3.55(s,2H),3.48(t,J＝11.6Hz,2H),3.35(s,2H),3.02(s,3H),2.19(s,3H),2.12(dd,J＝11.6,8.7Hz,2H),1.77(d,J＝11.2Hz,2H).HRMS(ESI,m/z)calcd for C 24H 30ClN 9O 3S[M+H] +,560.1959；found560.1990.
实施例47
4-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢-2H-噻喃-1,1-二氧化物(实施例47)的制备
Figure PCTCN2022098519-appb-000058
参考制备实施例46的方法，将g步骤中2-(甲磺酰基)乙胺原料等比例替换为4-氨基四氢-2H-硫代吡喃-1,1-二氧化物，即得实施例47. 1H NMR(600MHz,DMSO-d 6)δ12.00(s,1H),10.20(s,1H),8.09(s,2H),7.48–7.20(m,2H),6.81(s,1H),6.66(s,1H),5.09(s,1H),4.61(s,1H),4.47(s,2H),4.24(s,1H),3.96(s,2H),3.51(s,2H),3.47(s,2H),2.10(d,J＝8.3Hz,3H),2.04–1.97(m,4H),1.76(m,4H).HRMS(ESI,m/z)calcd for C 26H 32ClN 9O 3S[M+H] +,586.2116；found 586.2143.
实施例48
3-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢噻吩-1,1-二氧化物(实施例48)的制备
Figure PCTCN2022098519-appb-000059
参考制备实施例46的方法，将g步骤中2-(甲磺酰基)乙胺原料等比例替换为3-氨基四氢噻吩-1,1-二氧化物，即得实施例48. 1H NMR(600MHz,DMSO-d 6)δ12.64–11.96(m,1H),10.18(s,1H),8.07(s,1H),7.39(s,1H),7.19(d,J＝8.0Hz,1H),6.87(s,1H),6.69(s,1H),5.49(d,J＝6.6Hz,1H),4.62(t,J＝11.2Hz,1H),4.47(s,2H),4.30(s,1H),3.97(d,J＝8.9Hz,2H),3.57(s,1H),3.48(t,J＝11.6Hz,2H),3.08(s,2H),2.45(s,1H),2.19(s,3H),2.14–2.07(m,2H),1.76(d,J＝11.4Hz,2H).HRMS(ESI,m/z)calcd for C 25H 30ClN 9O 3S[M+H] +,572.1959；found 572.1992.
实施例49
N 6-(4-氟-3-吗啉代苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例49)的制备
Figure PCTCN2022098519-appb-000060
参考制备实施例44的方法，将g步骤中5-溴-2,4-二氟苯腈原料等比例替换为3-溴-4-氟苯腈，且2-(甲磺酰基)乙胺原料等比例替换为吗啉，即得实施例49. 1H NMR(600MHz,DMSO-d 6)δ12.78–11.85(m,1H),10.17(s,1H),8.07(m,1H),7.41(s,1H),7.10–6.90(m,3H),4.63(s,1H),4.47(d,J＝4.1Hz,2H),3.97(dd,J＝10.9,3.4Hz,2H),3.71(s,4H),3.48(t,J＝11.5Hz,2H),2.94(s,4H),2.19(s,3H),2.12(d,J＝9.5Hz,2H),1.77(d,J＝11.0Hz,2H).HRMS(ESI,m/z)calcd for C 25H 30FN 9O 2[M+H] +,508.2585；found 508.2607.
实施例50
N 6-(4-氟-3-硫代吗啉代苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例50)的制备
Figure PCTCN2022098519-appb-000061
参考制备实施例49的方法，将g步骤中吗啉原料等比例替换为硫代吗啉，即得实施例50. 1H NMR(600MHz,DMSO-d 6)δ12.62–11.84(m,1H),10.56–9.84(m,1H),8.00(s,1H),7.34(s,1H),7.05(d,J＝7.6Hz,1H),7.01–6.60(m,3H),4.57(s,1H),4.40(s,2H),3.91(d,J＝10.7Hz,2H),3.44–3.39(m,2H),3.11(d,J＝8.4Hz,4H),2.66–2.54(m,4H),2.13(s,3H),2.05(d,J＝9.9Hz,2H),1.70(d,J＝11.3Hz,2H).HRMS(ESI,m/z)calcd for C 25H 30FN 9OS[M+H] +,524.2356；found 524.2377.
