WO2023001123A1 - New pyridopyrimidine derivative - Google Patents

New pyridopyrimidine derivative Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
independently
optionally substituted
halogen
general formula
Prior art date
Application number
PCT/CN2022/106363
Other languages
French (fr)
Chinese (zh)
Inventor
罗会兵
姜佳俊
Original Assignee
上海艾力斯医药科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海艾力斯医药科技股份有限公司 filed Critical 上海艾力斯医药科技股份有限公司
Priority to CN202280051354.1A priority Critical patent/CN117677624A/en
Publication of WO2023001123A1 publication Critical patent/WO2023001123A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—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.

Abstract

Provided in the present invention are a new pyridopyrimidine derivative, a pharmaceutically acceptable salt, an ester, a stereoisomer or a tautomer, and a pharmaceutical composition containing same and the use thereof. The compound of the present invention shows an excellent inhibitory effect on KRAS mutations (particularly a KRAS G12D mutation and a KRAS G12V mutation).

Description

新型吡啶并嘧啶衍生物Novel Pyridopyrimidine Derivatives 技术领域technical field
本发明涉及一种吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体、及包含它们的药物组合物及其用途，本发明还涉及该吡啶并嘧啶衍生物的制备方法。更具体而言，本发明的吡啶并嘧啶衍生物以通式(1)表示，并且对于KRAS突变、特别是对于KRAS G12D突变、KRAS G12V突变表现出优异的抑制作用。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.
背景技术Background technique
RAS蛋白是一种位于细胞膜上的分子量为21kDa的鸟嘌呤三核苷酸磷酸(GTP)结合蛋白，由188或189个氨基酸构成。RAS蛋白的活性状态对细胞的生长、分化、细胞骨架、蛋白质运输和分泌等都具有影响，其活性则是通过与GTP或鸟嘌呤二核苷酸磷酸(GDP)的结合进行调节。当RAS蛋白与GDP结合时，处于“失活”状态；当有上游特定的细胞生长因子刺激时，鸟嘌呤核苷酸交换因子(GEF)催化RAS蛋白释放出GDP，与GTP结合，处于“活化”状态。与GTP结合的RAS蛋白能够活化下游的蛋白，激活下游信号通路。RAS蛋白本身具有弱的GTP酶活性，能够水解GTP得到GDP，从而实现从活化状态到失活状态的转化。在这个水解过程中，还需要GTP酶激活蛋白(GAP)参与，它能与RAS蛋白相互作用并大大促进其水解GTP到GDP的能力。任何在RAS蛋白中的影响其自身的GTP酶活性或其与GAP相互作用或其水解GTP得到GDP的能力的突变，将会导致所述RAS蛋白处于延长的活化状态，延长活化的RAS蛋白继续给予下游蛋白生长信号，导致细胞不停地生长和分化，最终可能导致癌症。RAS基因家族三个成员：KRAS、NRAS和HRAS。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. 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). 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. In this hydrolysis process, 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. 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. There are three members of the RAS gene family: KRAS, NRAS and HRAS.
KRAS突变是最常见的致癌驱动因子，存在于多种肿瘤中：肺腺癌(32％)、结直肠癌(41％)、胰腺癌(86％)。KRAS突变又以第12位密码子的G12突变最为常见，例如，在KRAS突变的肺腺癌、结直肠癌及胰腺癌中，G12突变又分别占85％、68％及91％；G12突变包括G12C、G12D、G12V、G12R等突变形式。在KRAS G12突变的肺腺癌、结直肠癌、胰腺癌患者中，KRAS G12D突变患者分别占比17％、45％、45％， KRAS G12V突变患者分别占比23％、30％、35％(例如，参见Moore，A.R.et al.Nat Rev Drug Discov 19，533(2020))。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. For example, in KRAS-mutated lung adenocarcinoma, colorectal cancer, and pancreatic cancer, G12 mutations accounted for 85%, 68%, and 91% respectively; G12 mutations include G12C, G12D, G12V, G12R and other mutant forms. Among patients with KRAS G12 mutations in lung adenocarcinoma, colorectal cancer, and pancreatic cancer, patients with KRAS G12D mutations accounted for 17%, 45%, and 45%, respectively, and patients with KRAS G12V mutations accounted for 23%, 30%, and 35% ( See, eg, Moore, A.R. et al. Nat Rev Drug Discov 19, 533 (2020)).
关于抑制KRAS突变的研究近年来备受关注，虽然在该领域取得了一定进展，但目前还没有针对KRAS G12D和/或KRAS G12V突变的批准治疗化合物，因此仍需要继续开发有效、稳定、安全的小分子KRAS G12D和/或KRAS G12V抑制剂，用于治疗由KRAS G12D和/或KRAS G12V突变介导的疾病，例如癌症。Research on inhibiting KRAS mutations has attracted much attention in recent years. Although some progress has been made in this field, there are currently no approved therapeutic compounds for KRAS G12D and/or KRAS G12V mutations. Therefore, it is still necessary to continue to develop effective, stable and safe drugs. 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.
发明内容Contents of the invention
本发明提供一种通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体(以下，有时也称为本发明化合物)。本发明化合物对于KRAS突变，特别是KRAS G12D突变、KRAS G12V突变表现出优异的抑制作用，可以用于治疗和/或预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病。还可以用作KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)的抑制剂。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).
具体而言，本发明提供以下通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，Specifically, the present invention provides pyridopyrimidine derivatives represented by the following general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
Figure PCTCN2022106363-appb-000001
Figure PCTCN2022106363-appb-000001
X为单键、O、NR 7、S、S(＝O)、S(＝O) 2、P(＝O)R 7或C(R 7) 2； X is a single bond, O, NR 7 , S, S(=O), S(=O) 2 , P(=O)R 7 or C(R 7 ) 2 ;
Y为单键、O、S或-(C(R 7) 2) q-； Y is a single bond, O, S or -(C(R 7 ) 2 ) q -;
Z为NH、NR 1、CH 2、CHR 1或C(R 1) 2； Z is NH, NR 1 , CH 2 , CHR 1 or C(R 1 ) 2 ;
每个R 1独立地为氘、卤素、氰基、羟基、-N(R 5) 2、任选被一个或多个R 1a取代的C 1-C 6烷基、任选被一个或多个R 1b取代的C 1-C 6烷基-O-、任选被一个或多个R 1c取代的C 2-C 6烯基、任选被一个或多个R 1d取代的C 2-C 6炔基、-C(＝O)R 5、-CO 2R 5、-C(＝O)N(R 5) 2或5-6元杂芳基，或键合于同一环原子上两个R 1形成氧代基，或键合于相邻两个环原子上的R 1形成键，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；所 述5-6元杂芳基、4-10元杂环烷基、4-10元杂环烯基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 1 is independently deuterium, halogen, cyano, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 1a , optionally substituted by one or more C 1 -C 6 alkyl-O-substituted by R 1b , C 2 -C 6 alkenyl optionally substituted by one or more R 1c , C 2 -C 6 optionally substituted by one or more R 1d Alkynyl, -C(=O)R 5 , -CO 2 R 5 , -C(=O)N(R 5 ) 2 or 5-6 membered heteroaryl, or two R bonded to the same ring atom 1 forms an oxo group, or R 1 bonded to two adjacent ring atoms forms a bond, or two R 1 bonded to different or the same ring atoms form a 3-7 membered group together with the atoms they are connected to Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl; said 5-6 membered heteroaryl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl The heteroatoms are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
每个R 1a、R 1b、R 1c和R 1d各自独立地为氘、氰基、卤素或羟基； each R 1a , R 1b , R 1c and R 1d is independently deuterium, cyano, halogen or hydroxyl;
n为0、1、2、3、4、5、6或7；n is 0, 1, 2, 3, 4, 5, 6 or 7;
L为-(CR 6aR 6b) n1-、-O-(CR 6aR 6b) n2-、-S-(CR 6aR 6b) n3-或-N(R 5)(CR 6aR 6b) n4-； 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 - ;
R 2为H、-C(＝O)R 5、-CO 2R 5、-N(R 5) 2、C 1-C 6烷基、C 1-C 6烷基-O-、任选被一个或多个R 2a取代的3-10元环烷基、任选被一个或多个R 2b取代的4-10元杂环烷基、任选被一个或多个R 2d取代的C 6-C 10芳基、任选被一个或多个R 2e取代的5-10元杂芳基、-N(R 5)C(＝NH)N(R 5) 2、-C(O)N(R 5) 2、-C(＝O)O-C 1-C 6烷基或任选被一个或多个R 2c取代的C 6-C 10芳基-C(＝O)NR 5-；所述4-10元杂环烷基、5-10元杂芳基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； R 2 is H, -C(=O)R 5 , -CO 2 R 5 , -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, optionally 3-10 membered cycloalkyl substituted by one or more R 2a , 4-10 membered heterocycloalkyl optionally substituted by one or more R 2b , C 6 optionally substituted by one or more R 2d - C 10 aryl, 5-10 membered heteroaryl optionally substituted by one or more R 2e , -N(R 5 )C(=NH)N(R 5 ) 2 , -C(O)N(R 5 ) 2 , -C(=O)OC 1 -C 6 alkyl or C 6 -C 10 aryl optionally substituted by one or more R 2c -C(=O)NR 5 -; the 4- The heteroatoms in the 10-membered heterocycloalkyl group and the 5-10-membered heteroaryl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、氘、氰基、-C(＝O)R 5、-CO 2R 5、任选被一个或多个R 2-a取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、任选被一个或多个R 2-b取代的C 1-C 4烷基-O-、苯基-Q-、FO 2S-苯基-Q-、苯基-C(＝O)N(R 5)-、任选被一个或多个C 1-C 4烷基取代的吡唑基、任选被一个或多个C 1-C 4烷基取代的咪唑基、-N(R 5) 2、(C 1-C 4烷基)-O-(C 1-C 4烷基)、＝O、(任选被一个或多个卤素取代的C 1-C 4烷基)-C(＝O)-、-SO 2F、(C 1-C 4烷基)-SO 2-、(C 1-C 4烷基)-O-(C 1-C 4烷基)-O-、-CH 2OC(＝O)N(R 5) 2、(C 1-C 4烷基)-O-C(＝O)-N(R 5)CH 2-、-CH 2N(R 5)C(＝O)N(R 5) 2、(C 1-C 4烷基)-C(＝O)N(R 5)CH 2-、(吡唑基)-CH 2-、(咪唑基)-CH 2-、(C 1-C 4烷基)-SO 2-N(R 5)CH 2-、(4-10元杂环烷基)-C(＝O)-OCH 2-、(R 5) 2N-C(＝O)-O-、(C 1-C 4烷基)-O-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-、苯基-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH 2-；所述苯基-C(＝O)N(R 5)-和苯基-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-中的苯基任选被一个或多个独立地选自-C(＝O)R 5、卤素、氰基和羟基的基团取代；所述(4-10元杂环烷基)-C(＝O)-OCH 2-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH 2-中的4-10元杂环烷基任选被＝O取代；所述(4-10元杂环烷基)-C(＝O)-OCH 2-、(4-10元杂环烷基)-C(＝O)-O-和(4-10元杂环烷基)-CH 2-中的4-10元杂环烷基中的杂原子各自独立地选自N、O和S 中的一种或多种，杂原子个数为1、2或3个； Each R 2a , R 2b and R 2c is independently halogen, hydroxyl, deuterium, cyano, -C(=O)R 5 , -CO 2 R 5 , optionally substituted by one or more R 2-a C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkyl-O- optionally substituted by one or more R 2-b , benzene Base-Q-, FO 2 S-phenyl-Q-, phenyl-C(=O)N(R 5 )-, pyrazolyl optionally substituted by one or more C 1 -C 4 alkyl groups, Imidazolyl optionally substituted by one or more C 1 -C 4 alkyl groups, -N(R 5 ) 2 , (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), = O, (C 1 -C 4 alkyl optionally substituted by one or more halogen)-C(=O)-, -SO 2 F, (C 1 -C 4 alkyl)-SO 2 -, (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl)-O-, -CH 2 OC(=O)N(R 5 ) 2 , (C 1 -C 4 alkyl)-OC( =O)-N(R 5 )CH 2 -, -CH 2 N(R 5 )C(=O)N(R 5 ) 2 , (C 1 -C 4 alkyl)-C(=O)N( R 5 )CH 2 -, (pyrazolyl)-CH 2 -, (imidazolyl)-CH 2 -, (C 1 -C 4 alkyl)-SO 2 -N(R 5 )CH 2 -, (4 -10-membered heterocycloalkyl)-C(=O)-OCH 2 -, (R 5 ) 2 NC(=O)-O-, (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O-, phenyl-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O-, (4 -10-membered heterocycloalkyl)-C(=O)-O- or (4-10-membered heterocycloalkyl)-CH 2 -; the phenyl-C(=O)N(R 5 )- and The phenyl in phenyl-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O- is optionally selected from one or more independently selected from -C(=O)R 5 , halogen, cyano and hydroxyl group substitution; the (4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -, (4-10 membered heterocycloalkyl)-C(=O )-O- or (4-10 membered heterocycloalkyl)-CH 2 -, the 4-10 membered heterocycloalkyl is optionally substituted by =O; the (4-10 membered heterocycloalkyl)-C (=O)-OCH 2 -, (4-10 membered heterocycloalkyl)-C(=O)-O- and (4-10 membered heterocycloalkyl)-CH 2 - The heteroatoms in the cycloalkyl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
Q独立地为连接键或-O-；Q is independently a linker or -O-;
每个R 2-a和R 2-b独立地为氘、氰基、卤素或羟基； each R 2-a and R 2-b is independently deuterium, cyano, halogen or hydroxyl;
每个R 2d和R 2e各自独立地为卤素、羟基、氰基、-C(＝O)R 5、-CO 2R 5、任选被一个或多个卤素或羟基取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基-O-或-N(R 5) 2； Each R 2d and R 2e is independently halogen, hydroxy, cyano, -C(=O)R 5 , -CO 2 R 5 , C 1 -C 4 optionally substituted with one or more halogen or hydroxy Alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkyl optionally substituted by one or more halogen or hydroxyl -O- or -N(R 5 ) 2 ;
R 3为任选被一个或多个R 3a取代的C 6-C 10芳基或任选被一个或多个R 3b取代的5-14元杂芳基；所述5-14元杂芳基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
每个R 3a和R 3b各自独立地为氘、卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-b取代的C 1-C 6烷基-O-、任选被一个或多个R 3-c取代的C 1-C 6烷基-S-、任选被一个或多个R 3-d取代的C 2-C 6烯基、任选被一个或多个R 3-e取代的C 2-C 6炔基、-N(R 5) 2、-(CH 2)-C(＝O)N(R 5) 2、任选被一个或多个R 3-f取代的3-6元环烷基或三唑基； Each R 3a and R 3b is independently deuterium, 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 -b substituted C 1 -C 6 alkyl-O-, optionally one or more R 3-c substituted C 1 -C 6 alkyl-S-, optionally one or more R 3-d Substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl optionally substituted by one or more R 3-e , -N(R 5 ) 2 , -(CH 2 )-C(=O) N(R 5 ) 2 , 3-6 membered cycloalkyl or triazolyl optionally substituted by one or more R 3-f ;
每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为氘、卤素、氰基、羟基、C 1-C 4烷基、C 1-C 4烷基-O-或3-6元环烷基； Each of 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为H、氘、-N(R 5) 2、卤素、羟基、氰基、任选被一个或多个卤素或氘取代的C 1-C 6烷基、任选被一个或多个卤素或氘取代的C 1-C 6烷基-O-、C 2-C 6烯基或C 2-C 6炔基； 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和n4各自独立地为0、1、2或3；n1, n2, n3 and n4 are each independently 0, 1, 2 or 3;
每个R 5独立地为H或C 1-C 6烷基； each R 5 is independently H or C 1 -C 6 alkyl;
每个R 6a和R 6b各自独立地为H、氘、卤素、氰基、羟基或任选被一个或多个卤素或氘取代的C 1-C 4烷基； 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;
每个R 7独立地为H、氘、卤素、氰基、羟基、-N(R 5) 2、任选被一个或多个R 7a取代的C 1-C 6烷基、任选被一个或多个R 7b取代的C 1-C 6烷基-O-、任选被一个或多个R 7c取代的C 2-C 6烯基、任选被一个或多个R 7d取代的C 2-C 6炔基、-C(＝O)R 5、-CO 2R 5或-C(＝O)N(R 5) 2，或键合于同一环原子上两个R 7形成氧代基，或键合于相邻两个环原子上的R 7形成键，或键合于不同或相同环原子上的两个R 7与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；所述4-10元杂环烷基、4-10元杂环烯基中的杂原子各自独立地选自N、O和S 中的一种或多种，杂原子个数为1、2或3个； Each R 7 is independently H, deuterium, halogen, cyano, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 7a , optionally substituted by one or C 1 -C 6 alkyl-O- substituted by multiple R 7b , C 2 -C 6 alkenyl optionally substituted by one or more R 7c , C 2 - optionally substituted by one or more R 7d C 6 alkynyl, -C(=O)R 5 , -CO 2 R 5 or -C(=O)N(R 5 ) 2 , or two R 7 bonded to the same ring atom to form an oxo group, Or bonded to two adjacent ring atoms R 7 form a bond, or two R 7 bonded to different or identical ring atoms form a 3-7 membered cycloalkyl, 4- 10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl; the heteroatoms in the 4-10-membered heterocycloalkyl and 4-10-membered heterocycloalkenyl are each independently selected from N, O and S One or more of , the number of heteroatoms is 1, 2 or 3;
每个R 7a、R 7b、R 7c和R 7d各自独立地为氘、氰基、卤素或羟基； each R 7a , R 7b , R 7c and R 7d is independently deuterium, cyano, halogen or hydroxyl;
q为1或2；q is 1 or 2;
上述各取代基存在多个时，彼此可以相同，也可以不同。When the above-mentioned substituents are present in plural, they may be the same as or different from each other.
本发明还提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体：The present invention also provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers:
Figure PCTCN2022106363-appb-000002
Figure PCTCN2022106363-appb-000002
Figure PCTCN2022106363-appb-000003
Figure PCTCN2022106363-appb-000003
本发明还提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，The present invention also provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
Figure PCTCN2022106363-appb-000004
Figure PCTCN2022106363-appb-000004
本发明进一步提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，The present invention further provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
Figure PCTCN2022106363-appb-000005
Figure PCTCN2022106363-appb-000005
本发明进一步提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，The present invention further provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
Figure PCTCN2022106363-appb-000006
Figure PCTCN2022106363-appb-000006
Figure PCTCN2022106363-appb-000007
Figure PCTCN2022106363-appb-000007
Figure PCTCN2022106363-appb-000008
Figure PCTCN2022106363-appb-000008
本发明提供一种药物组合物，其包含本发明化合物和任选的药学上可接受的载体。The present invention provides a pharmaceutical composition comprising a compound of the present invention and optionally a pharmaceutically acceptable carrier.
本发明提供一种用于治疗和/或预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病的方法，包括给予对象有效量的本发明化合物或本发明上述的药物组合物。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 .
本发明提供一种用于治疗和/或预防癌症的方法，包括给予对象有 效量的本发明化合物或本发明上述的药物组合物。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.
本发明提供本发明化合物或本发明上述的药物组合物在制备用于治疗和/或预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病的药物中的用途。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).
本发明提供本发明化合物或本发明上述的药物组合物在制备用于治疗和/或预防癌症的药物中的用途。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.
本发明提供本发明化合物或本发明上述的药物组合物在制备KRAS突变抑制剂(特别是KRAS G12D突变抑制剂、KRAS G12V突变抑制剂)中的用途。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).
发明效果Invention effect
本发明化合物对于KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)表现出优异的抑制作用，可以用于治疗/预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病，特别是癌症。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.
另外，本发明化合物可以用作KRAS突变抑制剂(特别是KRAS G12D突变抑制剂、KRAS G12V突变抑制剂)。In addition, the compounds of the present invention can be used as KRAS mutation inhibitors (especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors).
本发明化合物对于KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)，表现出优异的抑制效果。The compound of the present invention shows an excellent inhibitory effect on KRAS mutations (especially KRAS G12D mutations and KRAS G12V mutations).
具体实施方式detailed description
下面将结合具体实施方式对本发明的实施方案进行更为详细的说明，但是本领域的技术人员将会理解，下列描述的具体实施方式仅用于说明本发明，而不应视为对本发明的保护范围的限定。相反，本发明意图涵盖可被包括在由权利要求所限定的本发明范围之内的所有替代、修改和等同的方式。在没有特别说明的情况下，本发明的各实施方案可以以任意地方式进行组合，由此而得的技术方案的转换、变形、改变也包括在本发明的范围之中。The embodiments of the present invention will be described in more detail below in conjunction with specific embodiments, but those skilled in the art will understand that the specific embodiments described below are only used to illustrate the present invention, and should not be regarded as protection of the present invention Scope limitation. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents as may be included within the scope of the present invention as defined by the claims. Unless otherwise specified, the various embodiments of the present invention can be combined in any manner, and the conversion, deformation and change of the technical solutions thus obtained are also included in the scope of the present invention.
定义definition
本发明中，“任选”、“任选的”或“任选地”是指随后描述的事件或状况可以发生或不发生，该描述同时包括该事件或状况发生和不发生的 情况。例如，“任选(地)被R取代”是指可以被R取代，也可以不被R取代，且该描述同时包括被R取代和不被R取代的情况。In the present invention, "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. For example, "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.
本发明中，“被取代的”或“被取代”是指基团中的一个或多个氢原子(以能被取代的氢原子的总数目为上限)，优选为1-5个氢原子，更优选为1、2、3或4个氢原子彼此独立地被相应数目的取代基取代，只要取代后的化合物是稳定的即可。本发明中，具有取代基时，取代基可以存在一个或多个；存在多个取代基团时，各取代基团可以相同，也可以彼此不同。另外，取代基可以键合于所被取代的基团的相同原子上，也可以键合于基团的不同原子上，只要取代后的化合物是稳定的即可。In the present invention, "substituted" or "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. In the present invention, 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. In addition, 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.
本发明中，“独立地”或“独立的”指其中多于一个基团选自大量可能的取代基，而那些取代基彼此可以相同或不同。例如，“R x选自-OR或-N(R) 2；每个R独立地选自H或C 1-C 4烷基”，其中R基团每次出现时都是独立的，它们彼此可以相同也可以不同。 In the present invention, "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. For example, "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.
本发明中，“基”和“基团”表示一价基团或者根据需要的符合化合价的二价以上的基团，例如“环烷基”包括从环烷烃中去除一个氢原子而得到的一价基团，也包括从其中的相同的碳原子或不同的两个以上碳原子上去除两个以上氢原子而得到的二价以上的基团。当“环烷基”作为末端基团时，其自然为一价基团，当环烷基在结构中作为连接基团时，其为二价以上的基团。本发明中，一价或二价以上的基团通常是指一价基团或二价基团，但是根据需要，该基团可以为更高的化合价(例如三价、四价、五价、六价等)。In the present invention, "group" and "group" represent a monovalent group or a group with a valence of more than two according to the need, for example, "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. When the "cycloalkyl group" is used as a terminal group, it is naturally a monovalent group, and when a cycloalkyl group is used as a linking group in the structure, it is a group with more than two valences. In the present invention, 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.).
本发明中，“C d-C e”(d和e表示1以上的整数，d＜e)包括d至e个碳的任何一种具体情况，例如C 1-C 6包括C 1、C 2、C 3、C 4、C 5、C 6，也包括d至e中的任何一个范围，例如C 1-C 6包括C 1-C 3、C 1-C 4、C 1-C 5、C 2-C 5、C 2-C 4、C 3-C 6等各个范围；同理，“d-e元”(d和e表示3以上的整数，d＜e)表示环原子数为d至e个，例如3-6元环包括3元环、4元环、5元环、6元环，也包括d至e中的任何一个范围，例如3-6元环包括3-4元环、3-5元环、4-6元环、4-5元环等。本领域技术人员可以毫无疑义地且毫无困难地对d和e进行组合。 In the present invention, "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-membered ring, 4-6-membered ring, 4-5-membered ring, etc. The person skilled in the art can combine d and e without doubt and without difficulty.
本发明中，“卤素”是指氟、氯、溴、碘等，优选氟、氯、溴，更优选氟、氯。In the present invention, "halogen" means fluorine, chlorine, bromine, iodine, etc., preferably fluorine, chlorine, bromine, more preferably fluorine, chlorine.
本发明中，“C 1-C 6烷基”是指从含有1-6个碳原子的烷烃部分去除一个氢原子而衍生得到的直链或支链的烷基，其优选为“C 1-C 4烷基”，具体地，C 1-C 6烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、异己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3，3-二甲基丁基、2，2-二甲基丁基、1，1-二甲基丁基、1，2-二甲基丁基、1，3-二甲基丁基、2，3-二甲基丁基、2-乙基丁基、1-甲基-2-甲基丙基等；所述“C 1-C 4烷基”是指从含有1-4个碳原子的烷烃部分去除一个以上氢原子而衍生得到的直链或支链的烷基，具体地，C 1-C 4烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。 In the present invention, "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-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, etc.; the "C 1 -C 4 alkyl "refers to a linear or branched alkyl group derived from the removal of more than one hydrogen atom from an alkane moiety containing 1-4 carbon atoms, specifically, a C 1 -C 4 alkyl group includes but is not limited to methyl, ethyl Base, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl.
本发明中，“C 2-C 6烯基”是指从含有至少一个碳碳双键的2-6个碳原子的烯烃部分去除一个氢原子而衍生得到的直链或支链的烯烃基，其优选为“C 2-C 4烯基”，具体地，C 2-C 6烯基包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1，3-丁二烯-1-基、1-戊烯-3-基、2-戊烯-1-基、3-戊烯-1-基、3-戊烯-2-基、1，3-戊二烯-1-基、1，4-戊二烯-3-基、1-己烯-3-基。优选的是，“C 2-C 6烯基”中含有一个碳碳双键。另外，本发明中，“C 2-C 4烯基”是指上述“C 2-6烯基”中，碳原子为2-4的情况，具体地，包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、1，3-丁二烯-1-基。 In the present invention, "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. Preferably, "C 2 -C 6 alkenyl" contains a carbon-carbon double bond. In addition, in the present invention, "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.
本发明中，“C 2-C 6炔基”是指从含有至少一个碳碳叁键的2-6个碳原子的炔烃部分去除一个氢原子而衍生得到的直链或支链的炔烃基，其优选为“C 2-4炔基”，具体地，C 2-C 6炔基可以列举乙炔基、丙炔基、2-丁炔-1-基、2-戊炔-1-基、3-戊炔-1-基、4-甲基-2-戊炔-1-基、2-己炔-1-基、2-己炔-2-基、3-己炔-1-基、3-己炔-2-基等。优选的是，“C 2-C 6炔基”中含有一个碳碳叁键。另外，本发明中，“C 2-C 4炔基”是指上述“C 2-C 6炔基”中，碳原子为2-4的情况，具体地，可以列举乙炔基、丙炔基、2-丁炔-1-基。 In the present invention, "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. Preferably, "C 2 -C 6 alkynyl" contains a carbon-carbon triple bond. In addition, in the present invention, "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.
本发明中，“C 1-C 6烷氧基”或者“C 1-C 6烷氧-O-”是指上文所定义的“C 1-C 6烷基”通过氧原子与分子其余部分连接的基团，即“C 1-C 6烷基-O-”基团，其优选为“C 1-C 4烷氧基”或者“C 1-C 4烷基-O-”，其包括但不限于，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、 仲丁氧基、叔丁氧基、新戊氧基、正己氧基等；所述的“C 1-C 4烷氧基”是指上文所定义的“C 1-C 4烷基”通过氧原子与分子其余部分连接的基团，即“C 1-C 4烷基-O-”基团，包括但不限于，甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基。 In the present invention, "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 not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butyl Oxygen.
本发明中，“C 1-C 6烷硫基”或者“C 1-C 6烷氧-S-”是指上文所定义的“C 1-C 6烷基”通过硫原子与分子其余部分连接的基团，即“C 1-C 6烷基-S-”基团，其优选为“C 1-C 4烷硫基”或者“C 1-C 4烷基-O-”，其包括但不限于，例如甲基硫基、乙基硫基、正丙基硫基、异丙基硫基、正丁基硫基、异丁基硫基、仲丁基硫基、叔丁基硫基、新戊基硫基、正己基硫基等；所述的“C 1-C 4烷硫基”是指上文所定义的“C 1-C 4烷硫基”通过硫原子与分子其余部分连接的基团，即“C 1-C 4烷基-S-”基团，包括但不限于，甲基硫基、乙基硫基、正丙基硫基、异丙基硫基、正丁基硫基、异丁基硫基、仲丁基硫基、叔丁基硫基。 In the present invention, "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 rest of the molecule The attached group, that is, "C 1 -C 4 alkyl-S-" group, includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butyl Sylthio, isobutylthio, sec-butylthio, tert-butylthio.
本发明中，“-NH(R)”或“-N(R) 2”是指氨基(-NH 2)的一个氢原子或者两个氢原子被R基团取代的情况，对于所述R基团，只要符合本发明中“-NH(R)”或“-N(R) 2”中的定义，没有任何限定。当氮原子为环结构上的环原子时，其形成为“-N(R)-”或“-N＝”的结构。 In the present invention, "-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. For the 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. When a nitrogen atom is a ring atom on a ring structure, it forms a structure of "-N(R)-" or "-N=".
本发明中，“环原子”是指形成环结构的原子，包括但不限于C、N、O、P和S；“环碳原子”是指形成环结构的碳原子；“环杂原子”是指除碳原子之外的环原子，包括但不限于环原子N、O、P和S。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.
本发明中，“环烷基”是指饱和或部分不饱和的非芳香性的环状烃基，它可以是一价基团或根据需要的二价以上的基团，包括单环环烷基和多环环烷基，多环环烷基包括螺环环烷基、并环环烷基和桥环环烷基，所述“螺环环烷基”是指单环之间共用一个环碳原子(称螺原子)的多环环烷基，所述“并环环烷基”是指基团中的每个环与其他环共用相邻的一对环碳原子的多环环烷基，所述“桥环环烷基”是指任意两个环共用两个不直接连接的环碳原子的多环环烷基。另外，所述“环烷基”还包括碳环原子被氧代的情况，如碳环原子被C(＝O)替代的情况。In the present invention, "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. (referred to as a spiro atom) polycyclic 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. In addition, the "cycloalkyl" also includes the case where the carbon ring atom is substituted by oxo, such as the case where the carbon ring atom is replaced by C(=O).
本发明中，“3-10元环烷基”是指包括3-10个环碳原子的饱和或部分不饱和的非芳香性的单环或多环(例如双环、三环或更多环的桥环、并环或螺环)环烷基，包括但不限于环丙基、环丁基、环戊基、环己基、 环庚基、环辛基、
Figure PCTCN2022106363-appb-000009
等。“3-7元环烷基”是指包括3-7个环碳原子的环烷基，包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。“5-10元环烷基”是指包括5-10个环碳原子的环烷基，包括但不限于环戊基、环己基、环庚基、环辛基等。“3-6元环烷基”是指包括3-6个环碳原子的环烷基。“3-4元环烷基”是指包括3-4个环碳原子的环烷基。 In the present invention, "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,
Figure PCTCN2022106363-appb-000009
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.
本发明中，“杂环基”是指其中一个或多个(优选1个、2个、3个或4个)环原子为选自N、O和S的环杂原子的饱和或部分不饱和的非芳香性的环状烃基，它可以是一价基团或根据需要的二价以上的基团，包括单环杂环基和多环杂环基，多环杂环基包括双环、三环或更多环的螺环杂环基、并环杂环基和桥环杂环基，所述“螺环杂环基”是指单环之间共用一个环原子(称螺原子)的多环杂环基，所述“并环杂环基”是指基团中的每个环与其他环共用相邻的一对环原子的多环杂环基，所述“桥环杂环基”是指任意两个环共用两个不直接连接的环原子的多环杂环基。另外，杂环基还包括环原子C、S被氧代的情况，如环原子C、S被C(＝O)、S(＝O)、S(＝O) 2替代的情况。 In the present invention, "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, the "paracyclic 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, and the "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. In addition, the heterocyclic group also includes the case where the ring atoms C and S are replaced by oxo, such as the case where the ring atoms C and S are replaced by C(=O), S(=O), and S(=O) 2 .
本发明中，“4-10元杂环烷基”是指包括4-10个环原子的饱和单环或多环(例如双环、三环或更多环的桥环、并环或螺环)杂环烷基，优选含有1个、2个或3个选自N、O和S的环杂原子，具体地，4-10元杂环烷基包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、四氢呋喃基、四氢吡咯基
Figure PCTCN2022106363-appb-000010
(例如
Figure PCTCN2022106363-appb-000011
又例如
Figure PCTCN2022106363-appb-000012
“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或其混合)、吡咯烷酮基、四氢噻吩基、咪唑烷基、吡唑烷基、1，2-噁唑烷基、1，3-噁唑烷基、1，2-噻唑烷基、1，3-噻唑烷基、四氢-2H-吡喃基、四氢-2H-噻喃基、哌啶基、哌啶酮基、哌嗪基、吗啉基、1，4-二氧杂环己烷基、1，4-氧硫杂 环己烷基、2，3，4，5-四氢吡啶基、
Figure PCTCN2022106363-appb-000013
(例如
Figure PCTCN2022106363-appb-000014
又例如
Figure PCTCN2022106363-appb-000015
“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或其混合)、
Figure PCTCN2022106363-appb-000016
(例如
Figure PCTCN2022106363-appb-000017
)、
Figure PCTCN2022106363-appb-000018
(例如
Figure PCTCN2022106363-appb-000019
)、
Figure PCTCN2022106363-appb-000020
(例如
Figure PCTCN2022106363-appb-000021
)、
Figure PCTCN2022106363-appb-000022
(例如
Figure PCTCN2022106363-appb-000023
)、
Figure PCTCN2022106363-appb-000024
(例如
Figure PCTCN2022106363-appb-000025
)、
Figure PCTCN2022106363-appb-000026
(例如
Figure PCTCN2022106363-appb-000027
)、
Figure PCTCN2022106363-appb-000028
(例如
Figure PCTCN2022106363-appb-000029
)、
Figure PCTCN2022106363-appb-000030
(例如
Figure PCTCN2022106363-appb-000031
)、
Figure PCTCN2022106363-appb-000032
(例如
Figure PCTCN2022106363-appb-000033
)、
Figure PCTCN2022106363-appb-000034
(例如
Figure PCTCN2022106363-appb-000035
)、
Figure PCTCN2022106363-appb-000036
(例如
Figure PCTCN2022106363-appb-000037
)或
Figure PCTCN2022106363-appb-000038
(例如
Figure PCTCN2022106363-appb-000039
)；“5-10元杂环烷基”是指包括5-10个环原子的饱和杂环烷基，优选含有1个、2个或3个选自N、O和S的环杂原子，具体地，5-10元杂环烷基包括但不限于上述“4-10元杂环烷基”中环原子为5-10的基团，其中“5-10元含1个氮原子的杂环烷基”是指上述“5-10元杂环烷基”中的一个环原子为N原子的基团。“4-7元杂环烷基”是指包括4-7个环原子的饱和杂环烷基，优选含有1个、2个或3个选自N、O和S的环杂原子，具体地，4-7元杂环烷基包括但不限于上述“4-10元杂环烷基”中环原子为4-7的基团。 In the present invention, "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
Figure PCTCN2022106363-appb-000010
(For example
Figure PCTCN2022106363-appb-000011
another example
Figure PCTCN2022106363-appb-000012
"*" 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-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl , piperidinyl, piperidinone, piperazinyl, morpholinyl, 1,4-dioxanyl, 1,4-oxathione, 2,3,4,5- Tetrahydropyridyl,
Figure PCTCN2022106363-appb-000013
(For example
Figure PCTCN2022106363-appb-000014
another example
Figure PCTCN2022106363-appb-000015
"*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof),
Figure PCTCN2022106363-appb-000016
(For example
Figure PCTCN2022106363-appb-000017
),
Figure PCTCN2022106363-appb-000018
(For example
Figure PCTCN2022106363-appb-000019
),
Figure PCTCN2022106363-appb-000020
(For example
Figure PCTCN2022106363-appb-000021
),
Figure PCTCN2022106363-appb-000022
(For example
Figure PCTCN2022106363-appb-000023
),
Figure PCTCN2022106363-appb-000024
(For example
Figure PCTCN2022106363-appb-000025
),
Figure PCTCN2022106363-appb-000026
(For example
Figure PCTCN2022106363-appb-000027
),
Figure PCTCN2022106363-appb-000028
(For example
Figure PCTCN2022106363-appb-000029
),
Figure PCTCN2022106363-appb-000030
(For example
Figure PCTCN2022106363-appb-000031
),
Figure PCTCN2022106363-appb-000032
(For example
Figure PCTCN2022106363-appb-000033
),
Figure PCTCN2022106363-appb-000034
(For example
Figure PCTCN2022106363-appb-000035
),
Figure PCTCN2022106363-appb-000036
(For example
Figure PCTCN2022106363-appb-000037
)or
Figure PCTCN2022106363-appb-000038
(For example
Figure PCTCN2022106363-appb-000039
); "5-10 membered heterocycloalkyl" refers to a saturated heterocycloalkyl group comprising 5-10 ring atoms, preferably containing 1, 2 or 3 ring heteroatoms selected from N, O and S, Specifically, 5-10 membered heterocycloalkyl groups include but are not limited to groups with 5-10 ring atoms in the above-mentioned "4-10 membered heterocycloalkyl groups", wherein "5-10 membered heterocyclic rings containing 1 nitrogen atom "Alkyl" refers to a group in which one ring atom in the above-mentioned "5- to 10-membered heterocycloalkyl" is an N atom. "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".
本发明中，“4-10元杂环烯基”是指在上述“4-10元杂环烷基”的环结构中存在至少一个碳碳双键的基团，优选存在一个碳碳双键，具体地，所述4-10元杂环烯基包括但不限于4，5-二氢异噁唑基、4，5-二氢噁唑基、2，5-二氢噁唑基、2，3-二氢噁唑基、3，4-二氢-2H-吡咯基、2，3-二氢-1H-吡咯基、2，5-二氢-1H-咪唑基、4，5-二氢-1H-咪唑基、4，5-二氢-1H- 吡唑基、4，5-二氢-3H-吡唑基、4，5-二氢噻唑基、2，5-二氢噻唑基、2H-吡喃基、4H-吡喃基、2H-噻喃基、4H-噻喃基、1，2-异噁嗪基、1，4-异噁嗪基、6H-1，3-噁嗪基、
Figure PCTCN2022106363-appb-000040
(例如
Figure PCTCN2022106363-appb-000041
)、
Figure PCTCN2022106363-appb-000042
(例如
Figure PCTCN2022106363-appb-000043
)等。 In the present invention, "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-dihydrothiazolyl , 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 1,2-isoxazinyl, 1,4-isoxazinyl, 6H-1,3-oxa Azinyl,
Figure PCTCN2022106363-appb-000040
(For example
Figure PCTCN2022106363-appb-000041
),
Figure PCTCN2022106363-appb-000042
(For example
Figure PCTCN2022106363-appb-000043
)Wait.
本发明中，“芳基”是指具有芳香性的环状烃基，它可以是一价基团或根据需要的二价以上的基团，包括单环芳基和稠环芳基，“稠环芳基”是指基团中的每个环与其他环共用相邻的一对环碳原子的含有多个环(优选含有2个或3个环)的芳基。本发明中，“C 6-C 10芳基”是指包括6-10个环碳原子的芳基，包括苯基、萘基(例如
Figure PCTCN2022106363-appb-000044
)。 In the present invention, "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. In the present invention, "C 6 -C 10 aryl" refers to an aryl group including 6-10 ring carbon atoms, including phenyl, naphthyl (such as
Figure PCTCN2022106363-appb-000044
).
本发明中，“杂芳基”是指其中一个或多个(优选1-5个，更优选1个、2个、3个或4个)环原子为选自N、O和S的环杂原子的具有芳香性的环状烃基，它可以是一价基团或根据需要的二价以上的基团，包括单环杂芳基和稠环杂芳基，所述“稠环杂芳基”是指基团中的每个环与其他环共用相邻的一对环原子的含有多个环(优选含有2个或3个环)的杂芳基。In the present invention, "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.
本发明中，“5-14元杂芳基”是指包括5-14个环原子的杂芳基，优选含有1个、2个、3个或4个选自N、O和S的环杂原子，具体地，5-14元杂芳基包括但不限于呋喃基、咪唑基、异噁唑基、噻唑基、异噻唑基、噁二唑基、噁唑基、吡啶基(例如
Figure PCTCN2022106363-appb-000045
)、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、四唑基、吲嗪基、噻二唑基、噻吩基、三唑基、三嗪基、苯并咪唑基、苯并呋喃基、苯并噻吩基(例如
Figure PCTCN2022106363-appb-000046
)、苯并噁二唑基、苯并噻二唑基、苯并噻唑基、苯并异噻唑基、呋喃并吡啶基、吲唑基、吲哚基、异吲哚基、异喹啉基、嘌呤基、喹啉基、 喹唑啉基、喹喔啉基、噻吩并吡啶基、苯并恶唑基、噁三唑基、噌啉基、邻二氮杂菲基、二氮萘基、萘啶基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基或三唑并吡啶基。本发明中，“5-10元杂芳基”是指包括5-10个环原子的杂芳基，优选含有1个、2个、3个或4个选自N、O和S的环杂原子，具体地，5-10元杂芳基包括但不限于上述“5-14元杂芳基”中环原子为5-10的基团。“5-6元杂芳基”是指包括5-6个环原子的杂芳基，优选含有1个、2个、3个或4个选自N、O和S的环杂原子，具体地，5-6元杂芳基包括但不限于上述“5-14元杂芳基”中环原子为5-6的基团。 In the present invention, "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.
