WO2023001123A1 - Nouveau dérivé de pyridopyrimidine - Google Patents

Nouveau dérivé de pyridopyrimidine Download PDF

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Publication number
WO2023001123A1
WO2023001123A1 PCT/CN2022/106363 CN2022106363W WO2023001123A1 WO 2023001123 A1 WO2023001123 A1 WO 2023001123A1 CN 2022106363 W CN2022106363 W CN 2022106363W WO 2023001123 A1 WO2023001123 A1 WO 2023001123A1
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alkyl
independently
optionally substituted
halogen
general formula
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PCT/CN2022/106363
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English (en)
Chinese (zh)
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罗会兵
姜佳俊
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上海艾力斯医药科技股份有限公司
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Priority to CN202280051354.1A priority Critical patent/CN117677624A/zh
Publication of WO2023001123A1 publication Critical patent/WO2023001123A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • 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
    • C07D498/22—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 four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a pyridopyrimidine derivative, a pharmaceutically acceptable salt, an ester, a stereoisomer or a tautomer, a pharmaceutical composition containing them and a use thereof.
  • the present invention also relates to the pyridopyrimidine Methods for the preparation of derivatives. More specifically, the pyridopyrimidine derivative of the present invention is represented by the general formula (1), and exhibits an excellent inhibitory effect on KRAS mutation, particularly KRAS G12D mutation, KRAS G12V mutation.
  • RAS protein is a guanine trinucleotide phosphate (GTP) binding protein with a molecular weight of 21 kDa located on the cell membrane, consisting of 188 or 189 amino acids.
  • GTP guanine trinucleotide phosphate
  • the active state of RAS protein has an influence on cell growth, differentiation, cytoskeleton, protein transport and secretion, etc., and its activity is regulated by combining with GTP or guanine dinucleotide phosphate (GDP).
  • GTP guanine trinucleotide phosphate
  • the RAS protein When the RAS protein binds to GDP, it is in an "inactive" state; when stimulated by specific upstream cell growth factors, the guanine nucleotide exchange factor (GEF) catalyzes the RAS protein to release GDP, binds to GTP, and is in an "activated” state. "state.
  • the RAS protein combined with GTP can activate downstream proteins and activate downstream signaling pathways.
  • RAS protein itself has weak GTPase activity and can hydrolyze GTP to obtain GDP, thereby realizing the conversion from an activated state to an inactive state.
  • GTPase-activating protein GAP is also required to participate, which can interact with RAS protein and greatly promote its ability to hydrolyze GTP to GDP.
  • RAS protein Any mutation in the RAS protein that affects its own GTPase activity or its interaction with GAP or its ability to hydrolyze GTP to obtain GDP will cause the RAS protein to be in a prolonged activated state, and the prolonged activated RAS protein continues to give Downstream protein growth signals that cause cells to grow and differentiate incessantly, which can eventually lead to cancer.
  • RAS gene family There are three members of the RAS gene family: KRAS, NRAS and HRAS.
  • KRAS mutations are the most common oncogenic driver, present in a variety of tumors: lung adenocarcinoma (32%), colorectal cancer (41%), pancreatic cancer (86%).
  • the KRAS mutation is the most common G12 mutation at the 12th codon.
  • G12 mutations accounted for 85%, 68%, and 91% respectively; G12 mutations include G12C, G12D, G12V, G12R and other mutant forms.
  • KRAS G12D and/or KRAS G12V mutations Small molecule KRAS G12D and/or KRAS G12V inhibitors for the treatment of diseases mediated by KRAS G12D and/or KRAS G12V mutations, such as cancer.
  • the present invention provides a pyridopyrimidine derivative represented by the general formula (1), a pharmaceutically acceptable salt, an ester, a stereoisomer or a tautomer (hereinafter, may also be referred to as the compound of the present invention).
  • the compound of the present invention exhibits excellent inhibitory effect on KRAS mutations, especially KRAS G12D mutations and KRAS G12V mutations, and can be used for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations and KRAS G12V mutations). It can also be used as an inhibitor of KRAS mutations (especially KRAS G12D mutations, KRAS G12V mutations).
  • the present invention provides pyridopyrimidine derivatives represented by the following general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
  • Y is a single bond, O, S or -(C(R 7 ) 2 ) q -;
  • Z is NH, NR 1 , CH 2 , CHR 1 or C(R 1 ) 2 ;
  • each R 1a , R 1b , R 1c and R 1d is independently deuterium, cyano, halogen or hydroxyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • L is -(CR 6a R 6b ) n1 -, -O-(CR 6a R 6b ) n2 -, -S-(CR 6a R 6b ) n3 - or -N(R 5 )(CR 6a R 6b ) n4 - ;
  • Q is independently a linker or -O-;
  • each R 2-a and R 2-b is independently deuterium, cyano, halogen or hydroxyl;
  • R 3 is C 6 -C 10 aryl optionally substituted by one or more R 3a or 5-14 membered heteroaryl optionally substituted by one or more R 3b ; said 5-14 membered heteroaryl
  • the heteroatoms in are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f is independently deuterium, halogen, cyano, hydroxyl, C 1 -C 4 alkane Base, C 1 -C 4 alkyl-O- or 3-6 membered cycloalkyl;
  • R 4 is H, deuterium, -N(R 5 ) 2 , halogen, hydroxyl, cyano, C 1 -C 6 alkyl optionally substituted by one or more halogen or deuterium, optionally one or more halogen Or deuterium-substituted C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • n1, n2, n3 and n4 are each independently 0, 1, 2 or 3;
  • each R 5 is independently H or C 1 -C 6 alkyl
  • each R 6a and R 6b is independently H, deuterium, halogen, cyano, hydroxyl, or C 1 -C 4 alkyl optionally substituted with one or more halogen or deuterium;
  • each R 7a , R 7b , R 7c and R 7d is independently deuterium, cyano, halogen or hydroxyl;
  • q 1 or 2;
  • the present invention also provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers:
  • the present invention also provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
  • the present invention further provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
  • the present invention further provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention and optionally a pharmaceutically acceptable carrier.
  • the present invention provides a method for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations, KRAS G12V mutations), comprising administering to an object an effective amount of the compound of the present invention or the above-mentioned pharmaceutical composition of the present invention .
  • KRAS mutations especially KRAS G12D mutations, KRAS G12V mutations
  • the present invention provides a method for treating and/or preventing cancer, comprising administering to an object an effective amount of the compound of the present invention or the above-mentioned pharmaceutical composition of the present invention.
  • the present invention provides the use of the compound of the present invention or the above-mentioned pharmaceutical composition of the present invention in the preparation of medicines for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations and KRAS G12V mutations).
  • the present invention provides the use of the compound of the present invention or the above-mentioned pharmaceutical composition of the present invention in the preparation of medicines for treating and/or preventing cancer.
  • the present invention provides the use of the compound of the present invention or the above-mentioned pharmaceutical composition of the present invention in the preparation of KRAS mutation inhibitors (especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors).
  • KRAS mutation inhibitors especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors.
  • the compound of the present invention shows excellent inhibitory effect on KRAS mutation (especially KRAS G12D mutation, KRAS G12V mutation), and can be used for treating/preventing diseases mediated by KRAS mutation (especially KRAS G12D mutation, KRAS G12V mutation), especially is cancer.
  • the compounds of the present invention can be used as KRAS mutation inhibitors (especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors).
  • the compound of the present invention shows an excellent inhibitory effect on KRAS mutations (especially KRAS G12D mutations and KRAS G12V mutations).
  • “optional”, “optional” or “optionally” means that the subsequently described event or situation may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation.
  • “optionally (optionally) substituted by R” means that it may or may not be substituted by R, and the description includes both the cases of being substituted by R and not being substituted by R.
  • substituted refers to one or more hydrogen atoms in the group (the total number of hydrogen atoms that can be replaced is the upper limit), preferably 1-5 hydrogen atoms, More preferably, 1, 2, 3 or 4 hydrogen atoms are independently substituted by the corresponding number of substituents, as long as the substituted compound is stable.
  • substituents when there are substituents, one or more substituents may exist; when there are a plurality of substituents, each substituent may be the same or different from each other.
  • the substituent may be bonded to the same atom of the group to be substituted, or may be bonded to a different atom of the group, as long as the substituted compound is stable.
  • independently or “independently” means that more than one group is selected from a large number of possible substituents, and those substituents may be the same or different from each other.
  • R x is selected from -OR or -N(R) 2 ; each R is independently selected from H or C 1 -C 4 alkyl", wherein each occurrence of the R group is independently, and they are each other Can be the same or different.
  • group and “group” represent a monovalent group or a group with a valence of more than two according to the need
  • cycloalkyl includes a group obtained by removing a hydrogen atom from a cycloalkane.
  • a valent group also includes a divalent or higher group obtained by removing two or more hydrogen atoms from the same carbon atom or two or more different carbon atoms.
  • a monovalent or more than divalent group usually refers to a monovalent group or a divalent group, but according to needs, the group can be a higher valence (such as trivalent, tetravalent, pentavalent, Hexavalent, etc.).
  • C d -C e (d and e represent an integer greater than 1, d ⁇ e) includes any specific situation of d to e carbons, for example, C 1 -C 6 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , also includes any range from d to e, for example, C 1 -C 6 includes C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 2 -C 5 , C 2 -C 4 , C 3 -C 6 and other ranges; similarly, "de element” (d and e represent integers above 3, d ⁇ e) means that the number of ring atoms is from d to e , For example, 3-6 membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, and any range from d to e, for example, 3-6-membered rings include 3-4-membered rings, 3- 5-
  • halogen means fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, bromine, more preferably fluorine, chlorine.