实施例51
N 6-{4-氯-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例51)的制备
Figure PCTCN2022098519-appb-000062
参考制备实施例46的方法，将g步骤中2-(甲磺酰基)乙胺原料等比例替换为四氢-2H-吡喃-4-胺，即得实施例51. 1H NMR(600MHz,DMSO-d 6)δ11.92(s,1H),10.13(s,1H),8.00(s,1H),7.31(s,1H),7.09(d,J＝7.8Hz,1H),6.74(s,1H),6.69–6.08(m,2H),4.67(s,1H),4.54(s,1H),4.39(s,2H),3.89(d,J＝6.7Hz,2H),3.70(s,2H),3.42–3.38(m,2H),2.15–2.00(m,5H),1.69(s,4H),1.36(s,2H),1.17(s,2H).HRMS(ESI,m/z)calcd for C 26H 32ClN 9O 2[M+H] +,538.2446；found 538.2470.
实施例52
N 6-{4-氟-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例52)的制备
Figure PCTCN2022098519-appb-000063
参考制备实施例51的方法，将g步骤中3-溴-4-氯苯腈原料等比例替换为3-溴-4-氟苯腈，即得实施例52. 1H NMR(600MHz,DMSO-d 6)δ12.65–11.94(m,1H),10.21(s,1H),8.09(s,1H),7.34(s,1H),6.98–6.34(m,4H),5.06(s,1H),4.62(s,1H),4.44(s,2H),3.97(d,J＝8.2Hz,2H),3.78(s,2H),3.48(t,J＝11.6Hz,2H),3.39–3.17(m,4H),2.21(m,3H),2.11(dt,J＝11.9,8.2Hz,2H),1.76(d,J＝10.8Hz,2H),1.44–1.37(m,2H).HRMS(ESI,m/z)calcd for C 26H 32FN 9O 2[M+H] +,522.2741；found 522.2765.
实施例53
N 6-{4-氟-3-[(四氢吡喃-3-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例53)的制备
Figure PCTCN2022098519-appb-000064
参考制备实施例52的方法，将g步骤中四氢-2H-吡喃-4- 胺原料等比例替换为四氢吡喃-3-胺，即得实施例53. 1H NMR(600MHz,DMSO-d 6)δ12.07(s,1H),10.28(s,1H),8.12(d,J＝13.4Hz,1H),7.43(s,1H),7.00–6.94(m,1H),6.80(d,J＝7.9Hz,1H),6.73–6.31(m 2H),5.43(s,1H),4.67(s,1H),4.48(s,2H),4.01(d,J＝8.4Hz,2H),3.82(d,J＝7.1Hz,2H),3.70(d,J＝5.2Hz,1H),3.59–3.49(m,4H),2.23(s,3H),2.15(d,J＝9.0Hz,4H),1.81(d,J＝11.7Hz,2H).HRMS(ESI,m/z)calcd for C 25H 30FN 9O 2[M+H] +,508.2585；found 508.2611.
实施例54
2-{[2-氟-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇(实施例54)的制备
Figure PCTCN2022098519-appb-000065
参考制备实施例53的方法，将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为氧杂环丁烷-3-胺，即得实施例54. 1H NMR(600MHz,DMSO-d 6)δ12.77–11.82(m,1H),10.80–9.60(m,1H),8.03(s,1H),7.34(s,1H),6.92(dd,J＝11.4,8.5Hz,1H),6.85–6.22(m,3H),4.77(s,1H),4.73(s,1H),4.64(s,1H),4.43(s,2H),3.97(dd,J＝10.9,3.7Hz,2H),3.47(m,4H),2.19(s,3H),2.12(dt,J＝11.6,8.4Hz,2H),1.78(d,J＝12.4Hz,2H),1.07(s,3H).HRMS(ESI,m/z)calcd for C 24H 30FN 9O 2[M+H] +,496.2585；found 496.2610.