Figure PCTCN2022106363-appb-000045
), pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, indolizinyl, thiadiazolyl, thienyl, triazolyl, triazinyl, benzimidazolyl, benzene Furanyl, benzothienyl (e.g.
Figure PCTCN2022106363-appb-000046
), benzoxadiazolyl, benzothiadiazolyl, benzothiazolyl, benzisothiazolyl, furopyridyl, indazolyl, indolyl, isoindolyl, isoquinolyl, Purinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienopyridyl, benzoxazolyl, oxatriazolyl, cinnolinyl, o-phenanthrenyl, naphthyl, naphthalene Pyridyl, pteridyl, carbazolyl, carbalinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl or triazolopyridyl. In the present invention, "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".
本发明中，“氨基保护基”是指连接在氨基上且在一定条件下容易脱除的化学基团，其包括但不限于烷氧羰基类、酰基类、烷基类；例如叔丁氧羰基、苄氧羰基、芴甲氧羰基、烯丙氧羰基、邻苯二甲酰基、苄基、对甲氧基苄基、三苯甲基等。本领域技术人员可以参照本领域常用教科书Greene’s Protective Groups in Organic Synthesis(4 th edition)进行适当的选择和操作。 In the present invention, "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.
本发明中，“羟基保护基”是指连接在羟基上且在一定条件下容易脱除的化学基团，其包括但不限于甲基、甲氧基甲基、乙酰基、叔丁基二甲基硅基和甲硅烷基等。本领域技术人员可以参照本领域常用教科书Greene’s Protective Groups in Organic Synthesis(4 th edition)进行适当的选择和操作。 In the present invention, "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.
本发明中，“炔基保护基”是指连接在炔基上且在一定条件下容易脱除的化学基团，其包括但不限于三异丙基硅基等。本领域技术人员可以参照本领域常用教科书Greene’s Protective Groups in Organic Synthesis(4 th edition)进行适当的选择和操作。 In the present invention, "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.
本发明所述的“一至多个”、“一个以上”是指取代基的数量的上限可以为所取代基团中所有化学上可以被取代的位置，可以为1-6个，可以为1-5个，可以为1-3个，可以为1-2个，可以为1个。"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.
本发明所述的“任选被取代基取代”中，取代基的数量可以为0个(即，未被取代)，或者为1至待取代基团中的所有化学上可以被取代的 位置的数量，可以为1-6个，可以为1-5个，可以为1-4个，可以为1-3个，可以为1-2个或1个。In the "optionally substituted by substituents" described in the present invention, 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.
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2022106363-appb-000047
及
Figure PCTCN2022106363-appb-000048
是指，相应的基团R通过该位点与化合物中的其它片段、基团进行连接。 Those skilled in the art can understand that, according to the practice used in this field, the application describes the structural formula used in the group
Figure PCTCN2022106363-appb-000047
and
Figure PCTCN2022106363-appb-000048
means that the corresponding group R is connected to other fragments and groups in the compound through this site.
本发明中，“药学上可接受的”指其在合理的医学判断范围内，适于接触人类和动物的组织而没有过度毒性、刺激或其它问题或并发症，与合理的益处/风险比相称的那些化合物、物质、组合物和剂型。In the context of the present invention, "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.
本发明中，“药学上可接受的载体”指的是一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙甲纤维素其及衍生物、醋酸纤维素及其衍生物、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁/钙、氢化植物油、硬脂酸富马酸钠)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂等。In the present invention, "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. "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of 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.
本发明中，针对药物或药理学活性剂而言，“有效量”是指无毒的但能达到预期效果的药物或药理学活性剂的足够用量。有效量的确定因人而异，取决于患者的年龄、体重和病症情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。In the present invention, for a drug or a pharmacologically active agent, 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.
本发明中，“活性成分”、“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。As used herein, "active ingredient", "active substance" or "active agent" refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
本发明中，“患者”、“个体”或“对象”包括人、动物、脊椎动物、哺乳动物、啮齿动物(例如豚鼠、仓鼠、大鼠、小鼠)、鼠科动物(例如小鼠)、犬科动物(例如狗)、灵长目动物、类人猿(如猴或无尾猿)、猴(如狨猴、狒狒)、无尾猿(例如大猩猩、黑猩猩、猩猩、长臂猿)。在一些实施方案中，“患者”为人。In the present invention, "patient", "individual" or "subject" 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). In some embodiments, a "patient" is a human.
本发明中，“治疗”指治疗性疗法或缓解性措施。涉及具体病症时， 治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。“治疗”也可以指与不接受治疗的期望存活相比延长生存期。In the present invention, "treatment" refers to therapeutic therapy or palliative measures. In relation to a specific condition, 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.
本发明中，“预防”是指获得或发生疾病或障碍的风险降低。In the context of the present invention, "prevention" means a reduction in the risk of acquiring or developing a disease or disorder.
本发明中，当带“*”的碳原子为手性碳原子时，其为R构型、S构型或其混合。In the present invention, when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture thereof.
本发明中，本发明通式(1)所示的化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当通式(1)化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。In the present invention, 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. When a compound contains one chiral center, 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. When 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. The term "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. For example a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof. When 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.
本发明化合物可能具有两种源于轴不对称的阻转异构体，其是因当取代基R 3为芳基、杂芳基等环状基团(特别是在连接键的两端邻位具有取代基或在连接键的邻位具有空间结构较大的基团时)时和被取代的吡啶并嘧啶环之间的连接键由于空间位阻致使旋转受阻而产生。有关本发明的阻转异构体，其中化合物具有通式(1)的结构，或通式(1)化合 物具有由不对称碳等产生的异构体，它表示每种异构化合物中存在的一对阻转异构体中的任一种。且作为药物，具有优异活性的阻转异构体是优选的。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集，还可以通过与其它手性化合物成键或成盐等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95％。通式(1)化合物具有源于不对称碳、轴向不对称等的光学异构体，必要时单一异构体可通过本领域已知的方法，例如结晶或色谱法(例如手性色谱)等方法进行拆分获得。 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. Regarding the atropisomers of the present invention, wherein 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., it means that the present in each isomer compound Either of a pair of atropisomers. And as a drug, 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. The term "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.
如前所述，本发明提供了上述各类结构所示化合物，或其顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其中“其混合物形式”包括前述的任一立体异构体(例如顺反异构体、对映异构体、非对映异构体、阻转异构体)和/或混合物(内消旋体、外消旋体)之间的任意形式的混合，例如顺反异构体的混合物，对映异构体和非对映异构体的混合物，非对映异构体的混合物，阻转异构体的混合物，或顺反异构体和外消旋体的混合，对映异构体和非对映异构体混合物的混合，阻转异构体与非对映异构体混合物的混合等。As mentioned above, 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.
本发明化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氘(D)，氚( 3H)，碘-125( 125I)或C-14( 14C)。本发明化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, 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.
具体而言，本发明提供了下述通式(1)所示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，Specifically, the present invention provides pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the following general formula (1),
Figure PCTCN2022106363-appb-000049
Figure PCTCN2022106363-appb-000049
X为单键、O、NR 7、S、S(＝O)、S(＝O) 2、P(＝O)R 7或C(R 7) 2； X is a single bond, O, NR 7 , S, S(=O), S(=O) 2 , P(=O)R 7 or C(R 7 ) 2 ;
Y为单键、O、S或-(C(R 7) 2) q-； Y is a single bond, O, S or -(C(R 7 ) 2 ) q -;
Z为NH、NR 1、CH 2、CHR 1或C(R 1) 2； Z is NH, NR 1 , CH 2 , CHR 1 or C(R 1 ) 2 ;
每个R 1独立地为氘、卤素、氰基、羟基、-N(R 5) 2、任选被一个或多个R 1a取代的C 1-C 6烷基、任选被一个或多个R 1b取代的C 1-C 6烷基-O-、任选被一个或多个R 1c取代的C 2-C 6烯基、任选被一个或多个R 1d取代的C 2-C 6炔基、-C(＝O)R 5、-CO 2R 5、-C(＝O)N(R 5) 2或5-6元杂芳基，或键合于同一环原子上两个R 1形成氧代基，或键合于相邻两个环原子上的R 1形成键，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；所述5-6元杂芳基、4-10元杂环烷基、4-10元杂环烯基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 1 is independently deuterium, halogen, cyano, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 1a , optionally substituted by one or more C 1 -C 6 alkyl-O-substituted by R 1b , C 2 -C 6 alkenyl optionally substituted by one or more R 1c , C 2 -C 6 optionally substituted by one or more R 1d Alkynyl, -C(=O)R 5 , -CO 2 R 5 , -C(=O)N(R 5 ) 2 or 5-6 membered heteroaryl, or two R bonded to the same ring atom 1 forms an oxo group, or R 1 bonded to two adjacent ring atoms forms a bond, or two R 1 bonded to different or the same ring atoms form a 3-7 membered group together with the atoms they are connected to Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl; said 5-6 membered heteroaryl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl The heteroatoms are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
每个R 1a、R 1b、R 1c和R 1d各自独立地为氘、氰基、卤素或羟基； each R 1a , R 1b , R 1c and R 1d is independently deuterium, cyano, halogen or hydroxyl;
n为0、1、2、3、4、5、6或7；n is 0, 1, 2, 3, 4, 5, 6 or 7;
L为-(CR 6aR 6b) n1-、-O-(CR 6aR 6b) n2-、-S-(CR 6aR 6b) n3-或-N(R 5)(CR 6aR 6b) n4-； 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 - ;
R 2为H、-C(＝O)R 5、-CO 2R 5、-N(R 5) 2、C 1-C 6烷基、C 1-C 6烷基-O-、任选被一个或多个R 2a取代的3-10元环烷基、任选被一个或多个R 2b取代的4-10元杂环烷基、任选被一个或多个R 2d取代的C 6-C 10芳基、任选被一个或多个R 2e取代的5-10元杂芳基、-N(R 5)C(＝NH)N(R 5) 2、-C(O)N(R 5) 2、-C(＝O)O-C 1-C 6烷基或任选被一个或多个R 2c取代的C 6-C 10芳基-C(＝O)NR 5-；所述4-10元杂环烷基、5-10元杂芳基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； R 2 is H, -C(=O)R 5 , -CO 2 R 5 , -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, optionally 3-10 membered cycloalkyl substituted by one or more R 2a , 4-10 membered heterocycloalkyl optionally substituted by one or more R 2b , C 6 optionally substituted by one or more R 2d - C 10 aryl, 5-10 membered heteroaryl optionally substituted by one or more R 2e , -N(R 5 )C(=NH)N(R 5 ) 2 , -C(O)N(R 5 ) 2 , -C(=O)OC 1 -C 6 alkyl or C 6 -C 10 aryl optionally substituted by one or more R 2c -C(=O)NR 5 -; the 4- The heteroatoms in the 10-membered heterocycloalkyl group and the 5-10-membered heteroaryl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、氘、氰基、-C(＝O)R 5、-CO 2R 5、任选被一个或多个R 2-a取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、任选被一个或多个R 2-b取代的C 1-C 4烷基-O-、苯基-Q-、FO 2S-苯基-Q-、苯基-C(＝O)N(R 5)-、任选被一个或多个C 1-C 4烷基取代的吡唑基、任选被一个或多个C 1-C 4烷基取代的咪唑基、-N(R 5) 2、(C 1-C 4烷基)-O-(C 1-C 4烷基)、＝O、(任选被一个或多个卤素取代的C 1-C 4烷基)-C(＝O)-、-SO 2F、(C 1-C 4烷基)-SO 2-、(C 1-C 4烷基)-O-(C 1-C 4烷基)-O-、-CH 2OC(＝O)N(R 5) 2、(C 1-C 4烷基)-O-C(＝O)-N(R 5)CH 2-、-CH 2N(R 5)C(＝O)N(R 5) 2、(C 1-C 4烷基)-C(＝O)N(R 5)CH 2-、(吡唑基)-CH 2-、(咪唑基)-CH 2-、(C 1-C 4烷基)-SO 2-N(R 5)CH 2-、(4-10元杂环烷基)-C(＝O)-OCH 2-、(R 5) 2N-C(＝O)-O-、(C 1-C 4烷基)-O-(C 1-C 4烷 基)-N(R 5)-C(＝O)-O-、苯基-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH 2-；所述苯基-C(＝O)N(R 5)-和苯基-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-中的苯基任选被一个或多个独立地选自-C(＝O)R 5、卤素、氰基和羟基的基团取代；所述(4-10元杂环烷基)-C(＝O)-OCH 2-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH 2-中的4-10元杂环烷基任选被＝O取代；所述(4-10元杂环烷基)-C(＝O)-OCH 2-、(4-10元杂环烷基)-C(＝O)-O-和(4-10元杂环烷基)-CH 2-中的4-10元杂环烷基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 2a , R 2b and R 2c is independently halogen, hydroxyl, deuterium, cyano, -C(=O)R 5 , -CO 2 R 5 , optionally substituted by one or more R 2-a C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkyl-O- optionally substituted by one or more R 2-b , benzene Base-Q-, FO 2 S-phenyl-Q-, phenyl-C(=O)N(R 5 )-, pyrazolyl optionally substituted by one or more C 1 -C 4 alkyl groups, Imidazolyl optionally substituted by one or more C 1 -C 4 alkyl groups, -N(R 5 ) 2 , (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), = O, (C 1 -C 4 alkyl optionally substituted by one or more halogen)-C(=O)-, -SO 2 F, (C 1 -C 4 alkyl)-SO 2 -, (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl)-O-, -CH 2 OC(=O)N(R 5 ) 2 , (C 1 -C 4 alkyl)-OC( =O)-N(R 5 )CH 2 -, -CH 2 N(R 5 )C(=O)N(R 5 ) 2 , (C 1 -C 4 alkyl)-C(=O)N( R 5 )CH 2 -, (pyrazolyl)-CH 2 -, (imidazolyl)-CH 2 -, (C 1 -C 4 alkyl)-SO 2 -N(R 5 )CH 2 -, (4 -10-membered heterocycloalkyl)-C(=O)-OCH 2 -, (R 5 ) 2 NC(=O)-O-, (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O-, phenyl-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O-, (4 -10-membered heterocycloalkyl)-C(=O)-O- or (4-10-membered heterocycloalkyl)-CH 2 -; the phenyl-C(=O)N(R 5 )- and The phenyl in phenyl-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O- is optionally selected from one or more independently selected from -C(=O)R 5 , halogen, cyano and hydroxyl group substitution; the (4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -, (4-10 membered heterocycloalkyl)-C(=O )-O- or (4-10 membered heterocycloalkyl)-CH 2 -, the 4-10 membered heterocycloalkyl is optionally substituted by =O; the (4-10 membered heterocycloalkyl)-C (=O)-OCH 2 -, (4-10 membered heterocycloalkyl)-C(=O)-O- and (4-10 membered heterocycloalkyl)-CH 2 - The heteroatoms in the cycloalkyl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
Q独立地为连接键或-O-；Q is independently a linker or -O-;
每个R 2-a和R 2-b独立地为氘、氰基、卤素或羟基； each R 2-a and R 2-b is independently deuterium, cyano, halogen or hydroxyl;
每个R 2d和R 2e各自独立地为卤素、羟基、氰基、-C(＝O)R 5、-CO 2R 5、任选被一个或多个卤素或羟基取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基-O-或-N(R 5) 2； Each R 2d and R 2e is independently halogen, hydroxy, cyano, -C(=O)R 5 , -CO 2 R 5 , C 1 -C 4 optionally substituted with one or more halogen or hydroxy Alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkyl optionally substituted by one or more halogen or hydroxyl -O- or -N(R 5 ) 2 ;
R 3为任选被一个或多个R 3a取代的C 6-C 10芳基或任选被一个或多个R 3b取代的5-14元杂芳基；所述5-14元杂芳基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
每个R 3a和R 3b各自独立地为氘、卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-b取代的C 1-C 6烷基-O-、任选被一个或多个R 3-c取代的C 1-C 6烷基-S-、任选被一个或多个R 3-d取代的C 2-C 6烯基、任选被一个或多个R 3-e取代的C 2-C 6炔基、-N(R 5) 2、-(CH 2)-C(＝O)N(R 5) 2、任选被一个或多个R 3-f取代的3-6元环烷基或三唑基； Each R 3a and R 3b is independently deuterium, 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 -b substituted C 1 -C 6 alkyl-O-, optionally one or more R 3-c substituted C 1 -C 6 alkyl-S-, optionally one or more R 3-d Substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl optionally substituted by one or more R 3-e , -N(R 5 ) 2 , -(CH 2 )-C(=O) N(R 5 ) 2 , 3-6 membered cycloalkyl or triazolyl optionally substituted by one or more R 3-f ;
每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为氘、卤素、氰基、羟基、C 1-C 4烷基、C 1-C 4烷基-O-或3-6元环烷基； Each of 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为H、氘、-N(R 5) 2、卤素、羟基、氰基、任选被一个或多个卤素或氘取代的C 1-C 6烷基、任选被一个或多个卤素或氘取代的C 1-C 6烷基-O-、C 2-C 6烯基或C 2-C 6炔基； 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和n4各自独立地为0、1、2或3；n1, n2, n3 and n4 are each independently 0, 1, 2 or 3;
每个R 5独立地为H或C 1-C 6烷基； each R 5 is independently H or C 1 -C 6 alkyl;
每个R 6a和R 6b各自独立地为H、氘、卤素、氰基、羟基或任选被一个或多个卤素或氘取代的C 1-C 4烷基； 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;
每个R 7独立地为H、氘、卤素、氰基、羟基、-N(R 5) 2、任选被一个或多个R 7a取代的C 1-C 6烷基、任选被一个或多个R 7b取代的C 1-C 6烷基-O-、任选被一个或多个R 7c取代的C 2-C 6烯基、任选被一个或多个R 7d取代的C 2-C 6炔基、-C(＝O)R 5、-CO 2R 5或-C(＝O)N(R 5) 2，或键合于同一环原子上两个R 7形成氧代基，或键合于相邻两个环原子上的R 7形成键，或键合于不同或相同环原子上的两个R 7与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；所述4-10元杂环烷基、4-10元杂环烯基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 7 is independently H, deuterium, halogen, cyano, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 7a , optionally substituted by one or C 1 -C 6 alkyl-O- substituted by multiple R 7b , C 2 -C 6 alkenyl optionally substituted by one or more R 7c , C 2 - optionally substituted by one or more R 7d C 6 alkynyl, -C(=O)R 5 , -CO 2 R 5 or -C(=O)N(R 5 ) 2 , or two R 7 bonded to the same ring atom to form an oxo group, Or bonded to two adjacent ring atoms R 7 form a bond, or two R 7 bonded to different or identical ring atoms form a 3-7 membered cycloalkyl, 4- 10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl; the heteroatoms in the 4-10-membered heterocycloalkyl and 4-10-membered heterocycloalkenyl are each independently selected from N, O and S One or more of , the number of heteroatoms is 1, 2 or 3;
每个R 7a、R 7b、R 7c和R 7d各自独立地为氘、氰基、卤素或羟基； each R 7a , R 7b , R 7c and R 7d is independently deuterium, cyano, halogen or hydroxyl;
q为1或2；q is 1 or 2;
上述各取代基存在多个时，彼此可以相同，也可以不同。When the above-mentioned substituents are present in plural, they may be the same as or different from each other.
在本发明的一个实施方式中，本发明提供了下述通式(1)所示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，In one embodiment of the present invention, the present invention provides pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the following general formula (1),
Figure PCTCN2022106363-appb-000050
Figure PCTCN2022106363-appb-000050
X为O或NR 7； X is 0 or NR 7 ;
Y为-(C(R 7) 2) q-； Y is -(C(R 7 ) 2 ) q -;
Z为NH或NR 1； Z is NH or NR 1 ;
每个R 1独立地为卤素、任选被一个或多个R 1a取代的C 1-C 6烷基，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-10元杂环烷基；所述4-10元杂环烷基中杂原子选自N，杂原子个数为1、2或3个； 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;
每个R 1a独立地为氘、氰基、卤素或羟基； each R 1a is independently deuterium, cyano, halogen or hydroxy;
n为0、1、2或3；n is 0, 1, 2 or 3;
L为-O-(CR 6aR 6b) n2-； L is -O-(CR 6a R 6b ) n2 -;
R 2为任选被一个或多个R 2b取代的4-10元杂环烷基；所述4-10元杂环烷基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
每个R 2b独立地为卤素、羟基、氘、氰基或任选被一个或多个R 2-a取代的C 1-C 4烷基； each R 2b is independently halogen, hydroxy, deuterium, cyano, or C 1 -C 4 alkyl optionally substituted by one or more R 2-a ;
每个R 2-a独立地为氘、氰基、卤素或羟基； each R 2-a is independently deuterium, cyano, halogen or hydroxy;
R 3为任选被一个或多个R 3a取代的C 6-C 10芳基或任选被一个或多个R 3b取代的5-14元杂芳基；所述5-14元杂芳基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
每个R 3a和R 3b各自独立地为氘、卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-e取代的C 2-C 6炔基、-N(R 5) 2或-(CH 2) n5-C(＝O)N(R 5) 2； Each R 3a and R 3b is independently deuterium, 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, -N(R 5 ) 2 or -(CH 2 ) n5 -C(=O)N(R 5 ) 2 ;
每个R 3-a和R 3-e各自独立地为氘、卤素、氰基、羟基或C 1-C 4烷基； Each R 3-a and R 3-e is independently deuterium, halogen, cyano, hydroxyl or C 1 -C 4 alkyl;
R 4为H、氘、卤素、羟基、氰基或任选被一个或多个卤素或氘取代的C 1-C 6烷基； R 4 is H, deuterium, halogen, hydroxyl, cyano or C 1 -C 6 alkyl optionally substituted by one or more halogen or deuterium;
n2为0、1、2或3；n2 is 0, 1, 2 or 3;
每个n5独立地为0、1、2或3；each n5 is independently 0, 1, 2 or 3;
每个R 5独立地为H或C 1-C 6烷基； each R 5 is independently H or C 1 -C 6 alkyl;
每个R 6a和R 6b各自独立地为H、氘、卤素、氰基、羟基或任选被一个或多个卤素或氘取代的C 1-C 4烷基； 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;
每个R 7独立地为H、氘、卤素、氰基、羟基或任选被一个或多个R 7a取代的C 1-C 6烷基； each R 7 is independently H, deuterium, halogen, cyano, hydroxyl, or C 1 -C 6 alkyl optionally substituted by one or more R 7a ;
每个R 7a独立地为氘、氰基、卤素或羟基； each R 7a is independently deuterium, cyano, halogen or hydroxy;
q为1或2；q is 1 or 2;
上述各取代基存在多个时，彼此可以相同，也可以不同When the above-mentioned substituents are present in plural, they may be the same as or different from each other.
在本发明的一个实施方式中，通式(1)所示的吡啶并嘧啶衍生物为下述通式(1′)所示的吡啶并嘧啶衍生物，In one embodiment of the present invention, the pyridopyrimidine derivative represented by the general formula (1) is a pyridopyrimidine derivative represented by the following general formula (1′),
Figure PCTCN2022106363-appb-000051
Figure PCTCN2022106363-appb-000051
其中，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Wherein, "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
在本发明的一个实施方式中，本发明的通式(1)可以用下述通式(2) 或通式(3)表示，In one embodiment of the present invention, the general formula (1) of the present invention can be represented by the following general formula (2) or general formula (3),
Figure PCTCN2022106363-appb-000052
Figure PCTCN2022106363-appb-000052
其中，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Wherein, "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
在本发明的一个实施方式中，本发明的通式(1)可以用下述通式(4)、通式(5)或通式(6)表示，In one embodiment of the present invention, general formula (1) of the present invention can be represented by following general formula (4), general formula (5) or general formula (6),
Figure PCTCN2022106363-appb-000053
Figure PCTCN2022106363-appb-000053
Figure PCTCN2022106363-appb-000054
Figure PCTCN2022106363-appb-000054
其中m为1、2或3，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Wherein, m is 1, 2 or 3, and "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
在本发明的一个实施方式中，本发明的通式(1)可以用下述通式(2)、通式(2’)、通式(3)或通式(3’)表示，In one embodiment of the present invention, 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'),
Figure PCTCN2022106363-appb-000055
Figure PCTCN2022106363-appb-000055
其中，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Wherein, "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
在本发明的一个实施方式中，本发明的通式(1)可以用下述通式(4)、通式(4’)、通式(5)、通式(5’)、通式(6)或通式(6’)表示，In one embodiment of the present invention, 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,
Figure PCTCN2022106363-appb-000056
Figure PCTCN2022106363-appb-000056
Figure PCTCN2022106363-appb-000057
Figure PCTCN2022106363-appb-000057
其中m为1、2或3，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Where m is 1, 2 or 3, "*" means that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
在本发明的一个实施方式中，本发明的通式(1)可以用下述通式(7)、通式(8)、通式(9)、通式(10)、通式(11)、通式(12)、通式(13)、通式(14)、通式(15)、通式(16)、通式(17)、通式(18)或通式(19)表示，In one embodiment of the present invention, 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),
Figure PCTCN2022106363-appb-000058
Figure PCTCN2022106363-appb-000058
Figure PCTCN2022106363-appb-000059
Figure PCTCN2022106363-appb-000059
在本发明的一个实施方式中，X优选为O、NR 7或S，更优选为O或NR 7，其中，在X中，R 7独立地优选为H或C 1-C 6烷基，更优选为H或C 1-C 4烷基，最优选为H。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，Y优选为-(C(R 7) 2) q-，其中q优选为1，在Y中，R 7独立地优选为H、卤素、羟基或C 1-C 6烷基，进一步优选一个R 7为H、卤素、羟基或C 1-C 4烷基、一个R 7为H，更优选两个R 7均为H。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，Y优选为-(C(R 7) 2) q-，其中q优选为1或2，在Y中，优选R 7独立地为H、卤素、羟基或C 1-C 6烷基，进一步优选R 7独立地为H或C 1-C 4烷基，更优选R 7独立地为H。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，Z优选为NH或CHR 1，其中，在Z中，R 1优选为-N(R 5) 2，进一步优选Z为NH。 In one embodiment of the present invention, Z is preferably NH or CHR 1 , wherein, in Z, R 1 is preferably -N(R 5 ) 2 , more preferably Z is NH.
在本发明的一个实施方式中，Z优选为NH。In one embodiment of the invention, Z is preferably NH.
在本发明的一个实施方式中，优选各R 1独立地为氘、卤素、羟基、-N(R 5) 2、C 1-C 6烷基、C 1-C 6烷基-O-，或键合于同一环原子上两个R 1形成氧代基，或键合于相邻两个环原子上的R 1形成键，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基；更优选各R 1独立地为卤素、羟基、C 1-C 6烷基、C 1-C 6烷基-O-，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-10元杂环烷基；进一步优选各R 1独立地为C 1-C 4烷基，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-7元杂环烷基。 In one embodiment of the present invention, preferably 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 a C1 - C4 alkane group, or two R 1 bonded to different or the same ring atom together with the atoms to which they are attached form a 4-7 membered heterocycloalkyl group.
在本发明的一个实施方式中，在键合于相邻两个环原子上的R 1形成键时，即，在不违反化合价的前提下，相邻两个环原子之间形成双键。 In one embodiment of the present invention, when R 1 bonded to two adjacent ring atoms forms a bond, that is, a double bond is formed between two adjacent ring atoms without violating the valence.
在本发明的一个实施方式中，在键合于不同环原子上的两个R 1与它们所相连的原子一起形成杂环烷基、杂环烯基或环烷基时，所形成 的杂环烷基、杂环烯基或环烷基与R 1所键合的六元环形成并环结构或桥环结构；优选与R 1所键合的六元环形成桥环结构，该桥环结构的桥键可为-(CH 2) 1-3-基团，优选为-(CH 2) 1-2-基团。 In one embodiment of the present invention, when two R 1 bonded to different ring atoms form heterocycloalkyl, heterocycloalkenyl or cycloalkyl together with the atoms they are connected to, 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.
在本发明的一个实施方式中，在键合于相同环原子上的两个R 1与它们所相连的原子一起形成杂环烷基、杂环烯基或环烷基时，是指在R 1所键合的六元环上形成螺环，螺原子即上述环原子。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，优选每个R 1独立地为C 1-C 4烷基，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-7元杂环烷基。 In one embodiment of the present invention, it is preferred that 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.
在本发明的一个实施方式中，作为R 1中的杂环烷基、杂环烯基中的杂原子，优选为1或2个选自N、O和S中的杂原子；更优选为1个或2个N原子。 In one embodiment of the present invention, as the 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.
在本发明的一个实施方式中，作为R 1中的杂环烷基、杂环烯基、杂芳基中的杂原子，优选为1或2个选自N、O和S中的杂原子；更优选为1个或2个N原子。 In one embodiment of the present invention, as the heteroatom in the heterocycloalkyl group, heterocycloalkenyl group and heteroaryl group in R, preferably 1 or 2 heteroatoms selected from N, O and S; More preferably, it is 1 or 2 N atoms.
在本发明的一个实施方式中，每个R 1a、R 1b、R 1c和R 1d各自独立地为卤素或羟基。 In one embodiment of the present invention, each of R 1a , R 1b , R 1c and R 1d is independently halogen or hydroxyl.
在本发明的一个实施方式中，R 1a、R 1b、R 1c和R 1d出现的数目各自独立地为1、2、3或4，优选为1或2。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，n优选为1、2、3或4，更优选为1、2或3。In one embodiment of the present invention, n is preferably 1, 2, 3 or 4, more preferably 1, 2 or 3.
在本发明的一个实施方式中，n优选为1或2。In one embodiment of the present invention, n is preferably 1 or 2.
在本发明的一个实施方式中，
Figure PCTCN2022106363-appb-000060
优选为
Figure PCTCN2022106363-appb-000061
Figure PCTCN2022106363-appb-000062
进一步优选为
Figure PCTCN2022106363-appb-000063
Figure PCTCN2022106363-appb-000064
In one embodiment of the invention,
Figure PCTCN2022106363-appb-000060
preferably
Figure PCTCN2022106363-appb-000061
Figure PCTCN2022106363-appb-000062
is further preferably
Figure PCTCN2022106363-appb-000063
Figure PCTCN2022106363-appb-000064
在本发明的一个实施方式中，
Figure PCTCN2022106363-appb-000065
优选为
Figure PCTCN2022106363-appb-000066
Figure PCTCN2022106363-appb-000067
更优选为
Figure PCTCN2022106363-appb-000068
In one embodiment of the invention,
Figure PCTCN2022106363-appb-000065
preferably
Figure PCTCN2022106363-appb-000066
Figure PCTCN2022106363-appb-000067
more preferably
Figure PCTCN2022106363-appb-000068
在本发明的一个实施方式中，L优选为-(CR 6aR 6b) n1-或-O-(CR 6aR 6b) n2-，更优选为-O-(CR 6aR 6b) n2-。 In one embodiment of the present invention, L is preferably -(CR 6a R 6b ) n1 - or -O-(CR 6a R 6b ) n2 -, more preferably -O-(CR 6a R 6b ) n2 -.
在本发明的一个实施方式中，L优选为-O-(CR 6aR 6b) n2-。 In one embodiment of the present invention, L is preferably -O-(CR 6a R 6b ) n2 -.
在本发明的一个实施方式中，L优选为-O-CH 2-。 In one embodiment of the present invention, L is preferably -O-CH 2 -.
在本发明的一个实施方式中，R 6a和R 6b优选各自独立地为H、氘、卤素、羟基或C 1-C 4烷基；更优选R 6a为H且R 6b为H、氘、卤素、羟 基或C 1-C 4烷基；进一步优选R 6a和R 6b都为H。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，优选每个R 6a和R 6b各自独立地为H或氘。 In one embodiment of the invention, preferably each R 6a and R 6b is independently H or deuterium.
在本发明的一个实施方式中，n1、n2、n3和n4优选各自独立地为1或2；更优选各自独立地为1。In one embodiment of the present invention, n1, n2, n3 and n4 are preferably each independently 1 or 2; more preferably each independently is 1.
在本发明的一个实施方式中，优选n2为1。In one embodiment of the present invention, n2 is preferably 1.
在本发明的一个实施方式中，L为-O-(CR 6aR 6b) n2-、-S-(CR 6aR 6b) n3-或-N(R 5)(CR 6aR 6b) n4-时，R 2键合于L基团中O、S或N原子；或者R 2键合于L基团中(CR 6aR 6b) n2、(CR 6aR 6b) n3或(CR 6aR 6b) n4一端；优选为后者。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，优选R 2为任选被一个或多个R 2a取代的3-10元环烷基、任选被一个或多个R 2b取代的4-10元杂环烷基、任选被一个或多个R 2d取代的C 6-C 10芳基或任选被一个或多个R 2e取代的5-10元杂芳基；更优选R 2为被一个或多个R 2a取代的3-10元环烷基或被一个或多个R 2b取代的4-10元杂环烷基；进一步优选R 2为被一个或多个R 2a取代的5-10元环烷基或被一个或多个R 2b取代的5-10元杂环烷基；更进一步优选R 2为被一个或多个R 2b取代的5-10元杂环烷基，特别优选R 2为被一个或多个R 2b取代的5-10元含1个氮原子的杂环烷基。 In one embodiment of the present invention, it is preferred that 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 is substituted by A 5-10 membered heterocycloalkyl group containing 1 nitrogen atom substituted by one or more R 2b .
在本发明的一个实施方式中，R 2选自被一个或多个R 2b取代的以下基团中的至少一个： In one embodiment of the present invention, R 2 is selected from at least one of the following groups substituted by one or more R 2b :
Figure PCTCN2022106363-appb-000069
Figure PCTCN2022106363-appb-000070
“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。
Figure PCTCN2022106363-appb-000069
Figure PCTCN2022106363-appb-000070
"*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
在本发明的一个实施方式中，优选R 2为被一个或多个R 2b取代的5-10元杂环烷基。 In one embodiment of the present invention, preferably R 2 is 5-10 membered heterocycloalkyl substituted by one or more R 2b .
在本发明的一个实施方式中，作为R 2中的杂环烷基、杂芳基中的 杂原子，优选为1或2个选自N、O和S中的杂原子；更优选为1个或2个N原子。 In one embodiment of the present invention, as the 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.
在本发明的一个实施方式中，优选每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、任选被一个或多个R 2-a取代的C 1-C 4烷基、任选被一个或多个R 2-b取代的C 1-C 4烷基-O-、C 2-C 4烯基、C 2-C 4炔基、-N(R 5) 2或(C 1-C 4烷基)-O-(C 1-C 4烷基)；更优选每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、任选被一个或多个R 2-a取代的C 1-C 4烷基或-N(R 5) 2；进一步优选每个R 2a、R 2b和R 2c各自独立地为卤素、羟基或C 1-C 4烷基；更进一步优选每个R 2a、R 2b和R 2c各自独立地为氟、氯、溴、碘、羟基、甲基、乙基、丙基或丁基。 In one embodiment of the present invention, preferably 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, bromine, iodine, hydroxyl, methyl, ethyl, propyl or butyl.
在本发明的一个实施方式中，优选每个R 2b独立地为卤素、羟基或C 1-C 4烷基。 In one embodiment of the present invention, preferably each R 2b is independently halogen, hydroxyl or C 1 -C 4 alkyl.
在本发明的一个实施方式中，优选每个R 2b独立地为氟、氯、溴、碘、羟基、甲基、乙基、丙基或丁基。 In one embodiment of the invention, preferably each R 2b is independently fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl or butyl.
在本发明的一个实施方式中，优选每个R 2-a和R 2-b独立地为卤素或羟基。 In one embodiment of the present invention, it is preferred that each of R 2-a and R 2-b is independently halogen or hydroxyl.
在本发明的一个实施方式中，优选每个R 2d和R 2e各自独立地为卤素、羟基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基或-N(R 5) 2；更优选每个R 2d和R 2e各自独立地为卤素、羟基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基或-N(R 5) 2；进一步优选每个R 2d和R 2e各自独立地为卤素、羟基或C 1-C 4烷基；更进一步优选每个R 2d和R 2e各自独立地为氟、氯、溴、碘、羟基、甲基、乙基、丙基或丁基。 In one embodiment of the present invention, it is preferred that 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.
在本发明的一个实施方式中，R 2a、R 2b、R 2c、R 2d和R 2e出现的数目各自独立地为1、2、3或4，优选为1或2。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，R 2-a和R 2-b出现的数目各自独立地为1、2、3或4，优选为1或2。 In one embodiment of the present invention, the number of occurrences of R 2-a and R 2-b are each independently 1, 2, 3 or 4, preferably 1 or 2.
在本发明的一个实施方式中，
Figure PCTCN2022106363-appb-000071
优选为
Figure PCTCN2022106363-appb-000072
In one embodiment of the invention,
Figure PCTCN2022106363-appb-000071
preferably
Figure PCTCN2022106363-appb-000072
在本发明的一个实施方式中，优选R 3为被一个或多个R 3a取代的 C 6-C 10芳基或被一个或多个R 3b取代的5-14元杂芳基；更优选R 3为被一个或多个R 3a取代的C 6-C 10芳基、且所述C 6-C 10芳基为苯基或萘基，或者R 3为被一个或多个R 3b取代的5-14元杂芳基、且所述5-14元杂芳基为5-10元杂芳基；进一步优选R 3为被一个或多个R 3a取代的C 6-C 10芳基、且所述C 6-C 10芳基为萘基(例如
Figure PCTCN2022106363-appb-000073
)，或者R 3为被一个或多个R 3b取代的5-14元杂芳基、且所述5-14元杂芳基为吡啶基(例如
Figure PCTCN2022106363-appb-000074
)、嘧啶基、喹啉基、喹唑啉基、吲哚基、吲唑基、苯并噻吩基(例如
Figure PCTCN2022106363-appb-000075
)或苯并噻唑基。 In one embodiment of the present invention, preferably 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
Figure PCTCN2022106363-appb-000073
), 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
Figure PCTCN2022106363-appb-000074
), pyrimidinyl, quinolinyl, quinazolinyl, indolyl, indazolyl, benzothienyl (for example
Figure PCTCN2022106363-appb-000075
) or benzothiazolyl.
在本发明的一个实施方式中，优选R 3为被一个或多个R 3a取代的C 6-C 10芳基、且所述C 6-C 10芳基为萘基，或者R 3为被一个或多个R 3b取代的5-14元杂芳基、且所述5-14元杂芳基为吡啶基、嘧啶基、喹啉基、喹唑啉基、吲哚基、吲唑基、苯并噻吩基或苯并噻唑基。 In one embodiment of the present invention, preferably 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.
在本发明的一个实施方式中，优选R 3为被一个或多个R 3a取代的
Figure PCTCN2022106363-appb-000076
被一个或多个R 3b取代的
Figure PCTCN2022106363-appb-000077
或被一个或多个R 3b取代的
Figure PCTCN2022106363-appb-000078
In one embodiment of the invention, preferably R 3 is substituted by one or more R 3a
Figure PCTCN2022106363-appb-000076
substituted by one or more R 3b
Figure PCTCN2022106363-appb-000077
or substituted by one or more R 3b
Figure PCTCN2022106363-appb-000078
在本发明的一个实施方式中，作为R 3中的杂芳基中的杂原子，优选为1或2个选自N、O和S中的杂原子；更优选为1个或2个N原子或S原子。 In one embodiment of the present invention, as the 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.
在本发明的一个实施方式中，优选每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-b取代的C 1-C 6烷基-O-、任选被一个或多个R 3-d取代的 C 2-C 6烯基、任选被一个或多个R 3-e取代的C 2-C 6炔基、-N(R 5) 2、任选被一个或多个R 3-f取代的3-6元环烷基或三唑基；更优选每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-e取代的C 2-C 6炔基或-N(R 5) 2；进一步优选每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 4烷基、任选被一个或多个R 3-e取代的C 2-C 4炔基或-N(R 5) 2；特别优选每个R 3a和R 3b各自独立地为-NH 2、甲基、乙基、丙基、丁基、一氟甲基、二氟甲基、三氟甲基、乙炔基、丙炔基、羟基、氰基、氟、氯、溴或碘。 In one embodiment of the present invention, it is preferred that 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 preferably each of R 3a and R 3b is independently halogen, hydroxyl, cyano, optionally substituted by one or more R 3-a C 1 -C 4 alkyl, C 2 -C 4 alkynyl optionally substituted by one or more R 3-e , or -N(R 5 ) 2 ; particularly preferably each of R 3a and R 3b is independently is -NH 2 , methyl, ethyl, propyl, butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethynyl, propynyl, hydroxyl, cyano, fluorine, chlorine, bromine or iodine.