  • C 1 -C 6 alkyl refers to a linear or branched alkyl derived from an alkane containing 1-6 carbon atoms by removing a hydrogen atom, which is preferably "C 1 - C 4 alkyl", specifically, C 1 -C 6 alkyl includes but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methyl Pentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-d
  • C 2 -C 6 alkenyl refers to a linear or branched alkenyl group derived by removing a hydrogen atom from an alkene moiety of 2-6 carbon atoms containing at least one carbon-carbon double bond, It is preferably "C 2 -C 4 alkenyl", specifically, C 2 -C 6 alkenyl includes but not limited to vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butene Base, 1,3-butadiene-1-yl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl.
  • C 2 -C 6 alkenyl contains a carbon-carbon double bond.
  • C 2 -C 4 alkenyl refers to the above-mentioned “C 2-6 alkenyl” in which carbon atoms are 2-4, specifically, including but not limited to vinyl, 1-propene 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadien-1-yl.
  • C 2 -C 6 alkynyl refers to a linear or branched alkyne group derived by removing a hydrogen atom from an alkyne moiety of 2-6 carbon atoms containing at least one carbon-carbon triple bond , which is preferably "C 2-4 alkynyl", specifically, C 2 -C 6 alkynyl can include ethynyl, propynyl, 2-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl, 4-methyl-2-pentyn-1-yl, 2-hexyn-1-yl, 2-hexyn-2-yl, 3-hexyn-1-yl, 3-hexyn-2-yl, etc.
  • C 2 -C 6 alkynyl contains a carbon-carbon triple bond.
  • C 2 -C 4 alkynyl refers to the case where the above-mentioned "C 2 -C 6 alkynyl” has 2 to 4 carbon atoms. Specifically, ethynyl, propynyl, 2-butyn-1-yl.
  • C 1 -C 6 alkoxy or “C 1 -C 6 alkoxy-O-” refers to the "C 1 -C 6 alkyl” defined above through the oxygen atom and the rest of the molecule
  • the linking group namely "C 1 -C 6 alkyl-O-” group, which is preferably “C 1 -C 4 alkoxy” or "C 1 -C 4 alkyl-O-", which includes But not limited to, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy, n-hexyloxy and the like; the "C 1 -C 4 alkoxy” refers to a group in which the "C 1 -C 4 alkyl” defined above is connected to the rest of the molecule through an oxygen atom, that is, “C 1 -C 4 Alkyl-O-” groups, including but
  • C 1 -C 6 alkylthio or “C 1 -C 6 alkoxy-S-” refers to the above-defined “C 1 -C 6 alkyl” through the sulfur atom and the rest of the molecule
  • the linking group namely "C 1 -C 6 alkyl-S-” group, which is preferably “C 1 -C 4 alkylthio” or “C 1 -C 4 alkyl-O-", which includes But not limited to, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio , neopentylthio, n-hexylthio, etc.; the "C 1 -C 4 alkylthio” refers to the "C 1 -C 4 alkylthio” defined above through the sulfur atom and the
  • -NH(R) or “-N(R) 2 " refers to the case where one or two hydrogen atoms of an amino group (-NH 2 ) are replaced by an R group.
  • R group There is no limitation as long as it conforms to the definition of "-NH(R)” or “-N(R) 2 " in the present invention.
  • ring atom refers to an atom forming a ring structure, including but not limited to C, N, O, P and S;
  • ring carbon atom refers to a carbon atom forming a ring structure;
  • ring heteroatom is refers to ring atoms other than carbon atoms, including but not limited to ring atoms N, O, P and S.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic cyclic hydrocarbon group, which can be a monovalent group or a group with more than two valences as required, including monocyclic cycloalkyl and Multicyclic cycloalkyl group, multicyclic cycloalkyl group includes spirocyclic cycloalkyl group, parallel ring cycloalkyl group and bridged ring cycloalkyl group.
  • the "paracyclic cycloalkyl group” refers to a polycyclic cycloalkyl group in which each ring in the group shares a pair of adjacent ring carbon atoms with other rings, so
  • the term “bridged cycloalkyl” refers to a polycyclic cycloalkyl group in which any two rings share two ring carbon atoms that are not directly connected.
  • 3-10 membered cycloalkyl refers to saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic, tricyclic or more rings) including 3-10 ring carbon atoms Bridged ring, asymmetric ring or spiro) cycloalkyl, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, Wait.
  • 3-7 membered cycloalkyl refers to a cycloalkyl group comprising 3-7 ring carbon atoms, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • 5-10 membered cycloalkyl refers to a cycloalkyl group comprising 5-10 ring carbon atoms, including but not limited to cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • 3-6 membered cycloalkyl means a cycloalkyl group comprising 3-6 ring carbon atoms.
  • 3-4 membered cycloalkyl means a cycloalkyl group comprising 3-4 ring carbon atoms.
  • heterocyclyl refers to saturated or partially unsaturated ring atoms in which one or more (preferably 1, 2, 3 or 4) ring atoms are ring heteroatoms selected from N, O and S
  • a non-aromatic cyclic hydrocarbon group which can be a monovalent group or a group with more than two valences as required, including monocyclic heterocyclic groups and polycyclic heterocyclic groups, polycyclic heterocyclic groups include bicyclic, tricyclic or more ring spiro heterocyclic group, ring heterocyclic group and bridged ring heterocyclic group.
  • heterocyclic group refers to a polycyclic heterocyclic group in which each ring in the group shares a pair of adjacent ring atoms with other rings
  • bridged ring heterocyclic group is refers to a polycyclic heterocyclyl group in which any two rings share two ring atoms that are not directly attached.
  • 4-10 membered heterocycloalkyl refers to a saturated monocyclic or polycyclic ring including 4-10 ring atoms (such as bicyclic, tricyclic or more ring bridged rings, fused rings or spiro rings) Heterocycloalkyl, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O and S, specifically, 4-10 membered heterocycloalkyl includes but not limited to azetidinyl, oxa Cyclobutyl, Thietanyl, Tetrahydrofuranyl, Tetrahydropyrrolyl (For example another example "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is R configuration, S configuration or a mixture thereof), pyrrolidone group, tetrahydrothiophenyl group, imidazolidinyl group, pyrazolidinyl group, 1 , 2-oxazolidinyl, 1,3-o
  • 4-7 membered heterocycloalkyl refers to a saturated heterocycloalkyl group comprising 4-7 ring atoms, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O and S, specifically ,
  • the 4-7 membered heterocycloalkyl group includes, but is not limited to, groups with 4-7 ring atoms in the above "4-10 membered heterocycloalkyl group”.
  • 4-10 membered heterocycloalkenyl refers to a group with at least one carbon-carbon double bond in the ring structure of the above-mentioned "4-10 membered heterocycloalkyl", preferably one carbon-carbon double bond , specifically, the 4-10 membered heterocyclenyl group includes but not limited to 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2 , 3-dihydrooxazolyl, 3,4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-imidazolyl, 4,5-di Hydrogen-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothi
  • aryl refers to an aromatic cyclic hydrocarbon group, which can be a monovalent group or a group with more than two valences as required, including single-ring aryl and condensed ring aryl
  • fused ring Aryl refers to an aryl group containing multiple rings (preferably containing 2 or 3 rings) in which each ring shares an adjacent pair of ring carbon atoms with other rings.
  • C 6 -C 10 aryl refers to an aryl group including 6-10 ring carbon atoms, including phenyl, naphthyl (such as ).
  • heteroaryl refers to a ring heteroaryl group in which one or more (preferably 1-5, more preferably 1, 2, 3 or 4) ring atoms are selected from N, O and S Atomic aromatic cyclic hydrocarbon groups, which can be monovalent groups or groups with more than two valences as required, including monocyclic heteroaryl groups and condensed ring heteroaryl groups, the "fused ring heteroaryl groups” refers to a heteroaryl group containing multiple rings (preferably containing 2 or 3 rings) in which each ring in the group shares an adjacent pair of ring atoms with other rings.
  • 5-14 membered heteroaryl refers to a heteroaryl group comprising 5-14 ring atoms, preferably containing 1, 2, 3 or 4 ring heteroaryls selected from N, O and S Atoms, specifically, 5-14 membered heteroaryl groups include but are not limited to furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridyl (e.g.
  • 5-10 membered heteroaryl refers to a heteroaryl group comprising 5-10 ring atoms, preferably containing 1, 2, 3 or 4 ring heteroaryls selected from N, O and S Atoms, specifically, 5-10 membered heteroaryl groups include, but are not limited to, groups with 5-10 ring atoms in the above "5-14 membered heteroaryl groups”.
  • 5-6 membered heteroaryl refers to a heteroaryl group comprising 5-6 ring atoms, preferably containing 1, 2, 3 or 4 ring heteroatoms selected from N, O and S, specifically ,
  • the 5-6 membered heteroaryl group includes, but is not limited to, groups with 5-6 ring atoms in the above "5-14 membered heteroaryl group”.
  • amino protecting group refers to a chemical group that is attached to an amino group and is easily removed under certain conditions, including but not limited to alkoxycarbonyls, acyls, and alkyls; for example, tert-butoxycarbonyl , benzyloxycarbonyl, fluorenylmethyloxycarbonyl, allyloxycarbonyl, phthaloyl, benzyl, p-methoxybenzyl, trityl, etc.
  • Those skilled in the art can refer to Greene's Protective Groups in Organic Synthesis ( 4th edition), a commonly used textbook in this field, for appropriate selection and operation.
  • hydroxyl protecting group refers to a chemical group that is attached to a hydroxyl group and is easily removed under certain conditions, including but not limited to methyl, methoxymethyl, acetyl, tert-butyldimethyl Silyl groups and silyl groups, etc.
  • Those skilled in the art can refer to Greene's Protective Groups in Organic Synthesis ( 4th edition), a commonly used textbook in this field, for appropriate selection and operation.
  • alkynyl protecting group refers to a chemical group that is attached to an alkynyl group and is easily removed under certain conditions, including but not limited to triisopropylsilyl and the like.
  • Those skilled in the art can refer to Greene's Protective Groups in Organic Synthesis ( 4th edition), a commonly used textbook in this field, for appropriate selection and operation.