实施例55
2-{[2-氯-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇(实施例55)的制备
Figure PCTCN2022098519-appb-000066
参考制备实施例51的方法，将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为氧杂环丁烷-3-胺，即得实施例55. 1H NMR(600MHz,DMSO-d 6)δ12.78–11.77(m,1H),10.16(s,1H),8.07(s,1H),7.39(s,1H),7.16(d,J＝8.0Hz,1H),6.81(s,1H),6.74–6.16(m,2H),4.85(s,1H),4.71(s,1H),4.64(d,J＝10.9Hz,1H),4.45(s,2H),3.97(d,J＝8.1Hz,2H),3.49(d,J＝11.7Hz,2H),3.42(s,2H),2.19(s,3H),2.14–2.08(m,2H),1.77(d,J＝11.3Hz,2H),1.07(s,3H).HRMS(ESI,m/z)calcd for C 24H 30ClN 9O 2[M+H] +,512.2289；found 512.2312.
实施例56
N 6-[(3，4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基]-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例56)的制备
Figure PCTCN2022098519-appb-000067
参考制备实施例52的方法，将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为乙醇胺，即得实施例56. 1H NMR(600MHz,DMSO-d 6)δ12.73–11.76(m,1H),10.13(s,1H),8.18–7.76(m,1H),7.26(s,1H),6.64–6.23(m,4H),5.66(s,1H),4.63(s,1H),4.36(s,2H),4.07–4.04(m,2H),3.97(dd,J＝11.0,3.3Hz,2H),3.50(t,J＝11.5Hz,2H),3.22(s,2H),2.19(s,3H),2.12(dt,J＝11.9,8.1Hz,2H),1.78(d,J＝11.0Hz,2H).HRMS(ESI,m/z)calcd for C 23H 27N 9O 2[M+H] +,462.2366；found 462.2386.
实施例57
N 4-(5-甲基-1H-吡唑-3-基)-N 6-((4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例57)的制备
Figure PCTCN2022098519-appb-000068
参考制备实施例52的方法，将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为2-(甲氨基)乙基-1-醇，即得实施例57. 1H NMR(600MHz,DMSO-d 6)δ12.80–11.78(m,1H),10.87–9.78(m,1H),8.49–7.72(m,1H),7.27(s,1H),6.76(s,1H),6.57(d,J＝5.9Hz,2H),4.75–4.60(m,1H),4.40–4.36(m,2H),4.17(s,2H),3.98(dd,J＝11.0,3.0Hz,2H),3.52–3.45(m,2H),3.38(dd,J＝6.6,4.0Hz,2H),2.93–2.52(m,3H),2.24–2.07(m,5H),1.78(d,J＝11.3Hz,2H).HRMS(ESI,m/z)calcd for C 24H 29N 9O 2[M+H] +,476.2522；found 476.2541.
实施例58
N 6-{4-氟-3-[(2-甲氧基乙基)甲氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例58)的制备
Figure PCTCN2022098519-appb-000069
参考制备实施例52的方法，将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为2-甲氧基-N-甲基乙基-1-胺，即得实施例58. 1H NMR(600MHz,DMSO-d 6)δ12.01(s,1H),10.23(s,1H),8.06(s,1H),7.42(s,1H),7.11–6.51(m,4H),4.64(s,1H),4.47(s,2H),3.97(d,J＝8.6Hz,2H),3.49(d,J＝11.2Hz,2H),3.43(s,3H),3.24(s,2H),3.16(s,3H),2.82(m,2H),2.22–2.08(m,5H),1.77(d,J＝11.1Hz,2H).HRMS(ESI,m/z)calcd for C 25H 32FN 9O 2[M+H] +,510.2741；found 510.2764.
实施例59
N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-N 6-((2,3,4,5-四氢苯并[b][1,4]氧杂氮杂-7-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例59)的制备
Figure PCTCN2022098519-appb-000070
参考制备实施例52的方法，将g步骤中四氢-2H-吡喃-4-胺原料等比例替换为2-甲氧基-N-甲基乙基-1-胺，即得实施例59. 1H NMR(600MHz,DMSO-d 6)δ12.72–11.75(m,1H),10.70–9.71(m,1H),8.00(s,1H),7.21(s,1H),6.81–6.00(m,4H),5.74–5.09(m,1H),4.56(s,1H),4.32(s,2H),3.92–3.81(m,4H),3.42(d,J＝10.5Hz,2H),2.97(s,2H),2.16–2.02(m,5H),1.77–1.68(m,4H).HRMS(ESI,m/z)calcd for C 24H 29N 9O 2[M+H] +,476.2522；found 476.2535.