在本发明的一个实施方式中，优选每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 4烷基、任选被一个或多个R 3-e取代的C 2-C 4炔基、-N(R 5) 2或-(CH 2) n5-C(＝O)N(R 5) 2。 In one embodiment of the present invention, it is preferred that each of R 3a and R 3b is independently halogen, hydroxyl, cyano, C 1 -C 4 alkyl optionally substituted by one or more R 3-a , any C 2 -C 4 alkynyl, -N(R 5 ) 2 or -(CH 2 ) n5 -C(=O)N(R 5 ) 2 substituted by one or more R 3-e .
在本发明的一个实施方式中，优选每个n5独立地为0或1；更优选为0。In one embodiment of the present invention, preferably each n5 is independently 0 or 1; more preferably 0.
在本发明的一个实施方式中，优选每个R 3a和R 3b各自独立地为-NH 2、-C(＝O)NH 2、甲基、乙基、丙基、丁基、一氟甲基、二氟甲基、三氟甲基、乙炔基、丙炔基、羟基、氰基、氟、氯、溴或碘。 In one embodiment of the present invention, preferably each R 3a and R 3b is independently -NH 2 , -C(=O)NH 2 , methyl, ethyl, propyl, butyl, monofluoromethyl , difluoromethyl, trifluoromethyl, ethynyl, propynyl, hydroxy, cyano, fluorine, chlorine, bromine or iodine.
在本发明的一个实施方式中，优选每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为卤素、羟基、C 1-C 4烷基或C 1-C 4烷基-O-；更优选每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为卤素、羟基或C 1-C 4烷基；进一步优选每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为卤素或羟基。 In one embodiment of the present invention, preferably 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.
在本发明的一个实施方式中，优选每个R 3-a和R 3-e各自独立地为氘、卤素或羟基。 In one embodiment of the present invention, it is preferred that each of R 3-a and R 3-e is independently deuterium, halogen or hydroxyl.
在本发明的一个实施方式中，R 3a和R 3b出现的数目各自独立地为1、2、3、4或5，优选为1、2或3。 In one embodiment of the present invention, the number of occurrences of R 3a and R 3b are each independently 1, 2, 3, 4 or 5, preferably 1, 2 or 3.
在本发明的一个实施方式中，R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f出现的数目各自独立地为1、2、3、4或5，优选为1、2或3。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，R 3优选为
Figure PCTCN2022106363-appb-000079
Figure PCTCN2022106363-appb-000080
Figure PCTCN2022106363-appb-000081
更优选为
Figure PCTCN2022106363-appb-000082
In one embodiment of the present invention, R3 is preferably
Figure PCTCN2022106363-appb-000079
Figure PCTCN2022106363-appb-000080
Figure PCTCN2022106363-appb-000081
more preferably
Figure PCTCN2022106363-appb-000082
在本发明的一个实施方式中，优选R 4为-N(R 5) 2、卤素、羟基、任选被一个或多个卤素取代的C 1-C 6烷基、任选被一个或多个卤素取代的C 1-C 6烷基-O-、C 2-C 6烯基或C 2-C 6炔基；更优选R 4为-N(R 5) 2、卤素、羟基或任选被一个或多个卤素取代的C 1-C 6烷基；进一步优选R 4为卤素、羟基或任选被一个或多个卤素取代的C 1-C 4烷基。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，优选R 4为卤素、羟基或任选被一个或多个卤素取代的C 1-C 4烷基。 In one embodiment of the present invention, it is preferred that R 4 is halogen, hydroxyl or C 1 -C 4 alkyl optionally substituted by one or more halogens.
在本发明的一个实施方式中，优选R 4为卤素。 In one embodiment of the invention, it is preferred that R4 is halogen.
在本发明的一个实施方式中，优选R 4为氟。 In one embodiment of the invention, preferably R4 is fluorine.
在本发明的一个实施方式中，优选每个R 5独立地为H或C 1-C 4烷基，更优选每个R 5独立地为H、甲基、乙基或丙基。 In one embodiment of the present invention, preferably each R 5 is independently H or C 1 -C 4 alkyl, more preferably each R 5 is independently H, methyl, ethyl or propyl.
在本发明的一个实施方式中，优选每个R 7独立地为H、卤素、羟基、-N(R 5) 2、任选被一个或多个R 7a取代的C 1-C 6烷基，或键合于同一环原子上两个R 7形成氧代基，或键合于相邻两个环原子上的R 7形成键，或键合于不同或相同环原子上的两个R 7与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；更优选每个R 7独立地为H、卤素、羟基、任选被一个或多个R 7a取代的C 1-C 6烷基，或键合于同一环原子上两个R 7形成氧代基，或键合于相邻两个环原子上的R 7形成键；进一步优选每个R 7独立地为H、卤素、羟基或任选被一个或多个R 7a取代的C 1-C 4烷基。 In one embodiment of the present invention, preferably 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 or C 1 -C 4 alkyl optionally substituted by one or more R 7a .
在本发明的一个实施方式中，优选每个R 7a、R 7b、R 7c和R 7d各自独立地为卤素或羟基。 In one embodiment of the present invention, preferably each of R 7a , R 7b , R 7c and R 7d is independently halogen or hydroxyl.
在本发明的一个实施方式中，R 7a、R 7b、R 7c和R 7d出现的数目各自独立地为1、2、3或4，优选为1或2。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，优选每个R 7独立地为H或C 1-C 4烷基。 In one embodiment of the present invention, preferably each R 7 is independently H or C 1 -C 4 alkyl.
在本发明的一个实施方式中，优选每个R 7独立地为H。 In one embodiment of the invention, preferably each R 7 is independently H.
在本发明的一个实施方式中，在键合于不同环原子上的两个R 7与它们所相连的原子一起形成杂环烷基、杂环烯基或环烷基时，所形成的杂环烷基、杂环烯基或环烷基与包含X和Y的环形成并环结构或桥环结构。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，在键合于相同环原子上的两个R 7与它们所相连的原子一起形成杂环烷基、杂环烯基或环烷基时，是指在包含X和Y的环上形成螺环，螺原子即上述环原子。 In one embodiment of the present invention, 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.
在本发明的一个实施方式中，作为R 7中的杂环烷基、杂环烯基中的杂原子，优选为1或2个选自N、O和S中的杂原子；更优选为1个或2个N原子。 In one embodiment of the present invention, as the 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.
在本发明的一个实施方式中，优选q为1。In one embodiment of the present invention, q is preferably 1.
在本发明的一个实施方式中，优选q为1或2。In one embodiment of the present invention, q is preferably 1 or 2.
在本发明中，各取代基存在多个时，彼此可以相同，也可以不同。In the present invention, when there are a plurality of substituents, they may be the same as or different from each other.
在本发明的一个实施方式中，提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体：In one embodiment of the present invention, the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers are provided:
Figure PCTCN2022106363-appb-000083
Figure PCTCN2022106363-appb-000083
本发明还提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，The present invention also provides the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
Figure PCTCN2022106363-appb-000084
Figure PCTCN2022106363-appb-000085
盐酸盐、
Figure PCTCN2022106363-appb-000086
盐酸盐。
Figure PCTCN2022106363-appb-000084
Figure PCTCN2022106363-appb-000085
Hydrochloride,
Figure PCTCN2022106363-appb-000086
Hydrochloride.
在本发明的一个实施方式中，提供以下吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，In one embodiment of the present invention, the following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers are provided,
Figure PCTCN2022106363-appb-000087
Figure PCTCN2022106363-appb-000087
在本发明的一个实施方式中，还提供以下化合物、药学上可接受的盐、酯、立体异构体或互变异构体，In one embodiment of the present invention, the following compounds, pharmaceutically acceptable salts, esters, stereoisomers or tautomers are also provided,
Figure PCTCN2022106363-appb-000088
Figure PCTCN2022106363-appb-000089
Figure PCTCN2022106363-appb-000090
盐酸盐、
Figure PCTCN2022106363-appb-000091
盐酸盐、
Figure PCTCN2022106363-appb-000092
Figure PCTCN2022106363-appb-000093
Figure PCTCN2022106363-appb-000094
Figure PCTCN2022106363-appb-000088
Figure PCTCN2022106363-appb-000089
Figure PCTCN2022106363-appb-000090
Hydrochloride,
Figure PCTCN2022106363-appb-000091
Hydrochloride,
Figure PCTCN2022106363-appb-000092
Figure PCTCN2022106363-appb-000093
Figure PCTCN2022106363-appb-000094
在本发明的一个实施方式中，在本发明的通式(1)所示的化合物中，当
Figure PCTCN2022106363-appb-000095
为
Figure PCTCN2022106363-appb-000096
R 3为
Figure PCTCN2022106363-appb-000097
R 4为F时，通式(1)所示的化合物可以通过以下的路径一制备得到： In one embodiment of the present invention, in the compound represented by general formula (1) of the present invention, when
Figure PCTCN2022106363-appb-000095
for
Figure PCTCN2022106363-appb-000096
R3 is
Figure PCTCN2022106363-appb-000097
When R is F, the compound shown in general formula (1) can be prepared by the following route one:
路径一path one
Figure PCTCN2022106363-appb-000098
Figure PCTCN2022106363-appb-000098
步骤1中，在使用溶剂或者不使用溶剂的条件下，使用4-氨基-2，6-二氯吡啶和氟化试剂，进行氟化反应；所述氟化试剂可以使用本领域公知的各类氟化试剂，例如可以为Selectfluoro(1-氯甲基-4-氟-1，4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐)；In 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);
步骤2中，在使用溶剂或者不使用溶剂的条件下，在碱性条件下，对步骤1的产物进行氨基保护反应；In step 2, the product of step 1 is subjected to an amino protection reaction under basic conditions with or without a solvent;
步骤3中，在使用溶剂或者不使用溶剂的条件下，在强碱存在下，使用步骤2的产物进行反应，所述强碱可以使用本领域常规的强碱，例如可以为LDA；In 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;
步骤4中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤3的产物进脱氨基保护基反应、水解反应；In 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;
步骤5中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，使用乙醇，对于步骤4的产物进行酯化反应；In 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;
步骤6中，在使用溶剂或者不使用溶剂的条件下，使用步骤5的产物，与三氯乙酰基异氰酸酯，进行取代反应；In 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;
步骤7中，在使用溶剂或者不使用溶剂的条件下，使用步骤6的产物，进行氨化闭环反应；In 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;
步骤8中，在使用溶剂或者不使用溶剂的条件下，使用步骤7的产物进行氯化反应；氯化试剂可以使用本领域已知的各种氯化试剂，例如为三氯氧磷、氯化亚砜等；In 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.;
步骤9中，在使用溶剂或者不使用溶剂的条件下，在碱性条件下，使用步骤8的产物进行取代反应；In step 9, the product of step 8 is used to perform a substitution reaction under basic conditions with or without a solvent;
步骤10中，在使用溶剂或者不使用溶剂的条件下，在碱性条件下，使用步骤9的产物与H-L-R 2进行取代反应； In 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;
步骤11中，在使用溶剂或者不使用溶剂的条件下，对步骤10的产物，进行脱羟基保护基(在四丁基氟化铵、四甲基氟化铵、氟化钾或CsF存在下)的反应，并对反应产物进行关环反应；In 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;
步骤12中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤11的产物进行脱氨基Cbz保护；进而，在碱性条件下，对产物的氨基进行Boc保护；In 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;
步骤13中，在使用溶剂或者不使用溶剂的条件下，在本领域公知的条件下，进行Suzuki偶联反应；In step 13, a Suzuki coupling reaction is carried out under conditions known in the art with or without a solvent;
步骤14中，在使用溶剂或者不使用溶剂的条件下，在四丁基氟化铵、四甲基氟化铵、氟化钾或CsF存在下，脱炔基TIPS保护基；进而在酸性条件下，对产物进行脱羟基保护基、脱氨基保护基，由此得到产物。In 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.
在本发明的一个实施方式中，在本发明的通式(1)所示的化合物中，当
Figure PCTCN2022106363-appb-000099
为
Figure PCTCN2022106363-appb-000100
时，通式(1)所示的化合物可以通过以下的路径二制备得到： In one embodiment of the present invention, in the compound represented by general formula (1) of the present invention, when
Figure PCTCN2022106363-appb-000099
for
Figure PCTCN2022106363-appb-000100
, the compound shown in general formula (1) can be prepared by the following route two:
路径二path two
Figure PCTCN2022106363-appb-000101
Figure PCTCN2022106363-appb-000101
步骤1中，在使用溶剂或者不使用溶剂的条件下，使用起始化合物，在本领域公知的条件下，进行Suzuki偶联反应；In 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;
步骤2中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤1的产物进行脱氨基保护基的反应，得到产物。In 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.
在本发明的一个实施方式中，在本发明的通式(1)所示的化合物中，当
Figure PCTCN2022106363-appb-000102
为
Figure PCTCN2022106363-appb-000103
R 3为
Figure PCTCN2022106363-appb-000104
时，通式(1)所示的化合物可以通过以下的路径三制备得到： In one embodiment of the present invention, in the compound represented by general formula (1) of the present invention, when
Figure PCTCN2022106363-appb-000102
for
Figure PCTCN2022106363-appb-000103
R3 is
Figure PCTCN2022106363-appb-000104
, the compound shown in general formula (1) can be prepared by the following route three:
路径三path three
Figure PCTCN2022106363-appb-000105
Figure PCTCN2022106363-appb-000105
步骤1中，在使用溶剂或者不使用溶剂的条件下，在碱性条件下，对2-溴-4-甲基-6-氨基吡啶进行氨基保护反应；In step 1, 2-bromo-4-methyl-6-aminopyridine is subjected to an amino protection reaction under basic conditions with or without a solvent;
步骤2中，在使用溶剂或者不使用溶剂的条件下，在钯催化的条件下，对步骤1的产物进行硼化反应，所述钯催化剂可以使用本领域常规的钯催化剂，例如可以为[1，1′-双(二苯基膦)二茂铁]二氯化钯；In 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;
步骤3中，在使用溶剂或者不使用溶剂的条件下，使用步骤2的产物，在本领域公知的条件下，进行Suzuki偶联反应；In 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;
步骤4中，在使用溶剂或者不使用溶剂的条件下，在乙酸银存在下，对步骤3的产物进行碘化反应；In 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;
步骤5中，在使用溶剂或者不使用溶剂的条件下，在催化剂存在下，对步骤4的产物进行偶联反应，所述催化剂可以使用本领域常规的催化剂，例如可以为CuI、Cu 2O； In 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 ;
步骤6中，在使用溶剂或者不使用溶剂的条件下，在氧化剂存在下，对步骤5的产物进行氧化反应，所述氧化剂可以使用本领域常规的氧化剂，例如可以为mCPBA、H 2O 2、Oxone； In 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;
步骤7中，在使用溶剂或者不使用溶剂的条件下，对步骤6的产物进行氯化反应；可以使用本领域公知的氯化试剂，例如可以为三氯氧磷、二氯亚砜；In 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;
步骤8中，在使用溶剂或者不使用溶剂的条件下，对步骤7的产物进行取代反应；In step 8, the product of step 7 is subjected to a substitution reaction with or without a solvent;
步骤9中，在使用溶剂或者不使用溶剂的条件下，对步骤8的产物进行氨化关环反应；In 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;
步骤10中，在使用溶剂或者不使用溶剂的条件下，对步骤9的产物进行氯化反应；可以使用本领域公知的氯化试剂，例如可以为三氯氧磷、二氯亚砜；In 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;
步骤11中，在使用溶剂或者不使用溶剂的条件下，在碱性条件下，对步骤10的产物进行取代反应；In step 11, the product of step 10 is subjected to a substitution reaction under basic conditions with or without a solvent;
步骤12中，在使用溶剂或者不使用溶剂的条件下，在碱性条件下，使步骤11的产物与H-L-R 2进行取代反应； In step 12, the product of step 11 is subjected to a substitution reaction with HLR 2 under basic conditions with or without a solvent;
步骤13中，在使用溶剂或者不使用溶剂的条件下，在四丁基氟化铵、四甲基氟化铵、氟化钾或CsF存在下，对步骤12的产物进行脱羟基保护基的反应；In 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 ;
步骤14中，在使用溶剂或者不使用溶剂的条件下，在钯催化条件下，对步骤13的产物进行关环反应，所述催化剂可以使用本领域常规的钯催化剂，例如可以为Pd 2dba 3/XantPhos，Pd(OAc) 2/XantPhos等； In 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.;
步骤15中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤14的产物脱氨基保护基反应，得到最终产物。In step 15, the product of step 14 is deaminated and protected under acidic conditions with or without a solvent to obtain the final product.
在本发明的一个实施方式中，在本发明的通式(1)所示的化合物中， 当
Figure PCTCN2022106363-appb-000106
为
Figure PCTCN2022106363-appb-000107
时，通式(1)所示的化合物可以通过以下的路径四制备得到： In one embodiment of the present invention, in the compound represented by the general formula (1) of the present invention, when
Figure PCTCN2022106363-appb-000106
for
Figure PCTCN2022106363-appb-000107
, the compound shown in general formula (1) can be prepared by the following route four:
Figure PCTCN2022106363-appb-000108
Figure PCTCN2022106363-appb-000108
步骤1中，在使用溶剂或者不使用溶剂的条件下，碱性条件下，进行取代反应；In step 1, a substitution reaction is carried out under basic conditions with or without a solvent;
步骤2中，在使用溶剂或者不使用溶剂的条件下，碱性条件下，对步骤1的产物进行取代反应；In step 2, the product of step 1 is subjected to a substitution reaction under basic conditions with or without a solvent;
步骤3中，在使用溶剂或者不使用溶剂的条件下，在四丁基氟化铵、四甲基氟化铵、氟化钾或CsF存在下，对步骤2的产物，进行脱羟基保护基的反应，并进行关环反应；In 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;
步骤4中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤3的产物进行脱氨基Cbz保护反应；进而，在碱性条件下，对产物的氨基进行Boc保护反应；In 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;
步骤5中，在使用溶剂或者不使用溶剂的条件下，在本领域公知的条件下，对步骤4的产物进行Suzuki偶联反应；In 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;
步骤6中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤5的产物进行脱氨基保护基的反应，得到产物。In 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.
在本发明的一个实施方式中，在本发明的通式(1)所示的化合物中，当
Figure PCTCN2022106363-appb-000109
为
Figure PCTCN2022106363-appb-000110
时，通式(1)所示的化合物可以通过以下的路径五制备得到： In one embodiment of the present invention, in the compound represented by general formula (1) of the present invention, when
Figure PCTCN2022106363-appb-000109
for
Figure PCTCN2022106363-appb-000110
, the compound shown in general formula (1) can be prepared by the following route five:
Figure PCTCN2022106363-appb-000111
Figure PCTCN2022106363-appb-000111
步骤1中，在使用溶剂或者不使用溶剂的条件下，碱性条件下，进行取代反应；In step 1, a substitution reaction is carried out under basic conditions with or without a solvent;
步骤2中，在使用溶剂或者不使用溶剂的条件下，碱性条件下，对步骤1的产物进行取代反应；In step 2, the product of step 1 is subjected to a substitution reaction under basic conditions with or without a solvent;
步骤3中，在使用溶剂或者不使用溶剂的条件下，在四丁基氟化铵、四甲基氟化铵、氟化钾或CsF存在下，对步骤2的产物，进行脱羟基保护基的反应，并进行关环反应；In 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;
步骤4中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤3的产物进行脱氨基Cbz保护反应；进而，在碱性条件下，对 产物的氨基进行Boc保护反应；In 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;
步骤5中，在使用溶剂或者不使用溶剂的条件下，在本领域公知的条件下，对步骤4的产物进行Suzuki偶联反应；In 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;
步骤6中，在使用溶剂或者不使用溶剂的条件下，在酸性条件下，对步骤5的产物进行脱氨基保护基的反应，得到产物。In 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.
本发明的制备方法中，各个步骤中所使用的溶剂只要是对反应为惰性的溶剂即可，所述的溶剂可以选自：N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜、甲苯、苯、二甲苯、三甲苯、环己烷、己烷、二氯甲烷、氯仿、1，2-二氯乙烷、四氢呋喃、乙醚、二噁烷、1，2-二甲氧基乙烷、乙酸甲酯、乙酸乙酯、丙酮、甲基乙基酮、乙腈、甲醇、乙醇、异丙醇、叔丁醇、水中的一种和其混合物。In the preparation method of the present invention, as long as the solvent used in each step is an inert solvent to the reaction, 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.
本发明的制备方法中，作为各类碱，可以使用各种无机碱或有机碱，作为所述无机碱，可以列举碱金属氢氧化物(例如氢氧化钾、氢氧化钠)、碱金属碳酸盐(例如碳酸钾、碳酸钠)和碱金属氢化物(例如氢化钠)、碱土金属氢氧化物(例如氢氧化钙、氢氧化钡)等，作为有机碱，可以列举甲胺、乙胺、丙胺、N，N-二异丙基乙胺、三甲胺、三乙胺、二环己基胺、乙醇胺、二乙醇胺、三乙醇胺、葡甲胺、二乙醇胺、乙二胺、吡啶、甲基吡啶、喹啉中的一种和其混合物。In the preparation method of the present invention, as various types of bases, 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. Salts (such as potassium carbonate, sodium carbonate), alkali metal hydrides (such as sodium hydride), alkaline earth metal hydroxides (such as calcium hydroxide, barium hydroxide), etc., as 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.
本发明的制备方法中，作为各类强碱，可以使用本领域已知的各类强碱，例如可以列举氢氧化钾、氢氧化钠、叔丁醇钾、叔丁醇钠、二异丙基氨基锂(LDA)、二异丙基氨基钠等。In the preparation method of the present invention, as 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.
本发明的制备方法中，提供酸性环境时，可以使用本领域公知的各种酸，所述的酸可以选自：甲酸、乙酸、丙酸、三氟乙酸、柠檬酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、安息香酸、邻苯二甲酸、抗坏血酸、苯磺酸、对甲苯磺酸、甲基磺酸、乙基磺酸；盐酸、硫酸、硝酸、碳酸、氢溴酸、磷酸、氢碘酸。In the preparation method of the present invention, when an acidic environment is provided, various acids known in the art can be used, and 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.
在本发明的一个实施方式中，提供一种药物组合物，包括本发明的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体以及任选的药学上可接受的载体。本发明的药物组合物包括任选的药学上可接受的载体是指，该组合物可以含有药学上可接受的载体，也可以不含有药学上可接受的载体。In one embodiment of the present invention, there is provided 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.
在本发明的一个实施方式中，提供治疗和/或预防由KRAS突变(特 别是KRAS G12D突变、KRAS G12V突变)介导的疾病的方法，包括给予对象有效量的本发明化合物。In one embodiment of the present invention, a method for treating and/or preventing diseases mediated by KRAS mutations (especially KRAS G12D mutations, KRAS G12V mutations) is provided, comprising administering an effective amount of the compound of the present invention to a subject.
在本发明的一个实施方式中，提供一种用于治疗和/或预防癌症的方法，包括给予对象有效量的本发明化合物。In one embodiment of the present invention, a method for treating and/or preventing cancer is provided, comprising administering to a subject an effective amount of the compound of the present invention.
本发明还提供本发明化合物在制备用于治疗和/或预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病的药物中的用途。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).
本发明提供本发明化合物在制备用于治疗和/或预防癌症的药物中的用途。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.
本发明还提供本发明化合物在制备KRAS突变抑制剂(特别是KRAS G12D突变抑制剂、KRAS G12V突变抑制剂)中的用途。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).
本发明还提供治疗和/或预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病的方法，包括给予对象有效量的本发明上述的药物组合物。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.
在本发明的一个实施方式中，提供一种用于治疗和/或预防癌症的方法，包括给予对象有效量的本发明上述的药物组合物。In one embodiment of the present invention, a method for treating and/or preventing cancer is provided, comprising administering an effective amount of the above-mentioned pharmaceutical composition of the present invention to a subject.
本发明还提供本发明上述的药物组合物在制备用于治疗和/或预防由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病的药物中的用途。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).
本发明提供本发明上述的药物组合物在制备用于治疗和/或预防癌症的药物中的用途。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.
本发明还提供本发明上述的药物组合物在制备KRAS突变抑制剂(特别是KRAS G12D突变抑制剂、KRAS G12V突变抑制剂)中的用途。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).
本发明中，KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病为癌症，例如可以列举结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结直肠癌、非小细胞肺癌、小细胞肺癌、食道癌、胃癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种。In the present invention, the disease mediated by KRAS mutation (especially KRAS G12D mutation, KRAS G12V 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.
本发明还包含通式(1)所示化合物在药学上可接受的盐。术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明化合物中含有相对酸性的功能团时，可以 通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。代表性碱加成盐包括例如与碱金属、碱土金属、季铵阳离子形成的盐，例如钠盐、锂盐、钾盐、钙盐、镁盐、四甲基季铵盐、四乙基季铵盐等；胺盐，包括与氨(NH3)、伯胺、仲胺或叔胺形成的盐，如甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐等。当本发明化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸(例如盐酸)、有机酸(例如甲酸)。具体可参见Berge et al.，″Pharmaceutical Salts″，Journal of Pharmaceutical Science 66：1-19(1977)、或、Handbook of Pharmaceutical Salts：Properties，Selection，and Use(P.Heinrich Stahl and Camille G.Wermuth，ed.，Wiley-VCH，2002)。The present invention also includes pharmaceutically acceptable salts of the compounds represented by the general formula (1). The term "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. When the compounds of the present invention contain relatively acidic functional groups, 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. When compounds of the present invention contain relatively basic functional groups, 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. Salt. The pharmaceutically acceptable acid includes inorganic acid (such as hydrochloric acid), organic acid (such as formic acid). For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camille G.Wermuth, ed., Wiley-VCH, 2002).
除了盐的形式，本发明化合物还存在前药形式。本发明所描述的前药是指可在生理学条件下或通过溶剂分解而转化成本发明所述的生物学活性化合物(如通式(1)化合物)的化合物。因此，术语“前药”是指药物可接受的生物学活性化合物的前体。In addition to salt forms, 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.
本发明所述的药物组合物，可以采用本领域众所周知的方法来制备，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法和冷冻干燥法等。本发明所述药物组合物可以通过任何方便的给药途径施用给预防和/或治疗对象，包括但不限于，经口服、直肠、肠胃外(例如注射，包括皮下、皮内、肌肉内、静脉内等)、局部(包括例如透皮、鼻内、眼部、口腔和舌下)、肺部(例如利用气溶胶经口或鼻的吸入或吹入治疗)等。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.
适于口服给药的固体剂型包括片剂、丸剂、胶囊剂、散剂、粉剂、颗粒剂等。制备这些固体剂型时，除了本发明所述的化合物、其立体异构体或其药学上可接受的盐外，可以加入本领域常规采用的赋形剂、填料或增容剂、粘合剂、崩解剂、稳定剂、润湿剂、吸附剂、润滑剂或包封材料中的一种或多种。Solid dosage forms suitable for oral administration include tablets, pills, capsules, powders, powders, granules, and the like. When preparing these 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.
适于口服给药的液体剂型包括溶液剂、悬浮剂、乳浊剂、糖浆剂或酊剂等。除了本发明所述的化合物、其立体异构体或其药学上可接受的盐外，液体剂型可包含本领域常规采用的稀释剂、增溶剂、乳化 剂、润湿剂、悬浮剂、甜味剂、矫味剂、芳香剂或防腐剂中的一种或多种。Liquid dosage forms suitable for oral administration include solutions, suspensions, emulsions, syrups or tinctures and the like. In addition to the compounds of the present invention, their stereoisomers, or pharmaceutically acceptable salts thereof, liquid dosage forms may contain diluents, solubilizers, emulsifiers, wetting agents, suspending agents, sweeteners, and One or more of agents, flavoring agents, fragrances or preservatives.
适于局部给药的剂型包括软膏剂、散剂、贴剂、滴剂、喷射剂、吸入剂等，作为活性成分的本发明所述化合物、其立体异构体或其药学上可接受的盐在无菌条件下和药学上可接受的载体一起混合。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.
适于直肠给药的剂型包括栓剂，包括本发明所述的化合物、其立体异构体或其药学上可接受的盐以及合适的基质。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.
适于肠胃外注射的剂型包括生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。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.
药物制剂优选为单位剂量形式。在该形式中，制剂被细分成含有适当量的活性组分的单位剂量。可以将单位剂量形式包装成含有离散量的制剂的包装，如包装的片剂、胶囊剂。The pharmaceutical formulations are preferably in unit dosage form. In such 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.
实施例Example
以下通过实施例具体说明本发明，但本发明绝不限于这些实施例。下列实施例中未注明具体条件的反应步骤，均可以按照本领域内的常规方法和条件，或按照商品说明书进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。The present invention will be specifically described below by way of examples, but the present invention is by no means limited to these examples. The reaction steps without specific conditions indicated in the following examples can be carried out according to the conventional methods and conditions in the art, or according to the commercial instructions. The reagents or instruments used were not indicated by the manufacturer, and they were all commercially available conventional products.
本发明中的英文缩写含义如下所示：English abbreviation meaning in the present invention is as follows:
mCPBA：间氯过氧苯甲酸，H 2O 2：过氧化氢；Oxone：单过硫酸氢钾；Pd 2dba 3/XantPhos：三(二亚苄基丙酮)二钯/4，5-双二苯基膦-9，9-二甲基氧杂蒽；Pd(OAc) 2/XantPhos：乙酸钯/4，5-双二苯基膦-9，9-二甲基氧杂蒽；LDA：二异丙基氨基锂；PMB：对甲氧基苄基；Boc：叔丁氧羰基；TBS(TBDMS)：叔丁基二甲基硅基；TIPS：三异丙基硅基；MOM：甲氧基甲基(CH 3OCH 2-)；Cbz：苄氧羰基；DMSO：二甲基亚砜；ACN：乙腈；CDCl 3：氘代氯仿；DMSO-d6：氘代二甲基亚砜；Et：乙基；eq：当量；LCMS：液质联用；HPLC：高效液相色谱。中间体1：2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶的制备 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 sulfoxide; ACN: acetonitrile; CDCl 3 : deuterated chloroform; DMSO-d6: deuterated dimethyl sulfoxide; base; eq: equivalent; LCMS: liquid chromatography-mass spectrometry; HPLC: high performance liquid chromatography. Intermediate 1: Preparation of 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine
Figure PCTCN2022106363-appb-000112
Figure PCTCN2022106363-appb-000112
步骤1：2，6-二氯-3-氟吡啶-4-胺Step 1: 2,6-Dichloro-3-fluoropyridin-4-amine
Figure PCTCN2022106363-appb-000113
Figure PCTCN2022106363-appb-000113
将2，6-二氯吡啶-4-胺(6.52g，39.99mmol，1eq)溶于N，N-二甲基甲酰胺(30mL)和乙腈(30mL)中，加入Selectfluoro(1-氯甲基-4-氟-1，4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐)(17g，47.99mmol，1.2eq)，80℃反应半小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-10％)，得到2，6-二氯-3-氟吡啶-4-胺(4.2g，产率：58.03％)，白色固体。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. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-10%) to obtain 2,6-dichloro-3-fluoropyridin-4-amine (4.2g, yield: 58.03%) , white solid.
MS m/z：181.1/183.1[M+H] + MS m/z: 181.1/183.1[M+H] +
步骤2：叔丁基-N-[(叔丁氧基)羰基]-N-(2，6-二氯-3-氟吡啶-4-基)氨基甲酯Step 2: tert-Butyl-N-[(tert-butoxy)carbonyl]-N-(2,6-dichloro-3-fluoropyridin-4-yl)aminomethyl ester
Figure PCTCN2022106363-appb-000114
Figure PCTCN2022106363-appb-000114
将2，6-二氯-3-氟吡啶-4-胺(4.2g，23.21mmol，1eq)溶于二氯甲烷(40mL)中，加入Boc酸酐(10.29g，47.15mmol，2.03eq)，4-二甲氨基吡啶(457.28mg，3.74mmol，0.16eq)，室温反应16小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-20％)，得到叔丁基-N-[(叔丁氧基)羰基]-N-(2，6-二氯-3-氟吡啶-4-基)氨基甲酯(7.0g，产率：79.13％)，白色固体。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. The 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.
MS m/z：381.1/383.1[M+H] + MS m/z: 381.1/383.1[M+H] +
1H NMR(400MHz，DMSO-d 6)δ8.06-8.01(m，1H)，1.42(s，18H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.06-8.01 (m, 1H), 1.42 (s, 18H).
步骤3：叔丁基-4-((叔丁氧羰基)氨基)-2，6-二氯-5-氟尼古丁酯Step 3: tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotine ester
Figure PCTCN2022106363-appb-000115
Figure PCTCN2022106363-appb-000115
将叔丁基-N-[(叔丁氧基)羰基]-N-(2，6-二氯-3-氟吡啶-4-基)氨基甲酯(5.84g，15.32mmol，1eq)溶于四氢呋喃(30mL)中，-78℃滴加二异丙基氨基锂(2M，15.32mL，2eq)，2小时升到室温。反应液加水淬灭，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-20％)，得到叔丁基-4-((叔丁氧羰基)氨基)-2，6-二氯-5-氟尼古丁酯(5.0g，产率：85.62％)，棕色固体。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. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 0-20%) to obtain tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5- Flunicotine ester (5.0 g, yield: 85.62%), brown solid.
MS m/z：381.1/383.1[M+H] + MS m/z: 381.1/383.1[M+H] +
1H NMR(400MHz，DMSO-d 6)δ10.06(s，1H)，1.54(s，9H)，1.45(s，9H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.06(s, 1H), 1.54(s, 9H), 1.45(s, 9H).
步骤4：2，6-二氯-3-氟吡啶-4-胺Step 4: 2,6-Dichloro-3-fluoropyridin-4-amine
Figure PCTCN2022106363-appb-000116
Figure PCTCN2022106363-appb-000116
将叔丁基-4-((叔丁氧羰基)氨基)-2，6-二氯-5-氟尼古丁酯(13g，34.10mmol，1eq)溶于二氯甲烷(100mL)中，加入三氟乙酸(30mL)，室温反应16小时。LCMS监测反应完全。反应液浓缩，得到2，6-二氯-3-氟吡啶-4-胺(7.67g，粗品)，棕色固体，直接用于下一步。Dissolve tert-butyl-4-((tert-butoxycarbonyl)amino)-2,6-dichloro-5-fluoronicotine ester (13g, 34.10mmol, 1eq) in dichloromethane (100mL) and add trifluoro Acetic acid (30 mL) was reacted at room temperature for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to give 2,6-dichloro-3-fluoropyridin-4-amine (7.67 g, crude product) as a brown solid, which was directly used in the next step.
MS m/z：225.1[M+H] + MS m/z: 225.1[M+H] +
步骤5：乙基-4-氨基-2，6-二氯-5-氟尼古丁酯Step 5: Ethyl-4-amino-2,6-dichloro-5-fluoronicotine ester
Figure PCTCN2022106363-appb-000117
Figure PCTCN2022106363-appb-000117
将2，6-二氯-3-氟吡啶-4-胺(7.67g，34.09mmol，1eq)溶于乙醇(100mL)中，加入浓硫酸(102.35g，1.02mol，30eq)，80℃反应40小时。冷却至室温，向反应液加入饱和碳酸氢钠水溶液，调节PH＝7。乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到乙基-4-氨基-2，6-二氯-5-氟尼古丁酯(8.0g，产率：92.76％)，棕色固体。Dissolve 2,6-dichloro-3-fluoropyridin-4-amine (7.67g, 34.09mmol, 1eq) in ethanol (100mL), add concentrated sulfuric acid (102.35g, 1.02mol, 30eq), and react at 80°C for 40 Hour. After cooling to room temperature, saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 7. Extracted with ethyl acetate, 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 ethyl-4-amino-2,6-dichloro-5-fluoronicotine ester (8.0 g, yield : 92.76%), brown solid.
MS m/z：253.1/255.1[M+H] + MS m/z: 253.1/255.1[M+H] +
步骤6：乙基-2，6-二氯-5-氟-4-(3-(2，2，2-三氯乙酰基)脲基)尼古丁酯Step 6: Ethyl-2,6-dichloro-5-fluoro-4-(3-(2,2,2-trichloroacetyl)ureido)nicotine ester
Figure PCTCN2022106363-appb-000118
Figure PCTCN2022106363-appb-000118
将乙基-4-氨基-2，6-二氯-5-氟尼古丁酯(1.13g，4.47mmol，1eq)溶于四氢呋喃(10mL)中，加入三氯乙酰基异氰酸酯(993.57mg，5.27mmol，1.18eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-50％)，得到乙基-2，6-二氯-5-氟-4-(3-(2，2，2-三氯乙酰基)脲基)尼古丁酯(1.5g，产率：76.14％)，白色固体。Ethyl-4-amino-2,6-dichloro-5-fluoronicotine ester (1.13g, 4.47mmol, 1eq) was dissolved in tetrahydrofuran (10mL), trichloroacetyl isocyanate (993.57mg, 5.27mmol, 1.18eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The 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.
MS m/z：441.9/443.9[M+H] + MS m/z: 441.9/443.9[M+H] +
步骤7：5，7-二氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚Step 7: 5,7-Dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol
Figure PCTCN2022106363-appb-000119
Figure PCTCN2022106363-appb-000119
将乙基-2，6-二氯-5-氟-4-(3-(2，2，2-三氯乙酰基)脲基)尼古丁酯(3.0g，6.80mmol，1eq)溶于甲醇(40mL)中，加入氨甲醇溶液(7M，2.77mL，2.85eq)，室温反应2小时。LCMS监测反应完全。反应液浓缩，残留物用甲基叔丁基醚打浆，得到5，7-二氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚(1.8g，产率：100％)，白色固体。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.
MS m/z：250.1/252.1[M+H] + MS m/z: 250.1/252.1[M+H] +
步骤8：2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶Step 8: 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine
Figure PCTCN2022106363-appb-000120
Figure PCTCN2022106363-appb-000120
将5，7-二氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚(1.8g，7.20mmol，1eq)溶于三氯氧磷(40mL)中，室温滴加N，N-二异丙基乙胺(4.61g，35.64mmol，4.95eq)，100℃反应过夜。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-30％)，得到2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(650mg，产率：31.47％)，白色固体。Dissolve 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (1.8g, 7.20mmol, 1eq) in phosphorus oxychloride (40mL), drip at room temperature Add N,N-diisopropylethylamine (4.61g, 35.64mmol, 4.95eq) and react overnight at 100°C. LCMS monitored the reaction to be complete. The 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.
MS m/z：287.8/289.8[M+H] +。 MS m/z: 287.8/289.8 [M+H] + .
中间体2：N，N-二(4-甲氧苄基)-4-甲基-6-(2，4，5-三氯-8-氟吡啶并[4，3-d]嘧啶-7-基)-5-(三氟甲基)吡啶-2-胺的制备Intermediate 2: N,N-bis(4-methoxybenzyl)-4-methyl-6-(2,4,5-trichloro-8-fluoropyrido[4,3-d]pyrimidine-7 Preparation of -yl)-5-(trifluoromethyl)pyridin-2-amine
Figure PCTCN2022106363-appb-000121
Figure PCTCN2022106363-appb-000121
步骤1：6-溴-N，N-二(4-甲氧苄基)-4-甲基吡啶-2-胺Step 1: 6-Bromo-N,N-bis(4-methoxybenzyl)-4-methylpyridin-2-amine
Figure PCTCN2022106363-appb-000122
Figure PCTCN2022106363-appb-000122
将6-溴-4-甲基吡啶-2-胺(20g，106.9mmol，1.0eq)完全溶于N，N-二甲基甲酰胺(330mL)，氮气保护，降温至0℃，加入钠氢(12.8g，320.7mmol，2.0eq)，加完自然升温至室温，室温搅拌1小时，加入对甲氧基苄氯(37.7g，240.5mmol，2.25eq)，室温搅拌2小时，直至原料反应完全，冰水浴降温，加入冰水(650mL)，析出固体，抽滤，滤饼冰水(65mL)洗涤，减压真空旋干，得到6-溴-N，N-二(4-甲氧苄基)-4-甲基吡啶-2-胺，黄色固体(49g，收率：100％)。直接用于下一步反应。Completely dissolve 6-bromo-4-methylpyridin-2-amine (20g, 106.9mmol, 1.0eq) in N,N-dimethylformamide (330mL), protect with nitrogen, cool to 0°C, add sodium hydrogen (12.8g, 320.7mmol, 2.0eq), naturally warmed to room temperature after adding, stirred at room temperature for 1 hour, added p-methoxybenzyl chloride (37.7g, 240.5mmol, 2.25eq), stirred at room temperature for 2 hours, until the raw material was completely reacted , cooled in an ice-water bath, added ice-water (650mL), precipitated solids, filtered with suction, washed the filter cake with ice-water (65mL), and spin-dried under reduced pressure to obtain 6-bromo-N, N-bis(4-methoxybenzyl )-4-methylpyridin-2-amine, yellow solid (49 g, yield: 100%). used directly in the next reaction.