  • “One to more” and “more than one” in the present invention mean that the upper limit of the number of substituents can be all chemically substituted positions in the substituted group, which can be 1-6, and can be 1-6. 5, can be 1-3, can be 1-2, can be 1.
  • the number of substituents can be 0 (that is, unsubstituted), or 1 to all chemically substituted positions in the group to be substituted
  • the quantity can be 1-6, 1-5, 1-4, 1-3, 1-2 or 1.
  • pharmaceutically acceptable means that, within the scope of sound medical judgment, it is suitable for contact with human and animal tissues without undue toxicity, irritation or other problems or complications, commensurate with a reasonable benefit/risk ratio those compounds, substances, compositions and dosage forms.
  • pharmaceutically acceptable carrier refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and low toxicity.
  • Cosmetic herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • pharmacologically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hypromellose and its derivatives, cellulose acetate and its derivatives substances, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium/calcium stearate, hydrogenated vegetable oil, sodium stearate fumarate), calcium sulfate, vegetable oils (such as soybean oil, Sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, Antioxidants, preservatives, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, hypromel
  • an "effective amount" refers to a sufficient amount of a drug or a pharmacologically active agent that is non-toxic but can achieve the desired effect.
  • the determination of the effective amount varies from person to person, depending on the patient's age, body weight and disease conditions, and also on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine tests.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • patient includes humans, animals, vertebrates, mammals, rodents (such as guinea pigs, hamsters, rats, mice), murines (such as mice), Canines (eg dogs), primates, apes (eg monkeys or apes), monkeys (eg marmosets, baboons), apes (eg gorillas, chimpanzees, orangutans, gibbons).
  • a "patient” is a human.
  • treatment refers to therapeutic therapy or palliative measures.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • Treatment can also refer to prolonging survival as compared to expected survival if not receiving treatment.
  • prevention means a reduction in the risk of acquiring or developing a disease or disorder.
  • the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof.
  • the compound represented by the general formula (1) of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • the compound contains enantiomers.
  • the present invention includes both these isomers and mixtures of isomers, such as racemic mixtures. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • compounds of general formula (1) contain more than one chiral center, diastereoisomers may exist.
  • the present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, Atropisomers, etc., the compound of the present invention can also be in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesoform, racemate, atropisomer equivalent mixture, etc. exist.
  • a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof For example a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof.
  • the compounds described herein contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation.
  • the compound of the present invention may have two kinds of atropisomers originating from axial asymmetry, which is because when the substituent R3 is cyclic groups such as aryl and heteroaryl (especially at the two ends of the connecting bond, the ortho-position When there is a substituent or a group with a larger spatial structure at the adjacent position of the linkage) and the linkage between the substituted pyridopyrimidine ring is produced due to steric hindrance resulting in hindered rotation.
  • the compound has the structure of the general formula (1), or the compound of the general formula (1) has isomers produced by asymmetric carbons, etc.
  • the present in each isomer compound Either of a pair of atropisomers.
  • an atropisomer having excellent activity is preferable.
  • These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution through bond formation or salt formation with other chiral compounds.
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the compound of general formula (1) has optical isomers derived from asymmetric carbon, axial asymmetry, etc., and if necessary, single isomers can be obtained by methods known in the art, such as crystallization or chromatography (such as chiral chromatography) and other methods to split and obtain.
  • the present invention provides the compounds shown in the above various structures, or their cis-trans isomers, mesomers, racemates, enantiomers, diastereoisomers, atropisomers, Isomers or mixtures thereof, wherein "the mixture thereof” includes any of the aforementioned stereoisomers (such as cis-trans isomers, enantiomers, diastereoisomers, atropisomers) Mixtures in any form between and/or mixtures (meso, racemate), e.g.
  • mixtures of cis-trans isomers mixtures of enantiomers and diastereomers, diastereoisomers Mixtures of isomers, mixtures of atropisomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and diastereoisomers, atropisomers with Mixing of diastereomeric mixtures, etc.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes, such as deuterium (D), tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • the present invention provides pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the following general formula (1),
  • Y is a single bond, O, S or -(C(R 7 ) 2 ) q -;
  • Z is NH, NR 1 , CH 2 , CHR 1 or C(R 1 ) 2 ;
  • each R 1a , R 1b , R 1c and R 1d is independently deuterium, cyano, halogen or hydroxyl;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • L is -(CR 6a R 6b ) n1 -, -O-(CR 6a R 6b ) n2 -, -S-(CR 6a R 6b ) n3 - or -N(R 5 )(CR 6a R 6b ) n4 - ;
  • Q is independently a linker or -O-;
  • each R 2-a and R 2-b is independently deuterium, cyano, halogen or hydroxyl;
  • R 3 is C 6 -C 10 aryl optionally substituted by one or more R 3a or 5-14 membered heteroaryl optionally substituted by one or more R 3b ; said 5-14 membered heteroaryl
  • the heteroatoms in are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f is independently deuterium, halogen, cyano, hydroxyl, C 1 -C 4 alkane Base, C 1 -C 4 alkyl-O- or 3-6 membered cycloalkyl;
  • R 4 is H, deuterium, -N(R 5 ) 2 , halogen, hydroxyl, cyano, C 1 -C 6 alkyl optionally substituted by one or more halogen or deuterium, optionally one or more halogen Or deuterium-substituted C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
  • n1, n2, n3 and n4 are each independently 0, 1, 2 or 3;
  • each R 5 is independently H or C 1 -C 6 alkyl
  • each R 6a and R 6b is independently H, deuterium, halogen, cyano, hydroxyl, or C 1 -C 4 alkyl optionally substituted with one or more halogen or deuterium;
  • each R 7a , R 7b , R 7c and R 7d is independently deuterium, cyano, halogen or hydroxyl;
  • q 1 or 2;
  • the present invention provides pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the following general formula (1),
  • X is 0 or NR 7 ;
  • Y is -(C(R 7 ) 2 ) q -;
  • Z is NH or NR 1 ;
  • Each R1 is independently halogen, C1 - C6 alkyl optionally substituted by one or more R1a , or two R1s bonded to different or the same ring atom together with the atoms to which they are attached Forming a 4-10 membered heterocycloalkyl group; the heteroatoms in the 4-10 membered heterocycloalkyl group are selected from N, and the number of heteroatoms is 1, 2 or 3;
  • each R 1a is independently deuterium, cyano, halogen or hydroxy
  • n 0, 1, 2 or 3;
  • L is -O-(CR 6a R 6b ) n2 -;
  • R 2 is a 4-10 membered heterocycloalkyl optionally substituted by one or more R 2b ; the heteroatoms in the 4-10 membered heterocycloalkyl are each independently selected from one of N, O and S or more, the number of heteroatoms is 1, 2 or 3;
  • each R 2b is independently halogen, hydroxy, deuterium, cyano, or C 1 -C 4 alkyl optionally substituted by one or more R 2-a ;
  • each R 2-a is independently deuterium, cyano, halogen or hydroxy
  • R 3 is C 6 -C 10 aryl optionally substituted by one or more R 3a or 5-14 membered heteroaryl optionally substituted by one or more R 3b ; said 5-14 membered heteroaryl
  • the heteroatoms in are independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
  • Each R 3-a and R 3-e is independently deuterium, halogen, cyano, hydroxyl or C 1 -C 4 alkyl;
  • R 4 is H, deuterium, halogen, hydroxyl, cyano or C 1 -C 6 alkyl optionally substituted by one or more halogen or deuterium;
  • n2 is 0, 1, 2 or 3;
  • each n5 is independently 0, 1, 2 or 3;
  • each R 5 is independently H or C 1 -C 6 alkyl
  • each R 6a and R 6b is independently H, deuterium, halogen, cyano, hydroxyl, or C 1 -C 4 alkyl optionally substituted with one or more halogen or deuterium;
  • each R 7 is independently H, deuterium, halogen, cyano, hydroxyl, or C 1 -C 6 alkyl optionally substituted by one or more R 7a ;
  • each R 7a is independently deuterium, cyano, halogen or hydroxy
  • q 1 or 2;
  • the pyridopyrimidine derivative represented by the general formula (1) is a pyridopyrimidine derivative represented by the following general formula (1′),
  • the general formula (1) of the present invention can be represented by the following general formula (2) or general formula (3),
  • general formula (1) of the present invention can be represented by following general formula (4), general formula (5) or general formula (6),
  • m is 1, 2 or 3
  • "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
  • general formula (1) of the present invention can be represented by following general formula (2), general formula (2'), general formula (3) or general formula (3'),
  • general formula (1) of the present invention can use following general formula (4), general formula (4 '), general formula (5), general formula (5 '), general formula ( 6) or general formula (6') representation,
  • general formula (1) of the present invention can use following general formula (7), general formula (8), general formula (9), general formula (10), general formula (11) , general formula (12), general formula (13), general formula (14), general formula (15), general formula (16), general formula (17), general formula (18) or general formula (19),
  • X is preferably O, NR 7 or S, more preferably O or NR 7 , wherein, in X, R 7 is independently preferably H or C 1 -C 6 alkyl, more preferably It is preferably H or C 1 -C 4 alkyl, most preferably H.
  • Y is preferably -(C(R 7 ) 2 ) q -, wherein q is preferably 1, and in Y, R 7 is independently preferably H, halogen, hydroxyl or C 1 -C 6 alkyl, more preferably one R 7 is H, halogen, hydroxyl or C 1 -C 4 alkyl, one R 7 is H, more preferably both R 7 are H.
  • Y is preferably -(C(R 7 ) 2 ) q -, wherein q is preferably 1 or 2, and in Y, preferably R 7 is independently H, halogen, hydroxyl or C 1 -C 6 alkyl, more preferably R 7 is independently H or C 1 -C 4 alkyl, more preferably R 7 is independently H.
  • Z is preferably NH or CHR 1 , wherein, in Z, R 1 is preferably -N(R 5 ) 2 , more preferably Z is NH.