实施例60采用如下路线进行制备：
Figure PCTCN2022098519-appb-000071
3-溴-4,6-二氯-1H-吡唑并[3,4-d]嘧啶(14)的合成
将中间体3(0.30g,1.59mmol)溶于8mL乙腈中，再加入NBS(0.31g,1.75mmol)，加热至70℃反应10h。TLC监测(PE:EA＝4:1)原料反应完毕，待反应冷却至室温，旋干溶剂，经柱层析(PE:EA＝20:1)得白色固体，产率94％。
3-溴-4,6-二氯-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶(15)的合成
将中间体14(0.10g,0.38mmol)、四氢-2H-吡喃-4-醇(0.04g,0.40mmol)、三苯基膦(0.11g,0.42mmol)溶于17mL四氢呋喃中，再缓慢加入DIAD 0.096mL，室温反应6h。TLC监测(PE:EA＝4:1)原料反应完毕，待反应冷却至室温，旋干溶剂，经柱层析(PE:EA＝20:1)得白色固体，产率48％。
3-溴-6-氯-N-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4-胺(16)的合成
将中间体15(0.02g,0.06mmol)溶于3mL DMF中，再依次5-甲基-1H-吡唑-3-胺(0.006g,0.06mmol)、N,N-二异丙基乙胺(0.014mL,0.08mmol)、碘化钾(0.012g,0.07mmol)，后65℃反应1h。TLC检测(DCM:MeOH＝15:1)，原料反应完全，待反应冷却至室温，加入水30mL，析出白色沉淀，抽滤，得到白色固体，产率88％。
3-溴-N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺(实施例60)的制备
将中间体16(0.08g,0.19mmol)溶于1.5mL异丙醇中，再加入2,4-二氟苄胺(0.028mL,0.24mmol)、三乙胺0.053mL，后在封管下加热至135℃反应15h。TLC监测(DCM:MeOH＝10:1)原料反应完毕，待反应冷却至室温，旋干溶剂，经柱层析(DCM:MeOH＝40:1)得白色固体，产率46％。 1H NMR(600MHz,DMSO-d 6)δ12.15(s,1H),8.05–7.84(m,2H),7.55–7.31(m,1H),7.19(s,1H),7.01(t,J＝7.5Hz,1H),6.84–6.02(m,1H),4.64(s,1H),4.53(m,2H),3.97(d,J＝8.5Hz,2H),3.48(t,J＝11.6Hz,2H),2.19(m,3H),2.05(s,2H),1.80(m,2H).HRMS(ESI,m/z)calcd for C 21H 21BrF 2N 8O[M+H] +,519.1068；found 519.1095.