MS m/z：427/429[M+H] + MS m/z: 427/429[M+H] +
步骤2：(6-(二(4-甲氧苄基)氨基)-4-甲基吡啶-2-基)硼酸Step 2: (6-(Bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid
Figure PCTCN2022106363-appb-000123
Figure PCTCN2022106363-appb-000123
将6-溴-N，N-二(4-甲氧苄基)-4-甲基吡啶-2-胺(20g，46.84mmol，1.0eq)完全溶于1，4-二氧六环(100mL)，加入[1，1′-双(二苯基膦)二茂铁]二氯化钯(3.42g，4.68mmol，0.1eq)，乙酸钾(9.2g，93.68mmol，2.0eq)，双(频哪醇合)二硼(23.8g，93.68mmol，2.0eq)，混合液在氮气保护下，80℃条件下搅拌反应3小时。冷却到室温，过滤，滤液减压浓缩，得到粗品(6-(二(4-甲氧苄基)氨基)-4-甲基吡啶-2-基)硼酸，黑色油状物(42g)。直接用于下一步。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. Cool to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain crude (6-(bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid as a black oil (42g). used directly in the next step.
MS m/z：393[M+H] + MS m/z: 393[M+H] +
步骤3：乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-4′-甲基-[2，2′-联吡啶]-5-羧酸酯Step 3: Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-[2,2'-bipyridine]-5-carboxylic acid ester
Figure PCTCN2022106363-appb-000124
Figure PCTCN2022106363-appb-000124
将(6-(二(4-甲氧苄基)氨基)-4-甲基吡啶-2-基)硼酸(122g，118.7mmol，1.0eq)完全溶于1，4-二氧六环(375mL)，加入[1，1′-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(6.68g，11.8mmol，0.1eq)，乙基4-氨基-6-氯-5-氟尼古丁酸酯(20g，91.3mmol，0.77eq)和磷酸钾(58.06g，273.9mmol，2.3eq)，再加入水(95mL)，混合液在氮气保护，45℃条件下搅拌反应2小时。冷却到室温，加入饱和食盐水(500mL)稀释，加乙酸乙酯(500mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝100∶15，体积比)得到粗品乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-4′-甲基-[2，2′-联吡啶]-5-羧酸酯，黄色固体(44g)。(6-(Bis(4-methoxybenzyl)amino)-4-methylpyridin-2-yl)boronic acid (122 g, 118.7 mmol, 1.0 eq) was completely dissolved in 1,4-dioxane (375 mL ), added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (6.68g, 11.8mmol, 0.1eq), ethyl 4-amino-6-chloro -5-fluoronicotinate (20g, 91.3mmol, 0.77eq) and potassium phosphate (58.06g, 273.9mmol, 2.3eq), then added water (95mL), the mixture was stirred under nitrogen protection at 45°C for reaction 2 Hour. Cool to room temperature, dilute with saturated brine (500 mL), and extract with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=100:15, volume ratio) to obtain crude ethyl-4-amino-6'-(bis(4 -methoxybenzyl)amino)-3-fluoro-4'-methyl-[2,2'-bipyridine]-5-carboxylate, yellow solid (44 g).
MS m/z：531.2[M+H] + MS m/z: 531.2[M+H] +
步骤4：乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-3′-碘-4′-甲基-[2，2′-联吡啶]-5-羧酸酯Step 4: Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-3'-iodo-4'-methyl-[2,2'-bipyridine] -5-carboxylate
Figure PCTCN2022106363-appb-000125
Figure PCTCN2022106363-appb-000125
将乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-4′-甲基-[2，2′-联吡啶]-5-羧酸酯(44g，83.0mmol，1.0eq)，乙酸银(30.5g，182.6mmol，2.2eq)溶于无水N，N-二甲基甲酰胺中，在氮气保护下加入碘单质(63.2g，249.0mmol，3.0eq)，室温搅拌反应2小时。加饱和亚硫酸钠水溶液稀释，加乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝5∶1，体积比)，得到乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-3′-碘-4′-甲基-[2，2′-联吡啶]-5-羧酸酯，黄色固体(23.6g，收率43.3％)。Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-[2,2'-bipyridine]-5-carboxylate ( 44g, 83.0mmol, 1.0eq), silver acetate (30.5g, 182.6mmol, 2.2eq) was dissolved in anhydrous N, N-dimethylformamide, and iodine element (63.2g, 249.0mmol, 3.0eq), stirred at room temperature for 2 hours. Diluted with saturated aqueous sodium sulfite solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=5:1, volume ratio) to obtain ethyl-4- Amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-3'-iodo-4'-methyl-[2,2'-bipyridine]-5-carboxylate, yellow Solid (23.6 g, 43.3% yield).
MS m/z：657.1[M+H] + MS m/z: 657.1[M+H] +
步骤5：乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯Step 5: Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[2,2 '-bipyridine]-5-carboxylate
Figure PCTCN2022106363-appb-000126
Figure PCTCN2022106363-appb-000126
将乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-3′-碘-4′-甲基-[2，2′-联吡啶]-5-羧酸酯(23.6g，36.0mmol，1.0eq)，碘化亚铜(13.7g，72.0mmol，2.0eq)溶于无水N，N-二甲基甲酰胺中，在氮气保护下加入三氟甲基(1，10-二氮杂菲)铜(I)(16.6g，53.0mmol，1.5eq)，氮气保护，室温搅拌反应2小时。加饱和氯化钠溶液稀释，加乙酸乙酯萃取，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝5∶1，体积比)，得到乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯，黄色固体(22g，收率100％)。Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-3'-iodo-4'-methyl-[2,2'-bipyridine]-5 - carboxylate (23.6g, 36.0mmol, 1.0eq), cuprous iodide (13.7g, 72.0mmol, 2.0eq) was dissolved in anhydrous N,N-dimethylformamide, added three Fluoromethyl(1,10-phenanthroline)copper(I) (16.6g, 53.0mmol, 1.5eq), under nitrogen protection, stirred at room temperature for 2 hours. Diluted with saturated sodium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=5:1, volume ratio) to obtain ethyl- 4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[2,2'-bipyridine]- 5-Carboxylate, yellow solid (22 g, yield 100%).
MS m/z：599[M+H] + MS m/z: 599[M+H] +
步骤6：4-氨基-6′-(二(4-甲氧苄基)氨基)-5-(乙氧羰基)-3-氟-4′-甲基 -3′-(三氟甲基)-[2，2′-联吡啶]-1-氧化物Step 6: 4-Amino-6'-(bis(4-methoxybenzyl)amino)-5-(ethoxycarbonyl)-3-fluoro-4'-methyl-3'-(trifluoromethyl) -[2,2′-bipyridine]-1-oxide
Figure PCTCN2022106363-appb-000127
Figure PCTCN2022106363-appb-000127
将乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯(22g，36.8mmol，1.0eq)，溶于1，2-二氯乙烷(400mL)加入间氯过氧苯甲酸(25.4g，147.2mmol，4.0eq)。室温搅拌反应1小时。加水稀释，加二氯甲烷萃取，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝4∶1，体积比)，得到4-氨基-6′-(二(4-甲氧苄基)氨基)-5-(乙氧羰基)-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-1-氧化物，黄色固体(13.6g，收率61.5％)。Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[2,2'- Bipyridyl]-5-carboxylate (22g, 36.8mmol, 1.0eq), dissolved in 1,2-dichloroethane (400mL) was added m-chloroperoxybenzoic acid (25.4g, 147.2mmol, 4.0eq). The reaction was stirred at room temperature for 1 hour. Diluted with water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=4:1, volume ratio) to obtain 4-amino-6'-( Bis(4-methoxybenzyl)amino)-5-(ethoxycarbonyl)-3-fluoro-4′-methyl-3′-(trifluoromethyl)-[2,2′-bipyridine]- 1-oxide, yellow solid (13.6 g, yield 61.5%).
MS m/z：615.2[M+H] + MS m/z: 615.2[M+H] +
步骤7：乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-6-氯-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯Step 7: Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-6-chloro-3-fluoro-4'-methyl-3'-(trifluoromethyl)- [2,2'-bipyridyl]-5-carboxylate
Figure PCTCN2022106363-appb-000128
Figure PCTCN2022106363-appb-000128
将4-氨基-6′-(二(4-甲氧苄基)氨基)-5-(乙氧羰基)-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-1-氧化物(13.6g，22.1mmol，1.0eq)溶于三氯氧磷(20mL)，110℃搅拌1小时。旋干溶剂，残留物硅胶柱层析(石油醚/乙酸乙酯＝1∶1，体积比)，得到乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-6-氯-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯，黄色固体(5.7g，收率40.7％)。4-amino-6'-(bis(4-methoxybenzyl)amino)-5-(ethoxycarbonyl)-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[ 2,2'-Bipyridyl]-1-oxide (13.6g, 22.1mmol, 1.0eq) was dissolved in phosphorus oxychloride (20mL), stirred at 110°C for 1 hour. The solvent was spin-dried, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=1:1, volume ratio) to obtain ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)- 6-Chloro-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[2,2'-bipyridine]-5-carboxylate, yellow solid (5.7g, yield 40.7% ).
MS m/z：633.3/635.3[M+H] + MS m/z: 633.3/635.3[M+H] +
1H NMR(400MHz，DMSO-d 6)δ7.19-7.16(m，4H)，7.02(s，1H)，6.89-6.85(m，4H)，6.76(s，1H)，4.68(s，4H)，4.39-4.33(m，2H)，3.72(s，6H)，2.34(s，3H)，1.34-1.29(m，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.19-7.16(m, 4H), 7.02(s, 1H), 6.89-6.85(m, 4H), 6.76(s, 1H), 4.68(s, 4H ), 4.39-4.33(m, 2H), 3.72(s, 6H), 2.34(s, 3H), 1.34-1.29(m, 3H).
步骤8：乙基-6′-(二(4-甲氧苄基)氨基)-6-氯-3-氟-4′-甲基 -4-(3-(2，2，2-三氯乙酰基)脲基)-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯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
Figure PCTCN2022106363-appb-000129
Figure PCTCN2022106363-appb-000129
将乙基-4-氨基-6′-(二(4-甲氧苄基)氨基)-6-氯-3-氟-4′-甲基-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯(5.7g，9.28mmol，1.0eq)，溶于四氢呋喃(93mL)，氮气保护，降温至15℃，加入三氯乙酰异氰酸酯(2.27g，12.07mmol，1.3eq)。15℃搅拌反应0.5小时。旋干溶剂，得到粗品，加入甲基叔丁醚(20mL)，石油醚(10mL)，打浆0.5小时，过滤，旋干，得到乙基-6′-(二(4-甲氧苄基)氨基)-6-氯-3-氟-4′-甲基-4-(3-(2，2，2-三氯乙酰基)脲基)-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯，白色固体(7.1g，收率93.3％)。直接用于下一步。Ethyl-4-amino-6'-(bis(4-methoxybenzyl)amino)-6-chloro-3-fluoro-4'-methyl-3'-(trifluoromethyl)-[2 , 2′-bipyridine]-5-carboxylate (5.7g, 9.28mmol, 1.0eq), dissolved in tetrahydrofuran (93mL), under nitrogen protection, cooled to 15°C, added trichloroacetyl isocyanate (2.27g, 12.07mmol , 1.3eq). The reaction was stirred at 15°C for 0.5 hours. The solvent was spin-dried to obtain the crude product, and methyl tert-butyl ether (20mL) and petroleum ether (10mL) were added, beating for 0.5 hours, filtered, and spin-dried to obtain 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, white solid (7.1 g, yield 93.3%). used directly in the next step.
MS m/z：820.1/822.1[M+H] + MS m/z: 820.1/822.1[M+H] +
步骤9：7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚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
Figure PCTCN2022106363-appb-000130
Figure PCTCN2022106363-appb-000130
将乙基-6′-(二(4-甲氧苄基)氨基)-6-氯-3-氟-4′-甲基-4-(3-(2，2，2-三氯乙酰基)脲基)-3′-(三氟甲基)-[2，2′-联吡啶]-5-羧酸酯(7.1g，8.66mmol，1.0eq)置入100mL三口烧瓶中，氮气保护，降温至15℃，加入氨甲醇溶液(7M，56mL)，15℃反应，搅拌0.5小时。旋干溶剂，得到粗品，加入甲基叔丁醚(20mL)，石油醚(10mL)，打浆0.5小时，过滤，旋干，得到7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚，白色固体(6.1g，收率100％)。直接用于下一步。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. Spin to dry the solvent to obtain the crude product, add methyl tert-butyl ether (20mL), petroleum ether (10mL), make a slurry for 0.5 hours, filter, and spin dry to obtain 7-(6-(bis(4-methoxybenzyl)amino) -4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol, white solid (6.1 g, yield 100%). used directly in the next step.
MS m/z：630.3/632.3[M+H] + MS m/z: 630.3/632.3[M+H] +
步骤10：N，N-二(4-甲氧苄基)-4-甲基-6-(2，4，5-三氯-8-氟吡啶并 [4，3-d]嘧啶-7-基)-5-(三氟甲基)吡啶-2-胺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
Figure PCTCN2022106363-appb-000131
Figure PCTCN2022106363-appb-000131
将7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚(2.5g，3.97mmol，1eq)溶于三氯氧磷(30mL)，室温加入N，N-二异丙基乙胺(2.56g，19.84mmol，5eq)。110℃反应3小时。反应液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-20％)，得到N，N-二(4-甲氧苄基)-4-甲基-6-(2，4，5-三氯-8-氟吡啶并[4，3-d]嘧啶-7-基)-5-(三氟甲基)吡啶-2-胺(750mg，产率：28.34％)，黄色固体。7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-5-chloro-8-fluoropyrido[4 ,3-d]pyrimidine-2,4-diol (2.5g, 3.97mmol, 1eq) was dissolved in phosphorus oxychloride (30mL), and N,N-diisopropylethylamine (2.56g, 19.84mmol , 5eq). React at 110°C for 3 hours. The 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.
MS m/z：666.1/668.1[M+H] +。 MS m/z: 666.1/668.1 [M+H] + .
中间体3：(1R，2R，5S)-苯甲基-2-(((叔-丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯的制备Intermediate 3: (1R,2R,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2 .1] Preparation of octane-8-carboxylate
Figure PCTCN2022106363-appb-000132
Figure PCTCN2022106363-appb-000132
步骤1：(1R，2R，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 1: (1R,2R,5S)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022106363-appb-000133
Figure PCTCN2022106363-appb-000133
将(1R，2R，5S)-8-苯甲基-2-乙基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(1.0g，3.29mmol，1eq)(参考文献：WO2019/183133A1)溶于四氢呋喃(10mL)中，0℃加入四氢铝锂(162.26mg，4.27mmol，1.3eq)，0℃反应1小时。LCMS监测反应完全。加入十水硫酸钠淬灭反应。过滤，滤液浓缩，得到(1R，2R，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.0g，粗品)，棕色液体，直接投入下一步反应。(1R,2R,5S)-8-Benzyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (1.0g, 3.29 mmol, 1eq) (reference: WO2019/183133A1) was dissolved in tetrahydrofuran (10mL), and lithium aluminum tetrahydride (162.26mg, 4.27mmol, 1.3eq) was added at 0°C, and reacted at 0°C for 1 hour. LCMS monitored the reaction to be complete. The reaction was quenched by adding sodium sulfate decahydrate. Filtration, and the filtrate was concentrated to give (1R, 2R, 5S)-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, crude product), brown liquid, directly put into next step reaction.
MS m/z：277.1[M+H] + MS m/z: 277.1[M+H] +
步骤2：(1R，2R，5S)-苯甲基-2-(((叔-丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 2: (1R,2R,5S)-Benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate
Figure PCTCN2022106363-appb-000134
Figure PCTCN2022106363-appb-000134
将(1R，2R，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.0g，3.62mmol，1eq)溶于二氯甲烷(10mL)中，加入三乙胺(732.38mg，7.24mmol，1.01mL，2eq)，4-二甲氨基吡啶(22.11mg，0.181mmol，0.05eq)，二甲基叔丁基氯硅烷(818.16mg，5.43mmol，1.5eq)，室温反应2小时。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残余物经HPLC纯化得到(1R，2R，5S)-苯甲基-2-(((叔-丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(570mg，产率：40.33％)，无色液体。(1R,2R,5S)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0g, 3.62mmol, 1eq) was dissolved in dichloromethane (10mL), triethylamine (732.38mg, 7.24mmol, 1.01mL, 2eq), 4-dimethylaminopyridine (22.11mg, 0.181mmol, 0.05eq), dimethyl tert Butylchlorosilane (818.16mg, 5.43mmol, 1.5eq) was reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The 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.
MS m/z：391.2[M+H] + MS m/z: 391.2[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Pack CN 150*30mm*5um；Column: YMC-Pack CN 150*30mm*5um;
流动相：[Heptane-EtOH]；B％：0％-80％，9min.。Mobile phase: [Heptane-EtOH]; B%: 0%-80%, 9min.
实施例1：化合物1Example 1: Compound 1
6-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)-4-甲基-5-(三氟甲基)吡啶-2-胺6-((5aR, 6R, 9S)-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]cyclohepta Trien-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine
Figure PCTCN2022106363-appb-000135
Figure PCTCN2022106363-appb-000135
步骤1：(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2，5-二氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-2-(((叔 丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000136
Figure PCTCN2022106363-appb-000136
将N，N-二(4-甲氧苄基)-4-甲基-6-(2，4，5-三氯-8-氟吡啶并[4，3-d]嘧啶-7-基)-5-(三氟甲基)吡啶-2-胺(530mg，0.794mmol，1eq)溶于二氯甲烷(5mL)中，加入N，N-二异丙基乙胺(205.43mg，1.59mmol，2eq)，-30℃滴加(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(310.42mg，0.794mmol，1eq)的二氯甲烷(2mL)溶液，-30℃反应1小时。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：0-30％)，得到(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2，5-二氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(480mg，产率：59.15％)，黄色固体。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 (530mg, 0.794mmol, 1eq) was dissolved in dichloromethane (5mL), and N,N-diisopropylethylamine (205.43mg, 1.59mmol, 2eq), -30°C drop (1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl) oxo)methyl)-3,8-diazabis Cyclo[3.2.1]octane-8-carboxylate (310.42mg, 0.794mmol, 1eq) in dichloromethane (2mL) was reacted at -30°C for 1 hour. LCMS monitored the reaction to be complete. The 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: 0-30%) to obtain (1R, 2R, 5S)-benzyl-3-(7-(6-(bis(4- Methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-2,5-dichloro-8-fluoropyrido[4,3-d]pyrimidine-4 -yl)-2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (480mg , yield: 59.15%), yellow solid.
MS m/z：1020.3/1022.3[M+H] + MS m/z: 1020.3/1022.3[M+H] +
步骤2：(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000137
Figure PCTCN2022106363-appb-000137
将(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-2，5-二氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(480mg，0.470mmol，1eq)溶于二氯甲烷(5mL)中，加入叔丁醇钠(90.36mg，0.940mmol，2eq)，室温滴加((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(112.27mg，0.705mmol，1.5eq)的二氯甲烷(2mL)溶液，室温反应1小时。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-40％)，得到(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(440mg，产率：81.83％)，黄色固体。(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 (480 mg, 0.470 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and sodium tert-butoxide (90.36 mg , 0.940mmol, 2eq), room temperature was added dropwise ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (112.27mg, 0.705mmol, 1.5eq) in dichloromethane (2mL ) solution at room temperature for 1 hour. LCMS monitored the reaction to be complete. The 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 (tetrahydrofuran/petroleum ether: 0-40%) to obtain (1R, 2R, 5S)-benzyl-3-(7-(6-(bis(4-methoxy Benzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-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-carboxylate (440 mg, yield: 81.83%), yellow solid.
MS m/z：1143.6/1145.6[M+H] + MS m/z: 1143.6/1145.6[M+H] +
步骤3：(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000138
Figure PCTCN2022106363-appb-000138
将(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(440mg，0.385mmol，1eq)溶于四氢呋喃(5mL)中，加入四丁基氟化铵(1M，0.85mL，2.2eq)，室温反应1小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩， 得(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(390mg，粗品)。(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-carboxylic acid Ethyl ester (440mg, 0.385mmol, 1eq) was dissolved in tetrahydrofuran (5mL), tetrabutylammonium fluoride (1M, 0.85mL, 2.2eq) was added, and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, and the filtrate was concentrated to give (1R, 2R, 5S)-benzyl-3-(7-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethane Base) pyridin-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 (390 mg, crude).
MS m/z：1029.3/1031.3[M+H] + MS m/z: 1029.3/1031.3[M+H] +
步骤4：(5aR，6R，9S)-苯甲基-2-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000139
Figure PCTCN2022106363-appb-000139
将(1R，2R，5S)-苯甲基-3-(7-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-5-氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(190mg，0.185mmol，1eq)溶于二氧六环(5mL)中，加入碳酸铯(180.40mg，0.554mmol，3eq)，4，5-双(二苯基膦)-9，9-二甲基氧杂蒽(26.70mg，0.046mmol，0.25eq)，三(二亚苄基丙酮)二钯(33.80mg，0.037mmol，0.2eq)，氮气保护下80℃反应1小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经HPLC纯化，得到(5aR，6R，9S)-苯甲基-2-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(15mg，产率：8.18％)。(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 (190mg, 0.185mmol, 1eq) dissolved in dioxo To hexacyclic (5mL), add cesium carbonate (180.40mg, 0.554mmol, 3eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (26.70mg, 0.046mmol, 0.25 eq), tris(dibenzylideneacetone)dipalladium (33.80mg, 0.037mmol, 0.2eq), react at 80°C for 1 hour under the protection of nitrogen. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with ethyl acetate. 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 (5aR, 6R, 9S)-benzyl-2-(6-(di(4-methoxybenzyl)amino)-4-methyl-3-( Trifluoromethyl)pyridin-2-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]cyclo Heptatriene-14-carboxylate (15 mg, yield: 8.18%).
MS m/z：993.4[M+H] + MS m/z: 993.4[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*30mm*5um；Column: Phenomenex C18 80*30mm*5um;
流动相：[Water(ammonia hydroxide v/v)-ACN]；B％：70％-90％，12minMobile phase: [Water(ammonia hydroxide v/v)-ACN]; B%: 70%-90%, 12min
步骤5：6-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)-4-甲基-5-(三氟甲基)吡啶-2-胺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
Figure PCTCN2022106363-appb-000140
Figure PCTCN2022106363-appb-000140
将(5aR，6R，9S)-苯甲基-2-(6-(二(4-甲氧苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(15mg，0.015mmol，1eq)溶于三氟乙酸(2mL)中，加入三氟甲磺酸(6.80mg，0.045mmol，3eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经HPLC纯化得6-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)-4-甲基-5-(三氟甲基)吡啶-2-胺(8mg，产率：85.62％)(5aR, 6R, 9S)-benzyl-2-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-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 (15mg , 0.015mmol, 1eq) was dissolved in trifluoroacetic acid (2mL), added trifluoromethanesulfonic acid (6.80mg, 0.045mmol, 3eq), and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 6-((5aR, 6R, 9S)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline-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]cycloheptatrien-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (8 mg, yield: 85.62%)
MS m/z：619.4[M+H] + MS m/z: 619.4[M+H] +
19F NMR(376MHz，CDCl 3)δ-55.05(s，3F)，-145.84(br s，1F)，-173.20(br s，1F). 19 F NMR (376MHz, CDCl 3 ) δ-55.05(s, 3F), -145.84(br s, 1F), -173.20(br s, 1F).
1H NMR(400MHz，CDCl 3)δ6.46(s，1H)，5.33(br d，J＝53.6Hz，1H)，5.03(m，1H)，4.80(s，2H)，4.47(dd，J＝1.7，13.2Hz，1H)，4.37-4.16(m，3H)，4.09(br d，J＝7.0Hz，1H)，3.78(br s，1H)，3.60(br s，1H)，3.49-3.23(m，3H)，3.17(br d，J＝13.0Hz，1H)，3.05-3.03(m，1H)，2.47(d，J＝1.5Hz，3H)，2.40-2.18(m，3H)，2.06-1.81(m，7H). 1 H NMR (400MHz, CDCl 3 ) δ6.46(s, 1H), 5.33(br d, J=53.6Hz, 1H), 5.03(m, 1H), 4.80(s, 2H), 4.47(dd, J =1.7, 13.2Hz, 1H), 4.37-4.16(m, 3H), 4.09(br d, J=7.0Hz, 1H), 3.78(br s, 1H), 3.60(br s, 1H), 3.49-3.23 (m, 3H), 3.17(br d, J=13.0Hz, 1H), 3.05-3.03(m, 1H), 2.47(d, J=1.5Hz, 3H), 2.40-2.18(m, 3H), 2.06 -1.81(m, 7H).
13C NMR(101MHz，CDCl 3)δ164.05，162.22，158.99，156.82，156.79，152.88，152.75，150.21，148.98，147.68，141.97，141.80，125.92，123.20，115.38，115.07，110.74，100.82，98.64，96.89，73.36，72.86，70.70， 64.94，60.41，60.23，57.12，56.91，54.19，53.67，42.92，42.71，36.06，28.12，25.72，25.56，20.32，20.29. 13 C NMR(101MHz，CDCl 3 )δ164.05，162.22，158.99，156.82，156.79，152.88，152.75，150.21，148.98，147.68，141.97，141.80，125.92，123.20，115.38，115.07，110.74，100.82，98.64，96.89 ,73.36,72.86,70.70,64.94,60.41,60.23,57.12,56.91,54.19,53.67,42.92,42.71,36.06,28.12,25.72,25.56,20.32,20.29.
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*30mm*5um；Column: Phenomenex C18 80*30mm*5um;
流动相：[Water(ammonia hydroxide v/v)-ACN]；B％：38％-58％，12min。Mobile phase: [Water(ammonia hydroxide v/v)-ACN]; B%: 38%-58%, 12min.
实施例2：化合物2Example 2: Compound 2
5-乙炔基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚5-Ethynyl-6-fluoro-4-((5aR, 6R, 9S)-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] cycloheptatrien-2-yl) naphthalene-2-ol
Figure PCTCN2022106363-appb-000141
Figure PCTCN2022106363-appb-000141
步骤1：(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000142
Figure PCTCN2022106363-appb-000142
将2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(413mg，1.44mmol，1eq)溶于二氯甲烷(5mL)中，加入N，N-二异丙基乙胺(558.14mg，4.32mmol，3eq)，-30℃滴加(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(562.25mg，1.44mmol，1eq)的二氯甲烷(2mL)溶液，2小时后升到室温。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水 洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(600mg，产率：65.02％)，白色固体。2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (413mg, 1.44mmol, 1eq) was dissolved in dichloromethane (5mL) and N,N-diiso Propylethylamine (558.14mg, 4.32mmol, 3eq), (1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methanol was added dropwise at -30°C A solution of -3,8-diazabicyclo[3.2.1]octane-8-carboxylate (562.25 mg, 1.44 mmol, 1 eq) in dichloromethane (2 mL) was warmed to room temperature after 2 hours. LCMS monitored the reaction to be complete. The reaction solution was diluted with water, extracted with ethyl acetate, 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 (1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilane Base) oxo) methyl) -3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (600 mg, yield: 65.02%), white solid.
MS m/z：640.3/642.3[M+H] + MS m/z: 640.3/642.3[M+H] +
步骤2：(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000143
Figure PCTCN2022106363-appb-000143
将(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(600mg，0.936mmol，1eq)溶于二氯甲烷(2mL)中，加入((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(149.01mg，0.936mmol，1eq)，叔丁醇钠(179.90mg，1.87mmol，2eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：30-50％)，得到(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg，产率：69.94％)，棕色固体。(1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoro Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (600mg, 0.936mmol, 1eq) was dissolved in dichloro To methane (2mL), add ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (149.01mg, 0.936mmol, 1eq), sodium tert-butoxide (179.90mg, 1.87 mmol, 2eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 30-50%) to obtain (1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl )Oxo)methyl)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500mg, yield: 69.94%), brown solid.
MS m/z：763.3/765.3[M+H] + MS m/z: 763.3/765.3[M+H] +
步骤3：(5aR，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000144
Figure PCTCN2022106363-appb-000144
将(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg，0.655mmol，1eq)溶于四氢呋喃(10mL)中，加入四丁基氟化铵(1M，0.98mL，1.5eq)，室温反应3小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：70-100％)，得到(5aR，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(400mg，产率：99.67％)，黄色固体。(1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxy)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-di Azabicyclo[3.2.1]octane-8-carboxylate (500mg, 0.655mmol, 1eq) was dissolved in tetrahydrofuran (10mL), tetrabutylammonium fluoride (1M, 0.98mL, 1.5eq) was added, React at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 70-100%) to obtain (5aR, 6R, 9S)-benzyl-2-chloro-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 (400 mg, yield: 99.67%), yellow solid.
MS m/z：613.2/615.2[M+H] + MS m/z: 613.2/615.2[M+H] +
步骤4：(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000145
Figure PCTCN2022106363-appb-000145
将(5aR，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(559mg，0.912mmol，1eq)溶于三氟乙酸(5mL)中，加入三氟甲磺酸(410.53mg，2.74 mmol，3eq)，室温反应1小时。反应液浓缩，残留物溶于二氯甲烷(10mL)，加入Boc酸酐(238.80mg，1.09mmol，1.2eq)，三乙胺(461.34mg，4.56mmol，5eq)，室温反应1小时。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：40-70％)，得到(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(640mg，产率：100％)，黄色固体。(5aR, 6R, 9S)-benzyl-2-chloro-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-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (559mg, 0.912mmol, 1eq) was dissolved in trifluoroacetic acid (5mL), added trifluoromethanesulfonic acid (410.53mg, 2.74 mmol, 3eq), and reacted at room temperature 1 hour. The reaction solution was concentrated, the residue was dissolved in dichloromethane (10 mL), Boc anhydride (238.80 mg, 1.09 mmol, 1.2 eq) and triethylamine (461.34 mg, 4.56 mmol, 5 eq) were added and reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 40-70%) to obtain (5aR, 6R, 9S)-tert-butyl-2-chloro-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 (640 mg, yield: 100%), yellow solid.
MS m/z：579.2/581.2[M+H] + MS m/z: 579.2/581.2[M+H] +
步骤5：(5aR，6R，9S)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000146
Figure PCTCN2022106363-appb-000146
将(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(584mg，1.01mmol，1eq)溶于二氧六环(6mL)和水(2mL)中，加入((2-氟-6-(甲氧基甲氧基)-8-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(775.39mg，1.51mmol，1.5eq)，碳酸铯(657.23mg，2.02mmol，3eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(67.44mg，0.101mmol，0.1eq)，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：30-60％)，得到(5aR，6R，9S)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(400mg，产率：42.68％)，棕色 固体。(5aR, 6R, 9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (584 mg, 1.01 mmol, 1 eq) was dissolved in dioxane (6 mL) and water (2 mL), and ((2-fluoro-6-(methoxy methoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropyl Silane (775.39mg, 1.51mmol, 1.5eq), cesium carbonate (657.23mg, 2.02mmol, 3eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1- Biphenyl-2-yl)palladium(II) (67.44mg, 0.101mmol, 0.1eq), under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 30-60%) to obtain (5aR, 6R, 9S)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-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-meth Naphtho[1,8-ab]cycloheptatriene-14-carboxylate (400 mg, yield: 42.68%), brown solid.
MS m/z：929.5[M+H] + MS m/z: 929.5[M+H] +
步骤6：(5aR，6R，9S)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000147
Figure PCTCN2022106363-appb-000147
将(5aR，6R，9S)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(180mg，0.1937mmol，1eq)溶于N，N-二甲基甲酰胺(3mL)中，加入氟化铯(147.14mg，0.9686mmol，5eq)，室温反应1小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，得到(5aR，6R，9S)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(150mg，粗品)，棕色固体，直接投入下一步反应。(5aR, 6R, 9S)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) Naphthalene-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-carboxylate (180mg, 0.1937mmol, 1eq) was dissolved in N,N-dimethylformamide (3mL), cesium fluoride (147.14mg, 0.9686mmol, 5eq) was added, and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate afforded (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 (150 mg, crude product), The brown solid was put directly into the next reaction.
MS m/z：773.3[M+H] + MS m/z: 773.3[M+H] +
步骤7：5-乙炔基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚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
Figure PCTCN2022106363-appb-000148
Figure PCTCN2022106363-appb-000148
将(5aR，6R，9S)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(150mg，0.194mmol，1eq)溶于乙腈(5mL)中，加入盐酸/二氧六环(4M，5mL，20mmol)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到5-乙炔基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚(60mg，产率：49.17％)，白色固体。(5aR, 6R, 9S)-tert-butyl-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-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 (150 mg, 0.194 mmol, 1 eq) dissolved in acetonitrile (5 mL), add hydrochloric acid/dioxane (4M, 5 mL, 20 mmol), and react at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 5-ethynyl-6-fluoro-4-((5aR, 6R, 9S)-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-pentaza Hetero-6,9-methanonaphtho[1,8-ab]cycloheptatrien-2-yl)naphthalene-2-ol (60 mg, yield: 49.17%), white solid.
MS m/z：629.2[M+H] + MS m/z: 629.2[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-110.77(s，1F)，-147.067(s，1F)，-172.23(s，1F). 19 F NMR (376MHz, DMSO-d 6 ) δ-110.77(s, 1F), -147.067(s, 1F), -172.23(s, 1F).
1H NMR(400MHz，DMSO-d 6)δ10.15(br s，1H)，7.96(ddd，J＝2.4，6.1，8.9Hz，1H)，7.46(dt，J＝4.9，9.0Hz，1H)，7.37(s，1H)，7.15(dd，J＝2.0，38.4Hz，1H)，5.28(br d，J＝54.0Hz，1H)，4.90-4.77(m，1H)，4.60-4.47(m，1H)，4.46-4.27(m，1H)，4.14-3.96(m，4H)，3.66-3.51(m，2H)，3.26-3.00(m，4H)，2.95-2.78(m，1H)，2.18-1.96(m，3H)，1.92-1.49(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.15 (br s, 1H), 7.96 (ddd, J=2.4, 6.1, 8.9Hz, 1H), 7.46 (dt, J=4.9, 9.0Hz, 1H) , 7.37(s, 1H), 7.15(dd, J=2.0, 38.4Hz, 1H), 5.28(br d, J=54.0Hz, 1H), 4.90-4.77(m, 1H), 4.60-4.47(m, 1H), 4.46-4.27(m, 1H), 4.14-3.96(m, 4H), 3.66-3.51(m, 2H), 3.26-3.00(m, 4H), 2.95-2.78(m, 1H), 2.18- 1.96(m, 3H), 1.92-1.49(m, 7H).
13C NMR(101MHz，DMSO-d 6)δ164.01，163.66，162.29，162.22，161.21，156.95，156.75，154.53，151.74，151.62，151.53，151.41，146.65，146.61，142.62，142.54，142.45，142.37，133.88，132.93，130.99，125.42，123.20，122.80，116.53，116.27，111.98，104.32(dd，J＝7.3，16.1Hz，1C)，101.80，101.56，99.21，99.14，97.49，97.41，92.15，91.86，75.32，75.22，73.41，72.35，70.53，70.23，65.38，65.19，60.30，60.11，56.82，56.51，56.29，53.90，53.68，53.46，42.96，42.79，36.08，28.12，28.02，25.57，25.48，25.42. 13 C NMR(101MHz，DMSO-d 6 )δ164.01，163.66，162.29，162.22，161.21，156.95，156.75，154.53，151.74，151.62，151.53，151.41，146.65，146.61，142.62，142.54，142.45，142.37，133.88 , 132.93, 130.99, 125.42, 123.20, 122.80, 116.53, 116.27, 111.98, 104.32 (dd, J=7.3, 16.1Hz, 1C), 101.80, 101.56, 99.21, 99.14, 97.45, 97.41, 79.28, 92.16, , 73.41, 72.35, 70.53, 70.23, 65.38, 65.19, 60.30, 60.11, 56.82, 56.51, 56.29, 53.90, 53.68, 53.46, 42.96, 42.79, 36.08, 28.12, 28.02, 25.57, 25.48
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*40mm*3um；Column: Phenomenex C18 80*40mm*3um;
流动相：[Water(ammonia hydroxide v/v)-ACN]；B％：25％-65％，9min.。Mobile phase: [Water(ammonia hydroxide v/v)-ACN]; B%: 25%-65%, 9min.
实施例3：化合物3Example 3: Compound 3
5-乙基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚5-Ethyl-6-fluoro-4-((5aR, 6R, 9S)-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] cycloheptatrien-2-yl) naphthalene-2-ol
Figure PCTCN2022106363-appb-000149
Figure PCTCN2022106363-appb-000149
步骤1：5-乙基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚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
Figure PCTCN2022106363-appb-000150
Figure PCTCN2022106363-appb-000150
将5-乙炔基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚(100mg，0.159mmol，1eq)溶于N，N-二甲基甲酰胺(5mL)中，加入钯碳(10％，10mg)，通入氢气(15psi)，室温反应16小时。LCMS检测反应完全。反应液过滤，浓缩，残留物经HPLC纯化，得到5-乙基-6-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六 氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚(26mg，产率：25.83％)，白色固体。5-ethynyl-6-fluoro-4-((5aR, 6R, 9S)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-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]cycloheptatrien-2-yl)naphthalene-2-ol (100mg, 0.159mmol, 1eq) was dissolved in N,N-dimethylformamide (5mL) and palladium on carbon ( 10%, 10 mg), hydrogen gas (15 psi) was passed through, and the reaction was carried out at room temperature for 16 hours. LCMS detected that the reaction was complete. The reaction solution was filtered and concentrated, and the residue was purified by HPLC to obtain 5-ethyl-6-fluoro-4-((5aR, 6R, 9S)-1-fluoro-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]cycloheptatrien-2-yl)naphthalene-2-ol (26 mg, yield: 25.83%), white solid.
MS m/z：633.2[M+H] + MS m/z: 633.2[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-119.59(s，1F)，-144.68(s，1F)，-172.19(s，1F). 19 F NMR (376MHz, DMSO-d 6 ) δ-119.59(s, 1F), -144.68(s, 1F), -172.19(s, 1F).
1H NMR(400MHz，DMSO-d 6)δ9.94(br d，J＝5.4Hz，1H)，7.83-7.66(m，1H)，7.40-7.24(m，2H)，7.00(d，J＝42.0Hz，1H)，5.29(d，J＝53.6Hz，1H)，4.85(br d，J＝12.8Hz，1H)，4.62-4.35(m，2H)，4.21-4.00(m，3H)，3.75-3.57(m，2H)，3.19-3.00(m，3H)，2.92-2.81(m，1H)，2.41(br s，1H)，2.44-2.35(m，1H)，2.27-1.96(m，4H)，1.93-1.55(m，8H)，0.92-0.69(m，3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.94(br d, J=5.4Hz, 1H), 7.83-7.66(m, 1H), 7.40-7.24(m, 2H), 7.00(d, J= 42.0Hz, 1H), 5.29(d, J=53.6Hz, 1H), 4.85(br d, J=12.8Hz, 1H), 4.62-4.35(m, 2H), 4.21-4.00(m, 3H), 3.75 -3.57(m, 2H), 3.19-3.00(m, 3H), 2.92-2.81(m, 1H), 2.41(br s, 1H), 2.44-2.35(m, 1H), 2.27-1.96(m, 4H ), 1.93-1.55(m, 8H), 0.92-0.69(m, 3H).
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*40mm*3um；Column: Phenomenex C18 80*40mm*3um;
流动相：[Water(ammonia hydroxide v/v)-ACN]；B％：47％-87％，9min.。Mobile phase: [Water(ammonia hydroxide v/v)-ACN]; B%: 47%-87%, 9min.
实施例4：化合物4Example 4: Compound 4
(5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-2-(8-甲基萘-1-基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐(5aR, 6R, 9S)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methoxy)-2-(8-methyl Naphthalene-1-yl)-5a, 6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14-pentaaza-6,9-methanophthalene And [1,8-ab] cycloheptatriene carboxylate
Figure PCTCN2022106363-appb-000151
Figure PCTCN2022106363-appb-000151
步骤1：(5aR，6R，9S)-叔丁基-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-2-(8-甲基萘-1-基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000152
Figure PCTCN2022106363-appb-000152
将(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(270mg，0.466mmol，1eq)溶于二氧六环(3mL)和水(1mL)中，加入(8-甲基萘-1-基)硼酸(130.10mg，0.699mmol，1.5eq)，碳酸铯(303.85mg，0.932mmol，2eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(31.18mg，0.0466mmol，0.1eq)，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：30-60％)，得到(5aR，6R，9S)-叔丁基-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-2-(8-甲基萘-1-基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(150mg，产率：46.98％)，棕色固体。(5aR, 6R, 9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab]heptatriene-14-carboxylate (270mg, 0.466mmol, 1eq) was dissolved in dioxane (3mL) and water (1mL) and (8-methylnaphthalen-1-yl) was added Boronic acid (130.10mg, 0.699mmol, 1.5eq), cesium carbonate (303.85mg, 0.932mmol, 2eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1- Biphenyl-2-yl)palladium(II) (31.18mg, 0.0466mmol, 0.1eq), under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 30-60%) to obtain (5aR, 6R, 9S)-tert-butyl-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-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate (150 mg, yield : 46.98%), brown solid.