  • Z is preferably NH.
  • each R 1 is independently deuterium, halogen, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, or Two R1s bonded to the same ring atom form an oxo group, or R1s bonded to two adjacent ring atoms form a bond, or two R1s bonded to different or same ring atoms form a bond with them The connected atoms together form a 3-7-membered cycloalkyl group, a 4-10-membered heterocycloalkyl group; more preferably each R 1 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl -O-, or two R1s bonded to different or the same ring atoms form a 4-10 membered heterocycloalkyl group together with the atoms to which they are attached; further preferably each R1 is independently
  • the formed heterocycle Alkyl, heterocycloalkenyl or cycloalkyl form a bridged ring structure or a bridged ring structure with the six - membered ring to which R is bonded; preferably form a bridged ring structure with the six-membered ring to which R is bonded, and the bridged ring structure
  • the bridging bond of can be a -(CH 2 ) 1-3 - group, preferably a -(CH 2 ) 1-2 - group.
  • R 1 bonded to the same ring atom when two R 1 bonded to the same ring atom together form a heterocycloalkyl group, a heterocycloalkenyl group or a cycloalkyl group with the atoms to which they are attached, it means that when R 1 A spiro ring is formed on the bonded six-membered ring, and the spiro atom is the above-mentioned ring atom.
  • each R 1 is independently C 1 -C 4 alkyl, or two R 1 bonded to different or the same ring atoms form 4- 7-membered heterocycloalkyl.
  • heteroatom in the heterocycloalkyl and heterocycloalkenyl in R preferably 1 or 2 heteroatoms selected from N, O and S; more preferably 1 or 2 N atoms.
  • heteroatom in the heterocycloalkyl group preferably 1 or 2 heteroatoms selected from N, O and S; More preferably, it is 1 or 2 N atoms.
  • each of R 1a , R 1b , R 1c and R 1d is independently halogen or hydroxyl.
  • the number of occurrences of R 1a , R 1b , R 1c and R 1d is 1, 2, 3 or 4, preferably 1 or 2, independently.
  • n is preferably 1, 2, 3 or 4, more preferably 1, 2 or 3.
  • n is preferably 1 or 2.
  • L is preferably -(CR 6a R 6b ) n1 - or -O-(CR 6a R 6b ) n2 -, more preferably -O-(CR 6a R 6b ) n2 -.
  • L is preferably -O-(CR 6a R 6b ) n2 -.
  • L is preferably -O-CH 2 -.
  • R 6a and R 6b are preferably each independently H, deuterium, halogen, hydroxyl or C 1 -C 4 alkyl; more preferably R 6a is H and R 6b is H, deuterium, halogen , hydroxyl or C 1 -C 4 alkyl; more preferably both R 6a and R 6b are H.
  • each R 6a and R 6b is independently H or deuterium.
  • n1, n2, n3 and n4 are preferably each independently 1 or 2; more preferably each independently is 1.
  • n2 is preferably 1.
  • R 2 when L is -O-(CR 6a R 6b ) n2 -, -S-(CR 6a R 6b ) n3 - or -N(R 5 )(CR 6a R 6b ) n4 - , R 2 is bonded to O, S or N atom in L group; or R 2 is bonded to (CR 6a R 6b ) n2 , (CR 6a R 6b ) n3 or (CR 6a R 6b ) n4 in L group One end; preferably the latter.
  • R2 is a 3-10 membered cycloalkyl optionally substituted by one or more R2a , a 4-10 membered heterocycloalkane optionally substituted by one or more R2b C 6 -C 10 aryl optionally substituted by one or more R 2d or 5-10 membered heteroaryl optionally substituted by one or more R 2e ; more preferably R 2 is substituted by one or more A 3-10 membered cycloalkyl group substituted by R 2a or a 4-10 membered heterocycloalkyl group substituted by one or more R 2b ; more preferably R 2 is a 5-10 membered cycloalkane substituted by one or more R 2a group or a 5-10 membered heterocycloalkyl group substituted by one or more R 2b ; more preferably R 2 is a 5-10 membered heterocycloalkyl group substituted by one or more R 2b , especially preferably R 2
  • R 2 is selected from at least one of the following groups substituted by one or more R 2b :
  • R 2 is 5-10 membered heterocycloalkyl substituted by one or more R 2b .
  • heteroatom in the heterocycloalkyl group and heteroaryl group in R preferably 1 or 2 heteroatoms selected from N, O and S; more preferably 1 or 2 N atoms.
  • each of R 2a , R 2b and R 2c is independently halogen, hydroxyl, C 1 -C 4 alkyl optionally substituted by one or more R 2-a , any C 1 -C 4 alkyl - O-, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, -N(R 5 ) 2 or (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl); more preferably each of R 2a , R 2b and R 2c is independently halogen, hydroxyl, optionally replaced by one or more R 2-a Substituted C 1 -C 4 alkyl or -N(R 5 ) 2 ; further preferably each of R 2a , R 2b and R 2c is independently halogen, hydroxyl or C 1 -C 4 alkyl; still more preferably each R 2a , R 2b and R 2c are each independently fluorine, chlorine,
  • each R 2b is independently halogen, hydroxyl or C 1 -C 4 alkyl.
  • each R 2b is independently fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl or butyl.
  • each of R 2-a and R 2-b is independently halogen or hydroxyl.
  • each of R 2d and R 2e is independently halogen, hydroxy, C 1 -C 4 alkyl optionally substituted with one or more halogen or hydroxy, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, or -N(R 5 ) 2 ; more preferably each of R 2d and R 2e is independently halogen, hydroxy, C 1 optionally substituted with one or more halogen or hydroxy -C 4 alkyl or -N(R 5 ) 2 ; further preferably each R 2d and R 2e are independently halogen, hydroxyl or C 1 -C 4 alkyl; still more preferably each R 2d and R 2e are each independently independently fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl or butyl.
  • the number of occurrences of R 2a , R 2b , R 2c , R 2d and R 2e is 1, 2, 3 or 4, preferably 1 or 2, independently.
  • the number of occurrences of R 2-a and R 2-b are each independently 1, 2, 3 or 4, preferably 1 or 2.
  • R 3 is C 6 -C 10 aryl substituted by one or more R 3a or 5-14 membered heteroaryl substituted by one or more R 3b ; more preferably R 3 is C 6 -C 10 aryl substituted by one or more R 3a , and the C 6 -C 10 aryl is phenyl or naphthyl, or R 3 is 5 substituted by one or more R 3b -14-membered heteroaryl, and the 5-14-membered heteroaryl is a 5-10-membered heteroaryl; more preferably R 3 is a C 6 -C 10 aryl substituted by one or more R 3a , and the The C 6 -C 10 aryl is naphthyl (for example ), or R 3 is a 5-14 membered heteroaryl group substituted by one or more R 3b , and the 5-14 membered heteroaryl group is pyridyl (for example ), pyrimidinyl,
  • R 3 is a C 6 -C 10 aryl group substituted by one or more R 3a , and the C 6 -C 10 aryl group is naphthyl, or R 3 is a C 6 -C 10 aryl group substituted by one or more R 3a Or multiple R 3b substituted 5-14 membered heteroaryl, and the 5-14 membered heteroaryl is pyridyl, pyrimidinyl, quinolinyl, quinazolinyl, indolyl, indazolyl, benzene Thienyl or benzothiazolyl.
  • R 3 is substituted by one or more R 3a substituted by one or more R 3b or substituted by one or more R 3b
  • heteroatom in the heteroaryl group in R3 preferably 1 or 2 heteroatoms selected from N, O and S; more preferably 1 or 2 N atoms or S atoms.
  • each of R 3a and R 3b is independently halogen, hydroxyl, cyano, C 1 -C 6 alkyl optionally substituted by one or more R 3-a , any C 1 -C 6 alkyl-O- substituted by one or more R 3-b , C 2 -C 6 alkenyl optionally substituted by one or more R 3-d , optionally one or more C 2 -C 6 alkynyl substituted by R 3-e , -N(R 5 ) 2 , 3-6 membered cycloalkyl or triazolyl optionally substituted by one or more R 3-f ; more preferably Each R 3a and R 3b is independently halogen, hydroxyl, cyano, C 1 -C 6 alkyl optionally substituted by one or more R 3-a , optionally substituted by one or more R 3-e Substituted C 2 -C 6 alkynyl or -N(R 5 ) 2 ; further
  • each n5 is independently 0 or 1; more preferably 0.
  • each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f is independently halogen, hydroxyl, C 1 -C 4 alkyl or C 1 -C 4 alkyl-O-; more preferably each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3- Each f is independently halogen, hydroxyl or C 1 -C 4 alkyl; further preferably each of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f Each is independently halogen or hydroxy.
  • each of R 3-a and R 3-e is independently deuterium, halogen or hydroxyl.
  • the number of occurrences of R 3a and R 3b are each independently 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
  • the numbers of R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f are 1, 2, 3 independently , 4 or 5, preferably 1, 2 or 3.
  • R3 is preferably more preferably
  • R 4 is -N(R 5 ) 2 , halogen, hydroxyl, C 1 -C 6 alkyl optionally substituted by one or more halogens, optionally substituted by one or more Halogen substituted C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; more preferably R 4 is -N(R 5 ) 2 , halogen, hydroxyl or optionally C 1 -C 6 alkyl substituted by one or more halogens; more preferably R 4 is halogen, hydroxyl or C 1 -C 4 alkyl optionally substituted by one or more halogens.
  • R 4 is halogen, hydroxyl or C 1 -C 4 alkyl optionally substituted by one or more halogens.
  • R4 is halogen
  • R4 is fluorine
  • each R 5 is independently H or C 1 -C 4 alkyl, more preferably each R 5 is independently H, methyl, ethyl or propyl.