实施例61：本发明部分产物的体外酶抑制活性研究
实验材料：
Tecan
Figure PCTCN2022098519-appb-000072
酶标仪。
Figure PCTCN2022098519-appb-000073
Kinase Binding Assay试剂盒(包含Kinase Tracer 236、Eu‐Anti‐GST Antibody、激酶缓冲溶液(1X Kinase Buffer A))，384浅孔板，重组人PLK4蛋白(aa 1-836，含一个GST tag)。
重组人PLK4蛋白激酶浓度50ng/μL(Thermo Scientific:PV6395)，蒸馏水，DMSO。
实验方法：
首先将上述实施例制备化合物样品用DMSO配成20mM的溶液，之后根据测试需要，再用激酶缓冲溶液(1X Kinase Buffer A))稀释成200μM、40μM、10μM、1.6μM、0.32μM、0.064μM、0.0128μM、0.00256μM、0.000512、0.0001024μM；后向384孔板加入化合物样品(4μL)，再加入将8μL含重组人PLK4激酶(浓度为50ng/μL)和Eu‐Anti‐GST Antibody的激酶缓冲溶液、4μL含Tracer 236的激酶缓冲溶液，后在室温下孵育60分钟，读板。
结果评定方法：通过添加Eu标记抗体检测激酶“示踪剂”结合。示踪剂和抗体与激酶的结合导致高度的FRET，反之使用激酶抑制因子代替示踪剂会造成FRET丢失。铕供体由一个带30nm光栅的340nm激发滤镜激发，使用中心在665纳米处、带通为10纳米的滤光 片，以检测转移至Alexa Fluor 647示踪剂的能量。然后这一信号被替代为铕的峰值激发，这是使用一个615nm，10nm光栅的滤镜完成的。使用665纳米信号除以615纳米信号来计算“发射比”。所以每一个孔板反应的HTRF信号(665/615)比值被计算。结果被表征为Delta F(DF％)：
Figure PCTCN2022098519-appb-000074
计算抑制率(％activity)：在不加化合物样品的情况下，激酶活性的DF％被定义为100％。当加入化合物样品后，激酶活性率：
Figure PCTCN2022098519-appb-000075
计算IC 50：在加入化合物的情况下，激酶活性的DF％被绘制成Y-轴，化合物的浓度对数值被绘制成X-轴。IC 50值是通过数据拟合成S-型计量反应曲线获得(表1)。
表1部分实施例化合物得IC 50值
实施例 IC 50(nM) 实施例 IC 50(nM)
实施例2 453.9 实施例3 483.9
实施例4 206.0 实施例5 87.1
实施例6 5.5 实施例7 23.3
实施例8 0.3 实施例9 1.1
实施例10 0.1 实施例11 22.1
实施例12 78.4 实施例13 10.5
实施例14 6.5 实施例15 4.0
实施例16 0.2 实施例17 3.8
实施例18 2.7 实施例19 47.9
实施例20 7.9 实施例21 7.0
实施例22 0.7 实施例23 26.1
实施例24 2.1 实施例25 20.2
实施例26 27.6 实施例27 3.7
实施例28 1.1 实施例29 241.3
实施例30 117.9 实施例32 3.6
实施例35 20.7 实施例37 1.8
实施例39 282.1 实施例40 0.7
实施例43 13.9 实施例44 24.5
实施例45 35.4 实施例46 21.7
实施例47 41.1 实施例48 25.2
实施例49 21.8 实施例50 55.4
实施例51 24.2 实施例52 44.7
实施例53 42.1 实施例54 24.3
实施例55 8.8 实施例56 11.5
实施例57 27.1 实施例58 90.7
实施例59 38.2 实施例60 8.6
由上述可见本发明部分化合物具有明显的体外酶抑制活性，尤其化合物8、9、10、16、17、18、22、24、27、28、32、37和40所示化合物其体外酶抑制活性尤其突出，IC 50(nM)均在4.0以下，优于实验阳性对照centrinone。

Claims (10)

  1. 一种吡唑并嘧啶衍生物，其特征在于：衍生物为通式(I)所示的化合物，及其几何异构体,对映异构体或其药学上可接受的盐；通式(I)所示化合物如下：
    Figure PCTCN2022098519-appb-100001
    其中，R 1选自氢、C1-C6烷基、C1-C6卤代烷基、C1-C6羟烷基、未取代或被1-4个可相同或不同的R a取代的芳基、未取代或被1-2个下述基团取代的C3-C7环烷基、含1-2个杂原子的C3-C7脂肪环；下述基团为C1-C4烷基或氨基；所述环、含杂原子脂肪环中还可含1-2个羰基，所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合；
    R 2选自氢、卤素、氰基、甲酰胺、C1-C4烷基、C1-C4烷氧基、C3-C6环烷基、含杂原子的C3-C6脂肪环；
    A选自：
    Figure PCTCN2022098519-appb-100002
    R 3选自氢、卤素、C1-C6烷基、C3-C6环烷基、C1-C4烷氧基，未取代或被1-4个可相同或不同的R a取代的芳基；
    C环选自未取代或被1-4个可相同或不同的R a取代的芳基；
    R a选自卤素、C1-C4烷基或C1-C4卤代烷基；
    B选自含最多2个杂原子的C5-C7脂肪环或NHRc；
    Rc选自未取代或被1-4个可相同或不同的R b取代的：芳基、芳基甲基、芳基乙基、含1-2个杂原子的C5-C7脂肪环或C5-C7脂肪杂环并苯基甲基；
    R b选卤素，氰基，甲砜乙基氨基，C1-C4烷氧基，C1-C4烷氨基，C3-C7环烷基，含最多2个杂原子的C4-C7脂肪环，NR dR e；
    R d选自C1-C4烷氧基C1-C4烷基、C1-C6羟烷基、含1-2个杂原子的C4-C7脂肪环；
    R e选自氢、C1-C4烷基；
    上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；芳基为苯基，吡啶基，嘧啶基；
    当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜。