MS m/z：685.3[M+H] + MS m/z: 685.3[M+H] +
步骤2：(5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-2-(8-甲基萘-1-基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐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
Figure PCTCN2022106363-appb-000153
Figure PCTCN2022106363-appb-000153
将(5aR，6R，9S)-叔丁基-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-2-(8-甲基萘-1-基)-5a，6，7，8，9，10-六氢-5H-4-氧杂 -3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(150mg，0.219mmol，1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环溶液(4M，2mL)，室温反应3小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到(5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-2-(8-甲基萘-1-基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐(22mg，产率：17.18％)，白色固体。(5aR, 6R, 9S)-tert-butyl-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-14-carboxylate (150mg, 0.219mmol, 1eq) was dissolved in acetonitrile (2mL), and hydrochloric acid/dioxane solution (4M , 2mL), react at room temperature for 3 hours. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain (5aR, 6R, 9S)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-2-(8-methylnaphthalen-1-yl)-5a,6,7,8,9,10-hexahydro-5H-4-oxa-3,10a,11,13,14- Pentaaza-6,9-methonaphtho[1,8-ab]cycloheptatriene carboxylate (22 mg, yield: 17.18%), white solid.
MS m/z：585.2[M+H] + MS m/z: 585.2[M+H] +
19F NMR(377MHz，DMSO-d 6)δ-145.14(s，1F)，-172.17(s，1F). 19 F NMR (377MHz, DMSO-d 6 ) δ-145.14(s, 1F), -172.17(s, 1F).
1H NMR(400MHz，DMSO-d 6)δ8.25(br s，1HCOOH)，8.03(br d，J＝8.3Hz，1H)，7.87(br d，J＝8.1Hz，1H)，7.56(td，J＝7.6，10.4Hz，1H)，7.48-7.27(m，3H)，5.32(br d，J＝53.6Hz，1H)，4.92(br t，J＝12.7Hz，1H)，4.62-4.36(m，2H)，4.28-4.09(m，3H)，3.80-3.70(m，2H)，3.30-3.10(m，4H)，2.98-2.83(m，1H)，2.23-1.65(m，13H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.25(br s, 1HCOOH), 8.03(br d, J=8.3Hz, 1H), 7.87(br d, J=8.1Hz, 1H), 7.56(td , J=7.6, 10.4Hz, 1H), 7.48-7.27(m, 3H), 5.32(br d, J=53.6Hz, 1H), 4.92(br t, J=12.7Hz, 1H), 4.62-4.36( m, 2H), 4.28-4.09(m, 3H), 3.80-3.70(m, 2H), 3.30-3.10(m, 4H), 2.98-2.83(m, 1H), 2.23-1.65(m, 13H).
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Actus Triart C18 150*30mm*5um；Column: YMC-Actus Triart C18 150*30mm*5um;
流动相：[Water(FA)-ACN]；B％：3％-43％，9min.。Mobile phase: [Water(FA)-ACN]; B%: 3%-43%, 9min.
实施例5：化合物5Embodiment 5: Compound 5
(5aR，6R，9S)-2-(8-氯-7-氟萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯(5aR, 6R, 9S)-2-(8-chloro-7-fluoronaphthalen-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-pentaaza-6,9- Naphtho[1,8-ab]cycloheptatriene
Figure PCTCN2022106363-appb-000154
Figure PCTCN2022106363-appb-000154
步骤1：(5aR，6R，9S)-叔丁基-2-(8-氯-7-氟萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000155
Figure PCTCN2022106363-appb-000155
将(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(280mg，0.484mmol，1eq)溶于二氧六环(3mL)和水(1mL)中，加入2-(8-氯-7-氟萘-1-基)-4，4，5，5-四甲基-1，3，2-二噁硼戊环(222.37mg，0.725mmol，1.5eq)(参考WO2020146613A1中中间体C-4的方法制备)，碳酸铯(315.11mg，0.967mmol，2eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(32.33mg，0.048mmol，0.1eq)，氮气保护，80℃反应3小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：30-60％)，得到(5aR，6R，9S)-叔丁基-2-(8-氯-7-氟萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(140mg，产率：41.46％)，棕色固体。(5aR, 6R, 9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (280 mg, 0.484 mmol, 1 eq) was dissolved in dioxane (3 mL) and water (1 mL) and 2-(8-chloro-7-fluoronaphthalene was added -1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (222.37mg, 0.725mmol, 1.5eq) (refer to the method of intermediate C-4 in WO2020146613A1 prepared), cesium carbonate (315.11mg, 0.967mmol, 2eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium ( II) (32.33mg, 0.048mmol, 0.1eq), under nitrogen protection, react at 80°C for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 30-60%) to obtain (5aR, 6R, 9S)-tert-butyl-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-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate (140mg , yield: 41.46%), brown solid.
MS m/z：723.2/725.2[M+H] + MS m/z: 723.2/725.2[M+H] +
步骤2：(5aR，6R，9S)-2-(8-氯-7-氟萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯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
Figure PCTCN2022106363-appb-000156
Figure PCTCN2022106363-appb-000156
将(5aR，6R，9S)-叔丁基-2-(8-氯-7-氟萘-1-基)-1-氟-12-(((2R，7aS)-2- 氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(140mg，0.194mmol，1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环(4M，2mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到(5aR，6R，9S)-2-(8-氯-7-氟萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯(15mg，产率：12.44％)，白色固体。(5aR, 6R, 9S)-tert-butyl-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-Methonaphtho[1,8-ab]cycloheptatriene-14-carboxylate (140mg, 0.194mmol, 1eq) was dissolved in acetonitrile (2mL) and hydrochloric acid/dioxane was added (4M, 2mL), react at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain (5aR, 6R, 9S)-2-(8-chloro-7-fluoronaphthalen-1-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 (15 mg, yield: 12.44%), white solid.
MS m/z：623.2/625.2[M+H] + MS m/z: 623.2/625.2[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-112.87(s，1F)，-145.49(s，1F)，-172.14(s，1F). 19 F NMR (376MHz, DMSO-d 6 ) δ-112.87(s, 1F), -145.49(s, 1F), -172.14(s, 1F).
1H NMR(400MHz，DMSO-d 6)δ8.32-8.10(m，2H)，7.77-7.55(m，3H)，5.28(m，J＝54.0Hz，1H)，4.83(d，J＝13.0Hz，1H)，4.58-4.31(m，2H)，4.17-3.96(m，3H)，3.65-3.47(m，2H)，3.14-2.98(m，4H)，2.86-2.79(m，1H)，2.18-1.96(m，3H)，1.95-1.50(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.32-8.10(m, 2H), 7.77-7.55(m, 3H), 5.28(m, J=54.0Hz, 1H), 4.83(d, J=13.0 Hz, 1H), 4.58-4.31(m, 2H), 4.17-3.96(m, 3H), 3.65-3.47(m, 2H), 3.14-2.98(m, 4H), 2.86-2.79(m, 1H), 2.18-1.96(m, 3H), 1.95-1.50(m, 7H).
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 80*40mm*3um；Column: Phenomenex C18 80*40mm*3um;
流动相：[Water(ammonia hydroxide v/v)-ACN]；B％：25％-65％，9min.。Mobile phase: [Water(ammonia hydroxide v/v)-ACN]; B%: 25%-65%, 9min.
实施例6：化合物6Embodiment 6: Compound 6
(5aR，6R，9S)-2-(8-氯萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐(5aR, 6R, 9S)-2-(8-chloronaphthalen-1-yl)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-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 carboxylate
Figure PCTCN2022106363-appb-000157
Figure PCTCN2022106363-appb-000157
步骤1：(5aR，6R，9S)-叔丁基-2-(8-氯萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂 -3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000158
Figure PCTCN2022106363-appb-000158
将(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(209mg，0.361mmol，1eq)溶于1，4-二氧六环(1mL)中，加入水(0.3mL)，再加入2-(8-氯萘-1-基)-4，4，5，5-四甲基-1，3，2-二噁硼戊环(156.24mg，0.541mmol，1.5eq)(参考WO2020146613A1中中间体59的方法制备)，碳酸铯(325.81mg，1.08mmol，3eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(26.29mg，0.036mmol，0.1eq)。氮气保护下80℃反应5小时。LCMS监测反应完全。反应液浓缩。残留物经柱纯化(四氢呋喃/石油醚：10-100％)，得到(5aR，6R，9S)-叔丁基-2-(8-氯萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(135mg，产率：37.44％)，淡黄色固体。(5aR, 6R, 9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (209 mg, 0.361 mmol, 1 eq) was dissolved in 1,4-dioxane (1 mL), water (0.3 mL) was added, and 2-(8 -Chloronaphthalene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (156.24mg, 0.541mmol, 1.5eq) (refer to Intermediate 59 in WO2020146613A1 method), cesium carbonate (325.81mg, 1.08mmol, 3eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium (II) (26.29 mg, 0.036 mmol, 0.1 eq). React at 80°C for 5 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was concentrated. The residue was purified by column (THF/petroleum ether: 10-100%) to give (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-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate (135 mg, yield: 37.44%), Pale yellow solid.
MS m/z：705.1/707.1[M+H] + MS m/z: 705.1/707.1[M+H] +
步骤2：(5aR，6R，9S)-2-(8-氯萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐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
Figure PCTCN2022106363-appb-000159
Figure PCTCN2022106363-appb-000159
将(5aR，6R，9S)-叔丁基-2-(8-氯萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(135mg，0.135mmol，1eq)溶于乙腈(1mL)，加入盐酸/二氧六环溶液(1mL，4mol/L，4mol，30eq)。室温反应2小时，LCMS检测反应完全。反应液浓缩，粗品经HPLC纯化，得到产物(10mg，产率：8.55％)，黄色固体。(5aR, 6R, 9S)-tert-butyl-2-(8-chloronaphthalen-1-yl)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline Azin-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 (135 mg, 0.135 mmol, 1 eq) was dissolved in acetonitrile (1 mL), and hydrochloric acid/dioxane solution (1 mL, 4 mol /L, 4mol, 30eq). The reaction was carried out at room temperature for 2 hours, and the reaction was detected by LCMS to be complete. The reaction solution was concentrated, and the crude product was purified by HPLC to obtain the product (10 mg, yield: 8.55%) as a yellow solid.
MS m/z：605.1/607.1[M+H] + MS m/z: 605.1/607.1[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-145.38(s，1F)，-172.12(s，1F). 19 F NMR (376MHz, DMSO-d 6 ) δ-145.38(s, 1F), -172.12(s, 1F).
1H NMR(400MHz，DMSO-d 6)δ8.23(s，1.7HCOOH)，8.15(br d，J＝8.4Hz，1H)，8.08-7.99(m，1H)，7.77-7.47(m，4H)，5.33(m，J＝54.4Hz，1H)，4.99-4.83(m，1H)，4.62-4.37(m，2H)，4.26-4.10(m，3H)，3.94-3.86(m，2H)，3.30-3.13(m，4H)，2.96-2.85(m，1H)，2.25-2.01(m，3H)，1.96-1.65(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.23(s, 1.7HCOOH), 8.15(br d, J=8.4Hz, 1H), 8.08-7.99(m, 1H), 7.77-7.47(m, 4H ), 5.33(m, J=54.4Hz, 1H), 4.99-4.83(m, 1H), 4.62-4.37(m, 2H), 4.26-4.10(m, 3H), 3.94-3.86(m, 2H), 3.30-3.13(m, 4H), 2.96-2.85(m, 1H), 2.25-2.01(m, 3H), 1.96-1.65(m, 7H).
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Triart Prep C18 150*40mm*7um；Column: YMC-Triart Prep C18 150*40mm*7um;
流动相：[Water(FA)-ACN]；B％：0％-40％，9min.。Mobile phase: [Water(FA)-ACN]; B%: 0%-40%, 9min.
实施例7：化合物7Example 7: Compound 7
(5aR，6R，9S)-1-氟-2-(7-氟-8-甲基萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐(5aR, 6R, 9S)-1-fluoro-2-(7-fluoro-8-methylnaphthalene-1-yl)-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline Azin-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
Figure PCTCN2022106363-appb-000160
Figure PCTCN2022106363-appb-000160
步骤1：(5aR，6R，9S)-叔丁基-1-氟-2-(7-氟-8-甲基萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000161
Figure PCTCN2022106363-appb-000161
将(5aR，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(200mg，0.345mmol，1eq)溶于二氧六环(1mL)中，加入水(0.3mL)，再加入2-(7-氟-8-甲基萘-1-基)-4，4，5，5-四甲基-1，3，2-二噁硼戊环(98.84mg，0.345mmol，1eq)(参考WO2020146613A1中中间体C-8的方法制备)，碳酸铯(337.61mg，1.04mmol，3eq)，四三苯基膦钯(39.91mg，0.034mmol，0.1eq)。氮气保护下100℃反应2小时。LCMS监测反应完全。反应液浓缩。残留物经柱纯化(四氢呋喃/石油醚：10-100％)，得到(5aR，6R，9S)-叔丁基-1-氟-2-(7-氟-8-甲基萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(174mg，收率60.93％)，黄色固体。(5aR, 6R, 9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (200 mg, 0.345 mmol, 1 eq) was dissolved in dioxane (1 mL), water (0.3 mL) was added, and 2-(7-fluoro-8 -Methylnaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98.84mg, 0.345mmol, 1eq) (refer to Intermediate C- in WO2020146613A1 8), cesium carbonate (337.61mg, 1.04mmol, 3eq), tetrakistriphenylphosphine palladium (39.91mg, 0.034mmol, 0.1eq). React at 100°C for 2 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was concentrated. The residue was purified by column (THF/petroleum ether: 10-100%) to give (5aR,6R,9S)-tert-butyl-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-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate (174mg, yield 60.93%), yellow solid.
MS m/z：703.3[M+H] + MS m/z: 703.3[M+H] +
步骤2：(5aR，6R，9S)-1-氟-2-(7-氟-8-甲基萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯甲酸盐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
Figure PCTCN2022106363-appb-000162
Figure PCTCN2022106363-appb-000162
将(5aR，6R，9S)-叔丁基-1-氟-2-(7-氟-8-甲基萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10- 六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(174mg，0.210mmol，1eq)溶于乙腈(1mL)，加入氯化氢二氧六环溶液(1mL，4mol/L，4mol，19eq)。室温搅拌2小时，LCMS检测反应完全。粗品经HPLC纯化，得到产物(11mg，产率：7.37％)，白色固体。(5aR, 6R, 9S)-tert-butyl-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-pentaza Hetero-6,9-methanonaphtho[1,8-ab]cycloheptatriene-14-carboxylate (174mg, 0.210mmol, 1eq) was dissolved in acetonitrile (1mL) and hydrogen chloride dioxane solution was added (1 mL, 4mol/L, 4mol, 19eq). Stir at room temperature for 2 hours, and the reaction is complete as detected by LCMS. The crude product was purified by HPLC to obtain the product (11 mg, yield: 7.37%) as a white solid.
MS m/z：603.4[M+H] + MS m/z: 603.4[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-113.26(s，1F)，-145.55(m，1F)，-172.17(s，1F). 19 F NMR (376MHz, DMSO-d 6 ) δ-113.26(s, 1F), -145.55(m, 1F), -172.17(s, 1F).
1H NMR(400MHz，DMSO-d 6)δ8.21(s，1HCOOH)，8.09(br d，J＝7.5Hz，1H)，8.03-7.91(m，1H)，7.65-7.39(m，3H)，5.28(m，J＝53.6Hz，1H)，4.85(br d，J＝13.3Hz，1H)，4.59-4.33(m，2H)，4.20-3.97(m，3H)，3.74-3.64(m，2H)，3.19-3.01(m，4H)，2.89-2.78(m，1H)，2.17-1.61(m，13H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.21(s, 1HCOOH), 8.09(br d, J=7.5Hz, 1H), 8.03-7.91(m, 1H), 7.65-7.39(m, 3H) , 5.28(m, J=53.6Hz, 1H), 4.85(br d, J=13.3Hz, 1H), 4.59-4.33(m, 2H), 4.20-3.97(m, 3H), 3.74-3.64(m, 2H), 3.19-3.01(m, 4H), 2.89-2.78(m, 1H), 2.17-1.61(m, 13H).
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Triart Prep C18 150*40mm*7um；Column: YMC-Triart Prep C18 150*40mm*7um;
流动相：[Water(FA)-ACN]；B％：3％-43％，9min。Mobile phase: [Water(FA)-ACN]; B%: 3%-43%, 9min.
实施例8：化合物8Example 8: Compound 8
2-氨基-7-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)苯并[b]噻吩-3-甲酰胺2-amino-7-fluoro-4-((5aR, 6R, 9S)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-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]cycloheptatrien-2-yl)benzo[b]thiophene-3-carboxamide
Figure PCTCN2022106363-appb-000163
Figure PCTCN2022106363-appb-000163
步骤1：(5aR，6R，9S)-苯甲基-2-(2-((叔丁氧羰基)氨基)-3-氨基羰基-7-氟苯并[b]噻吩-4-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000164
Figure PCTCN2022106363-appb-000164
将(5aR，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(100.0mg，0.163mmol，1eq)溶于二氧六环(2mL)和水(0.5mL)中，加入叔丁基-(3-氰基-4-(5，5-二甲基-1，3，2-二噁硼己环-2-基)-7-氟苯并[b]噻吩-2-基)氨基甲酯(98.9mg，0.2447mmol，1.5eq)，碳酸铯(106.3mg，0.326mmol，2eq)，1，1-双(二苯基磷)二茂铁氯化钯(11.9mg，0.0163mmol，0.1eq)，氮气保护，80℃反应16小时。LCMS监测反应完全。反应液浓缩，残留物用水和乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩。残留物经柱层析纯化(乙酸乙酯/石油醚：60-100％)，得到产物(5aR，6R，9S)-苯甲基-2-(2-((叔丁氧羰基)氨基)-3-氨基羰基-7-氟苯并[b]噻吩-4-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(110mg，产率：76.1％)，白色固体。(5aR, 6R, 9S)-benzyl-2-chloro-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-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (100.0 mg, 0.163 mmol, 1 eq) was dissolved in dioxane (2 mL) and water (0.5 mL), and tert-butyl-(3-cyano -4-(5,5-dimethyl-1,3,2-dioxaborhexan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)aminomethyl ester (98.9mg, 0.2447mmol, 1.5eq), cesium carbonate (106.3mg, 0.326mmol, 2eq), 1,1-bis(diphenylphosphino)ferrocene palladium chloride (11.9mg, 0.0163mmol, 0.1eq), nitrogen protection, React at 80°C for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was extracted with water and ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filter and concentrate the filtrate. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 60-100%) to give the product (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-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 (110 mg, yield: 76.1%), white solid.
MS m/z：887.3[M+H] + MS m/z: 887.3[M+H] +
步骤2：2-氨基-7-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)苯并[b]噻吩-3-甲酰胺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
Figure PCTCN2022106363-appb-000165
Figure PCTCN2022106363-appb-000165
将(5aR，6R，9S)-苯甲基-2-(2-((叔丁氧羰基)氨基)-3-氨基羰基-7-氟苯并[b]噻吩-4-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(100mg，0.113mmol，1eq)溶于三氟乙酸(2mL)中，加入三氟甲磺酸(50.8mg，0.339mmol，3eq)，室温反应1小时。LCMS监测反应完全，反应液浓缩，残留物经HPLC分离纯化，得到2-氨基-7-氟-4-((5aR，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)苯并[b]噻吩-3-甲酰胺(3.0mg，产率：4.1％)，白色固体。(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-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 (100mg, 0.113mmol , 1eq) was dissolved in trifluoroacetic acid (2mL), added trifluoromethanesulfonic acid (50.8mg, 0.339mmol, 3eq), and reacted at room temperature for 1 hour. LCMS monitored that the reaction was complete, the reaction solution was concentrated, and the residue was separated and purified by HPLC to obtain 2-amino-7-fluoro-4-((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]cycloheptatrien-2-yl)benzo[b]thiophene-3-carboxamide (3.0 mg, yield: 4.1%), white solid.
MS m/z：653.2[M+H] + MS m/z: 653.2[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3um；流速：60mL/minColumn: Phenomenex C18 75*30mm*3um; flow rate: 60mL/min
流动相A：Water(0.05％氨水，v/v)流动相B：ACN；梯度：26％-66％v/v，9min；Mobile phase A: Water (0.05% ammonia water, v/v) Mobile phase B: ACN; Gradient: 26%-66% v/v, 9min;
检测波长：254/220nmDetection wavelength: 254/220nm
19F NMR(376MHz，DMSO-d 6)δ-117.18(s)，-146.17(s)，-172.16(s). 19 F NMR (376MHz, DMSO-d 6 ) δ-117.18(s), -146.17(s), -172.16(s).
1H NMR(400MHz，DMSO-d 6)δ9.83(br d，J＝3.1Hz，1H)，7.88(s，2H)，7.64-7.56(m，1H)，7.31-7.22(m，1H)，7.00-6.90(m，1H)，5.29(br d，J＝54.0Hz，1H)，4.77(br d，J＝11.4Hz，1H)，4.50(br d，J＝11.7Hz，1H)，4.41-4.30(m，1H)，4.16-4.08(m，1H)，4.06-3.99(m，1H)，3.96(br d，J＝7.0Hz，1H)，3.66-3.48(m，2H)，3.15-2.80(m，5H)，2.18-1.95(m，4H)，1.88-1.53(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.83(br d, J=3.1Hz, 1H), 7.88(s, 2H), 7.64-7.56(m, 1H), 7.31-7.22(m, 1H) , 7.00-6.90 (m, 1H), 5.29 (br d, J = 54.0Hz, 1H), 4.77 (br d, J = 11.4Hz, 1H), 4.50 (br d, J = 11.7Hz, 1H), 4.41 -4.30(m, 1H), 4.16-4.08(m, 1H), 4.06-3.99(m, 1H), 3.96(br d, J=7.0Hz, 1H), 3.66-3.48(m, 2H), 3.15- 2.80(m, 5H), 2.18-1.95(m, 4H), 1.88-1.53(m, 7H).
实施例9：化合物9Example 9: Compound 9
5-乙炔基-6-氟-4-((5aS，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡 咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚5-Ethynyl-6-fluoro-4-((5aS, 6R, 9S)-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] cycloheptatrien-2-yl) naphthalene-2-ol
Figure PCTCN2022106363-appb-000166
Figure PCTCN2022106363-appb-000166
步骤1：(1R，2S，5S)-8-苯甲基-2-乙基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯Step 1: (1R,2S,5S)-8-Benzyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate
Figure PCTCN2022106363-appb-000167
Figure PCTCN2022106363-appb-000167
将氢氯二茂锆(15.2g，56.8mmol，1.2eq)溶于四氢呋喃(450mL)中，氮气保护，室温滴加(1R，2S，5S)-8-苯甲基-2-乙基-4-氧亚基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(15.0g，47.3mmol，1.0eq)的四氢呋喃溶液(100mL)，室温反应30分钟，加入氢氯二茂锆(12.6g，47.3mmol，1.0eq)，室温反应10分钟，在0℃分批加入醋酸硼氢化钠(15.1g，71.0mmol，1.5eq)，室温反应2小时。LCMS监测反应完全。加入饱和碳酸氢钠水溶液，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：25-55％)，得到(1R，2S，5S)-8-苯甲基-2-乙基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(4.84g，产率：30.2％)，黄色液体。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. LCMS monitored the reaction to be complete. Saturated aqueous sodium bicarbonate solution was added, extracted with ethyl acetate, 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: 25-55%) to obtain (1R, 2S, 5S)-8-benzyl-2-ethyl-3,8-diazepine Heterobicyclo[3.2.1]octane-2,8-dicarboxylate (4.84 g, yield: 30.2%), yellow liquid.
MS m/z：319.1[M+H] + MS m/z: 319.1[M+H] +
步骤2：(1R，2S，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 2: (1R,2S,5S)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022106363-appb-000168
Figure PCTCN2022106363-appb-000168
将(1R，2S，5S)-8-苯甲基-2-乙基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(4.60g，14.45mmol，1eq)溶于四氢呋喃(100mL)中，0℃ 加入四氢铝锂(658mg，17.3mmol，1.2eq)，0℃反应1小时。LCMS监测反应完全。加入十水硫酸钠淬灭反应。过滤，滤液浓缩，得到(1R，2S，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(4.30g，粗品)，棕色液体，直接投入下一步反应。(1R,2S,5S)-8-Benzyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (4.60g, 14.45 mmol, 1eq) was dissolved in tetrahydrofuran (100mL), lithium aluminum tetrahydride (658mg, 17.3mmol, 1.2eq) was added at 0°C, and reacted at 0°C for 1 hour. LCMS monitored the reaction to be complete. The reaction was quenched by adding sodium sulfate decahydrate. Filtration, and the filtrate was concentrated to give (1R, 2S, 5S)-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (4.30 g, crude product), brown liquid, directly put into next step reaction.
MS m/z：277.1[M+H] + MS m/z: 277.1[M+H] +
步骤3：(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 3: (1R,2S,5S)-Benzyl-2-(((tert-Butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
Figure PCTCN2022106363-appb-000169
Figure PCTCN2022106363-appb-000169
将(1R，2S，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(3.99g，14.4mmol，1eq)溶于二氯甲烷(50mL)中，加入三乙胺(2.92g，28.9mmol，2eq)，4-二甲氨基吡啶(88.2mg，0.722mmol，0.05eq)，二甲基叔丁基氯硅烷(3.26g，21.7mmol，1.5eq)，室温反应2小时。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残余物经HPLC纯化得到(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.90g，产率：33.7％)，无色液体。(1R,2S,5S)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.99g, 14.4mmol, 1eq) was dissolved in dichloromethane (50mL), triethylamine (2.92g, 28.9mmol, 2eq), 4-dimethylaminopyridine (88.2mg, 0.722mmol, 0.05eq), dimethyl tert-butyl chloride were added Silane (3.26g, 21.7mmol, 1.5eq) was reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The 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.
MS m/z：391.2[M+H] + MS m/z: 391.2[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Pack CN 150*30mm*5um；流速：60mL/minColumn: YMC-Pack CN 150*30mm*5um; flow rate: 60mL/min
流动相A：Heptane流动相B：EtOH；梯度：0％-95％(v/v)，9min；Mobile phase A: Heptane Mobile phase B: EtOH; Gradient: 0%-95% (v/v), 9min;
检测波长：254/220nmDetection wavelength: 254/220nm
步骤4：(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000170
Figure PCTCN2022106363-appb-000170
将2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(1.98g，4.13mmol，60％含量，1eq)溶于二氯甲烷(20mL)中，加入N，N-二异丙基乙胺(1.60g，12.4mmol，3eq)，-30℃滴加(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.61g，4.13mmol，1eq)的二氯甲烷(6mL)溶液，室温反应2个小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.00g，产率：75.5％)，棕色固体。2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (1.98g, 4.13mmol, 60% content, 1eq) was dissolved in dichloromethane (20mL), and N , N-diisopropylethylamine (1.60g, 12.4mmol, 3eq), -30 ° C was added dropwise (1R, 2S, 5S)-benzyl-2-(((tert-butyldimethylsilyl ) oxo)methyl)-3,8-diazabicyclo[3.2.1]octane-8-formyl ester (1.61g, 4.13mmol, 1eq) in dichloromethane (6mL) solution, room temperature reaction 2 hours. 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. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-40%) to obtain (1R, 2S, 5S)-benzyl-2-(((tert-butyldimethylsilane Base) oxo) methyl) -3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (2.00 g, yield: 75.5%), brown solid.
MS m/z：640.1[M+H] + MS m/z: 640.1[M+H] +
步骤5：(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000171
Figure PCTCN2022106363-appb-000171
将(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.90g，2.96mmol，1eq)溶于二氯甲烷(30mL)中，加入((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(472mg，2.96mmol，1 eq)，叔丁醇钠(570mg，5.93mmol，2eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：30-50％)，得到(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.00g，产率：44.2％)，棕色固体。(1R, 2S, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(2,5,7-trichloro-8-fluoro Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.90g, 2.96mmol, 1eq) was dissolved in di Chloromethane (30mL), add ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (472mg, 2.96mmol, 1 eq), sodium tert-butoxide (570mg, 5.93 mmol, 2eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 30-50%) to obtain (1R, 2S, 5S)-benzyl-2-(((tert-butyldimethylsilyl )Oxo)methyl)-3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolidazin-7a-yl)methoxy yl)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.00g, yield: 44.2%) , brown solid.
MS m/z：763.3[M+H] + MS m/z: 763.3[M+H] +
步骤6：(1R，2S，5S)-苯甲基-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000172
Figure PCTCN2022106363-appb-000172
将(1R，2S，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.60g，2.09mmol，1eq)溶于乙酸(13mL)，水(7mL)和四氢呋喃(3mL)的混合溶剂中，50℃反应16小时。LCMS监测反应完全。反应液加饱和碳酸氢钠水溶液调节PH至中性，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：50-100％)，得到(1R，2S，5S)-苯甲基-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.39g，粗品)，棕色固体，直接用于下一步。(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-di Azabicyclo[3.2.1]octane-8-carboxylate (1.60g, 2.09mmol, 1eq) was dissolved in a mixed solvent of acetic acid (13mL), water (7mL) and tetrahydrofuran (3mL), and reacted at 50°C 16 hours. LCMS monitored the reaction to be complete. The reaction solution was added with saturated aqueous sodium bicarbonate solution to adjust the pH to neutral, and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 50-100%) to obtain (1R, 2S, 5S)-benzyl -3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.39 g, crude), brown solid , used directly in the next step.
MS m/z：649.2[M+H] + MS m/z: 649.2[M+H] +
步骤7：(5aS，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000173
Figure PCTCN2022106363-appb-000173
将(1R，2S，5S)-苯甲基-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(430mg，0.662mmol，1eq)溶于二氧六环(6mL)中，加入(±)-2，2-双(二苯膦基)-1，1-联萘(41.2mg，0.0662mmol，0.1eq)，碳酸铯(431mg，1.32mmol，2eq)，三(二亚苄基丙酮)二钯(60.6mg，0.0662mmol，0.1eq)，氮气保护，100℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：70-100％)，得到(5aS，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(200mg，产率：16.4％)，棕色固体。(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 (430mg, 0.662mmol, 1eq) was dissolved in dioxane (6mL), and (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (41.2mg, 0.0662 mmol, 0.1eq), cesium carbonate (431mg, 1.32mmol, 2eq), tris(dibenzylideneacetone)dipalladium (60.6mg, 0.0662mmol, 0.1eq), under nitrogen protection, react at 100°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 70-100%) to obtain (5aS, 6R, 9S)-benzyl-2-chloro-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 (200 mg, yield: 16.4%), brown solid.
MS m/z：613.2[M+H] + MS m/z: 613.2[M+H] +
步骤8：(5aS，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000174
Figure PCTCN2022106363-appb-000174
将(5aS，6R，9S)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(200mg，0.326mmol， 1eq)溶于三氟乙酸(2mL)中，加入三氟甲磺酸(147mg，0.979mmol，3eq)，室温反应2小时。LCMS监测反应完全，反应液浓缩，残余物溶于二氯甲烷(5mL)，加入三乙胺(169mg，1.67mmol，5eq)，BOC酸酐(87.5mg，0.401mmol，1.2eq)，室温反应1小时。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：40-70％)，得到(5aS，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(160mg，产率：82.7％)，棕色液体。(5aS, 6R, 9S)-benzyl-2-chloro-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-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (200mg, 0.326mmol, 1eq) was dissolved in trifluoroacetic acid (2mL), added trifluoromethanesulfonic acid (147mg, 0.979mmol, 3eq), room temperature reaction 2 Hour. LCMS monitored that the reaction was complete, the reaction solution was concentrated, the residue was dissolved in dichloromethane (5mL), triethylamine (169mg, 1.67mmol, 5eq), BOC anhydride (87.5mg, 0.401mmol, 1.2eq) were added, and the reaction was carried out at room temperature for 1 hour . The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 40-70%) to obtain (5aS, 6R, 9S)-tert-butyl-2-chloro-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 (160 mg, yield: 82.7%), brown liquid.
MS m/z：579.2[M+H] + MS m/z: 579.2[M+H] +
步骤9：(5aS，6R，9S)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000175
Figure PCTCN2022106363-appb-000175
将(5aS，6R，9S)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(160mg，0.276mmol，1eq)溶于二氧六环(2mL)和水(0.6mL)中，加入((2-氟-6-(甲氧基甲氧基)-8-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(212mg，0.414mmol，1.5eq)，碳酸铯(180mg，0.553mmol，2eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(18.5mg，0.0276mmol，0.1eq)，氮气保护，80℃反应3小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：30-60％)，得到(5aS，6R，9S)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂 -3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(140mg，产率：54.5％)，黄色固体。(5aS, 6R, 9S)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (160 mg, 0.276 mmol, 1 eq) was dissolved in dioxane (2 mL) and water (0.6 mL), and ((2-fluoro-6-(methyl Oxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropane Silane (212mg, 0.414mmol, 1.5eq), cesium carbonate (180mg, 0.553mmol, 2eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-bis Phenyl-2-yl)palladium(II) (18.5mg, 0.0276mmol, 0.1eq), under nitrogen protection, react at 80°C for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 30-60%) to obtain (5aS, 6R, 9S)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-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-meth Epinaphtho[1,8-ab]cycloheptatriene-14-carboxylate (140 mg, yield: 54.5%), yellow solid.
MS m/z：929.5[M+H] + MS m/z: 929.5[M+H] +
步骤10：(5aS，6R，9S)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000176
Figure PCTCN2022106363-appb-000176
将(5aS，6R，9S)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(140mg，0.151mmol，1eq)溶于N，N-二甲基甲酰胺(3mL)中，加入氟化铯(114mg，0.753mmol，5eq)，室温反应1小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到(5aS，6R，9S)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(110mg，粗品)，棕色固体，直接投入下一步反应。(5aS, 6R, 9S)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) Naphthalene-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-carboxylate (140mg, 0.151mmol, 1eq) was dissolved in N,N-dimethylformamide (3mL), cesium fluoride (114mg, 0.753mmol, 5eq) was added, and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain (5aS, 6R, 9S)-tert-butyl-2-(8-ethynyl- 7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-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 (110 mg, crude product), a brown solid, was directly put into the next reaction.
MS m/z：773.3[M+H] + MS m/z: 773.3[M+H] +
步骤11：5-乙炔基-6-氟-4-((5aS，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚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
Figure PCTCN2022106363-appb-000177
Figure PCTCN2022106363-appb-000177
将(5aS，6R，9S)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(100mg，0.129mmol，1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环(4M，2mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到5-乙炔基-6-氟-4-((5aS，6R，9S)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚(20mg，产率：24.6％)，白色固体。(5aS, 6R, 9S)-tert-butyl-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-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 (100mg, 0.129mmol, 1eq) dissolved in acetonitrile (2 mL), add hydrochloric acid/dioxane (4M, 2 mL), and react at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 5-ethynyl-6-fluoro-4-((5aS, 6R, 9S)-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-pentaza Hetero-6,9-methanonaphtho[1,8-ab]cycloheptatrien-2-yl)naphthalene-2-ol (20 mg, yield: 24.6%), white solid.
MS m/z：629.2[M+H] + MS m/z: 629.2[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-110.89(s)，-148.69(s)，-172.26(s). 19 F NMR (376MHz, DMSO-d 6 ) δ-110.89(s), -148.69(s), -172.26(s).
1H NMR(400MHz，DMSO-d 6)δ10.21-10.05(m，1H)，7.96(dd，J＝5.9，9.2Hz，1H)，7.46(t，J＝9.0Hz，1H)，7.37(s，1H)，7.21-7.05(m，1H)，5.29(br d，J＝53.6Hz，1H)，4.77-4.65(m，1H)，4.59-4.42(m，1H)，4.29-3.95(m，4H)，3.88-3.79(m，1H)，3.78-3.65(m，1H)，3.57-3.42(m，2H)，3.19-3.02(m，3H)，2.90-2.80(m，1H)，2.65-2.55(m，1H)，2.14(br s，1H)，2.10-1.96(m，2H)，1.94-1.61(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.21-10.05 (m, 1H), 7.96 (dd, J=5.9, 9.2Hz, 1H), 7.46 (t, J=9.0Hz, 1H), 7.37( s, 1H), 7.21-7.05(m, 1H), 5.29(br d, J=53.6Hz, 1H), 4.77-4.65(m, 1H), 4.59-4.42(m, 1H), 4.29-3.95(m , 4H), 3.88-3.79(m, 1H), 3.78-3.65(m, 1H), 3.57-3.42(m, 2H), 3.19-3.02(m, 3H), 2.90-2.80(m, 1H), 2.65 -2.55(m, 1H), 2.14(br s, 1H), 2.10-1.96(m, 2H), 1.94-1.61(m, 7H).
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3um；流速：60mL/minColumn: Phenomenex C18 75*30mm*3um; flow rate: 60mL/min
流动相A：Water(0.05％氨水，v/v)流动相B：ACN；梯度：21％-61％v/v，9min；Mobile phase A: Water (0.05% ammonia water, v/v) Mobile phase B: ACN; Gradient: 21%-61% v/v, 9min;
检测波长：254/220nmDetection wavelength: 254/220nm
实施例10：化合物10Example 10: Compound 10
5-乙炔基-6-氟-4-((5aR，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五 氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚5-Ethynyl-6-fluoro-4-((5aR, 6S, 9R)-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] cycloheptatrien-2-yl) naphthalene-2-ol
Figure PCTCN2022106363-appb-000178
Figure PCTCN2022106363-appb-000178
步骤1：(1S，2R，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 1: (1S,2R,5R)-Benzyl-2-(((tert-Butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate
Figure PCTCN2022106363-appb-000179
Figure PCTCN2022106363-appb-000179
将(1S，2R，5R)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.50g，9.05mmol，1eq)溶于二氯甲烷(30mL)中，加入三乙胺(1.83g，18.1mmol，2eq)，4-二甲氨基吡啶(55.3mg，0.452mmol，0.05eq)，二甲基叔丁基氯硅烷(2.05g，13.57mmol，1.5eq)，室温反应2小时。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残余物经HPLC纯化得到(1S，2R，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.30g，产率：65.1％)，无色液体。(1S,2R,5R)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.50g, 9.05mmol, 1eq) was dissolved in dichloromethane (30mL), triethylamine (1.83g, 18.1mmol, 2eq), 4-dimethylaminopyridine (55.3mg, 0.452mmol, 0.05eq), dimethyl tert-butyl chloride were added Silane (2.05g, 13.57mmol, 1.5eq) was reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The 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.
MS m/z：391.2[M+H] + MS m/z: 391.2[M+H] +
HPLC分离条件：HPLC separation conditions:
柱子：YMC-Pack CN 150*30mm*5um；流速：60mL/minColumn: YMC-Pack CN 150*30mm*5um; flow rate: 60mL/min
流动相A：Heptane流动相B：EtOH；梯度：0％-95％(v/v)，9min；Mobile phase A: Heptane Mobile phase B: EtOH; Gradient: 0%-95% (v/v), 9min;
检测波长：254/220nmDetection wavelength: 254/220nm
步骤2：(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000180
Figure PCTCN2022106363-appb-000180
将2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(2.40g，5.02mmol，60％含量，1eq)溶于二氯甲烷(20mL)中，加入N，N-二异丙基乙胺(1.95g，15.06mmol，3eq)，-30℃滴加(1S，2R，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.96g，5.02mmol，1eq)的二氯甲烷(10mL)溶液，2小时缓慢升到室温。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.50g，产率：77.7％)，棕色固体。2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (2.40g, 5.02mmol, 60% content, 1eq) was dissolved in dichloromethane (20mL), and N , N-diisopropylethylamine (1.95g, 15.06mmol, 3eq), -30°C was added dropwise (1S, 2R, 5R)-benzyl-2-(((tert-butyldimethylsilyl )oxo)methyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.96g, 5.02mmol, 1eq) in dichloromethane (10mL) for 2 hours Slowly warm to room temperature. 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. Filtration, the filtrate was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 20-40%) to obtain (1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilane Base) oxo) methyl) -3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate (2.50 g, yield: 77.7%), brown solid.
MS m/z：640.1[M+H] + MS m/z: 640.1[M+H] +
步骤3：(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000181
Figure PCTCN2022106363-appb-000181
将(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.59g，4.04mmol，1eq)溶于二氯甲烷(20mL)中，加入((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(643mg，4.04mmol， 1eq)，叔丁醇钠(777mg，8.08mmol，2eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩。残留物经柱纯化(乙酸乙酯/石油醚：30-50％)，得到(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.40g，产率：77.8％)，白色固体。(1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2,5,7-trichloro-8-fluoro Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.59g, 4.04mmol, 1eq) was dissolved in di To methyl chloride (20mL), add ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl)methanol (643mg, 4.04mmol, 1eq), sodium tert-butoxide (777mg, 8.08mmol , 2eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated. The residue was purified by column (ethyl acetate/petroleum ether: 30-50%) to give (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 (2.40 g, yield: 77.8%), white solid.
MS m/z：763.3[M+H] + MS m/z: 763.3[M+H] +
步骤4：(1R，2R，5S)-苯甲基-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000182
Figure PCTCN2022106363-appb-000182
将(1R，2R，5S)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.70g，2.23mmol，1eq)溶于乙酸(13mL)，水(7mL)和四氢呋喃(3mL)的混合溶剂中，50℃反应16小时。LCMS监测反应完全。反应液加饱和碳酸氢钠调节溶液PH至中性，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：70-100％)，得到(1R，2R，5S)-苯甲基-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(470mg，产率：32.5％)，棕色固体。(1R, 2R, 5S)-benzyl-2-(((tert-butyldimethylsilyl)oxy)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-di Azabicyclo[3.2.1]octane-8-carboxylate (1.70g, 2.23mmol, 1eq) was dissolved in a mixed solvent of acetic acid (13mL), water (7mL) and tetrahydrofuran (3mL), and reacted at 50°C 16 hours. LCMS monitored the reaction to be complete. Add saturated sodium bicarbonate to the reaction solution to adjust the pH of the solution to neutral, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue through a column (ethyl acetate/petroleum ether : 70-100%) to obtain (1R, 2R, 5S)-benzyl-3-(5,7-dichloro-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 (470 mg, yield: 32.5%), brown solid.