  • each R 7 is independently H, halogen, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 7a , or bonded to two R on the same ring atom to form an oxo group, or bonded to R on two adjacent ring atoms to form a bond, or bonded to two R on different or same ring atoms and The atoms they are connected together form 3-7 membered cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl; more preferably each R is independently H, halogen, hydroxyl, optionally C 1 -C 6 alkyl substituted by one or more R 7a , or two R 7 bonded to the same ring atom to form an oxo group, or R 7 bonded to two adjacent ring atoms to form a bond ; further preferably each R 7 is independently H, halogen, hydroxyl, -N(
  • each of R 7a , R 7b , R 7c and R 7d is independently halogen or hydroxyl.
  • the number of occurrences of R 7a , R 7b , R 7c and R 7d is 1, 2, 3 or 4, preferably 1 or 2, independently.
  • each R 7 is independently H or C 1 -C 4 alkyl.
  • each R 7 is independently H.
  • heterocycloalkyl when two R7 bonded to different ring atoms form heterocycloalkyl, heterocycloalkenyl or cycloalkyl together with the atoms they are connected to, the formed heterocycle
  • the alkyl, heterocycloalkenyl or cycloalkyl forms a ring structure or a bridged ring structure with a ring comprising X and Y.
  • R 7 when two R 7 bonded to the same ring atom together form a heterocycloalkyl, heterocycloalkenyl or cycloalkyl with the atoms to which they are attached, it means A spiro ring is formed on the ring of Y and Y, and the spiro atom is the above-mentioned ring atom.
  • heteroatom in the heterocycloalkyl and heterocycloalkenyl in R preferably 1 or 2 heteroatoms selected from N, O and S; more preferably 1 or 2 N atoms.
  • q is preferably 1.
  • q is preferably 1 or 2.
  • the present invention also provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
  • the compound shown in general formula (1) of the present invention when for R3 is When R is F, the compound shown in general formula (1) can be prepared by the following route one:
  • step 1 4-amino-2,6-dichloropyridine and a fluorinating reagent are used to carry out a fluorinating reaction under the condition of using a solvent or not using a solvent; the fluorinating reagent can use various types of A fluorinating reagent, for example, Selectfluoro (1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt);
  • step 2 the product of step 1 is subjected to an amino protection reaction under basic conditions with or without a solvent;
  • step 3 under the condition of using a solvent or not using a solvent, in the presence of a strong base, the product of step 2 is used for the reaction, and the strong base can use a conventional strong base in the art, for example, it can be LDA;
  • step 4 the product of step 3 is subjected to a deamination protecting group reaction and a hydrolysis reaction under acidic conditions under the condition of using a solvent or not using a solvent;
  • step 5 under the condition of using a solvent or not using a solvent, under acidic conditions, using ethanol, the product of step 4 is subjected to an esterification reaction;
  • step 6 under the condition of using a solvent or not using a solvent, the product of step 5 is used to perform a substitution reaction with trichloroacetyl isocyanate;
  • step 7 under the condition of using a solvent or not using a solvent, the product of step 6 is used to perform amination ring-closure reaction;
  • step 8 under the condition of using a solvent or not using a solvent, the product of step 7 is used to carry out chlorination reaction;
  • the chlorination reagent can use various chlorination reagents known in the art, such as phosphorus oxychloride, chlorination Sulfoxide, etc.;
  • step 9 the product of step 8 is used to perform a substitution reaction under basic conditions with or without a solvent;
  • step 10 the product of step 9 is used to perform a substitution reaction with HLR 2 under alkaline conditions under the condition of using a solvent or not using a solvent;
  • step 11 the product of step 10 is dehydroxylated (in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride, potassium fluoride or CsF) under the condition of using a solvent or not using a solvent
  • the reaction, and ring-closing reaction is carried out to reaction product;
  • step 12 under the condition of using a solvent or not using a solvent, under acidic conditions, the product of step 11 is subjected to deamination Cbz protection; further, under basic conditions, the amino group of the product is subjected to Boc protection;
  • step 13 a Suzuki coupling reaction is carried out under conditions known in the art with or without a solvent;
  • step 14 in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride, potassium fluoride or CsF under the condition of using a solvent or not using a solvent, de-alkynyl TIPS protecting group; and then under acidic conditions , the product is subjected to dehydroxyl protecting group and deamino protecting group to obtain the product.
  • step 1 under the conditions of using a solvent or not using a solvent, the starting compound is used to perform a Suzuki coupling reaction under conditions known in the art;
  • step 2 the product of step 1 is subjected to a deamination protecting group reaction under acidic conditions under the condition of using a solvent or not using a solvent to obtain a product.
  • step 1 2-bromo-4-methyl-6-aminopyridine is subjected to an amino protection reaction under basic conditions with or without a solvent;
  • step 2 under the condition of using a solvent or not using a solvent, under the condition of palladium catalysis, the product of step 1 is subjected to a borylation reaction, and the palladium catalyst can use a conventional palladium catalyst in the art, for example, it can be [1 , 1'-bis(diphenylphosphino)ferrocene]palladium dichloride;
  • step 3 the product of step 2 is used to carry out a Suzuki coupling reaction under conditions known in the art under the condition of using a solvent or not using a solvent;
  • step 4 under the condition of using a solvent or not using a solvent, in the presence of silver acetate, the product of step 3 is subjected to an iodination reaction;
  • step 5 under the condition of using a solvent or not using a solvent, the product of step 4 is subjected to a coupling reaction in the presence of a catalyst, and the catalyst can use a conventional catalyst in the art, such as CuI, Cu2O ;
  • step 6 the product of step 5 is oxidized in the presence of an oxidizing agent under the condition of using a solvent or not using a solvent, and the oxidizing agent can use a conventional oxidizing agent in the field, such as mCPBA, H 2 O 2 , Oxone;
  • step 7 the product of step 6 is chlorinated under the condition of using a solvent or not using a solvent; chlorination reagents known in the art can be used, such as phosphorus oxychloride and thionyl chloride;
  • step 8 the product of step 7 is subjected to a substitution reaction with or without a solvent
  • step 9 under the condition of using a solvent or not using a solvent, the product of step 8 is subjected to an amination ring-closing reaction;
  • step 10 the product of step 9 is chlorinated under the condition of using a solvent or not using a solvent; chlorination reagents known in the art can be used, such as phosphorus oxychloride and thionyl chloride;
  • step 11 the product of step 10 is subjected to a substitution reaction under basic conditions with or without a solvent;
  • step 12 the product of step 11 is subjected to a substitution reaction with HLR 2 under basic conditions with or without a solvent;
  • step 13 under the condition of using a solvent or not using a solvent, in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride, potassium fluoride or CsF, the product of step 12 is subjected to the reaction of dehydroxyl protecting group ;
  • step 14 under the conditions of using a solvent or not using a solvent, the product of step 13 is subjected to a ring closure reaction under palladium catalytic conditions, and the catalyst can use a conventional palladium catalyst in the art, for example, it can be Pd 2 dba 3 /XantPhos, Pd(OAc) 2 /XantPhos, etc.;
  • step 15 the product of step 14 is deaminated and protected under acidic conditions with or without a solvent to obtain the final product.
  • step 1 a substitution reaction is carried out under basic conditions with or without a solvent
  • step 2 the product of step 1 is subjected to a substitution reaction under basic conditions with or without a solvent;
  • step 3 under the condition of using a solvent or not using a solvent, in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride, potassium fluoride or CsF, the product of step 2 is dehydroxylated. Reaction, and carry out ring closing reaction;
  • step 4 under the condition of using a solvent or not using a solvent, the product of step 3 is subjected to a deamination Cbz protection reaction under acidic conditions; furthermore, under basic conditions, the amino group of the product is subjected to a Boc protection reaction;
  • step 5 the product of step 4 is subjected to a Suzuki coupling reaction under conditions known in the art, using a solvent or not using a solvent;
  • step 6 the product of step 5 is subjected to a deamination protecting group reaction under acidic conditions with or without a solvent to obtain a product.
  • step 1 a substitution reaction is carried out under basic conditions with or without a solvent
  • step 2 the product of step 1 is subjected to a substitution reaction under basic conditions with or without a solvent;
  • step 3 under the condition of using a solvent or not using a solvent, in the presence of tetrabutylammonium fluoride, tetramethylammonium fluoride, potassium fluoride or CsF, the product of step 2 is dehydroxylated. Reaction, and carry out ring closing reaction;
  • step 4 under acidic conditions, the product of step 3 is subjected to deamination Cbz protection reaction under the condition of using a solvent or not using a solvent; then, under basic conditions, the amino group of the product is subjected to Boc protection reaction;
  • step 5 the product of step 4 is subjected to a Suzuki coupling reaction under conditions known in the art, using a solvent or not using a solvent;
  • step 6 the product of step 5 is subjected to a deamination protecting group reaction under acidic conditions with or without a solvent to obtain a product.
  • the solvent can be selected from: N,N-dimethylformamide, N,N-dimethyl Acetamide, dimethyl sulfoxide, toluene, benzene, xylene, trimethylbenzene, cyclohexane, hexane, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, ether, dioxane, 1 , one of 2-dimethoxyethane, methyl acetate, ethyl acetate, acetone, methyl ethyl ketone, acetonitrile, methanol, ethanol, isopropanol, tert-butanol, water and a mixture thereof.
  • various inorganic bases or organic bases can be used, and as the inorganic bases, alkali metal hydroxides (such as potassium hydroxide, sodium hydroxide), alkali metal carbonates, etc.
  • alkali metal hydroxides such as potassium hydroxide, sodium hydroxide
  • alkali metal carbonates etc.
  • Salts such as potassium carbonate, sodium carbonate
  • alkali metal hydrides such as sodium hydride
  • alkaline earth metal hydroxides such as calcium hydroxide, barium hydroxide
  • organic bases methylamine, ethylamine, propylamine , N, N-diisopropylethylamine, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinine One of the morphines and mixtures thereof.
  • various strong bases various strong bases known in the art can be used, for example, potassium hydroxide, sodium hydroxide, potassium tert-butoxide, sodium tert-butoxide, diisopropyl Lithium amide (LDA), sodium diisopropylamide, etc.