    当Rc选自C5-C7脂肪杂环并苯基甲基，且杂原子为N时，氮原子还可进一步被C1-C4烷基取代。
  2. 按权利要求1所述的吡唑并嘧啶衍生物，其特征在于：所述衍生物通式(I)所示的化合物，及其几何异构体，对映异构体或其药学上可接受的盐；
    其中，R 1选自氢，甲基，异丙基，三氟乙基，羟叔丁基，环己基，未取代或被1-4个可相同或不同的R a取代的芳基，含1-2个杂原子的C3-C7脂肪环；所述含杂原子脂肪环中还可含1-2个羰基，所述含杂原子的脂肪环中杂原子与芳酰胺、芳磺酰胺缩合；
    R 2选自氢，卤素或甲酰胺；
    A环部分选自
    Figure PCTCN2022098519-appb-100003
    R 3选自氢，卤素，甲基，乙基，环丙基，叔丁基，未取代或被1-4个可相同或不同的R a取代的芳基；
    C环选自未取代或被1-4个可相同或不同的R a取代的芳基；
    R a选自卤素，C1-C4烷基，C1-C4卤代烷基；
    B选自哌嗪基或NHRc；
    Rc选自未取代或被1-4个可相同或不同的R b取代的：苯基，吡啶基，嘧啶基，含1-2个杂原子的C5-C7脂肪环，C5-C7脂肪杂环并苯基甲基；
    R b选自卤素，氰基，甲砜乙基氨基，甲氧基，吗啉基，硫代吗啉基，C1-C4烷基、C1-C4烷氨基，NR dR e；
    R d选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环；
    R e选自氢、C1-C4烷基；
    上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；
    当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成亚砜或砜；
    当Rc选自C5-C7脂肪杂环并苯基甲基，且杂原子为N时氮原子其还可进一步被C1-C4烷基取代。
  3. 按权利要求2所述的吡唑并嘧啶类衍生物，其特征在于：所述衍生物通式(I)所示的化合物，及其几何异构体，对映异构体或其药学上可接受的盐；
    其中，R 1选自氢，甲基，异丙基，三氟乙基，羟叔丁基，环己基，对氟苯基，4-四氢吡喃，2-四氢吡喃，4-六氢吡啶；
    R 2选自氢，卤素或甲酰胺；
    A环部分选自
    Figure PCTCN2022098519-appb-100004
    R 3选自氢，卤素，甲基，乙基，环丙基，叔丁基，未取代或被1-4个可相同或不同的R a取代的苯基；
    C环选自未取代或被1-4个可相同或不同的R a取代的苯基；
    R a选自卤素，C1-C4烷基，C1-C4卤代烷基；
    B选自哌嗪基，
    Figure PCTCN2022098519-appb-100005
    未取代或被1-4个可相同或不同的R b取代的：4-六氢吡啶氨基，3-四氢吡咯氨基，苯氨基，苯甲氨基，1-(2，4-二氟苯基)乙氨基，2-苯基乙氨基；
    R b选自卤素，氰基，甲砜乙基氨基，甲氧基，吗啉基，硫代吗啉基，C1-C4烷基，C1-C4烷氨基，NR dR e
    R d选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环；
    R e选自氢、甲基；
    上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；
    当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
  4. 按权利要求3所述的吡唑并嘧啶类衍生物，其特征在于：所述衍生物通式(I)所示的化合物，及其几何异构体，对映异构体或其药学上可接受的盐；
    其中，R 1选自氢，甲基，异丙基，三氟乙基，羟叔丁基，环己基，对氟苯基，4-四氢吡喃，2-四氢吡喃，4-六氢吡啶；
    R 2选自氢，溴；
    A环部分选自
    Figure PCTCN2022098519-appb-100006
    R 3选自氢，卤素，甲基，乙基，环丙基，叔丁基，苯基，对氟苯基；
    C环选自苯基，3-氯苯基；
    B选自哌嗪基，
    Figure PCTCN2022098519-appb-100007
    未取代或被1-4个可相同或不同的R b取代的：4-六氢吡啶氨基，3-四氢吡咯氨基，苯氨基，苯甲氨基，1-(2，4-二氟苯基)乙氨基，2-苯基乙氨基，
    R b选自氯，溴，双氟，三氟，氰基，甲砜乙基氨基，甲氧基，吗啉基，硫代吗啉基，C1-C4烷基，C1-C4烷氨基，NR dR e；
    R d选自C1-C6羟烷基、C1-C4烷氧基C1-C4烷基、含1-2个杂原子的C4-C7脂肪环；
    R e选自氢、甲基；
    上述含1-2个杂原子的脂肪环时，杂原子为氮，氧或硫；
    当R d选自含1-2个杂原子的C4-C7脂肪环时杂原子为S时硫原子还可进一步氧化成砜。
  5. 按权利要求4所述的吡唑并嘧啶类衍生物，其特征在于：所述衍生物为：
    N-(5-甲基-1H-吡唑-3-基)-6-(哌嗪-1-基)-1H-吡唑[3,4-d]嘧啶-4-胺；
    N 4-(5-甲基-1H-吡唑-3-基)-N 6-(吡咯烷-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 4-(5-甲基-1H-吡唑-3-基)-N 6-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 4-(5-甲基-1H-吡唑-3-基)-N 6-苯基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 4-(5-甲基-1H-吡唑-3-基)-N 6-苯乙基-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(3-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(3-溴苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-溴苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(3,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 4-(5-甲基-1H-吡唑-3-基)-N 6-(2,4,6-三氟苄基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    4-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苄腈；