MS m/z：649.2[M+H] + MS m/z: 649.2[M+H] +
步骤5：(5aR，6S，9R)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000183
Figure PCTCN2022106363-appb-000183
将(1R，2R，5S)-苯甲基-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(470mg，0.724mmol，1eq)溶于二氧六环(5mL)中，加入(±)-2，2-双(二苯膦基)-1，1-联萘(45.06mg，0.0724mmol，0.1eq)，碳酸铯(472mg，1.45mmol，2eq)，三(二亚苄基丙酮)二钯(66.3mg，0.0724mmol，0.1eq)，氮气保护，100℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：70-100％)，得到(5aR，6S，9R)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(200mg，产率：45.1％)，棕色固体。(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 (470mg, 0.724mmol, 1eq) was dissolved in dioxane (5mL), and (±)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (45.06mg, 0.0724 mmol, 0.1eq), cesium carbonate (472mg, 1.45mmol, 2eq), tris(dibenzylideneacetone)dipalladium (66.3mg, 0.0724mmol, 0.1eq), under nitrogen protection, react at 100°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 70-100%) to obtain (5aR, 6S, 9R)-benzyl-2-chloro-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 (200 mg, yield: 45.1%), brown solid.
MS m/z：613.2[M+H] + MS m/z: 613.2[M+H] +
步骤6：(5aR，6S，9R)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000184
Figure PCTCN2022106363-appb-000184
将(5aR，6S，9R)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(200mg，0.326mmol， 1eq)溶于三氟乙酸(2mL)中，加入三氟甲磺酸(146.9mg，0.978mmol，3eq)，室温反应2小时。反应液浓缩，残余物溶于二氯甲烷(2mL)，加入三乙胺(169mg，1.67mmol，5eq)，BOC酸酐(87.5mg，0.400mmol，1.2eq)，室温反应1小时。LCMS监测反应完全，反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：40-70％)，得到(5aR，6S，9R)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(190mg，产率：98.2％)，棕色固体。(5aR, 6S, 9R)-benzyl-2-chloro-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-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (200mg, 0.326mmol, 1eq) was dissolved in trifluoroacetic acid (2mL), added trifluoromethanesulfonic acid (146.9mg, 0.978mmol, 3eq), and reacted at room temperature 2 hours. The 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. LCMS monitored that the reaction was complete, the reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 40-70%) to obtain (5aR, 6S, 9R)-tert-butyl-2-chloro-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 (190 mg, yield: 98.2%), brown solid.
MS m/z：579.2[M+H] + MS m/z: 579.2[M+H] +
步骤7：(5aR，6S，9R)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000185
Figure PCTCN2022106363-appb-000185
将(5aR，6S，9R)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(170mg，0.294mmol，1eq)溶于二氧六环(2mL)和水(0.6mL)中，加入((2-氟-6-(甲氧基甲氧基)-8-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(226mg，0.440mmol，1.5eq)，碳酸铯(191mg，0.587mmol，2eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(19.6mg，0.0294mmol，0.1eq)，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：40-70％)，得到(5aR，6S，9R)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂 -3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(210mg，产率：77.0％)，黄色固体。(5aR, 6S, 9R)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (170 mg, 0.294 mmol, 1 eq) was dissolved in dioxane (2 mL) and water (0.6 mL), and ((2-fluoro-6-(methyl Oxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-1-yl)ethynyl)triisopropane Methylsilane (226mg, 0.440mmol, 1.5eq), cesium carbonate (191mg, 0.587mmol, 2eq), methanesulfonyloxy(diadamantyl-n-butylphosphino)-2-amino-1,1-bis Phenyl-2-yl)palladium(II) (19.6mg, 0.0294mmol, 0.1eq), under nitrogen protection, react at 80°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 40-70%) to obtain (5aR, 6S, 9R)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxy methoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-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-meth Epinaphtho[1,8-ab]cycloheptatriene-14-carboxylate (210 mg, yield: 77.0%), yellow solid.
MS m/z：929.5[M+H] + MS m/z: 929.5[M+H] +
步骤8：(5aR，6S，9R)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000186
Figure PCTCN2022106363-appb-000186
将(5aR，6S，9R)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(190mg，0.204mmol，1eq)溶于N，N-二甲基甲酰胺(2mL)中，加入氟化铯(155mg，1.02mmol，5eq)，室温反应1小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，得到(5aR，6S，9R)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(100mg，粗品)，棕色固体，直接投入下一步反应。(5aR, 6S, 9R)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) Naphthalene-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-carboxylate (190mg, 0.204mmol, 1eq) was dissolved in N,N-dimethylformamide (2mL), cesium fluoride (155mg, 1.02mmol, 5eq) was added, and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate afforded (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 (100 mg, crude product), The brown solid was put directly into the next reaction.
MS m/z：773.3[M+H] + MS m/z: 773.3[M+H] +
步骤9：5-乙炔基-6-氟-4-((5aR，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚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
Figure PCTCN2022106363-appb-000187
Figure PCTCN2022106363-appb-000187
将(5aR，6S，9R)-叔丁基-2-(8-乙炔基-7-氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(100mg，0.129mmol，1eq)溶于乙腈(1mL)中，加入盐酸/二氧六环(4M，1mL)，室温反应1小时。LCMS检测反应完全。反应液浓缩，残留物经HPLC纯化，得到5-乙炔基-6-氟-4-((5aR，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚(16mg，产率：19.7％)，白色固体。(5aR, 6S, 9R)-tert-butyl-2-(8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-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 (100mg, 0.129mmol, 1eq) dissolved in acetonitrile (1 mL), add hydrochloric acid/dioxane (4M, 1 mL), and react at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated, and the residue was purified by HPLC to obtain 5-ethynyl-6-fluoro-4-((5aR, 6S, 9R)-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-pentaza Hetero-6,9-methanonaphtho[1,8-ab]cycloheptatrien-2-yl)naphthalene-2-ol (16 mg, yield: 19.7%), white solid.
MS m/z：629.2[M+H] + MS m/z: 629.2[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-110.84(s)，-110.91(s)，-148.05(s)，-148.70(s)，-172.15(s). 19 F NMR (376MHz, DMSO-d 6 ) δ-110.84(s), -110.91(s), -148.05(s), -148.70(s), -172.15(s).
1H NMR(400MHz，DMSO-d 6)δ10.14(br s，1H)，7.96(dd，J＝6.0，9.0Hz，1H)，7.55-7.35(m，2H)，7.20-7.05(m，1H)，5.29(br d，J＝54.9Hz，1H)，4.77-4.66(m，1H)，4.57-4.43(m，1H)，4.23-3.94(m，4H)，3.89-3.79(m，1H)，3.76-3.64(m，2H)，3.54-3.42(m，1H)，3.18-2.99(m，3H)，2.84(br d，J＝7.1Hz，2H)，2.19-1.96(m，3H)，1.91-1.64(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.14 (br s, 1H), 7.96 (dd, J=6.0, 9.0Hz, 1H), 7.55-7.35 (m, 2H), 7.20-7.05 (m, 1H), 5.29(br d, J=54.9Hz, 1H), 4.77-4.66(m, 1H), 4.57-4.43(m, 1H), 4.23-3.94(m, 4H), 3.89-3.79(m, 1H ), 3.76-3.64(m, 2H), 3.54-3.42(m, 1H), 3.18-2.99(m, 3H), 2.84(br d, J=7.1Hz, 2H), 2.19-1.96(m, 3H) , 1.91-1.64(m, 7H).
HPLC分离条件：HPLC separation conditions:
柱子：Phenomenex C18 75*30mm*3um；流速：60mL/minColumn: Phenomenex C18 75*30mm*3um; flow rate: 60mL/min
流动相A：Water(0.05％氨水，v/v)流动相B：ACN；梯度：25％-65％v/v，9min；Mobile phase A: Water (0.05% ammonia water, v/v) Mobile phase B: ACN; Gradient: 25%-65% v/v, 9min;
检测波长：254/220nmDetection wavelength: 254/220nm
实施例11：化合物11Example 11: Compound 11
5-乙炔基-6-氟-4-((5aS，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚5-Ethynyl-6-fluoro-4-((5aS, 6S, 9R)-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] cycloheptatrien-2-yl) naphthalene-2-ol
Figure PCTCN2022106363-appb-000188
Figure PCTCN2022106363-appb-000188
步骤1：(1S，2S，5R)-8-苯甲基-2-乙基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯Step 1: (1S,2S,5R)-8-Benzyl-2-ethyl-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate
Figure PCTCN2022106363-appb-000189
Figure PCTCN2022106363-appb-000189
将氢氯二茂锆(19.28g，72.21mmol，1.2eq)溶于四氢呋喃(200ml)中，氮气保护下缓慢加入(1S，2S，5R)-8-苯甲基-2-乙基-4-氧亚基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(20g，60.18mmol，1eq)的四氢呋喃(200ml)溶液，室温下反应0.5小时。氮气保护下加入氢氯二茂锆(16.06g，60.18mmol，1eq)，室温下反应0.5小时。0℃加入三乙酰氧基硼氢化钠(19.13g，90.27mmol，1.5eq)，氮气保护，室温下反应2小时。LCMS监测反应完全。反应液在0℃下用饱和碳酸氢钠溶液淬灭后过滤，滤液用乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。残留物经柱纯化(四氢呋喃/石油醚：0-27％)，得到(1S，2S，5R)-8-苯甲基-2-乙基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(11g，产率：57.4％)。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. Sodium triacetoxyborohydride (19.13g, 90.27mmol, 1.5eq) was added at 0°C, protected by nitrogen, and reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was quenched with saturated sodium bicarbonate solution at 0°C and filtered, and the filtrate was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column (THF/petroleum ether: 0-27%) to give (1S,2S,5R)-8-benzyl-2-ethyl-3,8-diazabicyclo[3.2.1 ] Octane-2,8-dicarboxylate (11 g, yield: 57.4%).
MS m/z：319.1[M+H] + MS m/z: 319.1[M+H] +
步骤2：(1S，2S，5R)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 2: (1S,2S,5R)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022106363-appb-000190
Figure PCTCN2022106363-appb-000190
将(1S，2S，5R)-8-苯甲基-2-乙基3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(11g，34.55mmol，1eq)溶于四氢呋喃(100ml)中，加入四氢 铝锂(1.97g，51.83mmol，1.5eq)，氮气保护，0℃下反应1小时。LCMS监测反应完全。往反应液中加入十水合硫酸钠淬灭反应。加无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(甲醇/二氯甲烷：0-10％)，得到(1S，2S，5R)-苯甲基2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(3.8g，产率：39.8％)。(1S, 2S, 5R)-8-Benzyl-2-ethyl 3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (11g, 34.55mmol, 1eq) was dissolved in tetrahydrofuran (100ml), and lithium aluminum tetrahydride (1.97g, 51.83mmol, 1.5eq) was added, under nitrogen protection, and reacted at 0°C for 1 hour. LCMS monitored the reaction to be complete. Sodium sulfate decahydrate was added to the reaction solution to quench the reaction. Add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate. The crude product was purified by column (methanol/dichloromethane: 0-10%) to give (1S,2S,5R)-benzyl 2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1 ] Octane-8-carboxylate (3.8 g, yield: 39.8%).
MS m/z：277.2[M+H] + MS m/z: 277.2[M+H] +
步骤3：(1S，2S，5R)-苯甲基2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 3: (1S,2S,5R)-Benzyl 2-(((tert-butyldimethylsilyl)oxo)methyl)-3,8-diazabicyclo[3.2.1] Octane-8-carboxylate
Figure PCTCN2022106363-appb-000191
Figure PCTCN2022106363-appb-000191
将(1S，2S，5R)-苯甲基2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(3.8g，13.75mmol，1eq)溶于二氯甲烷(50ml)中，依次加入三乙胺(4.17g，41.26mmol，5.74ml，3eq)、4-二甲氨基吡啶(168.0mg，1.38mmol，0.1eq)和叔丁基二甲基氯硅烷(3.73g，24.75mmol，1.8eq)，室温反应2小时。LCMS监测反应完全。反应液用二氯甲烷和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-16％)，得到(1S，2S，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(3.9g，产率：72.6％)。(1S,2S,5R)-Benzyl 2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.8g, 13.75mmol, 1eq ) was dissolved in dichloromethane (50ml), and triethylamine (4.17g, 41.26mmol, 5.74ml, 3eq), 4-dimethylaminopyridine (168.0mg, 1.38mmol, 0.1eq) and tert-butyldi Methylchlorosilane (3.73g, 24.75mmol, 1.8eq) was reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was extracted with dichloromethane and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (THF/petroleum ether: 0-16%) to give (1S,2S,5R)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.9 g, yield: 72.6%).
MS m/z：391.1[M+H] + MS m/z: 391.1[M+H] +
步骤4：(1S，2S，5R)-苯甲基2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000192
Figure PCTCN2022106363-appb-000192
将2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(5.74g，5.00mmol，1eq)溶于二氯甲烷(40mL)中，加入N，N-二异丙基乙胺(1.94g，15.00 mmol，2.61ml，3eq)和(1S，2S，5R)-苯甲基2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3，8-二氮杂和二环[3.2.1]辛烷-8-甲酸基酯(1.95g，5.00mmol，1eq)，-40℃反应1小时。LCMS监测反应完全。反应液用二氯甲烷和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-30％)，得到(1S，2S，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.5g，产率：78.0％)。Dissolve 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (5.74g, 5.00mmol, 1eq) in dichloromethane (40mL), add N,N-di Isopropylethylamine (1.94g, 15.00mmol, 2.61ml, 3eq) and (1S,2S,5R)-benzyl 2-(((tert-butyldimethylsilyl)oxy)methyl) -3,8-diaza and bicyclo[3.2.1]octane-8-carboxylate (1.95g, 5.00mmol, 1eq), reacted at -40°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was extracted with dichloromethane and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (THF/petroleum ether: 0-30%) to give (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 - Formyl ester (2.5 g, yield: 78.0%).
MS m/z：639.9[M+H] + MS m/z: 639.9[M+H] +
步骤5：(1S，2S，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000193
Figure PCTCN2022106363-appb-000193
将(1S，2S，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.5g，3.90mmol，1eq)和((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(614.7mg，3.86mmol，0.99eq)溶于二氯甲烷(30mL)中，0℃加入叔丁醇钠(749.6mg，7.80mmol，2eq)，室温反应1小时。LCMS监测反应完全。反应液倒入饱和氯化铵水溶液(pH中性)，用二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-15％)，得到(1S，2S，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.0g，产率：33.6％)。(1S, 2S, 5R)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl)-3-(2,5,7-trichloro-8-fluoro Pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.5g, 3.90mmol, 1eq) and (( 2R,7aS)-2-fluorohexahydro-1H-pyrrolidinazin-7a-yl)methanol (614.7mg, 3.86mmol, 0.99eq) was dissolved in dichloromethane (30mL), and sodium tert-butoxide ( 749.6mg, 7.80mmol, 2eq), react at room temperature for 1 hour. 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. The crude product was purified by column (THF/petroleum ether: 0-15%) to give (1S,2S,5R)-benzyl-2-(((tert-butyldimethylsilyl)oxo)methyl) -3-(5,7-dichloro-8-fluoro-2-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy)pyrido[4, 3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.0 g, yield: 33.6%).
MS m/z：763.2[M+H] + MS m/z: 763.2[M+H] +
步骤6：(5aS，6S，9R)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H- 吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000194
Figure PCTCN2022106363-appb-000194
将(1S，2S，5R)-苯甲基-2-(((叔丁基二甲基甲硅烷基)氧代)甲基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(500mg，0.655mmol，1eq)溶于四氢呋喃(4mL)中，加入四丁基氟化铵(1M，0.982mL，0.982mmol，1.5eq)。室温反应3小时。LCMS监测反应完全。反应液用乙酸乙酯和水萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品经柱纯化(四氢呋喃/石油醚：0-50％)，得到(5aS，6S，9R)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(450mg，粗品)。(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-di Azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 0.655 mmol, 1 eq) was dissolved in tetrahydrofuran (4 mL), and tetrabutylammonium fluoride (1M, 0.982 mL, 0.982 mmol, 1.5 eq). React at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was extracted with ethyl acetate and water, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by column (tetrahydrofuran/petroleum ether: 0-50%) to obtain (5aS, 6S , 9R)-benzyl-2-chloro-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]cyclo Heptatriene-14-carboxylate (450 mg, crude).
MS m/z：613.0[M+H] + MS m/z: 613.0[M+H] +
步骤7：(5aS，6S，9R)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000195
Figure PCTCN2022106363-appb-000195
将(5aS，6S，9R)-苯甲基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮 杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(640mg，1.04mmol，1eq)溶于三氟乙酸(4mL)中，加入三氟甲磺酸(470.0mg，3.13mmol，3eq)，室温下反应1小时。LCMS监测反应完全，反应液浓缩，残留物溶于二氯甲烷(4mL)中，加入三乙胺(528.2mg，5.22mmol，5eq)和二碳酸二叔丁酯(273.4mg，1.25mmol，1.2eq)，室温反应1小时。LCMS监测反应完全。反应液用二氯甲烷和水萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-40％)，得到(5aS，6S，9R)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(400mg，产率：66.2％)。(5aS, 6S, 9R)-benzyl-2-chloro-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-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (640mg, 1.04mmol, 1eq) was dissolved in trifluoroacetic acid (4mL), added trifluoromethanesulfonic acid (470.0mg, 3.13mmol, 3eq), at room temperature React for 1 hour. LCMS monitored that the reaction was complete, the reaction solution was concentrated, the residue was dissolved in dichloromethane (4mL), triethylamine (528.2mg, 5.22mmol, 5eq) and di-tert-butyl dicarbonate (273.4mg, 1.25mmol, 1.2eq ), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was extracted with dichloromethane and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (THF/petroleum ether: 0-40%) to give (5aS,6S,9R)-tert-butyl-2-chloro-1-fluoro-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 (400 mg, yield: 66.2%).
MS m/z：579.2[M+H] + MS m/z: 579.2[M+H] +
步骤8：(5aS，6S，9R)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯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
Figure PCTCN2022106363-appb-000196
Figure PCTCN2022106363-appb-000196
将(5aS，6S，9R)-叔丁基-2-氯-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(400mg，0.691mmol，1eq)、((2-氟-6-(甲氧基甲氧基)-8-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(424.9mg，0.829mmol，1.2eq)、甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(100.6mg，0.138mmol，0.2eq)和碳酸铯(675.2mg，2.07mmol，3eq)溶于二氧六环(3mL)和水(0.3mL)中，氮气保护，80℃反应2小时。LCMS监测反应完全。反应液用乙酸乙酯和水萃取。有机相用饱和食盐水洗涤， 无水硫酸钠干燥，过滤，滤液浓缩。粗品经柱纯化(四氢呋喃/石油醚：0-40％)，得到(5aS，6S，9R)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(640mg，产率：85％)。(5aS, 6S, 9R)-tert-butyl-2-chloro-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8 -ab] cycloheptatriene-14-carboxylate (400mg, 0.691mmol, 1eq), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5 -Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (424.9mg, 0.829mmol, 1.2eq), methanesulfonyloxy (Diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (100.6mg, 0.138mmol, 0.2eq) and cesium carbonate (675.2mg, 2.07mmol, 3eq) were dissolved in dioxane (3mL) and water (0.3mL), and reacted at 80°C for 2 hours under nitrogen protection. LCMS monitored the reaction to be complete. The reaction solution was extracted with ethyl acetate and water. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by column (THF/petroleum ether: 0-40%) to give (5aS,6S,9R)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy) -8-((triisopropylsilyl)ethynyl)naphthalene-1-yl)-12-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline azin-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 (640 mg, yield: 85%).
MS m/z：929.4[M+H] + MS m/z: 929.4[M+H] +
步骤9：6-氟-4-((5aS，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚盐酸盐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
Figure PCTCN2022106363-appb-000197
盐酸盐
Figure PCTCN2022106363-appb-000197
Hydrochloride
将(5aS，6S，9R)-叔丁基-1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-14-甲酸基酯(500mg，0.538mmol，1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环(4M，1mL)，室温反应1小时。LCMS监测反应完全。反应液浓缩，得到6-氟-4-((5aS，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚盐酸盐(400mg，粗品)。(5aS, 6S, 9R)-tert-butyl-1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) Naphthalene-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-carboxylate (500mg, 0.538mmol, 1eq) was dissolved in acetonitrile (2mL), added hydrochloric acid/dioxane (4M, 1mL), and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 6-fluoro-4-((5aS, 6S, 9R)-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]cycloheptatrien-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (400 mg, crude).
MS m/z：785.5[M+H] + MS m/z: 785.5[M+H] +
步骤10：5-乙炔基-6-氟-4-((5aS，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚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
Figure PCTCN2022106363-appb-000198
Figure PCTCN2022106363-appb-000198
将6-氟-4-((5aS，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚盐酸盐(400mg，0.510mmol，1eq)溶于N，N-二甲基甲酰胺(4mL)中，加入氟化铯(4.72g，31.07mmol，60.98eq)，室温反应6小时。LCMS监测反应完全。将反应液过滤，滤液经HPLC制备得到5-乙炔基-6-氟-4-((5aS，6S，9R)-1-氟-12-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5a，6，7，8，9，10-六氢-5H-4-氧杂-3，10a，11，13，14-五氮杂-6，9-甲桥萘并[1，8-ab]并环庚三烯-2-基)萘-2-酚(150mg，收率：46.8％)，白色固体。6-fluoro-4-((5aS, 6S, 9R)-1-fluoro-12-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy) -5a, 6, 7, 8, 9, 10-hexahydro-5H-4-oxa-3, 10a, 11, 13, 14-pentaaza-6, 9-methonaphtho[1,8- ab] cycloheptatrien-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (400mg, 0.510mmol, 1eq) dissolved in N,N- To dimethylformamide (4 mL), cesium fluoride (4.72 g, 31.07 mmol, 60.98 eq) was added and reacted at room temperature for 6 hours. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was prepared by HPLC to obtain 5-ethynyl-6-fluoro-4-((5aS, 6S, 9R)-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]cycloheptatrien-2-yl)naphthalene-2-ol (150 mg, yield: 46.8%), white solid.
MS m/z：628.9[M+H] + MS m/z: 628.9[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-110.74(s)，-145.56(s)，-172.09(s)，-172.21(s). 19 F NMR (376MHz, DMSO-d 6 ) δ-110.74(s), -145.56(s), -172.09(s), -172.21(s).
1H NMR(400MHz，DMSO-d 6)δ10.16(br s，1H)，8.00-7.93(m，1H)，7.46(dt，J＝4.4，9.0Hz，1H)，7.37(s，1H)，7.20-7.08(m，1H)，5.28(br d，J＝54.4Hz，1H)，4.89-4.77(m，1H)，4.54(br dd，J＝11.5，18.6Hz，1H)，4.42-4.29(m，1H)，4.16-3.95(m，4H)，3.66-3.50(m，2H)，3.14-3.00(m，4H)，2.88-2.79(m，1H)，2.16-1.51(m，11H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.16(br s, 1H), 8.00-7.93(m, 1H), 7.46(dt, J=4.4, 9.0Hz, 1H), 7.37(s, 1H) , 7.20-7.08(m, 1H), 5.28(br d, J=54.4Hz, 1H), 4.89-4.77(m, 1H), 4.54(br dd, J=11.5, 18.6Hz, 1H), 4.42-4.29 (m, 1H), 4.16-3.95(m, 4H), 3.66-3.50(m, 2H), 3.14-3.00(m, 4H), 2.88-2.79(m, 1H), 2.16-1.51(m, 11H) .
HPLC分离条件：HPLC separation conditions:
柱子：Agela DuraShell C18 150*25mm*5um；流速：25mL/minColumn: Agela DuraShell C18 150*25mm*5um; flow rate: 25mL/min
流动相A：Water(0.05％氨水，v/v)；流动相B：ACN(v/v)；梯度：24％-64％，9min；Mobile phase A: Water (0.05% ammonia water, v/v); Mobile phase B: ACN (v/v); Gradient: 24%-64%, 9min;
检测波长：254/220nmDetection wavelength: 254/220nm
实施例12：化合物12Example 12: Compound 12
5-乙炔基-6-氟-4-((6aR，7R，10S)-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五 氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-2-基)萘-2-酚5-Ethynyl-6-fluoro-4-((6aR, 7R, 10S)-1-fluoro-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-methyl-bridged ring Heptatrieno[4,5]cyclooctatetraen[1,2,3-de]naphthalene-2-yl)naphthalene-2-ol
Figure PCTCN2022106363-appb-000199
Figure PCTCN2022106363-appb-000199
步骤1：(1R，2S，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 1: (1R,2S,5S)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022106363-appb-000200
Figure PCTCN2022106363-appb-000200
将(1R，2S，5S)-8-苯甲基-2-乙基4-氧亚基-3，8-二氮杂二环[3.2.1]辛烷-2，8-二甲酸基酯(18.0g，54.16mmol，1eq)溶于四氢呋喃(200mL)中，氮气保护，室温加入硼烷二甲硫醚溶液(10M，27.0mL，270mmol，5eq)中，40℃反应过夜。LCMS监测反应完全。0℃缓慢加入甲醇淬灭反应，浓缩得到(1R，2S，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(20.0g，粗品)，黄色液体，直接投入下一步反应。(1R,2S,5S)-8-Benzyl-2-ethyl 4-oxyylidene-3,8-diazabicyclo[3.2.1]octane-2,8-dicarboxylate (18.0g, 54.16mmol, 1eq) was dissolved in tetrahydrofuran (200mL), under nitrogen protection, added borane dimethyl sulfide solution (10M, 27.0mL, 270mmol, 5eq) at room temperature, and reacted overnight at 40°C. LCMS monitored the reaction to be complete. Slowly add methanol at 0°C to quench the reaction, and concentrate to obtain (1R,2S,5S)-benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8- Formic acid ester (20.0g, crude product), a yellow liquid, was directly put into the next reaction.
MS m/z：277.2[M+H] + MS m/z: 277.2[M+H] +
步骤2：(1R，2S，5S)-8-苯甲基-3-叔丁基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯Step 2: (1R,2S,5S)-8-Benzyl-3-tert-butyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3, 8-dicarboxylate
Figure PCTCN2022106363-appb-000201
Figure PCTCN2022106363-appb-000201
将(1R，2S，5S)-苯甲基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(20.0g，72.38mmol，1eq)溶于四氢呋喃(200mL)中，加入三乙胺(14.65g，144.75mmol，2eq)，BOC酸酐(31.59g，144.75mmol，2eq)，室温反应2小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-20％)，得到(1R，2S，5S)-8-苯甲基-3-叔丁基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷 -3，8-二甲酸基酯(12.5g，产率：45.9％)，黄色油状物。(1R,2S,5S)-Benzyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (20.0g, 72.38mmol, 1eq) was dissolved in tetrahydrofuran (200mL), triethylamine (14.65g, 144.75mmol, 2eq) and BOC anhydride (31.59g, 144.75mmol, 2eq) were added and reacted at room temperature for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with ethyl acetate. 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: 0-20%) to obtain (1R, 2S, 5S)-8-benzyl-3-tert-butyl-2-(hydroxymethyl yl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (12.5 g, yield: 45.9%), yellow oil.
MS m/z：399.1[M+Na] + MS m/z: 399.1[M+Na] +
步骤3：(1R，2S，5S)-8-苯甲基-3-叔丁基-2-(((甲磺酰)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯Step 3: (1R,2S,5S)-8-Benzyl-3-tert-butyl-2-(((methylsulfonyl)oxy)methyl)-3,8-diazabicyclo[3.2 .1] Octane-3,8-dicarboxylate
Figure PCTCN2022106363-appb-000202
Figure PCTCN2022106363-appb-000202
将(1R，2S，5S)-8-苯甲基-3-叔丁基-2-(羟甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯(12.5g，33.21mmol，1eq)和N，N-二异丙基乙胺(12.87g，99.62mmol，3eq)溶于二氯甲烷(250mL)中，0℃加入甲烷磺酰氯(9.3g，81.19mmol，2.44eq)，室温反应1小时。LCMS监测反应完全。反应液加水淬灭，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-17％)，得到(1R，2S，5S)-8-苯甲基-3-叔丁基-2-(((甲磺酰)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯(13.0g，产率：86.1％).(1R, 2S, 5S)-8-benzyl-3-tert-butyl-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-3,8- Dicarboxylate (12.5g, 33.21mmol, 1eq) and N,N-diisopropylethylamine (12.87g, 99.62mmol, 3eq) were dissolved in dichloromethane (250mL), and methanesulfonyl chloride ( 9.3g, 81.19mmol, 2.44eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was quenched with water 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: 0-17%) to obtain (1R, 2S, 5S)-8-benzyl-3-tert-butyl-2-((( Methanesulfonyl)oxo)methyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (13.0g, yield: 86.1%).
MS m/z：399.0[M+H-56] + MS m/z: 399.0[M+H-56] +
步骤4：(1R，2R，5S)-8-苯甲基-3-叔丁基-2-(氰基甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯Step 4: (1R,2R,5S)-8-Benzyl-3-tert-butyl-2-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-3 , 8-dicarboxylate
Figure PCTCN2022106363-appb-000203
Figure PCTCN2022106363-appb-000203
将(1R，2S，5S)-8-苯甲基-3-叔丁基-2-(((甲磺酰)氧代)甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯(13.0g，28.60mmol，1eq)溶于N，N-二甲基甲酰胺(120mL)中，室温加入氰化钾(4.54g，69.72mmol，2.44eq)，100℃反应过夜。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-15％)，得到(1R，2R，5S)-8-苯甲基-3-叔丁基-2-(氰基甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯(7.76g，产率：70.4％)，无色油状物。(1R, 2S, 5S)-8-benzyl-3-tert-butyl-2-(((methylsulfonyl)oxo)methyl)-3,8-diazabicyclo[3.2.1 ] Octane-3,8-dicarboxylate (13.0g, 28.60mmol, 1eq) was dissolved in N,N-dimethylformamide (120mL), and potassium cyanide (4.54g, 69.72mmol, 2.44 eq), react overnight at 100°C. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with ethyl acetate. 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)-8-benzyl-3-tert-butyl-2-(cyano Methyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate (7.76 g, yield: 70.4%), colorless oil.
MS m/z：342.1[M+H] + MS m/z: 342.1[M+H] +
步骤5：(1R，2R，5S)-苯甲基-2-(2-甲氧基-2-氧亚基乙基)-3，8-二氮杂 二环[3.2.1]辛烷-8-甲酸基酯Step 5: (1R,2R,5S)-Benzyl-2-(2-methoxy-2-oxyethyleneethyl)-3,8-diazabicyclo[3.2.1]octane- 8-formyl ester
Figure PCTCN2022106363-appb-000204
Figure PCTCN2022106363-appb-000204
将(1R，2R，5S)-8-苯甲基-3-叔丁基-2-(氰基甲基)-3，8-二氮杂二环[3.2.1]辛烷-3，8-二甲酸基酯(7.7g，19.98mmol，1eq)溶于盐酸甲醇溶液(4M，74.52mL，298.06mmol，14.9eq)中，50℃反应过夜。LCMS监测反应完全。将反应液浓缩得到(1R，2R，5S)-苯甲基-2-(2-甲氧基-2-氧亚基乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(6.3g，粗品)，白色固体，直接投入下一步反应。(1R, 2R, 5S)-8-benzyl-3-tert-butyl-2-(cyanomethyl)-3,8-diazabicyclo[3.2.1]octane-3,8 -Dicarboxylate (7.7g, 19.98mmol, 1eq) was dissolved in methanolic hydrochloric acid solution (4M, 74.52mL, 298.06mmol, 14.9eq) and reacted overnight at 50°C. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain (1R, 2R, 5S)-benzyl-2-(2-methoxy-2-oxyethylene ethyl)-3,8-diazabicyclo[3.2.1]octane Alkane-8-carboxylate (6.3 g, crude product), a white solid, was directly put into the next reaction.
MS m/z：319.1[M+H] + MS m/z: 319.1[M+H] +
步骤6：2-((1R，2R，5S)-8-((苄氧基)羰基)-3，8-二氮杂二环[3.2.1]辛烷-2-基)乙酸Step 6: 2-((1R,2R,5S)-8-((Benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-2-yl)acetic acid
Figure PCTCN2022106363-appb-000205
Figure PCTCN2022106363-appb-000205
将(1R，2R，5S)-苯甲基-2-(2-甲氧基-2-氧亚基乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(6.3g，19.79mmol，1eq)溶于甲醇(60mL)中，加氢氧化锂水溶液(2.5M，15.8mL，39.5mmol，2eq)，室温反应过夜。LCMS监测反应完全。反应液浓缩，用稀盐酸水溶液调节pH至2，浓缩得到2-((1R，2R，5S)-8-((苄氧基)羰基)-3，8-二氮杂二环[3.2.1]辛烷-2-基)乙酸(6.0g，粗品)，无色油状物，直接投入下一步反应。(1R, 2R, 5S)-benzyl-2-(2-methoxy-2-oxyethylene ethyl)-3,8-diazabicyclo[3.2.1]octane-8- Formic acid ester (6.3g, 19.79mmol, 1eq) was dissolved in methanol (60mL), lithium hydroxide aqueous solution (2.5M, 15.8mL, 39.5mmol, 2eq) was added, and reacted overnight at room temperature. LCMS monitored the reaction to be complete. The 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.
MS m/z：305.1[M+H] + MS m/z: 305.1[M+H] +
步骤7：(1R，2R，5S)-苯甲基-2-(2-羟基乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 7: (1R,2R,5S)-Benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure PCTCN2022106363-appb-000206
Figure PCTCN2022106363-appb-000206
将2-((1R，2R，5S)-8-((苄氧基)羰基)-3，8-二氮杂二环[3.2.1]辛烷-2-基)乙酸(3.0g，9.87mmol，1eq)溶于四氢呋喃(30mL)，加入硼烷四氢呋喃溶液(1M，49.3mL，49.3mmol，5eq)，室温反应过夜。LCMS监测 反应完全。0℃缓慢加入甲醇淬灭反应，浓缩得到(1R，2R，5S)-苯甲基-2-(2-羟基乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.0g，粗品)，黄色液体，直接投入下一步反应。2-((1R,2R,5S)-8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octane-2-yl)acetic acid (3.0g, 9.87 mmol, 1eq) was dissolved in tetrahydrofuran (30mL), and borane tetrahydrofuran solution (1M, 49.3mL, 49.3mmol, 5eq) was added to react at room temperature overnight. LCMS monitored the reaction to be complete. Slowly add methanol at 0°C to quench the reaction, and concentrate to obtain (1R,2R,5S)-benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane- 8-Carboxylate (2.0 g, crude product), a yellow liquid, was directly put into the next reaction.
MS m/z：291.1[M+H] + MS m/z: 291.1[M+H] +
步骤8：(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯Step 8: (1R,2R,5S)-Benzyl-2-(2-((tert-Butyldimethylsilyl)oxo)ethyl)-3,8-diazabicyclo[3.2 .1] Octane-8-carboxylate
Figure PCTCN2022106363-appb-000207
Figure PCTCN2022106363-appb-000207
将(1R，2R，5S)-苯甲基-2-(2-羟基乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.0g，6.89mmol，1eq)溶于二氯甲烷(20mL)中，加入咪唑(1.41g，20.66mmol，3eq)，叔丁基二甲基氯硅烷(2.08g，13.78mmol，2eq)，室温反应过夜。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-50％)，得到(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(800mg，4步总产率：19.8％)，无色油状物。(1R, 2R, 5S)-benzyl-2-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0g, 6.89 mmol, 1eq) was dissolved in dichloromethane (20mL), imidazole (1.41g, 20.66mmol, 3eq) and tert-butyldimethylsilyl chloride (2.08g, 13.78mmol, 2eq) were added and reacted at room temperature overnight. LCMS monitored the reaction to be complete. The reaction solution was diluted with water and extracted with dichloromethane. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-50%) to obtain (1R, 2R, 5S)-benzyl-2 -(2-((tert-Butyldimethylsilyl)oxo)ethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (800 mg, 4 steps Overall yield: 19.8%), colorless oil.
MS m/z：405.2[M+H] + MS m/z: 405.2[M+H] +
步骤9：2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶Step 9: 2,4,5,7-Tetrachloro-8-fluoropyrido[4,3-d]pyrimidine
Figure PCTCN2022106363-appb-000208
Figure PCTCN2022106363-appb-000208
将5，7-二氯-8-氟吡啶并[4，3-d]嘧啶-2，4-二酚(3.0g，12.0mmol，1eq)溶于三氯氧磷(15mL)中，室温滴加N，N-二异丙基乙胺(7.74g，60.00mmol，5eq)，100℃反应2小时。LCMS监测反应完全。反应液浓缩得到2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(3.0g，粗品)，棕色液体，直接投入下一步反应。Dissolve 5,7-dichloro-8-fluoropyrido[4,3-d]pyrimidine-2,4-diol (3.0g, 12.0mmol, 1eq) in phosphorus oxychloride (15mL), drip at room temperature Add N,N-diisopropylethylamine (7.74g, 60.00mmol, 5eq), and react at 100°C for 2 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 2,4,5,7-tetrachloro-8-fluoropyrido[4,3-d]pyrimidine (3.0 g, crude product) as a brown liquid, which was directly put into the next reaction.
MS m/z：287.8[M+H] + MS m/z: 287.8[M+H] +
步骤10：(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代) 乙基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000209
Figure PCTCN2022106363-appb-000209
将2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(5.0g，10.5mmol，约60％含量，1.32eq)溶于二氯甲烷(60mL)中，加入N，N-二异丙基乙胺(3.07g，23.73mmol，3eq)，-30℃滴加(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(3.2g，7.91mmol，1eq)的二氯甲烷(10mL)溶液，2个小时缓慢升到室温。LCMS监测反应完全。反应液倒入饱和碳酸氢钠水溶液中淬灭，二氯甲烷萃取。有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-15％)，得到(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(2.6g，产率：50.2％)，橙色固体。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. The 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.
MS m/z：654.2[M+H] + MS m/z: 654.2[M+H] +
步骤11：(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯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
Figure PCTCN2022106363-appb-000210
Figure PCTCN2022106363-appb-000210
将(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛 烷-8-甲酸基酯(2.6g，3.97mmol，1eq)溶于二氯甲烷(50mL)中，加入((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(1.14g，7.14mmol，1.5eq)，叔丁醇钠(991.75mg，10.32mmol，2.6eq)，0℃反应1小时。LCMS监测反应完全。反应液倒入饱和氯化铵水溶液淬灭。二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-35％)，得到(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.7g，产率：55％)，黄色固体。(1R, 2R, 5S)-benzyl-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2,5,7-trichloro-8 -Fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.6g, 3.97mmol, 1eq) In dichloromethane (50 mL), add ((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (1.14g, 7.14mmol, 1.5eq), sodium tert-butoxide ( 991.75mg, 10.32mmol, 2.6eq), react at 0°C for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was quenched by pouring saturated ammonium chloride aqueous solution. Extract with dichloromethane, wash the organic phase with saturated brine, and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-35%) to obtain (1R, 2R, 5S)-benzyl-2-(2-((tert-butyldimethylsilane Base) oxo) ethyl) -3-(5,7-dichloro-8-fluoro-2-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl) methyl Oxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.7g, yield: 55% ), yellow solid.
MS m/z：777.3[M+H] + MS m/z: 777.3[M+H] +
步骤12：(6aR，7R，10S)-苯甲基-2-氯-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯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
Figure PCTCN2022106363-appb-000211
Figure PCTCN2022106363-appb-000211
将(1R，2R，5S)-苯甲基-2-(2-((叔丁基二甲基甲硅烷基)氧代)乙基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-甲酸基酯(1.2g，1.54mmol，1eq)溶于四氢呋喃(12mL)中，加入四丁基氟化铵(1M，4.63mL，3eq)，30℃反应5小时。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-30％)，得到(6aR，7R，10S)-苯甲基-2-氯-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯(900mg，产率：93.0％)，黄色固体。(1R, 2R, 5S)-benzyl-2-(2-((tert-butyldimethylsilyl)oxy)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 (1.2g, 1.54mmol, 1eq) was dissolved in tetrahydrofuran (12mL), and tetrabutylammonium fluoride (1M, 4.63mL, 3eq ), reacted at 30°C for 5 hours. 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. Filtration, the filtrate was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain (6aR, 7R, 10S)-benzyl-2-chloro-1-fluoro-13-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolidinazin-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 (900mg , yield: 93.0%), yellow solid.