  • potassium hydroxide sodium hydroxide
  • potassium tert-butoxide sodium tert-butoxide
  • diisopropyl Lithium amide LDA
  • sodium diisopropylamide etc.
  • the acid can be selected from: formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, Maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethylsulfonic acid; hydrochloric acid, sulfuric acid , nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid.
  • a pharmaceutical composition comprising the pyridopyrimidine derivative represented by general formula (1) of the present invention, a pharmaceutically acceptable salt, ester, stereoisomer or tautomer Construct and optional pharmaceutically acceptable carrier.
  • the optional pharmaceutically acceptable carrier included in the pharmaceutical composition of the present invention means that the composition may or may not contain a pharmaceutically acceptable carrier.
  • a method for treating and/or preventing diseases mediated by KRAS mutations comprising administering an effective amount of the compound of the present invention to a subject.
  • a method for treating and/or preventing cancer comprising administering to a subject an effective amount of the compound of the present invention.
  • the present invention also provides the use of the compound of the present invention in the preparation of medicines for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations and KRAS G12V mutations).
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for treating and/or preventing cancer.
  • the present invention also provides the use of the compound of the present invention in the preparation of KRAS mutation inhibitors (especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors).
  • KRAS mutation inhibitors especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors.
  • the present invention also provides a method for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations, KRAS G12V mutations), comprising administering an effective amount of the above-mentioned pharmaceutical composition of the present invention to the subject.
  • KRAS mutations especially KRAS G12D mutations, KRAS G12V mutations
  • a method for treating and/or preventing cancer comprising administering an effective amount of the above-mentioned pharmaceutical composition of the present invention to a subject.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition of the present invention in the preparation of medicines for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations and KRAS G12V mutations).
  • KRAS mutations especially KRAS G12D mutations and KRAS G12V mutations.
  • the present invention provides the use of the above-mentioned pharmaceutical composition of the present invention in the preparation of medicines for treating and/or preventing cancer.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition of the present invention in the preparation of KRAS mutation inhibitors (especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors).
  • KRAS mutation inhibitors especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors.
  • the disease mediated by KRAS mutation is cancer, for example, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer , testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophagus cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, One or more of leukemia and melanoma.
  • cancer for example, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer , testicular cancer, kidney cancer, head or neck cancer, bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophagus cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, One or more of leukemia and melanoma.
  • the present invention also includes pharmaceutically acceptable salts of the compounds represented by the general formula (1).
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent. Salt.
  • Representative base addition salts include, for example, salts with alkali metal, alkaline earth metal, quaternary ammonium cations, such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium Salts, etc.; amine salts, including salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as methylamine salts, dimethylamine salts, trimethylamine salts, triethylamine salts, ethylamine salts, etc.
  • quaternary ammonium cations such as sodium, lithium, potassium, calcium, magnesium, tetramethylquaternary ammonium, tetraethylquaternary ammonium Salts, etc.
  • amine salts including salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as methylamine salts
  • acid addition can be achieved by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a pharmaceutically acceptable acid includes inorganic acid (such as hydrochloric acid), organic acid (such as formic acid).
  • inorganic acid such as hydrochloric acid
  • organic acid such as formic acid.
  • the compounds of the invention also exist in prodrug forms.
  • the prodrugs described in the present invention refer to compounds that can be converted into the biologically active compounds described in the present invention (such as the compound of general formula (1)) under physiological conditions or by solvolysis. Accordingly, the term “prodrug” refers to a pharmaceutically acceptable precursor of a biologically active compound.
  • the pharmaceutical composition of the present invention can be prepared by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, and freeze-drying methods.
  • the pharmaceutical composition of the present invention can be administered to the object for prevention and/or treatment by any convenient route of administration, including but not limited to, oral, rectal, parenteral (such as injection, including subcutaneous, intradermal, intramuscular, intravenous intranasal, etc.), topical (including, for example, transdermal, intranasal, ophthalmic, buccal, and sublingual), pulmonary (eg, by oral or nasal inhalation or insufflation therapy with aerosols), and the like.
  • Solid dosage forms suitable for oral administration include tablets, pills, capsules, powders, powders, granules, and the like.
  • solid dosage forms in addition to the compounds of the present invention, their stereoisomers or pharmaceutically acceptable salts thereof, excipients, fillers or compatibilizers, binders, One or more of disintegrants, stabilizers, wetting agents, adsorbents, lubricants or encapsulating materials.
  • Liquid dosage forms suitable for oral administration include solutions, suspensions, emulsions, syrups or tinctures and the like.
  • liquid dosage forms may contain diluents, solubilizers, emulsifiers, wetting agents, suspending agents, sweeteners, and One or more of agents, flavoring agents, fragrances or preservatives.
  • Dosage forms suitable for topical administration include ointments, powders, patches, drops, sprays, inhalants, etc., as the active ingredient, the compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof are in Mixed together under aseptic conditions with pharmaceutically acceptable carriers.
  • Dosage forms suitable for rectal administration include suppositories comprising a compound of this invention, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in association with a suitable base.
  • Dosage forms suitable for parenteral injection include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • the pharmaceutical formulations are preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be packaged as packs containing discrete quantities of preparation, eg, packeted tablets, capsules.
  • mCPBA m-chloroperoxybenzoic acid, H 2 O 2 : hydrogen peroxide; Oxone: potassium monopersulfate; Pd 2 dba 3 /XantPhos: tris(dibenzylideneacetone)dipalladium/4,5-bisdi Phenylphosphine-9,9-dimethylxanthene; Pd(OAc) 2 /XantPhos: palladium acetate/4,5-bisdiphenylphosphine-9,9-dimethylxanthene; LDA: di Lithium isopropylamide; PMB: p-methoxybenzyl; Boc: tert-butoxycarbonyl; TBS (TBDMS): tert-butyldimethylsilyl; TIPS: triisopropylsilyl; MOM: methoxy Methyl (CH 3 OCH 2 -); Cbz: benzyloxycarbonyl; DMSO: dimethyl s
  • 2,6-Dichloropyridin-4-amine (6.52g, 39.99mmol, 1eq) was dissolved in N,N-dimethylformamide (30mL) and acetonitrile (30mL), and Selectfluoro (1-chloromethyl -4-Fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) salt) (17g, 47.99mmol, 1.2eq), react at 80°C for half an hour.
  • LCMS monitored the reaction to be complete.
  • the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate.
  • Step 2 tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester
  • 2,6-Dichloro-3-fluoropyridin-4-amine (4.2g, 23.21mmol, 1eq) was dissolved in dichloromethane (40mL), Boc anhydride (10.29g, 47.15mmol, 2.03eq) was added, 4 -Dimethylaminopyridine (457.28mg, 3.74mmol, 0.16eq), react at room temperature for 16 hours. LCMS monitored the reaction to be complete.
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to obtain tert-butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro- 3-fluoropyridin-4-yl)aminomethyl ester (7.0 g, yield: 79.13%), white solid.
  • tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester (5.84g, 15.32mmol, 1eq) was dissolved in In tetrahydrofuran (30mL), lithium diisopropylamide (2M, 15.32mL, 2eq) was added dropwise at -78°C and warmed to room temperature for 2 hours. The reaction solution was quenched with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 6 Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-50%) to obtain ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2- Trichloroacetyl)ureido)nicotine ester (1.5 g, yield: 76.14%), white solid.
  • Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester (3.0 g, 6.80 mmol, 1 eq) was dissolved in methanol ( 40mL), ammonia methanol solution (7M, 2.77mL, 2.85eq) was added, and reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was slurried with methyl tert-butyl ether to obtain 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.8 g, yield: 100%), white solid.
  • reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-30%) to obtain 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (650mg , yield: 31.47%), white solid.
  • 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine (20 g, 46.84 mmol, 1.0 eq) was completely dissolved in 1,4-dioxane (100 mL ), adding [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.42g, 4.68mmol, 0.1eq), potassium acetate (9.2g, 93.68mmol, 2.0eq), bis( Pinacolate) diboron (23.8g, 93.68mmol, 2.0eq), the mixture was stirred and reacted at 80°C for 3 hours under the protection of nitrogen.
  • Step 3 Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-[2,2'-bipyridine]-5-carboxylic acid ester
  • Step 4 Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-3'-iodo-4'-methyl-[2,2'-bipyridine] -5-carboxylate
  • Step 5 Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[2,2 '-bipyridine]-5-carboxylate
  • Step 6 4-Amino-6'-(bis(4-methoxybenzyl)amino)-5-(ethoxycarbonyl)-3-fluoro-4'-methyl-3'-(trifluoromethyl) -[2,2′-bipyridine]-1-oxide
  • Step 7 Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-6-chloro-3-fluoro-4'-methyl-3'-(trifluoromethyl)- [2,2'-bipyridyl]-5-carboxylate
  • Step 8 Ethyl-6'-(bis(4-methoxybenzyl)amino)-6-chloro-3-fluoro-4'-methyl-4-(3-(2,2,2-trichloro Acetyl)ureido)-3'-(trifluoromethyl)-[2,2'-bipyridine]-5-carboxylate
  • Step 9 7-(6-(Bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-8-fluoropyrido [4,3-d]pyrimidine-2,4-diol
  • Ethyl-6'-(bis(4-methoxybenzyl)amino)-6-chloro-3-fluoro-4'-methyl-4-(3-(2,2,2-trichloroacetyl )ureido)-3′-(trifluoromethyl)-[2,2′-bipyridine]-5-carboxylate (7.1g, 8.66mmol, 1.0eq) was placed in a 100mL three-necked flask, protected by nitrogen, Cool down to 15°C, add ammonia methanol solution (7M, 56mL), react at 15°C, and stir for 0.5 hours.