    N 6-(4-甲氧基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2，4-,二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    1-{6-[(4-氯苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇；
    1-{6-[(2,4-二氟苄基)氨基]-4-[(5-甲基-1H-吡唑-3-基)氨基]-1H-吡唑并[3,4-d]嘧啶-1-基}-2-甲基丙-2-醇；
    1-环己基-N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    1-环己基-N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-[(3,5-二氟吡啶-2-基)甲基]-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-1-甲基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-1-甲基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-1-异丙基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-1-异丙基-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-1-(4-氟苯基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1H-(2,2,2,-三氟乙基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-苯基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-环丙基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-叔丁基-1H-吡唑-3-基)-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-[5-(4-氟苯基)-1H-吡唑-3-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-[5-甲基噻唑-2-基]-1-(哌啶-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-苯基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-环丙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-叔丁基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-[5-(4-氟苯基)-1H-吡唑-3-基]-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-乙基-1H-吡唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟苄基)-N 4-(5-氯-1H-吲唑-3-基)-1H-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(2,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(3,4-二氟-5-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氯-3-{[2-(甲磺酰基)乙基]氨基}苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    4-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢-2H-噻喃-1,1-二氧化物；
    3-({2-氯-5-[({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基]苯基}氨基)四氢噻吩-1,1-二氧化物；
    N 6-(4-氟-3-吗啉代苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-(4-氟-3-硫代吗啉代苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-{4-氯-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-{4-氟-3-[(四氢-2H-吡喃-4-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-{4-氟-3-[(四氢吡喃-3-基)氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    2-{[2-氟-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇；
    2-{[2-氯-5-({4-[(5-甲基-1H-吡唑-3-基)氨基]-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-6-基}氨基)甲基)苯基]氨基}丙-1-醇；