MS m/z：627.2[M+H] + MS m/z: 627.2[M+H] +
步骤13：(6aR，7R，10S)-叔丁基-2-氯-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯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
Figure PCTCN2022106363-appb-000212
Figure PCTCN2022106363-appb-000212
将(6aR，7R，10S)-苯甲基-2-氯-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯(0.45g，0.717mmol，1eq)溶于三氟乙酸(1.5mL)中，0℃加入三氟甲磺酸(430.8mg，2.87mmol，4eq)，室温反应1小时。LCMS监测反应完全，往反应液中加入二氯甲烷稀释，浓缩。残留物溶于二氯甲烷(3mL)，加入三乙胺(215.6mg，2.13mmol，3eq)，BOC酸酐(232.4mg，1.07mmol，1.5eq)，室温反应过夜。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：0-30％)，得到(6aR，7R，10S)-叔丁基-2-氯-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯(380mg，产率：90.2％)，黄色固体。(6aR, 7R, 10S)-benzyl-2-chloro-1-fluoro-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-methylcycloheptatriene Na[4,5]cyclooctatetraene[1,2,3-de]naphthalene-15-carboxylate (0.45g, 0.717mmol, 1eq) was dissolved in trifluoroacetic acid (1.5mL), and trifluoroacetic acid (1.5mL) was added at 0°C Fluoromethanesulfonic acid (430.8 mg, 2.87 mmol, 4 eq) was reacted at room temperature for 1 hour. LCMS monitored the completion of the reaction, dichloromethane was added to the reaction solution for dilution and concentration. The residue was dissolved in dichloromethane (3 mL), triethylamine (215.6 mg, 2.13 mmol, 3 eq) and BOC anhydride (232.4 mg, 1.07 mmol, 1.5 eq) were added, and reacted overnight at room temperature. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 0-30%) to obtain (6aR, 7R, 10S)-tert-butyl-2-chloro-1-fluoro-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 (380mg, Yield: 90.2%), yellow solid.
MS m/z：593.2[M+H] + MS m/z: 593.2[M+H] +
步骤14：(6aR，7R，10S)-叔丁基1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯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
Figure PCTCN2022106363-appb-000213
Figure PCTCN2022106363-appb-000213
将(6aR，7R，10S)-叔丁基-2-氯-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯(0.21g，0.354mmol，1eq)溶于二氧六环(12mL)和水(4mL)中，加入((2-氟-6-(甲氧基甲氧基)-8-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)萘-1-基)乙炔基)三异丙基硅烷(363.0mg，0.708mmol，2eq)，碳酸铯(346.1mg，1.06mmol，3eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(51.6mg，0.071mmol，0.2eq)，氮气保护，80℃反应1小时。LCMS监测反应完全。往反应液中加入食盐水，乙酸乙酯萃取。有机相用无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱层析纯化(四氢呋喃/石油醚：0-28％)，得到(6aR，7R，10S)-叔丁基1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯(300mg，产率：89.8％)，黄色固体。(6aR, 7R, 10S)-tert-butyl-2-chloro-1-fluoro-13-(((2R, 7aS)-2-fluorohexahydro-1H-pyrroline azin-7a-yl)methoxy )-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methylcycloheptatriene Na[4,5]cyclooctatetraene[1,2,3-de]naphthalene-15-carboxylate (0.21 g, 0.354 mmol, 1 eq) was dissolved in dioxane (12 mL) and water (4 mL) , add ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Naphthalen-1-yl)ethynyl)triisopropylsilane (363.0mg, 0.708mmol, 2eq), cesium carbonate (346.1mg, 1.06mmol, 3eq), methanesulfonyloxy(diadamantyl-n-butyl Phosphino)-2-amino-1,1-biphenyl-2-yl)palladium(II) (51.6mg, 0.071mmol, 0.2eq), under nitrogen protection, react at 80°C for 1 hour. LCMS monitored the reaction to be complete. Add brine to the reaction liquid, and extract with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated, and the residue was purified by column chromatography (tetrahydrofuran/petroleum ether: 0-28%) to obtain (6aR, 7R, 10S)-tert-butyl 1-fluoro-2-(7-fluoro-3-( Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)-13-(((2R,7aS)-2-fluorohexahydro-1H-pyrroline Azin-7a-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7 , 10-methylcyclohepta[4,5]cyclooctatetraen[1,2,3-de]naphthalene-15-carboxylate (300 mg, yield: 89.8%), yellow solid.
MS m/z：943.5[M+H] + MS m/z: 943.5[M+H] +
步骤15：6-氟-4-((6aR，7R，10S)-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-2-基)-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚盐酸盐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
Figure PCTCN2022106363-appb-000214
Figure PCTCN2022106363-appb-000214
将(6aR，7R，10S)-叔丁基1-氟-2-(7-氟-3-(甲氧基甲氧基)-8-((三异丙基甲硅烷基)乙炔基)萘-1-基)-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-15-甲酸基酯(0.22g，0.233mmol，1eq)溶于乙腈(4mL)中，加入盐酸二氧六环溶液(4M，4mL)，室温反应1小时。LCMS监测反应完全。反应液浓缩得到6-氟-4-((6aR，7R，10S)-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-2-基)-5-((三异丙基甲硅烷基)乙炔基)萘-2-酚盐酸盐(180mg，粗品)，黄色油状物，直接投入下一步反应。(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 (0.22g, 0.233mmol, 1eq) was dissolved in acetonitrile (4mL), added dioxane hydrochloride solution (4M, 4mL), and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated to obtain 6-fluoro-4-((6aR, 7R, 10S)-1-fluoro-13-(((2R, 7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methyl Oxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methanocyclohepta Trieno[4,5]cyclooctatetraenyl[1,2,3-de]naphthalene-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride Salt (180mg, crude product), yellow oil, directly put into the next reaction.
MS m/z：799.5[M+H] + MS m/z: 799.5[M+H] +
步骤16：5-乙炔基-6-氟-4-((6aR，7R，10S)-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-2-基)萘-2-酚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
Figure PCTCN2022106363-appb-000215
Figure PCTCN2022106363-appb-000215
将6-氟-4-((6aR，7R，10S)-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-2-基)-5-((三异丙基甲 硅烷基)乙炔基)萘-2-酚盐酸盐(0.18g，0.225mmol，1eq)溶于N，N-二甲基甲酰胺(1.5mL)中，加入氟化铯(3.42g，22.5mmol，100eq)，室温反应1小时。LCMS监测反应完全。反应液过滤，滤液经HPLC纯化后得到粗品，再经过SFC拆分得到5-乙炔基-6-氟-4-((6aR，7R，10S)-1-氟-13-(((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-甲桥环庚三烯并[4，5]环辛四烯[1，2，3-de]萘-2-基)萘-2-酚(15mg，产率：10％)。6-fluoro-4-((6aR, 7R, 10S)-1-fluoro-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-methylcycloheptatrienol [4,5] cyclooctatetraenyl[1,2,3-de]naphthalene-2-yl)-5-((triisopropylsilyl)ethynyl)naphthalene-2-ol hydrochloride (0.18 g, 0.225mmol, 1eq) was dissolved in N,N-dimethylformamide (1.5mL), cesium fluoride (3.42g, 22.5mmol, 100eq) was added, and reacted at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was filtered, and the filtrate was purified by HPLC to obtain a crude product, and then resolved by SFC to obtain 5-ethynyl-6-fluoro-4-((6aR, 7R, 10S)-1-fluoro-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-methylcycloheptatrieno[4,5]cyclooctatetraene[1,2,3-de]naphthalene-2-yl)naphthalene-2- Phenol (15 mg, yield: 10%).
MS m/z：643.4[M+H] + MS m/z: 643.4[M+H] +
19F NMR(376MHz，DMSO-d 6)δ-110.83(s)，-147.83(s)，-149.31(s)，-172.10(s)，-172.15(s). 19 F NMR (376MHz, DMSO-d 6 ) δ-110.83(s), -147.83(s), -149.31(s), -172.10(s), -172.15(s).
1H NMR(400MHz，DMSO-d 6)δ10.25(br s，1H)，8.00-7.90(m，1H)，7.46(t，J＝8.9Hz，1H)，7.39-7.32(m，1H)，7.28-7.05(m，1H)，5.28(br d，J＝54.0Hz，1H)，4.98-4.83(m，1H)，4.47-4.38(m，1H)，4.18-3.77(m，4H)，3.64-3.46(m，2H)，3.44-3.37(m，1H)，3.18-2.97(m，4H)，2.89-2.77(m，1H)，2.65-2.55(m，1H)，2.48-2.38(m，1H)，2.16-1.92(m，4H)，1.90-1.32(m，7H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.25(br s, 1H), 8.00-7.90(m, 1H), 7.46(t, J=8.9Hz, 1H), 7.39-7.32(m, 1H) , 7.28-7.05(m, 1H), 5.28(br d, J=54.0Hz, 1H), 4.98-4.83(m, 1H), 4.47-4.38(m, 1H), 4.18-3.77(m, 4H), 3.64-3.46(m, 2H), 3.44-3.37(m, 1H), 3.18-2.97(m, 4H), 2.89-2.77(m, 1H), 2.65-2.55(m, 1H), 2.48-2.38(m , 1H), 2.16-1.92(m, 4H), 1.90-1.32(m, 7H).
HPLC分离条件：HPLC separation conditions:
柱子：Kromasil Eternity XT 150*30mm*10um；流速：30mL/minColumn: Kromasil Eternity XT 150*30mm*10um; flow rate: 30mL/min
流动相：A：Water(0.1％甲酸，v/v)流动相B：ACN；梯度：20％-60％(v/v)，9min；检测波长：254/220nmMobile phase: A: Water (0.1% formic acid, v/v) Mobile phase B: ACN; Gradient: 20%-60% (v/v), 9min; Detection wavelength: 254/220nm
SFC分离条件：SFC separation conditions:
柱子：DAICEL CHIRALPAK IC(250mm*30mm，10um)；流速：80mL/minColumn: DAICEL CHIRALPAK IC (250mm*30mm, 10um); flow rate: 80mL/min
流动相A：CO2，流动相B：甲醇(0.1％氨水，v/v)；梯度：50％-50％(v/v)；Mobile phase A: CO2, mobile phase B: methanol (0.1% ammonia water, v/v); gradient: 50%-50% (v/v);
检测波长：254/220nmDetection wavelength: 254/220nm
实施例13：化合物13Example 13: Compound 13
5，6-二氟-4-((6aS，7S，10R)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-2-基)萘-2-酚盐酸盐5,6-difluoro-4-((6aS, 7S, 10R)-1-fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline azin-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
Figure PCTCN2022106363-appb-000216
盐酸盐
Figure PCTCN2022106363-appb-000216
Hydrochloride
步骤1：苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯Step 1: Benzyl-(1S,2S,5R)-2-(2-((tert-butyldimethylsilyl)oxo)ethyl)-3,8-diazabicyclo[ 3.2.1] Octane-8-carboxylate
Figure PCTCN2022106363-appb-000217
Figure PCTCN2022106363-appb-000217
将苯甲基-(1S，2S，5R)-2-(2-羟基乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(1.18g，4.07mmol，1eq)溶于二氯甲烷(15mL)中，加入咪唑(830mg，12.21mmol，3eq)，0℃加入叔丁基二甲基氯硅烷(736mg，4.88mmol，1.2eq)，1小时后升到室温。LCMS监测反应完全。反应液加水稀释，二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(1.25g，产率：76％)，淡黄色油状物。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. The 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.
MS m/z：405[M+H] + MS m/z: 405[M+H] +
步骤2：苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯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
Figure PCTCN2022106363-appb-000218
Figure PCTCN2022106363-appb-000218
将2，4，5，7-四氯-8-氟吡啶并[4，3-d]嘧啶(884mg，3.09mmol，1eq)溶于二氯甲烷(20mL)中，加入N，N-二异丙基乙胺(1.2g，9.27mmol， 3eq)，-30℃滴加苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(1.25g，3.09mmol，1eq)的二氯甲烷(4mL)溶液，2小时后升到室温。LCMS监测反应完全。反应液加水稀释，乙酸乙酯萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥。过滤，滤液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：20-40％)，得到苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(1.2g，产率：59.47％)，白色固体。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. 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. 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 ylsilyl)oxo)ethyl)-3-(2,5,7-trichloro-8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazepine Bicyclo[3.2.1]octane-8-carboxylate (1.2 g, yield: 59.47%), white solid.
MS m/z：654/656[M+H] + MS m/z: 654/656[M+H] +
步骤3：苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯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
Figure PCTCN2022106363-appb-000219
Figure PCTCN2022106363-appb-000219
将苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3-(2，5，7-三氯-8-氟吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(1.3g，1.99mmol，1eq)溶于二氯甲烷(5mL)中，加入((2R，7aS)-2-氟六氢-1H-吡咯啉嗪-7a-基)甲醇(316mg，1.99mmol，1eq)，叔丁醇钠(382mg，3.98mmol，2eq)，室温反应1小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：30-50％)，得到苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(580mg，产率：37.56％)，棕色固体。Benzyl-(1S, 2S, 5R)-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-(2,5,7-trichloro- 8-fluoropyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.3g, 1.99mmol, 1eq) Dissolve in dichloromethane (5mL), add ((2R,7aS)-2-fluorohexahydro-1H-pyrrolinazin-7a-yl)methanol (316mg, 1.99mmol, 1eq), sodium tert-butoxide (382mg , 3.98mmol, 2eq), react at room temperature for 1 hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 30-50%) to obtain benzyl-(1S, 2S, 5R)-2-(2-((tert-butyldimethyl Silyl) oxo) ethyl) -3-(5,7-dichloro-8-fluoro-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidazine-7a(5H )-yl)methoxy)pyrido[4,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (580mg, yield Yield: 37.56%), brown solid.
MS m/z：777/779[M+H] + MS m/z: 777/779[M+H] +
步骤4：苯甲基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并 [1，2，3-de]萘-15-羧酸酯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
Figure PCTCN2022106363-appb-000220
Figure PCTCN2022106363-appb-000220
将苯甲基-(1S，2S，5R)-2-(2-((叔-丁基二甲基甲硅烷基)氧代)乙基)-3-(5，7-二氯-8-氟-2-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)吡啶并[4，3-d]嘧啶-4-基)-3，8-二氮杂二环[3.2.1]辛烷-8-羧酸酯(570mg，0.73mmol，1eq)溶于四氢呋喃(10mL)中，加入四丁基氟化铵(1M，1.1mL，1.5eq)，室温反应3小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：70-100％)，得到苯甲基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(265mg，产率：57.99％)，黄色固体。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]pyrimidin-4-yl) -3,8-diazabicyclo[3.2.1]octane-8-carboxylate (570 mg, 0.73 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), and tetrabutylammonium fluoride (1M, 1.1 mL, 1.5eq), react at room temperature for 3 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 70-100%) to obtain benzyl-(6aS, 7S, 10R)-2-chloro-1-fluoro-13-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxo Hetero-3,11a,12,14,15-pentaaza-7,10-methylenecyclohepta[4,5]cyclooctatetraeno[1,2,3-de]naphthalene-15 -Carboxylate (265 mg, yield: 57.99%), yellow solid.
MS m/z：627/629[M+H] + MS m/z: 627/629[M+H] +
步骤5：叔丁基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯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
Figure PCTCN2022106363-appb-000221
Figure PCTCN2022106363-appb-000221
将苯甲基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(260mg，0.42mmol，1eq)溶于三氟乙酸(2.5mL)中，加入三氟甲磺 酸(187mg，1.25mmol，3eq)，室温反应1小时。反应液浓缩，残留物溶于二氯甲烷(5mL)，加入Boc酸酐(110mg，0.5mmol，1.2eq)，三乙胺(212mg，2.1mmol，5eq)，室温反应1小时。反应液浓缩，残留物经柱纯化(乙酸乙酯/石油醚：40-70％)，得到叔丁基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(205mg，产率：82.45％)，黄色固体。Benzyl-(6aS, 7S, 10R)-2-chloro-1-fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl) Methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methylene Cyclohepta[4,5]cyclohexatetra[1,2,3-de]naphthalene-15-carboxylate (260 mg, 0.42 mmol, 1 eq) was dissolved in trifluoroacetic acid (2.5 mL), Add trifluoromethanesulfonic acid (187mg, 1.25mmol, 3eq) and react at room temperature for 1 hour. The reaction solution was concentrated, the residue was dissolved in dichloromethane (5 mL), Boc anhydride (110 mg, 0.5 mmol, 1.2 eq) and triethylamine (212 mg, 2.1 mmol, 5 eq) were added and reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by column (ethyl acetate/petroleum ether: 40-70%) to obtain tert-butyl-(6aS, 7S, 10R)-2-chloro-1-fluoro-13-(((2R ,7aS)-2-fluorotetrahydro-1H-pyrrolidinazin-7a(5H)-yl)methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxo Hetero-3,11a,12,14,15-pentaaza-7,10-methylenecyclohepta[4,5]cyclooctatetraeno[1,2,3-de]naphthalene-15 -Carboxylate (205 mg, yield: 82.45%), yellow solid.
MS m/z：593/595[M+H] + MS m/z: 593/595[M+H] +
步骤6：叔丁基-(6aS，7S，10R)-2-(7，8-二氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯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
Figure PCTCN2022106363-appb-000222
Figure PCTCN2022106363-appb-000222
将叔丁基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(40mg，0.068mmol，1eq)溶于二氧六环(1.5mL)和水(0.3mL)中，加入2-(7，8-二氟-3-(甲氧基甲氧基)萘-1-基)-4，4，5，5-四甲基-1，3，2-二噁硼戊环(48mg，0.135mmol，2eq)，磷酸钾(40mg，0.204mmol，3eq)，三二亚苄基丙酮二钯(12mg，0.0135mmol，0.2eq)，甲磺酰氧基(二金刚烷基-正丁基膦基)-2-氨基-1，1-联苯-2-基)钯(II)(14mg，0.027mmol，0.4eq)，氮气保护，90℃反应2小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：30-60％)，得到叔丁基-(6aS，7S，10R)-2-(7，8-二氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基 环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(8mg，产率：15.08％)，棕色固体。Tert-butyl-(6aS, 7S, 10R)-2-chloro-1-fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidazin-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]cyclohexatetraeno[1,2,3-de]naphthalene-15-carboxylate (40 mg, 0.068 mmol, 1 eq) was dissolved in dioxane (1.5 mL) and In water (0.3 mL), add 2-(7,8-difluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane (48mg, 0.135mmol, 2eq), potassium phosphate (40mg, 0.204mmol, 3eq), tridibenzylideneacetone dipalladium (12mg, 0.0135mmol, 0.2eq), methanesulfonyloxy (Diadamantyl-n-butylphosphino)-2-amino-1,1-biphenyl-2-yl)palladium (II) (14mg, 0.027mmol, 0.4eq), nitrogen protection, 90 ° C reaction 2 Hour. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 30-60%) to obtain tert-butyl-(6aS, 7S, 10R)-2-(7,8-difluoro-3-(methoxy Methoxy)naphthalen-1-yl)-1-fluoro-13-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidazin-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]Cyclooctatraeno[1,2,3-de]naphthalene-15-carboxylate (8 mg, yield: 15.08%), brown solid.
MS m/z：781[M+H] + MS m/z: 781[M+H] +
步骤7：5，6-二氟-4-((6aS，7S，10R)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-2-基)萘-2-酚盐酸盐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
Figure PCTCN2022106363-appb-000223
盐酸盐
Figure PCTCN2022106363-appb-000223
Hydrochloride
将叔丁基-(6aS，7S，10R)-2-(7，8-二氟-3-(甲氧基甲氧基)萘-1-基)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(8mg，0.01mmol，1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环(4M，1mL，4mmol)，室温反应1小时。LCMS检测反应完全。反应液浓缩，得到5，6-二氟-4-((6aS，7S，10R)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-2-基)萘-2-酚盐酸盐(5.6mg，产率：79％)，白色固体。Tert-butyl-(6aS, 7S, 10R)-2-(7,8-difluoro-3-(methoxymethoxy)naphthalene-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-oxo Hetero-3,11a,12,14,15-pentaaza-7,10-methylenecyclohepta[4,5]cyclooctatetraeno[1,2,3-de]naphthalene-15 -Carboxylate (8mg, 0.01mmol, 1eq) was dissolved in acetonitrile (2mL), hydrochloric acid/dioxane (4M, 1mL, 4mmol) was added, and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain 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-methylenecycloheptatrieno[4,5]cyclooctatetraeno[1,2,3-de]naphthalene-2-yl)naphthalene-2-ol hydrochloride (5.6 mg, yield : 79%), white solid.
MS m/z：637[M+H] + MS m/z: 637[M+H] +
1H NMR(400MHz，DMSO-d6)δ11.55(d，J＝29.4Hz，1H)，10.43(s，1H)，10.21(d，J＝10.4Hz，1H)，9.74(d，J＝10.6Hz，1H)，7.72(dd，J＝9.3，4.9Hz，1H)，7.57(t，J＝8.9Hz，1H)，7.41(d，J＝11.8Hz，1H)，7.15(s，1H)，5.57(d，J＝52.8Hz，1H)，5.30(dd，J＝13.8，9.0Hz，1H)，4.74-4.44(m，3H)，4.37-3.95(m，5H)，3.94-3.80(m，2H)，2.71(dt，J＝51.0，8.8Hz，2H)，2.39-2.26(m，1H)，2.17(tq，J＝12.7，5.8Hz，3H)，2.08-1.83(m，3H)，1.87-1.54(m，2H)，1.23(s，3H). 1 H NMR (400MHz, DMSO-d6) δ11.55(d, J=29.4Hz, 1H), 10.43(s, 1H), 10.21(d, J=10.4Hz, 1H), 9.74(d, J=10.6 Hz, 1H), 7.72(dd, J=9.3, 4.9Hz, 1H), 7.57(t, J=8.9Hz, 1H), 7.41(d, J=11.8Hz, 1H), 7.15(s, 1H), 5.57(d, J=52.8Hz, 1H), 5.30(dd, J=13.8, 9.0Hz, 1H), 4.74-4.44(m, 3H), 4.37-3.95(m, 5H), 3.94-3.80(m, 2H), 2.71(dt, J=51.0, 8.8Hz, 2H), 2.39-2.26(m, 1H), 2.17(tq, J=12.7, 5.8Hz, 3H), 2.08-1.83(m, 3H), 1.87 -1.54(m, 2H), 1.23(s, 3H).
实施例14：化合物14Example 14: Compound 14
2-氨基-7-氟-4-((6aS，7S，10R)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-2-基)苯并[b]噻吩-3-甲腈盐酸盐2-amino-7-fluoro-4-((6aS, 7S, 10R)-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 Methylcycloheptatrieno[4,5]cyclooctatraeno[1,2,3-de]naphthalen-2-yl)benzo[b]thiophene-3-carbonitrile hydrochloride
Figure PCTCN2022106363-appb-000224
盐酸盐
Figure PCTCN2022106363-appb-000224
Hydrochloride
步骤1：叔丁基-(6aS，7S，10R)-2-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯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
Figure PCTCN2022106363-appb-000225
Figure PCTCN2022106363-appb-000225
将叔丁基-(6aS，7S，10R)-2-氯-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(58mg，0.098mmol，1eq)溶于二甲基亚砜(1.5mL)中，加入叔丁基-(3-氰基-7-氟-4-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)苯并[b]噻吩-2-基)氨基甲酸酯(82mg，0.196mmol，2eq)，碳酸铯(96mg，0.294mmol，3eq)，二氯[双(二苯基膦苯基)醚]钯(II)(14mg，0.0196mmol，0.2eq)，氮气保护，85℃反应16小时。LCMS监测反应完全。反应液浓缩，残留物经柱纯化(四氢呋喃/石油醚：30-60％)，得到叔丁基-(6aS，7S，10R)-2-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基 环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(7.6mg，产率：9.1％)，棕色固体。Tert-butyl-(6aS, 7S, 10R)-2-chloro-1-fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidazin-7a(5H)-yl) Methoxy)-5,6,6a,7,8,9,10,11-octahydro-4-oxa-3,11a,12,14,15-pentaaza-7,10-methylene Cyclohepta[4,5]cyclohexatetra[1,2,3-de]naphthalene-15-carboxylate (58 mg, 0.098 mmol, 1 eq) was dissolved in dimethylsulfoxide (1.5 mL) In, add tert-butyl-(3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo [b]thiophen-2-yl)carbamate (82mg, 0.196mmol, 2eq), cesium carbonate (96mg, 0.294mmol, 3eq), dichloro[bis(diphenylphosphinephenyl)ether]palladium(II ) (14mg, 0.0196mmol, 0.2eq), under nitrogen protection, reacted at 85°C for 16 hours. LCMS monitored the reaction to be complete. The reaction solution was concentrated, and the residue was purified by column (tetrahydrofuran/petroleum ether: 30-60%) to obtain 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-pyrrolidazine-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]cyclohexatetra[1,2,3-de]naphthalene-15-carboxylate (7.6 mg, yield: 9.1%), brown solid.
MS m/z：849[M+H] + MS m/z: 849[M+H] +
步骤2：2-氨基-7-氟-4-((6aS，7S，10R)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-2-基)苯并[b]噻吩-3-甲腈盐酸盐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
Figure PCTCN2022106363-appb-000226
盐酸盐
Figure PCTCN2022106363-appb-000226
Hydrochloride
将叔丁基-(6aS，7S，10R)-2-(2-((叔丁氧基羰基)氨基)-3-氰基-7-氟苯并[b]噻吩-4-基)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-15-羧酸酯(7.6mg，0.009mmol，1eq)溶于乙腈(2mL)中，加入盐酸/二氧六环(4M，1mL，4mmol)，室温反应1小时。LCMS检测反应完全。反应液浓缩，得到2-氨基-7-氟-4-((6aS，7S，10R)-1-氟-13-(((2R，7aS)-2-氟四氢-1H-吡咯啉嗪-7a(5H)-基)甲氧基)-5，6，6a，7，8，9，10，11-八氢-4-氧杂-3，11a，12，14，15-五氮杂-7，10-亚甲基环庚三烯并[4，5]环辛四烯并[1，2，3-de]萘-2-基)苯并[b]噻吩-3-甲腈盐酸盐(5.6mg，产率：86.3％)，白色固体。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-methylene cycloheptatrieno [4,5] cyclooctatetraeno [1, 2,3-de]naphthalene-15-carboxylate (7.6mg, 0.009mmol, 1eq) was dissolved in acetonitrile (2mL), hydrochloric acid/dioxane (4M, 1mL, 4mmol) was added, and reacted at room temperature for 1 hour. LCMS detected that the reaction was complete. The reaction solution was concentrated to obtain 2-amino-7-fluoro-4-((6aS, 7S, 10R)-1-fluoro-13-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolidinazine- 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-2-yl)benzo[b]thiophene-3-carbonitrile hydrochloride Salt (5.6 mg, yield: 86.3%), white solid.
MS m/z：649[M+H] + MS m/z: 649[M+H] +
1H NMR(400MHz，DMSO-d 6)δ11.43(s，1H)，10.16(d，J＝10.2Hz，1H)，9.78(d，J＝10.7Hz，1H)，8.13(s，2H)，7.43(dd，J＝8.4，5.2Hz，1H)，7.14(t，J＝8.9Hz，1H)，5.76-5.43(m，1H)，5.23(d，J＝14.1Hz，1H)，4.68(d，J＝11.7Hz，1H)，4.61-4.43(m，2H)，4.30-4.10(m，3H)，3.99(d，J＝12.8Hz，1H)，3.90-3.69(m，2H)，3.38-3.15(m，2H)，2.77(t，J＝13.4Hz，1H)，2.32(q，J＝4.8，3.8Hz，1H)，2.18(tq，J＝13.6，6.1Hz，3H)，2.10-1.84(m，3H)，1.58(d，J＝8.3Hz，2H)，1.23(d，J＝6.4Hz，2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ11.43(s, 1H), 10.16(d, J=10.2Hz, 1H), 9.78(d, J=10.7Hz, 1H), 8.13(s, 2H) , 7.43(dd, J=8.4, 5.2Hz, 1H), 7.14(t, J=8.9Hz, 1H), 5.76-5.43(m, 1H), 5.23(d, J=14.1Hz, 1H), 4.68( d, J=11.7Hz, 1H), 4.61-4.43(m, 2H), 4.30-4.10(m, 3H), 3.99(d, J=12.8Hz, 1H), 3.90-3.69(m, 2H), 3.38 -3.15(m, 2H), 2.77(t, J=13.4Hz, 1H), 2.32(q, J=4.8, 3.8Hz, 1H), 2.18(tq, J=13.6, 6.1Hz, 3H), 2.10- 1.84 (m, 3H), 1.58 (d, J=8.3Hz, 2H), 1.23 (d, J=6.4Hz, 2H).
测试实施例1：对Ba/F3 KRAS-G12D、Ba/F3 KRAS-G12V稳转细胞株和含KRAS G12D突变的AGS肿瘤细胞株的增殖抑制活性：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:
本测试实施例1用于测定本发明化合物在体外对小鼠原B细胞Ba/F3稳定表达KRAS G12D/V突变蛋白的Ba/F3 KRAS-G12D和Ba/F3 KRAS-G12V细胞，及表达KRAS G12D突变蛋白的胃癌AGS细胞的增殖抑制活性。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.
细胞来源：Ba/F3 KRAS-G12D和Ba/F3 KRAS-G12V购自康源博创生物科技(北京)有限公司，货号分别为KC-1259和KC-1261；AGS购自上海拜力生物科技有限公司。Cell source: 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.
取处于对数生长期的细胞接种在96孔板中(Ba/F3 KRAS-G12D，Ba/F3 KRAS-G12V，AGS细胞分别为8000,8000,4000个/孔，90μl/孔)，37℃、5％CO 2培养1天后加入梯度稀释的待测化合物。具体如下：取事先溶解在DMSO中的化合物储存液(10mM)，倍比(4倍)稀释为10个梯度浓度，并用培养基在另一96孔板中稀释到目的浓度的10倍，然后在接种细胞的96孔板中加入化合物溶液10μl/孔，即到达目的浓度(10000，2500，625，156，39，10，2.5，0.6，0.15，0.04nM)。每个浓度设3个复孔，并设空白对照。放入37℃、5％CO 2中继续培养72h后，每孔加入50μl
Figure PCTCN2022106363-appb-000227
2.0试剂(荧光素酶ATP生物发光检测试剂，购自Promega，货号G9243)，震荡2min，室温孵育8min后，检测荧光发光强度(收光时间为100ms)。计算各浓度化合物对细胞增殖的抑制率。 Cells in the logarithmic growth phase were inoculated in 96-well plates (Ba/F3 KRAS-G12D, Ba/F3 KRAS-G12V, AGS cells were 8000, 8000, 4000 cells/well, 90 μl/well), 37 ° C, After 1 day of incubation in 5% CO 2 , serially diluted test compounds were added. 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 μl/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. Place in 37°C, 5% CO 2 and continue to culture for 72h, add 50μl per well
Figure PCTCN2022106363-appb-000227
2.0 reagent (luciferase ATP bioluminescent detection reagent, purchased from Promega, product number G9243), shaking for 2 minutes, and after incubating at room temperature for 8 minutes, detect the fluorescence intensity (light collection time is 100ms). The inhibitory rate of each concentration compound on cell proliferation was calculated.
细胞增殖抑制率(％)＝[(发光强度 72小时含细胞培养基对照组-发光强度 72小时化 合物组)/(发光强度 72小时含细胞培养基对照组-发光强度 72小时无细胞培养基对照组)]×100％。 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%.
使用GraphPad Prism 8.3软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值，结果见下表。 GraphPad Prism 8.3 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain a dose-effect curve, and the IC 50 value was calculated accordingly. The results are shown in the table below.
Figure PCTCN2022106363-appb-000228
Figure PCTCN2022106363-appb-000228
5μM≤C＜10μM5μM≤C＜10μM
测试结果表明本发明化合物对表达KRAS G12D/V突变蛋白的Ba/F3 KRAS-G12D和Ba/F3 KRAS-G12V细胞、表达KRAS G12D突变蛋白的胃癌AGS细胞具有良好的增殖抑制活性。这表明，本发明化合物对于KRAS突变，特别是KRAS G12D突变、KRAS G12V突变表现出优异的抑制作用，可以用于治疗/预防由KRAS突变，特别是KRAS G12D突变、KRAS G12V突变介导的疾病(例如癌症)。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. This shows that 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).
产业实用性Industrial applicability
本发明提供一种新型的吡啶并嘧啶衍生物，其对于KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)表现出优异的抑制作用，因此，可以用于预防和/或治疗由KRAS突变介导的疾病。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.

Claims (21)

  1. 通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，pyridopyrimidine derivatives represented by general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
    Figure PCTCN2022106363-appb-100001
    Figure PCTCN2022106363-appb-100001
    X为单键、O、NR 7、S、S(＝O)、S(＝O) 2、P(＝O)R 7或C(R 7) 2； X is a single bond, O, NR 7 , S, S(=O), S(=O) 2 , P(=O)R 7 or C(R 7 ) 2 ;
    Y为单键、O、S或-(C(R 7) 2) q-； Y is a single bond, O, S or -(C(R 7 ) 2 ) q -;
    Z为NH、NR 1、CH 2、CHR 1或C(R 1) 2； Z is NH, NR 1 , CH 2 , CHR 1 or C(R 1 ) 2 ;
    每个R 1独立地为氘、卤素、氰基、羟基、-N(R 5) 2、任选被一个或多个R 1a取代的C 1-C 6烷基、任选被一个或多个R 1b取代的C 1-C 6烷基-O-、任选被一个或多个R 1c取代的C 2-C 6烯基、任选被一个或多个R 1d取代的C 2-C 6炔基、-C(＝O)R 5、-CO 2R 5、-C(＝O)N(R 5) 2或5-6元杂芳基，或键合于同一环原子上两个R 1形成氧代基，或键合于相邻两个环原子上的R 1形成键，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；所述5-6元杂芳基、4-10元杂环烷基、4-10元杂环烯基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 1 is independently deuterium, halogen, cyano, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 1a , optionally substituted by one or more C 1 -C 6 alkyl-O-substituted by R 1b , C 2 -C 6 alkenyl optionally substituted by one or more R 1c , C 2 -C 6 optionally substituted by one or more R 1d Alkynyl, -C(=O)R 5 , -CO 2 R 5 , -C(=O)N(R 5 ) 2 or 5-6 membered heteroaryl, or two R bonded to the same ring atom 1 forms an oxo group, or R 1 bonded to two adjacent ring atoms forms a bond, or two R 1 bonded to different or the same ring atoms form a 3-7 membered group together with the atoms they are connected to Cycloalkyl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl; said 5-6 membered heteroaryl, 4-10 membered heterocycloalkyl, 4-10 membered heterocycloalkenyl The heteroatoms are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    每个R 1a、R 1b、R 1c和R 1d各自独立地为氘、氰基、卤素或羟基； each R 1a , R 1b , R 1c and R 1d is independently deuterium, cyano, halogen or hydroxyl;
    n为0、1、2、3、4、5、6或7；n is 0, 1, 2, 3, 4, 5, 6 or 7;
    L为-(CR 6aR 6b) n1-、-O-(CR 6aR 6b) n2-、-S-(CR 6aR 6b) n3-或-N(R 5)(CR 6aR 6b) n4-； 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 - ;
    R 2为H、-C(＝O)R 5、-CO 2R 5、-N(R 5) 2、C 1-C 6烷基、C 1-C 6烷基-O-、任选被一个或多个R 2a取代的3-10元环烷基、任选被一个或多个R 2b取代的4-10元杂环烷基、任选被一个或多个R 2d取代的C 6-C 10芳基、任选被一个或多个R 2e取代的5-10元杂芳基、-N(R 5)C(＝NH)N(R 5) 2、-C(O)N(R 5) 2、-C(＝O)O-C 1-C 6烷基或任选被一个或多个R 2c取代的C 6-C 10芳基-C(＝O)NR 5-；所述4-10元杂环烷基、5-10元杂芳基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； R 2 is H, -C(=O)R 5 , -CO 2 R 5 , -N(R 5 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, optionally 3-10 membered cycloalkyl substituted by one or more R 2a , 4-10 membered heterocycloalkyl optionally substituted by one or more R 2b , C 6 optionally substituted by one or more R 2d - C 10 aryl, 5-10 membered heteroaryl optionally substituted by one or more R 2e , -N(R 5 )C(=NH)N(R 5 ) 2 , -C(O)N(R 5 ) 2 , -C(=O)OC 1 -C 6 alkyl or C 6 -C 10 aryl optionally substituted by one or more R 2c -C(=O)NR 5 -; the 4- The heteroatoms in the 10-membered heterocycloalkyl group and the 5-10-membered heteroaryl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、氘、氰基、-C(＝O)R 5、-CO 2R 5、任选被一个或多个R 2-a取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、任选被一个或多个R 2-b取代的C 1-C 4烷基-O-、苯基-Q-、FO 2S-苯基-Q-、苯基-C(＝O)N(R 5)-、任选被一个或多个C 1-C 4烷基取代的吡唑基、任选被一个或多个C 1-C 4烷基取代的咪唑基、-N(R 5) 2、(C 1-C 4烷基)-O-(C 1-C 4烷基)、＝O、(任选被一个或多个卤素取代的C 1-C 4烷基)-C(＝O)-、-SO 2F、(C 1-C 4烷基)-SO 2-、(C 1-C 4烷基)-O-(C 1-C 4烷基)-O-、-CH 2OC(＝O)N(R 5) 2、(C 1-C 4烷基)-O-C(＝O)-N(R 5)CH 2-、-CH 2N(R 5)C(＝O)N(R 5) 2、(C 1-C 4烷基)-C(＝O)N(R 5)CH 2-、(吡唑基)-CH 2-、(咪唑基)-CH 2-、(C 1-C 4烷基)-SO 2-N(R 5)CH 2-、(4-10元杂环烷基)-C(＝O)-OCH 2-、(R 5) 2N-C(＝O)-O-、(C 1-C 4烷基)-O-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-、苯基-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH 2-；所述苯基-C(＝O)N(R 5)-和苯基-(C 1-C 4烷基)-N(R 5)-C(＝O)-O-中的苯基任选被一个或多个独立地选自-C(＝O)R 5、卤素、氰基和羟基的基团取代；所述(4-10元杂环烷基)-C(＝O)-OCH 2-、(4-10元杂环烷基)-C(＝O)-O-或(4-10元杂环烷基)-CH 2-中的4-10元杂环烷基任选被＝O取代；所述(4-10元杂环烷基)-C(＝O)-OCH 2-、(4-10元杂环烷基)-C(＝O)-O-和(4-10元杂环烷基)-CH 2-中的4-10元杂环烷基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 2a , R 2b and R 2c is independently halogen, hydroxyl, deuterium, cyano, -C(=O)R 5 , -CO 2 R 5 , optionally substituted by one or more R 2-a C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkyl-O- optionally substituted by one or more R 2-b , benzene Base-Q-, FO 2 S-phenyl-Q-, phenyl-C(=O)N(R 5 )-, pyrazolyl optionally substituted by one or more C 1 -C 4 alkyl groups, Imidazolyl optionally substituted by one or more C 1 -C 4 alkyl groups, -N(R 5 ) 2 , (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl), = O, (C 1 -C 4 alkyl optionally substituted by one or more halogen)-C(=O)-, -SO 2 F, (C 1 -C 4 alkyl)-SO 2 -, (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl)-O-, -CH 2 OC(=O)N(R 5 ) 2 , (C 1 -C 4 alkyl)-OC( =O)-N(R 5 )CH 2 -, -CH 2 N(R 5 )C(=O)N(R 5 ) 2 , (C 1 -C 4 alkyl)-C(=O)N( R 5 )CH 2 -, (pyrazolyl)-CH 2 -, (imidazolyl)-CH 2 -, (C 1 -C 4 alkyl)-SO 2 -N(R 5 )CH 2 -, (4 -10-membered heterocycloalkyl)-C(=O)-OCH 2 -, (R 5 ) 2 NC(=O)-O-, (C 1 -C 4 alkyl)-O-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O-, phenyl-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O-, (4 -10-membered heterocycloalkyl)-C(=O)-O- or (4-10-membered heterocycloalkyl)-CH 2 -; the phenyl-C(=O)N(R 5 )- and The phenyl in phenyl-(C 1 -C 4 alkyl)-N(R 5 )-C(=O)-O- is optionally selected from one or more independently selected from -C(=O)R 5 , halogen, cyano and hydroxyl group substitution; the (4-10 membered heterocycloalkyl)-C(=O)-OCH 2 -, (4-10 membered heterocycloalkyl)-C(=O )-O- or (4-10 membered heterocycloalkyl)-CH 2 -, the 4-10 membered heterocycloalkyl is optionally substituted by =O; the (4-10 membered heterocycloalkyl)-C (=O)-OCH 2 -, (4-10 membered heterocycloalkyl)-C(=O)-O- and (4-10 membered heterocycloalkyl)-CH 2 - The heteroatoms in the cycloalkyl group are each independently selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;
    Q独立地为连接键或-O-；Q is independently a linker or -O-;
    每个R 2-a和R 2-b独立地为氘、氰基、卤素或羟基； each R 2-a and R 2-b is independently deuterium, cyano, halogen or hydroxyl;
    每个R 2d和R 2e各自独立地为卤素、羟基、氰基、-C(＝O)R 5、-CO 2R 5、任选被一个或多个卤素或羟基取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基-O-或-N(R 5) 2； Each R 2d and R 2e is independently halogen, hydroxy, cyano, -C(=O)R 5 , -CO 2 R 5 , C 1 -C 4 optionally substituted with one or more halogen or hydroxy Alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkyl optionally substituted by one or more halogen or hydroxyl -O- or -N(R 5 ) 2 ;
    R 3为任选被一个或多个R 3a取代的C 6-C 10芳基或任选被一个或多个R 3b取代的5-14元杂芳基；所述5-14元杂芳基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
    每个R 3a和R 3b各自独立地为氘、卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-b取代的C 1-C 6烷基-O-、任选被一个或多个R 3-c取代的C 1-C 6烷基-S-、任选被一个或多个R 3-d取代的C 2-C 6烯基、任选被一个或多个R 3-e取代的C 2-C 6炔基、 -N(R 5) 2、-(CH 2)-C(＝O)N(R 5) 2、任选被一个或多个R 3-f取代的3-6元环烷基或三唑基； Each R 3a and R 3b is independently deuterium, 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 -b substituted C 1 -C 6 alkyl-O-, optionally one or more R 3-c substituted C 1 -C 6 alkyl-S-, optionally one or more R 3-d Substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl optionally substituted by one or more R 3-e , -N(R 5 ) 2 , -(CH 2 )-C(=O) N(R 5 ) 2 , 3-6 membered cycloalkyl or triazolyl optionally substituted by one or more R 3-f ;
    每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为氘、卤素、氰基、羟基、C 1-C 4烷基、C 1-C 4烷基-O-或3-6元环烷基； Each of 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为H、氘、-N(R 5) 2、卤素、羟基、氰基、任选被一个或多个卤素或氘取代的C 1-C 6烷基、任选被一个或多个卤素或氘取代的C 1-C 6烷基-O-、C 2-C 6烯基或C 2-C 6炔基； 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和n4各自独立地为0、1、2或3；n1, n2, n3 and n4 are each independently 0, 1, 2 or 3;
    每个R 5独立地为H或C 1-C 6烷基； each R 5 is independently H or C 1 -C 6 alkyl;
    每个R 6a和R 6b各自独立地为H、氘、卤素、氰基、羟基或任选被一个或多个卤素或氘取代的C 1-C 4烷基； 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;
    每个R 7独立地为H、氘、卤素、氰基、羟基、-N(R 5) 2、任选被一个或多个R 7a取代的C 1-C 6烷基、任选被一个或多个R 7b取代的C 1-C 6烷基-O-、任选被一个或多个R 7c取代的C 2-C 6烯基、任选被一个或多个R 7d取代的C 2-C 6炔基、-C(＝O)R 5、-CO 2R 5或-C(＝O)N(R 5) 2，或键合于同一环原子上两个R 7形成氧代基，或键合于相邻两个环原子上的R 7形成键，或键合于不同或相同环原子上的两个R 7与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基、4-10元杂环烯基；所述4-10元杂环烷基、4-10元杂环烯基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； Each R 7 is independently H, deuterium, halogen, cyano, hydroxyl, -N(R 5 ) 2 , C 1 -C 6 alkyl optionally substituted by one or more R 7a , optionally substituted by one or C 1 -C 6 alkyl-O- substituted by multiple R 7b , C 2 -C 6 alkenyl optionally substituted by one or more R 7c , C 2 - optionally substituted by one or more R 7d C 6 alkynyl, -C(=O)R 5 , -CO 2 R 5 or -C(=O)N(R 5 ) 2 , or two R 7 bonded to the same ring atom to form an oxo group, Or bonded to two adjacent ring atoms R 7 form a bond, or two R 7 bonded to different or identical ring atoms form a 3-7 membered cycloalkyl, 4- 10-membered heterocycloalkyl, 4-10-membered heterocycloalkenyl; the heteroatoms in the 4-10-membered heterocycloalkyl and 4-10-membered heterocycloalkenyl are each independently selected from N, O and S One or more of , the number of heteroatoms is 1, 2 or 3;
    每个R 7a、R 7b、R 7c和R 7d各自独立地为氘、氰基、卤素或羟基； each R 7a , R 7b , R 7c and R 7d is independently deuterium, cyano, halogen or hydroxyl;
    q为1或2；q is 1 or 2;
    上述各取代基存在多个时，彼此可以相同，也可以不同。When the above-mentioned substituents are present in plural, they may be the same as or different from each other.