  • Step 10 N,N-bis(4-methoxybenzyl)-4-methyl-6-(2,4,5-trichloro-8-fluoropyrido[4,3-d]pyrimidine-7- base)-5-(trifluoromethyl)pyridin-2-amine
  • reaction solution was concentrated, and the residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-20%) to obtain N,N-bis(4-methoxybenzyl)-4-methyl-6-(2,4, 5-Trichloro-8-fluoropyrido[4,3-d]pyrimidin-7-yl)-5-(trifluoromethyl)pyridin-2-amine (750 mg, yield: 28.34%), yellow solid.
  • reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by HPLC to obtain (1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylate (570 mg, yield: 40.33%), colorless liquid.
  • Step 1 (1R,2R,5S)-Benzyl-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine -2-yl)-2,5-dichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-2-(((tert-butyldimethylsilyl)oxo) Methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 (1R,2R,5S)-Benzyl-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine -2-yl)-5-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-yl)-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1]octane-8 -formyl ester
  • Step 3 (1R,2R,5S)-Benzyl-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine -2-yl)-5-chloro-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3 -d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 (5aR,6R,9S)-Benzyl-2-(6-(di(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridine-2- Base)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10- Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 5 6-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl)methoxy)-5a , 6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab] Heptatrien-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine
  • Step 1 (1R,2R,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(2,5,7-trichloro-8 -Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 (1R,2R,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(5,7-dichloro-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 (5aR,6R,9S)-Benzyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 4 (5aR,6R,9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 5 (5aR,6R,9S)-tert-Butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene Base)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9, 10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid base ester
  • Step 6 (5aR,6R,9S)-tert-Butyl-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa -3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 7 5-ethynyl-6-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine-7a -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methyl bridge Naphtho[1,8-ab]cycloheptatrien-2-yl)naphth-2-ol
  • Step 1 5-Ethyl-6-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methyl bridge Naphtho[1,8-ab]cycloheptatrien-2-yl)naphth-2-ol
  • Step 1 (5aR,6R,9S)-tert-butyl-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)- 2-(8-Methylnaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza- 6,9-Naphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 2 (5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl)methoxy)-2-(8 -Methylnaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9- Naphtho[1,8-ab]cycloheptatriene carboxylate
  • Embodiment 5 Compound 5
  • Step 1 (5aR,6R,9S)-tert-butyl-2-(8-chloro-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorohexa Hydrogen-1H-pyrrolidinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-penta Aza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 2 (5aR,6R,9S)-2-(8-Chloro-7-fluoronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H- Pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6 , 9-methyl-naphtho[1,8-ab]cycloheptatriene
  • Embodiment 6 Compound 6
  • Step 1 (5aR,6R,9S)-tert-butyl-2-(8-chloronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H- Pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6 , 9-Naphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 2 (5aR,6R,9S)-2-(8-Chloronaphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine- 7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentapentaaza-6,9- Naphtho[1,8-ab]cycloheptatriene carboxylate
  • Step 1 (5aR,6R,9S)-tert-butyl-1-fluoro-2-(7-fluoro-8-methylnaphthalen-1-yl)-12-(((2R,7aS)-2-fluoro Hexahydro-1H-pyrrolidinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- Pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 2 (5aR,6R,9S)-1-fluoro-2-(7-fluoro-8-methylnaphthalen-1-yl)-12-(((2R,7aS)-2-fluorohexahydro-1H -pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza- 6,9-Naphtho[1,8-ab]cycloheptatriene carboxylate
  • Step 1 (5aR,6R,9S)-Benzyl-2-(2-((tert-butoxycarbonyl)amino)-3-aminocarbonyl-7-fluorobenzo[b]thiophen-4-yl)- 1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro- 5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 2 2-amino-7-fluoro-4-((5aR,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine-7a- Base) methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methyronaphthyl And[1,8-ab]cycloheptatrien-2-yl)benzo[b]thiophene-3-carboxamide
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; Gradient: 26%-66% v/v, 9min;
  • Step 1 (1R,2S,5S)-8-Benzyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate
  • Hydrochlorozirconocene (15.2g, 56.8mmol, 1.2eq) was dissolved in tetrahydrofuran (450mL), under nitrogen protection, (1R, 2S, 5S)-8-benzyl-2-ethyl-4 was added dropwise at room temperature -Oxylidene-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (15.0g, 47.3mmol, 1.0eq) in tetrahydrofuran (100mL), react at room temperature for 30 Minutes, zirconocene hydrochloride (12.6g, 47.3mmol, 1.0eq) was added, reacted at room temperature for 10 minutes, sodium acetate borohydride (15.1g, 71.0mmol, 1.5eq) was added in batches at 0°C, and reacted at room temperature for 2 hours.
  • Step 3 (1R,2S,5S)-Benzyl-2-(((tert-Butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
  • reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by HPLC to obtain (1R, 2S, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate (1.90 g, yield: 33.7%), colorless liquid.
  • Step 4 (1R,2S,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(2,5,7-trichloro-8 -Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 (1R,2S,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(5,7-dichloro-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 6 (1R,2S,5S)-Benzyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine -7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-formyl ester
  • Step 7 (5aS,6R,9S)-Benzyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 8 (5aS,6R,9S)-tert-Butyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 9 (5aS,6R,9S)-tert-Butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene Base)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9, 10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid base ester
  • Step 10 (5aS,6R,9S)-tert-Butyl-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa -3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 11 5-ethynyl-6-fluoro-4-((5aS,6R,9S)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine-7a -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methyl bridge Naphtho[1,8-ab]cycloheptatrien-2-yl)naphth-2-ol
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; Gradient: 21%-61% v/v, 9min;
  • Step 1 (1S,2R,5R)-Benzyl-2-(((tert-Butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
  • reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by HPLC to obtain (1S, 2R, 5R)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-di Azabicyclo[3.2.1]octane-8-carboxylate (2.30 g, yield: 65.1%), colorless liquid.
  • Step 2 (1R,2R,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(2,5,7-trichloro-8 -Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 3 (1R,2R,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(5,7-dichloro-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 (1R,2R,5S)-Benzyl-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazine -7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane- 8-formyl ester
  • Step 5 (5aR,6S,9R)-Benzyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 6 (5aR,6S,9R)-tert-Butyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • reaction solution was concentrated, the residue was dissolved in dichloromethane (2 mL), triethylamine (169 mg, 1.67 mmol, 5 eq) and BOC anhydride (87.5 mg, 0.400 mmol, 1.2 eq) were added and reacted at room temperature for 1 hour.
  • Step 7 (5aR,6S,9R)-tert-Butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene Base)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9, 10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid base ester
  • Step 8 (5aR,6S,9R)-tert-Butyl-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12- (((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa -3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate
  • Step 9 5-ethynyl-6-fluoro-4-((5aR,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine-7a -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methyl bridge Naphtho[1,8-ab]cycloheptatrien-2-yl)naphth-2-ol
  • Mobile phase A Water (0.05% ammonia water, v/v)
  • Mobile phase B ACN; Gradient: 25%-65% v/v, 9min;
  • Step 1 (1S,2S,5R)-8-Benzyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate
  • Hydrochlorozirconocene (19.28g, 72.21mmol, 1.2eq) was dissolved in tetrahydrofuran (200ml), and (1S, 2S, 5R)-8-benzyl-2-ethyl-4- Oxylidene-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (20g, 60.18mmol, 1eq) in tetrahydrofuran (200ml) was reacted at room temperature for 0.5 hours.
  • Hydrochlorozirconocene (16.06 g, 60.18 mmol, 1 eq) was added under nitrogen protection, and reacted at room temperature for 0.5 hours.
  • Step 4 (1S,2S,5R)-Benzyl 2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(2,5,7-trichloro-8- Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 5 (1S,2S,5R)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(5,7-dichloro-8-fluoro -2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8 -Diazabicyclo[3.2.1]octane-8-carboxylate
  • LCMS monitored the reaction to be complete.
  • the reaction solution was poured into a saturated aqueous ammonium chloride solution (neutral pH), and extracted with dichloromethane.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 6 (5aS,6S,9R)-Benzyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 7 (5aS,6S,9R)-tert-Butyl-2-chloro-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1 ,8-ab] cycloheptatriene-14-carboxylate
  • Step 8 (5aS,6S,9R)-tert-Butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)acetylene Base)naphthalen-1-yl)-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5a,6,7,8,9, 10-Hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylic acid base ester
  • Step 9 6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy base)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanonaphtho[1, 8-ab] cycloheptatrien-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 10 5-ethynyl-6-fluoro-4-((5aS,6S,9R)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine-7a -yl)methoxy)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methyl bridge Naphtho[1,8-ab]cycloheptatrien-2-yl)naphth-2-ol
  • Mobile phase A Water (0.05% ammonia water, v/v); Mobile phase B: ACN (v/v); Gradient: 24%-64%, 9min;
  • Step 4 (1R,2R,5S)-8-Benzyl-3-tert-butyl-2-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-3 , 8-dicarboxylate
  • Step 6 2-((1R,2R,5S)-8-((Benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-2-yl)acetic acid
  • reaction solution was concentrated, adjusted to pH 2 with dilute aqueous hydrochloric acid, and concentrated to obtain 2-((1R,2R,5S)-8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1 ]octane-2-yl)acetic acid (6.0g, crude product), a colorless oil, was directly put into the next reaction.
  • Step 7 (1R,2R,5S)-Benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 8 (1R,2R,5S)-Benzyl-2-(2-((tert-Butyldimethylsilyl)oxo)ethyl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate
  • Step 10 (1R,2R,5S)-Benzyl-2-(2-((tert-butyldimethylsilyl)oxo)ethyl)-3-(2,5,7-trichloro -8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (5.0 g, 10.5 mmol, about 60% content, 1.32 eq) was dissolved in dichloromethane (60 mL), Add N,N-diisopropylethylamine (3.07g, 23.73mmol, 3eq), and drop (1R,2R,5S)-benzyl-2-(2-((tert-butyldimethyl (3.2g, 7.91mmol, 1eq) in dichloromethane (10mL) The solution was slowly warmed to room temperature for 2 hours. LCMS monitored the reaction to be complete.