    N 6-[(3，4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基]-N4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 4-(5-甲基-1H-吡唑-3-基)-N 6-((4-甲基-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-基)甲基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 6-{4-氟-3-[(2-甲氧基乙基)甲氨基]苄基}-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-N 6-((2,3,4,5-四氢苯并[b][1,4]氧杂氮杂-7-基)甲基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺；
    3-溴-N 6-(2,4-二氟苄基)-N 4-(5-甲基-1H-吡唑-3-基)-1-(四氢-2H-吡喃-4-基)-1H-吡唑并[3,4-d]嘧啶-4,6-二胺。
  6. 按权利要求1-5任意一项所述吡唑并嘧啶衍生物的应用，其特征在于：所述通式I所示的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
  7. 按权利要求1-5任意一项所述吡唑并嘧啶衍生物的应用，其特征在于：所述通式I所示的化合物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药在制备预防或抗肿瘤药物中的应用。
  8. 一种药用组合物，其特征在于：包含权利要求1至6中任何一项的通式I所示的化合物及其几何异构体或药学上可接受的盐、水合物、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
  9. 按权利要求7所述药用组合物的应用，其特征在于：所述组合物在制备预防或治疗与PLK4激酶的表达或活性有关的疾病的药物中的应用。
  10. 按权利要求7所述药用组合物的应用，其特征在于：所述组合物在制备预防或抗肿瘤药物中的应用。
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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1469874A (zh) * 2000-09-15 2004-01-21 ��̩��˹ҩ��ɷ����޹�˾ 可用作蛋白激酶抑制剂的吡唑化合物
CN101611035A (zh) * 2006-12-28 2009-12-23 大正制药株式会社 吡唑并嘧啶化合物
CN101616920A (zh) * 2007-01-30 2009-12-30 比奥根艾迪克Ma公司 1-H-吡唑并(3,4b)嘧啶衍生物及其作为有丝分裂激酶调节剂的用途
CN101981037A (zh) * 2008-01-30 2011-02-23 吉宁特有限公司 吡唑并嘧啶pi3k抑制剂化合物及使用方法
WO2012030924A1 (en) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation Azolopyridine and azolopyrimidine compounds and methods of use thereof
CN105906630A (zh) * 2015-04-06 2016-08-31 四川百利药业有限责任公司 用作fgfr抑制剂的n-(1h-吡唑-5-基)嘧啶并吡唑-4,6-二取代胺类化合物
WO2020108613A1 (zh) * 2018-11-30 2020-06-04 江苏豪森药业集团有限公司 杂芳类衍生物调节剂、其制备方法和应用
WO2020118183A1 (en) * 2018-12-06 2020-06-11 Kapoor Tarun M 2,4-diaminopyrimidine bicycles for treating cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA90254C2 (ru) * 2003-11-17 2010-04-26 Астразенека Аб Производные пиразола и их применение в качестве ингибиторов рецепторных тирозинкиназ
US10519160B2 (en) * 2014-07-18 2019-12-31 The General Hospital Corporation Imaging agents for neural flux

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1469874A (zh) * 2000-09-15 2004-01-21 ��̩��˹ҩ��ɷ����޹�˾ 可用作蛋白激酶抑制剂的吡唑化合物
CN101611035A (zh) * 2006-12-28 2009-12-23 大正制药株式会社 吡唑并嘧啶化合物
CN101616920A (zh) * 2007-01-30 2009-12-30 比奥根艾迪克Ma公司 1-H-吡唑并(3,4b)嘧啶衍生物及其作为有丝分裂激酶调节剂的用途
CN101981037A (zh) * 2008-01-30 2011-02-23 吉宁特有限公司 吡唑并嘧啶pi3k抑制剂化合物及使用方法
WO2012030924A1 (en) * 2010-09-01 2012-03-08 Ambit Biosciences Corporation Azolopyridine and azolopyrimidine compounds and methods of use thereof
CN105906630A (zh) * 2015-04-06 2016-08-31 四川百利药业有限责任公司 用作fgfr抑制剂的n-(1h-吡唑-5-基)嘧啶并吡唑-4,6-二取代胺类化合物
WO2020108613A1 (zh) * 2018-11-30 2020-06-04 江苏豪森药业集团有限公司 杂芳类衍生物调节剂、其制备方法和应用
WO2020118183A1 (en) * 2018-12-06 2020-06-11 Kapoor Tarun M 2,4-diaminopyrimidine bicycles for treating cancer

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