  • reaction solution was quenched by pouring into saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-15%) to obtain (1R, 2R, 5S)-benzyl-2-(2-((tert-butyldimethyl Silyl) oxo) ethyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (2.6 g, yield: 50.2%), orange solid.
  • Step 11 (1R,2R,5S)-Benzyl-2-(2-((tert-butyldimethylsilyl)oxo)ethyl)-3-(5,7-dichloro-8 -Fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 12 (6aR,7R,10S)-Benzyl-2-chloro-1-fluoro-13-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol Oxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta Trieno[4,5]cyclooctatetraene[1,2,3-de]naphthalene-15-carboxylate
  • Step 13 (6aR,7R,10S)-tert-Butyl-2-chloro-1-fluoro-13-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol Oxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta Trieno[4,5]cyclooctatetraene[1,2,3-de]naphthalene-15-carboxylate
  • Step 14 (6aR,7R,10S)-tert-Butyl 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl ) Naphthalene-1-yl)-13-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-5,6,6a,7,8,9 , 10, 11-octahydro-4-oxa-3, 11a, 12, 14, 15-pentaaza-7, 10-methycloheptatrieno [4, 5] cyclooctatetraene [1, 2,3-de]naphthalene-15-carboxylate
  • Step 15 6-Fluoro-4-((6aR,7R,10S)-1-fluoro-13-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy base)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methylcycloheptane Ekeno[4,5]cyclooctatetraenyl[1,2,3-de]naphthalene-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride
  • Step 16 5-Ethynyl-6-fluoro-4-((6aR,7R,10S)-1-fluoro-13-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazine-7a -yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10- Methyl cycloheptatrieno[4,5]cyclooctatetraen[1,2,3-de]naphthalene-2-yl)naphthalene-2-ol
  • Mobile phase A: Water (0.1% formic acid, v/v)
  • Mobile phase B ACN; Gradient: 20%-60% (v/v), 9min; Detection wavelength: 254/220nm
  • Mobile phase A CO2
  • mobile phase B methanol (0.1% ammonia water, v/v); gradient: 50%-50% (v/v);
  • Step 1 Benzyl-(1S,2S,5R)-2-(2-((tert-butyldimethylsilyl)oxo)ethyl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate
  • Benzyl-(1S, 2S, 5R)-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.18g, 4.07 mmol, 1eq) was dissolved in dichloromethane (15mL), imidazole (830mg, 12.21mmol, 3eq) was added, and tert-butyldimethylsilyl chloride (736mg, 4.88mmol, 1.2eq) was added at 0°C. to room temperature. LCMS monitored the reaction to be complete.
  • reaction solution was diluted with water, extracted with dichloromethane, the organic phase was washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-40%) to obtain benzyl-(1S, 2S, 5R)-2-(2-((tert-butyldimethyl silyl)oxo)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.25 g, yield: 76%), pale yellow oil.
  • Step 2 Benzyl-(1S,2S,5R)-2-(2-((tert-butyldimethylsilyl)oxo)ethyl)-3-(2,5,7-tri Chloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (884 mg, 3.09 mmol, 1 eq) was dissolved in dichloromethane (20 mL), and N,N-diiso Propylethylamine (1.2g, 9.27mmol, 3eq), benzyl-(1S, 2S, 5R)-2-(2-((tert-butyldimethylsilyl)oxygen) was added dropwise at -30°C Ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.25g, 3.09mmol, 1eq) in dichloromethane (4mL) after 2 hours to room temperature.
  • Step 3 Benzyl-(1S,2S,5R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(5,7-dichloro- 8-Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidine-4- base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 4 Benzyl-(6aS,7S,10R)-2-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazine-7a(5H)- Base) methoxy) -5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-sub Methyl cycloheptatrieno[4,5]cyclohexatetraeno[1,2,3-de]naphthalene-15-carboxylate
  • Step 5 tert-butyl-(6aS,7S,10R)-2-chloro-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazine-7a(5H)- Base) methoxy) -5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-sub Methyl cycloheptatrieno[4,5]cyclohexatetraeno[1,2,3-de]naphthalene-15-carboxylate
  • Step 6 tert-butyl-(6aS,7S,10R)-2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-13-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4 -oxa-3,11a,12,14,15-pentaaza-7,10-methylenecyclohepta[4,5]cyclooctatetraeno[1,2,3-de]naphthalene -15-carboxylate
  • Step 7 5,6-Difluoro-4-((6aS,7S,10R)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazine-7a(5H )-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10 -Methylene cycloheptatrieno[4,5]cyclooctetatetra[1,2,3-de]naphthalene-2-yl)naphthalene-2-ol hydrochloride
  • Step 1 tert-butyl-(6aS,7S,10R)-2-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl) -1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolinazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9 , 10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methylenecycloheptatrieno[4,5]cyclooctatetraeno[ 1,2,3-de]naphthalene-15-carboxylate
  • Step 2 2-Amino-7-fluoro-4-((6aS, 7S, 10R)-1-fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidazine-7a( 5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7, 10-Methylenecycloheptatrieno[4,5]cyclooctatetraeno[1,2,3-de]naphthalen-2-yl)benzo[b]thiophene-3-carbonitrile hydrochloride
  • Test Example 1 Proliferation inhibitory activity on Ba/F3 KRAS-G12D, Ba/F3 KRAS-G12V stably transfected cell lines and AGS tumor cell lines containing KRAS G12D mutation:
  • This test example 1 is used to determine the Ba/F3 KRAS-G12D and Ba/F3 KRAS-G12V cells that the compound of the present invention stably expresses the KRAS G12D/V mutant protein in the original B cell Ba/F3 of the mouse in vitro, and expresses KRAS G12D Proliferation inhibitory activity of mutant proteins in gastric cancer AGS cells.
  • Ba/F3 KRAS-G12D and Ba/F3 KRAS-G12V were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd., the article numbers were KC-1259 and KC-1261 respectively; AGS was purchased from Shanghai Baili Biotechnology Co., Ltd. company.
  • the details are as follows: take the stock solution (10mM) of the compound dissolved in DMSO in advance, dilute it to 10 gradient concentrations by doubling ratio (4 times), and dilute it to 10 times of the target concentration in another 96-well plate with medium, and then in 10 ⁇ l/well of the compound solution was added to the 96-well plate inoculated with cells to reach the target concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicate wells were set up for each concentration, and a blank control was set up.
  • Cell proliferation inhibition rate (%) [(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours compound group)/(luminous intensity 72 hours containing cell medium control group -luminous intensity 72 hours without cell culture Base control group )] ⁇ 100%.
  • Test results show that the compound of the present invention has good growth inhibitory activity on Ba/F3 KRAS-G12D and Ba/F3 KRAS-G12V cells expressing KRAS G12D/V mutant protein and gastric cancer AGS cells expressing KRAS G12D mutant protein.
  • the compounds of the present invention have excellent inhibitory effects on KRAS mutations, particularly KRAS G12D mutations and KRAS G12V mutations, and can be used to treat/prevent diseases mediated by KRAS mutations, particularly KRAS G12D mutations and KRAS G12V mutations (such as cancer).
  • the present invention provides a novel pyridopyrimidine derivative, which exhibits excellent inhibitory effect on KRAS mutation (especially KRAS G12D mutation, KRAS G12V mutation), therefore, it can be used for the prevention and/or treatment of KRAS mutation-mediated disease.

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Abstract

La présente invention concerne un nouveau dérivé de pyridopyrimidine, un sel pharmaceutiquement acceptable, un ester, un stéréoisomère ou un tautomère, et une composition pharmaceutique les contenant et leur utilisation. Le composé de la présente invention présente un excellent effet inhibiteur sur des mutations de KRAS (en particulier une mutation de KRAS G12D et une mutation de KRAS G12V).
PCT/CN2022/106363 2021-07-19 2022-07-19 Nouveau dérivé de pyridopyrimidine WO2023001123A1 (fr)

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WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023205719A1 (fr) * 2022-04-21 2023-10-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale
WO2024022507A1 (fr) * 2022-07-29 2024-02-01 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un inhibiteur de kras g12d
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024041573A1 (fr) * 2022-08-25 2024-02-29 Zai Lab (Shanghai) Co., Ltd. Composés multi-hétérocycliques fusionnés utilisés en tant que modulateurs de kras g12d et leurs utilisations
WO2024061370A1 (fr) * 2022-09-23 2024-03-28 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, son procédé de préparation et son utilisation
WO2024120433A1 (fr) * 2022-12-07 2024-06-13 Jacobio Pharmaceuticals Co., Ltd. Composés cycliques fusionnés et leur utilisation

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US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023172940A1 (fr) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Méthodes de traitement du cancer du poumon réfractaire immunitaire
WO2023205719A1 (fr) * 2022-04-21 2023-10-26 Gilead Sciences, Inc. Composés modulateurs de kras g12d
WO2023240263A1 (fr) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Inhibiteurs de ras macrocycliques
WO2024022444A1 (fr) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Composé cyclique fusionné, son procédé de préparation et son application médicinale
WO2024022507A1 (fr) * 2022-07-29 2024-02-01 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un inhibiteur de kras g12d
WO2024041573A1 (fr) * 2022-08-25 2024-02-29 Zai Lab (Shanghai) Co., Ltd. Composés multi-hétérocycliques fusionnés utilisés en tant que modulateurs de kras g12d et leurs utilisations
WO2024061370A1 (fr) * 2022-09-23 2024-03-28 劲方医药科技(上海)有限公司 Composé cyclique fusionné à une pyrimidine, son procédé de préparation et son utilisation
WO2024120433A1 (fr) * 2022-12-07 2024-06-13 Jacobio Pharmaceuticals Co., Ltd. Composés cycliques fusionnés et leur utilisation

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