  2. 通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，pyridopyrimidine derivatives represented by general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
    Figure PCTCN2022106363-appb-100002
    Figure PCTCN2022106363-appb-100002
    X为O或NR 7； X is 0 or NR 7 ;
    Y为-(C(R 7) 2) q-； Y is -(C(R 7 ) 2 ) q -;
    Z为NH或NR 1； Z is NH or NR 1 ;
    每个R 1独立地为卤素、任选被一个或多个R 1a取代的C 1-C 6烷基，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-10元杂环烷基；所述4-10元杂环烷基中杂原子选自N，杂原子个数为1、2或3个； 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;
    每个R 1a独立地为氘、氰基、卤素或羟基； each R 1a is independently deuterium, cyano, halogen or hydroxy;
    n为0、1、2或3；n is 0, 1, 2 or 3;
    L为-O-(CR 6aR 6b) n2-； L is -O-(CR 6a R 6b ) n2 -;
    R 2为任选被一个或多个R 2b取代的4-10元杂环烷基；所述4-10元杂环烷基中杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
    每个R 2b独立地为卤素、羟基、氘、氰基或任选被一个或多个R 2-a取代的C 1-C 4烷基； each R 2b is independently halogen, hydroxy, deuterium, cyano, or C 1 -C 4 alkyl optionally substituted by one or more R 2-a ;
    每个R 2-a独立地为氘、氰基、卤素或羟基； each R 2-a is independently deuterium, cyano, halogen or hydroxy;
    R 3为任选被一个或多个R 3a取代的C 6-C 10芳基或任选被一个或多个R 3b取代的5-14元杂芳基；所述5-14元杂芳基中的杂原子各自独立地选自N、O和S中的一种或多种，杂原子个数为1、2或3个； 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;
    每个R 3a和R 3b各自独立地为氘、卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-e取代的C 2-C 6炔基、-N(R 5) 2或-(CH 2) n5-C(＝O)N(R 5) 2； Each R 3a and R 3b is independently deuterium, 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, -N(R 5 ) 2 or -(CH 2 ) n5 -C(=O)N(R 5 ) 2 ;
    每个R 3-a和R 3-e各自独立地为氘、卤素、氰基、羟基或C 1-C 4烷基； Each R 3-a and R 3-e is independently deuterium, halogen, cyano, hydroxyl or C 1 -C 4 alkyl;
    R 4为H、氘、卤素、羟基、氰基或任选被一个或多个卤素或氘取代的C 1-C 6烷基； R 4 is H, deuterium, halogen, hydroxyl, cyano or C 1 -C 6 alkyl optionally substituted by one or more halogen or deuterium;
    n2为0、1、2或3；n2 is 0, 1, 2 or 3;
    每个n5独立地为0、1、2或3；each n5 is independently 0, 1, 2 or 3;
    每个R 5独立地为H或C 1-C 6烷基； each R 5 is independently H or C 1 -C 6 alkyl;
    每个R 6a和R 6b各自独立地为H、氘、卤素、氰基、羟基或任选被一个或多个卤素或氘取代的C 1-C 4烷基； 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;
    每个R 7独立地为H、氘、卤素、氰基、羟基或任选被一个或多个R 7a取代的C 1-C 6烷基； each R 7 is independently H, deuterium, halogen, cyano, hydroxyl, or C 1 -C 6 alkyl optionally substituted by one or more R 7a ;
    每个R 7a独立地为氘、氰基、卤素或羟基； each R 7a is independently deuterium, cyano, halogen or hydroxy;
    q为1或2；q is 1 or 2;
    上述各取代基存在多个时，彼此可以相同，也可以不同。When the above-mentioned substituents are present in plural, they may be the same as or different from each other.
  3. 权利要求1所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivative, pharmaceutically acceptable salt, ester, stereoisomer or tautomer represented by the general formula (1) according to claim 1, wherein,
    X为O、NR 7或S，优选为O或NR 7，其中，在X中，R 7独立地为H或C 1-C 6烷基，优选为H或C 1-C 4烷基；和/或 X is O, NR 7 or S, preferably O or NR 7 , wherein, in X, R 7 is independently H or C 1 -C 6 alkyl, preferably H or C 1 -C 4 alkyl; and /or
    Y为-(C(R 7) 2) q-，其中q为1或2，在Y中，R 7独立地为H、卤素、羟基或C 1-C 6烷基，优选R 7独立地为H或C 1-C 4烷基，更优选R 7独立地为H；和/或 Y is -(C(R 7 ) 2 ) q -, wherein q is 1 or 2, in Y, R 7 is independently H, halogen, hydroxyl or C 1 -C 6 alkyl, preferably R 7 is independently H or C 1 -C 4 alkyl, more preferably R 7 is independently H; and/or
    Z为NH或CHR 1，优选为NH，其中，在Z中，R 1为-N(R 5) 2；和/或 Z is NH or CHR 1 , preferably NH, wherein, in Z, R 1 is -N(R 5 ) 2 ; and/or
    L为-(CR 6aR 6b) n1-或-O-(CR 6aR 6b) n2-，优选为-O-(CR 6aR 6b) n2-；和/或 L is -(CR 6a R 6b ) n1 - or -O-(CR 6a R 6b ) n2 -, preferably -O-(CR 6a R 6b ) n2 -; and/or
    R 6a和R 6b各自独立地为H、氘、卤素、羟基或C 1-C 4烷基；优选R 6a为H且R 6b为H、氘、卤素、羟基或C 1-C 4烷基；进一步优选R 6a和R 6b都为H；和/或 R 6a and R 6b are each independently H, deuterium, halogen, hydroxyl or C 1 -C 4 alkyl; preferably R 6a is H and R 6b is H, deuterium, halogen, hydroxyl or C 1 -C 4 alkyl; It is further preferred that both R 6a and R 6b are H; and/or
    n1、n2、n3和n4各自独立地为1或2；优选各自独立地为1。n1, n2, n3 and n4 are each independently 1 or 2; preferably each independently is 1.
  4. 权利要求1或3所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，通式(1)为下述通式(2)或通式(3)，The pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the general formula (1) according to claim 1 or 3, wherein the general formula (1) is the following Describe general formula (2) or general formula (3),
    Figure PCTCN2022106363-appb-100003
    Figure PCTCN2022106363-appb-100003
    优选通式(1)为下述通式(4)、通式(5)或通式(6)，Preferred general formula (1) is following general formula (4), general formula (5) or general formula (6),
    Figure PCTCN2022106363-appb-100004
    Figure PCTCN2022106363-appb-100004
    其中，m为1、2或3，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Wherein, m is 1, 2 or 3, and "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
  5. 权利要求2所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，通式(1)为下述通式(2)、通式(2’)、通式(3)或通式(3’)，The pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the general formula (1) according to claim 2, wherein the general formula (1) is the following general formula Formula (2), general formula (2'), general formula (3) or general formula (3'),
    Figure PCTCN2022106363-appb-100005
    Figure PCTCN2022106363-appb-100005
    Figure PCTCN2022106363-appb-100006
    Figure PCTCN2022106363-appb-100006
    优选通式(1)为下述通式(4)、通式(4’)、通式(5)、通式(5’)、通式(6)或通式(6’)，Preferred general formula (1) is following general formula (4), general formula (4 '), general formula (5), general formula (5 '), general formula (6) or general formula (6 '),
    Figure PCTCN2022106363-appb-100007
    Figure PCTCN2022106363-appb-100007
    Figure PCTCN2022106363-appb-100008
    Figure PCTCN2022106363-appb-100008
    其中，m为1、2或3，“*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合。Wherein, m is 1, 2 or 3, and "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of both.
  6. 根据权利要求1、3-4中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivatives represented by the general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers according to any one of claims 1, 3-4, wherein,
    每个R 1独立地为氘、卤素、羟基、-N(R 5) 2、C 1-C 6烷基、C 1-C 6烷基-O-，或键合于同一环原子上两个R 1形成氧代基，或键合于相邻两个环原子上的R 1形成键，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成3-7元环烷基、4-10元杂环烷基；和/或 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 of them bonded to the same ring atom R 1 forms an oxo group, or R 1 bonded to two adjacent ring atoms forms a bond, or two R 1 bonded to different or same ring atoms form together with the atoms to which they are attached 3-7 Membered cycloalkyl, 4-10 membered heterocycloalkyl; and/or
    每个R 1a、R 1b、R 1c和R 1d各自独立地为卤素或羟基；和/或 Each R 1a , R 1b , R 1c and R 1d is independently halogen or hydroxy; and/or
    R 1a、R 1b、R 1c和R 1d出现的数目各自独立地为1、2、3或4；和/或 The number of occurrences of R 1a , R 1b , R 1c and R 1d is each independently 1, 2, 3 or 4; and/or
    n为1、2、3或4；和/或n is 1, 2, 3 or 4; and/or
    R 2为任选被一个或多个R 2a取代的3-10元环烷基、任选被一个或多个R 2b取代的4-10元杂环烷基、任选被一个或多个R 2d取代的C 6-C 10芳基或任选被一个或多个R 2e取代的5-10元杂芳基；和/或 R 2 is 3-10 membered cycloalkyl optionally substituted by one or more R 2a , 4-10 membered heterocycloalkyl optionally substituted by one or more R 2b , optionally substituted by one or more R 2d substituted C 6 -C 10 aryl or 5-10 membered heteroaryl optionally substituted by one or more R 2e ; and/or
    每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、任选被一个或多个R 2-a取代的C 1-C 4烷基、任选被一个或多个R 2-b取代的C 1-C 4烷基-O-、C 2-C 4烯基、C 2-C 4炔基、-N(R 5) 2或(C 1-C 4烷基)-O-(C 1-C 4烷基)；和/或 Each 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 , optionally substituted by one or more R 2-b Substituted 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); and/or
    每个R 2d和R 2e各自独立地为卤素、羟基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基、C 2-C 4烯基、C 2-C 4炔基或-N(R 5) 2；和/或 Each 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 ; and/or
    每个R 2-a和R 2-b独立地为卤素或羟基；和/或 each R 2-a and R 2-b is independently halogen or hydroxy; and/or
    R 2a、R 2b、R 2c、R 2d和R 2e出现的数目各自独立地为1、2、3或4；和/或 The number of occurrences of R 2a , R 2b , R 2c , R 2d and R 2e is each independently 1, 2, 3 or 4; and/or
    R 2-a和R 2-b出现的数目各自独立地为1、2、3或4；和/或 The number of occurrences of R 2-a and R 2-b is each independently 1, 2, 3 or 4; and/or
    R 3为被一个或多个R 3a取代的C 6-C 10芳基或被一个或多个R 3b取代的5-14元杂芳基；和/或 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 ; and/or
    每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-b取代的C 1-C 6烷基-O-、任选被一个或多个R 3-d取代的C 2-C 6烯基、任选被一个或多个R 3-e取代的C 2-C 6炔基、-N(R 5) 2、任选被一个或多个R 3-f取代的3-6元环烷基或三唑基；和/或 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-b Substituted C 1 -C 6 alkyl-O-, C 2 -C 6 alkenyl optionally substituted by one or more R 3-d , C 2 - optionally substituted by one or more R 3-e C 6 alkynyl, -N(R 5 ) 2 , 3-6 membered cycloalkyl or triazolyl optionally substituted by one or more R 3-f ; and/or
    每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为卤素、羟基、C 1-C 4烷基或C 1-C 4烷基-O-；和/或 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-; and/or
    R 3a和R 3b出现的数目各自独立地为1、2、3、4或5；和/或 The number of occurrences of R 3a and R 3b is each independently 1, 2, 3, 4 or 5; and/or
    R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f出现的数目各自独立地为1、2、3、4或5；和/或 R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f occur in numbers each independently 1, 2, 3, 4 or 5; and/or
    R 4为-N(R 5) 2、卤素、羟基、任选被一个或多个卤素取代的C 1-C 6烷基、任选被一个或多个卤素取代的C 1-C 6烷基-O-、C 2-C 6烯基或C 2-C 6炔基；和/或 R 4 is -N(R 5 ) 2 , halogen, hydroxyl, C 1 -C 6 alkyl optionally substituted by one or more halogens, C 1 -C 6 alkyl optionally substituted by one or more halogens -O-, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; and/or
    每个R 5独立地为H或C 1-C 4烷基。 Each R 5 is independently H or C 1 -C 4 alkyl.
  7. 根据权利要求1、3-4、6中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivatives represented by the general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers according to any one of claims 1, 3-4, and 6, in,
    每个R 1独立地为卤素、羟基、C 1-C 6烷基、C 1-C 6烷基-O-，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-10元杂环烷基；和/或 Each R 1 is independently halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O-, or two R 1 bonded to different or the same ring atom and the Atoms together form a 4-10 membered heterocycloalkyl group; and/or
    R 1a、R 1b、R 1c和R 1d出现的数目各自独立地为1或2；和/或 The number of occurrences of R 1a , R 1b , R 1c and R 1d is each independently 1 or 2; and/or
    n为1、2或3；和/或n is 1, 2 or 3; and/or
    R 2为被一个或多个R 2a取代的3-10元环烷基或被一个或多个R 2b取代的4-10元杂环烷基；和/或 R 2 is a 3-10 membered cycloalkyl group substituted by one or more R 2a or a 4-10 membered heterocycloalkyl group substituted by one or more R 2b ; and/or
    每个R 2a、R 2b和R 2c各自独立地为卤素、羟基、任选被一个或多个R 2-a取代的C 1-C 4烷基或-N(R 5) 2；和/或 Each 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 , or -N(R 5 ) 2 ; and/or
    每个R 2d和R 2e各自独立地为卤素、羟基、任选被一个或多个卤素或羟基取代的C 1-C 4烷基或-N(R 5) 2；和/或 Each R 2d and R 2e is independently halogen, hydroxy, C 1 -C 4 alkyl optionally substituted with one or more halogen or hydroxy, or -N(R 5 ) 2 ; and/or
    R 2a、R 2b、R 2c、R 2d和R 2e出现的数目各自独立地为1或2；和/或 The number of occurrences of R 2a , R 2b , R 2c , R 2d and R 2e is each independently 1 or 2; and/or
    R 2-a和R 2-b出现的数目各自独立地为1或2；和/或 The number of occurrences of R 2-a and R 2-b is each independently 1 or 2; and/or
    R 3为被一个或多个R 3a取代的C 6-C 10芳基、且所述C 6-C 10芳基为苯基或萘基，或者R 3为被一个或多个R 3b取代的5-14元杂芳基、且所述5-14元杂芳基为5-10元杂芳基；和/或 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 substituted by one or more R 3b 5-14 membered heteroaryl, and the 5-14 membered heteroaryl is 5-10 membered heteroaryl; and/or
    每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 6烷基、任选被一个或多个R 3-e取代的C 2-C 6炔基或-N(R 5) 2；和/或 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 ; and/or
    每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为卤素、羟基或C 1-C 4烷基；和/或 Each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f is independently halogen, hydroxyl or C 1 -C 4 alkyl; and/or
    R 3a和R 3b出现的数目各自独立地为1、2或3；和/或 The number of occurrences of R 3a and R 3b is each independently 1, 2 or 3; and/or
    R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f出现的数目各自独立地为1、2或3；和/或 R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f occur in numbers each independently 1, 2 or 3; and/or
    R 4为-N(R 5) 2、卤素、羟基或任选被一个或多个卤素取代的C 1-C 6烷基；和/或 R 4 is -N(R 5 ) 2 , halogen, hydroxyl, or C 1 -C 6 alkyl optionally substituted by one or more halogens; and/or
    每个R 5独立地为H、甲基、乙基或丙基。 Each R 5 is independently H, methyl, ethyl or propyl.
  8. 根据权利要求1、3-4、6-7中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体， 其中，The pyridopyrimidine derivative represented by the general formula (1), pharmaceutically acceptable salt, ester, stereoisomer or tautomer according to any one of claims 1, 3-4, 6-7 body, of which,
    每个R 1独立地为C 1-C 4烷基，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-7元杂环烷基；和/或 Each R 1 is independently C 1 -C 4 alkyl, or two R 1 bonded to different or the same ring atoms together form a 4-7 membered heterocycloalkyl group with the atoms to which they are attached; and/or
    R 2为被一个或多个R 2a取代的5-10元环烷基或被一个或多个R 2b取代的5-10元杂环烷基；和/或 R is 5-10 membered cycloalkyl substituted by one or more R 2a or 5-10 membered heterocycloalkyl substituted by one or more R 2b ; and/or
    每个R 2a、R 2b和R 2c各自独立地为卤素、羟基或C 1-C 4烷基；和/或 Each R 2a , R 2b and R 2c is independently halogen, hydroxyl, or C 1 -C 4 alkyl; and/or
    每个R 2d和R 2e各自独立地为卤素、羟基或C 1-C 4烷基；和/或 Each R 2d and R 2e is independently halogen, hydroxy, or C 1 -C 4 alkyl; and/or
    R 3为被一个或多个R 3a取代的C 6-C 10芳基、且所述C 6-C 10芳基为萘基，或者R 3为被一个或多个R 3b取代的5-14元杂芳基、且所述5-14元杂芳基为吡啶基、嘧啶基、喹啉基、喹唑啉基、吲哚基、吲唑基、苯并噻吩基或苯并噻唑基；和/或 R 3 is C 6 -C 10 aryl substituted by one or more R 3a , and the C 6 -C 10 aryl is naphthyl, or R 3 is 5-14 substituted by one or more R 3b Member heteroaryl, and the 5-14 member heteroaryl is pyridyl, pyrimidyl, quinolinyl, quinazolinyl, indolyl, indazolyl, benzothienyl or benzothiazolyl; and /or
    每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 4烷基、任选被一个或多个R 3-e取代的C 2-C 4炔基或-N(R 5) 2；和/或 Each R 3a and R 3b is independently halogen, hydroxyl, cyano, C 1 -C 4 alkyl optionally substituted by one or more R 3-a , optionally substituted by one or more R 3-e Substituted C 2 -C 4 alkynyl or -N(R 5 ) 2 ; and/or
    每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e和R 3-f各自独立地为卤素或羟基；和/或 Each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e and R 3-f is independently halogen or hydroxyl; and/or
    R 4为卤素、羟基或任选被一个或多个卤素取代的C 1-C 4烷基。 R 4 is halogen, hydroxy, or C 1 -C 4 alkyl optionally substituted by one or more halogens.
  9. 根据权利要求1、3-4、6-8中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivative represented by the general formula (1), pharmaceutically acceptable salt, ester, stereoisomer or tautomer according to any one of claims 1, 3-4, 6-8 body, of which,
    R 2选自被一个或多个R 2b取代的以下基团中的至少一个： R 2 is selected from at least one of the following groups substituted by one or more R 2b :
    Figure PCTCN2022106363-appb-100009
    Figure PCTCN2022106363-appb-100010
    “*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合；和/或
    Figure PCTCN2022106363-appb-100009
    Figure PCTCN2022106363-appb-100010
    "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two; and/or
    每个R 2a、R 2b、R 2c、R 2d和R 2e各自独立地为氟、氯、溴、碘、羟基、甲基、乙基、丙基或丁基；和/或 Each R 2a , R 2b , R 2c , R 2d and R 2e is independently fluoro, chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl or butyl; and/or
    R 3为被一个或多个R 3a取代的
    Figure PCTCN2022106363-appb-100011
    被一个或多个R 3b取代的
    Figure PCTCN2022106363-appb-100012
    或被一个或多个R 3b取代的
    Figure PCTCN2022106363-appb-100013
    和/或     R 3 is substituted by one or more R 3a
    Figure PCTCN2022106363-appb-100011
    substituted by one or more R 3b
    Figure PCTCN2022106363-appb-100012
    or substituted by one or more R 3b
    Figure PCTCN2022106363-appb-100013
    and / or
    每个R 3a和R 3b各自独立地为-NH 2、甲基、乙基、丙基、丁基、一氟甲基、二氟甲基、三氟甲基、乙炔基、丙炔基、羟基、氰基、氟、氯、溴或碘。 Each R 3a and R 3b is independently -NH 2 , methyl, ethyl, propyl, butyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethynyl, propynyl, hydroxyl , cyano, fluorine, chlorine, bromine or iodine.
  10. 根据权利要求2或5所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivatives represented by the general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers according to claim 2 or 5, wherein,
    Z为NH；和/或Z is NH; and/or
    每个R 1独立地为C 1-C 4烷基，或键合于不同或相同环原子上的两个R 1与它们所相连的原子一起形成4-7元杂环烷基；和/或 Each R 1 is independently C 1 -C 4 alkyl, or two R 1 bonded to different or the same ring atoms together form a 4-7 membered heterocycloalkyl group with the atoms to which they are attached; and/or
    n为1或2；和/或n is 1 or 2; and/or
    L为-O-(CR 6aR 6b) n2-；和/或 L is -O-(CR 6a R 6b ) n2 -; and/or
    R 2为被一个或多个R 2b取代的5-10元杂环烷基；和/或 R 2 is 5-10 membered heterocycloalkyl substituted by one or more R 2b ; and/or
    每个R 2b独立地为卤素、羟基或C 1-C 4烷基；和/或 Each R 2b is independently halogen, hydroxy, or C 1 -C 4 alkyl; and/or
    R 3为被一个或多个R 3a取代的C 6-C 10芳基、且所述C 6-C 10芳基为萘基，或者R 3为被一个或多个R 3b取代的5-14元杂芳基、且所述5-14元杂芳基为吡啶基、嘧啶基、喹啉基、喹唑啉基、吲哚基、吲唑基、苯并噻吩基或苯并噻唑基；和/或 R 3 is C 6 -C 10 aryl substituted by one or more R 3a , and the C 6 -C 10 aryl is naphthyl, or R 3 is 5-14 substituted by one or more R 3b Member heteroaryl, and the 5-14 member heteroaryl is pyridyl, pyrimidyl, quinolinyl, quinazolinyl, indolyl, indazolyl, benzothienyl or benzothiazolyl; and /or
    每个R 3a和R 3b各自独立地为卤素、羟基、氰基、任选被一个或多个R 3-a取代的C 1-C 4烷基、任选被一个或多个R 3-e取代的C 2-C 4炔基、-N(R 5) 2或-(CH 2) n5-C(＝O)N(R 5) 2；和/或 Each R 3a and R 3b is independently halogen, hydroxyl, cyano, C 1 -C 4 alkyl optionally substituted by one or more R 3-a , optionally substituted by one or more R 3-e Substituted C 2 -C 4 alkynyl, -N(R 5 ) 2 or -(CH 2 ) n5 -C(=O)N(R 5 ) 2 ; and/or
    每个R 3-a和R 3-e各自独立地为氘、卤素或羟基；和/或 Each R 3-a and R 3-e is independently deuterium, halogen or hydroxyl; and/or
    R 4为卤素、羟基或任选被一个或多个卤素取代的C 1-C 4烷基；和/或 R 4 is halogen, hydroxyl, or C 1 -C 4 alkyl optionally substituted by one or more halogens; and/or
    n2为1；和/或n2 is 1; and/or
    每个n5独立地为0或1；和/或each n5 is independently 0 or 1; and/or
    每个R 6a和R 6b各自独立地为H或氘；和/或 each R 6a and R 6b is independently H or deuterium; and/or
    每个R 7独立地为H或C 1-C 4烷基。 Each R 7 is independently H or C 1 -C 4 alkyl.
  11. 根据权利要求2、5或10所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivatives represented by the general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers according to claim 2, 5 or 10, wherein,
    Figure PCTCN2022106363-appb-100014
    为
    Figure PCTCN2022106363-appb-100015
    Figure PCTCN2022106363-appb-100016
    和/或
    Figure PCTCN2022106363-appb-100014
    for
    Figure PCTCN2022106363-appb-100015
    Figure PCTCN2022106363-appb-100016
    and / or
    L为-O-CH 2-；和/或 L is -O -CH2-; and/or
    R 2选自被一个或多个R 2b取代的以下基团中的至少一个： R 2 is selected from at least one of the following groups substituted by one or more R 2b :
    Figure PCTCN2022106363-appb-100017
    Figure PCTCN2022106363-appb-100018
    “*”表示带“*”的碳原子为手性碳原子时，其为R构型、S构型或二者的混合；和/或
    Figure PCTCN2022106363-appb-100017
    Figure PCTCN2022106363-appb-100018
    "*" indicates that when the carbon atom with "*" is a chiral carbon atom, it is in R configuration, S configuration or a mixture of the two; and/or
    每个R 2b独立地为氟、氯、溴、碘、羟基、甲基、乙基、丙基或丁基；和/或 Each R is independently fluoro , chloro, bromo, iodo, hydroxy, methyl, ethyl, propyl or butyl; and/or
    R 3为被一个或多个R 3a取代的
    Figure PCTCN2022106363-appb-100019
    被一个或多个R 3b取代的
    Figure PCTCN2022106363-appb-100020
    或被一个或多个R 3b取代的
    Figure PCTCN2022106363-appb-100021
    和/或     R 3 is substituted by one or more R 3a
    Figure PCTCN2022106363-appb-100019
    substituted by one or more R 3b
    Figure PCTCN2022106363-appb-100020
    or substituted by one or more R 3b
    Figure PCTCN2022106363-appb-100021
    and / or
    每个R 3a和R 3b各自独立地为-NH 2、-C(＝O)NH 2、甲基、乙基、丙基、丁基、一氟甲基、二氟甲基、三氟甲基、乙炔基、丙炔基、羟基、氰基、氟、氯、溴或碘；和/或 Each R 3a and R 3b is independently -NH 2 , -C(=O)NH 2 , methyl, ethyl, propyl, butyl, monofluoromethyl, difluoromethyl, trifluoromethyl , ethynyl, propynyl, hydroxy, cyano, fluoro, chloro, bromo, or iodo; and/or
    R 4为卤素；和/或 R 4 is halogen; and/or
    每个R 7独立地为H。 each R 7 is independently H.
  12. 根据权利要求1、6-9中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivatives represented by the general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers according to any one of claims 1, 6-9, wherein,
    每个R 7独立地为H、卤素、羟基、任选被一个或多个R 7a取代的C 1-C 6烷基，或键合于同一环原子上两个R 7形成氧代基，或键合于相邻两个环原子上的R 7形成键；和/或 Each R 7 is independently H, halogen, hydroxyl, C 1 -C 6 alkyl optionally substituted by one or more R 7a , or two R 7 are bonded to the same ring atom to form an oxo group, or R7 bonded to two adjacent ring atoms form a bond; and/or
    每个R 7a、R 7b、R 7c和R 7d各自独立地为卤素或羟基；和/或 Each R 7a , R 7b , R 7c and R 7d is independently halogen or hydroxy; and/or
    R 7a、R 7b、R 7c和R 7d出现的数目各自独立地为1、2、3或4。 The number of occurrences of R 7a , R 7b , R 7c and R 7d is 1, 2, 3 or 4 each independently.
  13. 根据权利要求1-12中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，通式(1)为下述通式(7)、通式(8)、通式(9)、通式(10)、通式(11)、通式(12)、通式(13)、通式(14)、通式(15)、通式(16)、通式(17)、通式(18)或通式(19)，The pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the general formula (1) according to any one of claims 1-12, wherein the general formula (1) is the 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),
    Figure PCTCN2022106363-appb-100022
    Figure PCTCN2022106363-appb-100022
    Figure PCTCN2022106363-appb-100023
    Figure PCTCN2022106363-appb-100023
  14. 根据权利要求1-13中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其中，The pyridopyrimidine derivatives represented by the general formula (1), pharmaceutically acceptable salts, esters, stereoisomers or tautomers according to any one of claims 1-13, wherein,
    Figure PCTCN2022106363-appb-100024
    为
    Figure PCTCN2022106363-appb-100025
    Figure PCTCN2022106363-appb-100026
    Figure PCTCN2022106363-appb-100027
    优选为
    Figure PCTCN2022106363-appb-100028
    和/或
    Figure PCTCN2022106363-appb-100024
    for
    Figure PCTCN2022106363-appb-100025
    Figure PCTCN2022106363-appb-100026
    Figure PCTCN2022106363-appb-100027
    preferably
    Figure PCTCN2022106363-appb-100028
    and / or
    R 3为
    Figure PCTCN2022106363-appb-100029
    Figure PCTCN2022106363-appb-100030
    优选为
    Figure PCTCN2022106363-appb-100031
    和/或     R3 is
    Figure PCTCN2022106363-appb-100029
    Figure PCTCN2022106363-appb-100030
    preferably
    Figure PCTCN2022106363-appb-100031
    and / or
    R 4为卤素；优选为氟；和/或 R 4 is halogen; preferably fluorine; and/or
    Figure PCTCN2022106363-appb-100032
    为
    Figure PCTCN2022106363-appb-100033
    Figure PCTCN2022106363-appb-100032
    for
    Figure PCTCN2022106363-appb-100033
  15. 根据权利要求1-14中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其为下述化合物中的至少一种，The pyridopyrimidine derivative, pharmaceutically acceptable salt, ester, stereoisomer or tautomer represented by the general formula (1) according to any one of claims 1-14, which is the following at least one of the compounds,
    Figure PCTCN2022106363-appb-100034
    Figure PCTCN2022106363-appb-100034
    Figure PCTCN2022106363-appb-100035
    Figure PCTCN2022106363-appb-100035
  16. 根据权利要求1-14中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，其为以下化合物中的至少一种，The pyridopyrimidine derivative, pharmaceutically acceptable salt, ester, stereoisomer or tautomer represented by the general formula (1) according to any one of claims 1-14, which is the following compound at least one of the
    Figure PCTCN2022106363-appb-100036
    Figure PCTCN2022106363-appb-100037
    盐酸盐、
    Figure PCTCN2022106363-appb-100038
    盐酸盐。
    Figure PCTCN2022106363-appb-100036
    Figure PCTCN2022106363-appb-100037
    Hydrochloride,
    Figure PCTCN2022106363-appb-100038
    Hydrochloride.
  17. 以下所示吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，The following pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers,
    Figure PCTCN2022106363-appb-100039
    Figure PCTCN2022106363-appb-100039
    Figure PCTCN2022106363-appb-100040
    Figure PCTCN2022106363-appb-100041
    盐酸盐、
    Figure PCTCN2022106363-appb-100042
    盐酸盐、
    Figure PCTCN2022106363-appb-100043
    Figure PCTCN2022106363-appb-100040
    Figure PCTCN2022106363-appb-100041
    Hydrochloride,
    Figure PCTCN2022106363-appb-100042
    Hydrochloride,
    Figure PCTCN2022106363-appb-100043
    Figure PCTCN2022106363-appb-100044
    Figure PCTCN2022106363-appb-100044
  18. 药物组合物，包括权利要求1-16中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体以及任选的药学上可接受的载体。A pharmaceutical composition comprising the pyridopyrimidine derivative represented by the general formula (1) according to any one of claims 1-16, a pharmaceutically acceptable salt, ester, stereoisomer or tautomer and Optional pharmaceutically acceptable carrier.
  19. 权利要求1-16中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，或者权利要求18所述的药物组合物在制备用于治疗和/或预防疾病的药物中的用途，所述疾病为由KRAS突变(特别是KRAS G12D突变、KRAS G12V突变)介导的疾病，优选为癌症。The pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the general formula (1) according to any one of claims 1-16, or the pyridopyrimidine derivatives represented by claim 18 Use of the above-mentioned pharmaceutical composition in the preparation of medicines for treating and/or preventing diseases, the diseases are diseases mediated by KRAS mutations (especially KRAS G12D mutations, KRAS G12V mutations), preferably cancer.
  20. 根据权利要求19所述的用途，其中，所述疾病选自结肠癌、胰腺癌、乳腺癌、前列腺癌、肺癌、脑癌、卵巢癌、子宫颈癌、睾丸癌、肾癌、头或颈癌、骨癌、皮肤癌、直肠癌、肝癌、结直肠癌、非小细胞肺癌、小细胞肺癌、食道癌、胃癌、甲状腺癌、膀胱癌、淋巴瘤、白血病和黑色素瘤中的一种或多种。The use according to claim 19, wherein the disease is selected from colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, brain cancer, ovarian cancer, cervical cancer, testicular cancer, kidney cancer, head or neck cancer One or more of bone cancer, skin cancer, rectal cancer, liver cancer, colorectal cancer, non-small cell lung cancer, small cell lung cancer, esophageal cancer, stomach cancer, thyroid cancer, bladder cancer, lymphoma, leukemia, and melanoma .
  21. 权利要求1-16中任一项所述的通式(1)表示的吡啶并嘧啶衍生物、药学上可接受的盐、酯、立体异构体或互变异构体，或者权利要求18所述的药物组合物在制备KRAS突变抑制剂(特别是KRAS G12D突变抑制剂、KRAS G12V突变抑制剂)中的用途。The pyridopyrimidine derivatives, pharmaceutically acceptable salts, esters, stereoisomers or tautomers represented by the general formula (1) according to any one of claims 1-16, or the pyridopyrimidine derivatives represented by claim 18 Use of the above pharmaceutical composition in the preparation of KRAS mutation inhibitors (especially KRAS G12D mutation inhibitors, KRAS G12V mutation inhibitors).
PCT/CN2022/106363 2021-07-19 2022-07-19 New pyridopyrimidine derivative WO2023001123A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280051354.1A CN117677624A (en) 2021-07-19 2022-07-19 Novel pyridopyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110816356 2021-07-19
CN202110816356.2 2021-07-19

Publications (1)

Publication Number Publication Date
WO2023001123A1 true WO2023001123A1 (en) 2023-01-26

Family

ID=84980042

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/106363 WO2023001123A1 (en) 2021-07-19 2022-07-19 New pyridopyrimidine derivative

Country Status (2)

Country Link
CN (1) CN117677624A (en)
WO (1) WO2023001123A1 (en)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023205719A1 (en) * 2022-04-21 2023-10-26 Gilead Sciences, Inc. Kras g12d modulating compounds
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024022444A1 (en) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Fused ring compound, preparation method therefor and medicinal application thereof
WO2024022507A1 (en) * 2022-07-29 2024-02-01 江苏恒瑞医药股份有限公司 Pharmaceutical composition comprising kras g12d inhibitor
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2024041573A1 (en) * 2022-08-25 2024-02-29 Zai Lab (Shanghai) Co., Ltd. Fused multi-heterocyclic compounds as kras g12d modulators and uses thereof
WO2024061370A1 (en) * 2022-09-23 2024-03-28 劲方医药科技(上海)有限公司 Pyrimidine-fused ring compound, and preparation method therefor and use thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110603258A (en) * 2017-05-11 2019-12-20 阿斯利康(瑞典)有限公司 Heteroaryl compounds that inhibit G12C mutant RAS proteins
WO2020239123A1 (en) * 2019-05-31 2020-12-03 上海翰森生物医药科技有限公司 Aromatic heterocyclic derivative modulator and preparation method therefor and use thereof
CN112074520A (en) * 2018-05-08 2020-12-11 阿斯利康(瑞典)有限公司 Tetracycloheteroaryl compounds
CN112390818A (en) * 2019-08-12 2021-02-23 劲方医药科技(上海)有限公司 Substituted heteroaromatic dihydro pyrimidone derivatives, preparation method and medical application thereof
WO2021108683A1 (en) * 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2022188729A1 (en) * 2021-03-07 2022-09-15 Jacobio Pharmaceuticals Co., Ltd. Fused ring derivatives useful as kras g12d inhibitors
WO2022194245A1 (en) * 2021-03-17 2022-09-22 劲方医药科技(上海)有限公司 Pyrimidine-fused cyclic compound, preparation method therefor and use thereof
WO2022199587A1 (en) * 2021-03-24 2022-09-29 南京明德新药研发有限公司 Pyrimidine heterocyclic compound and application thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110603258A (en) * 2017-05-11 2019-12-20 阿斯利康(瑞典)有限公司 Heteroaryl compounds that inhibit G12C mutant RAS proteins
CN112074520A (en) * 2018-05-08 2020-12-11 阿斯利康(瑞典)有限公司 Tetracycloheteroaryl compounds
WO2020239123A1 (en) * 2019-05-31 2020-12-03 上海翰森生物医药科技有限公司 Aromatic heterocyclic derivative modulator and preparation method therefor and use thereof
CN112390818A (en) * 2019-08-12 2021-02-23 劲方医药科技(上海)有限公司 Substituted heteroaromatic dihydro pyrimidone derivatives, preparation method and medical application thereof
WO2021108683A1 (en) * 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2022188729A1 (en) * 2021-03-07 2022-09-15 Jacobio Pharmaceuticals Co., Ltd. Fused ring derivatives useful as kras g12d inhibitors
WO2022194245A1 (en) * 2021-03-17 2022-09-22 劲方医药科技(上海)有限公司 Pyrimidine-fused cyclic compound, preparation method therefor and use thereof
WO2022199587A1 (en) * 2021-03-24 2022-09-29 南京明德新药研发有限公司 Pyrimidine heterocyclic compound and application thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11912723B2 (en) 2022-02-09 2024-02-27 Quanta Therapeutics, Inc. KRAS modulators and uses thereof
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023205719A1 (en) * 2022-04-21 2023-10-26 Gilead Sciences, Inc. Kras g12d modulating compounds
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024022444A1 (en) * 2022-07-27 2024-02-01 江苏恒瑞医药股份有限公司 Fused ring compound, preparation method therefor and medicinal application thereof
WO2024022507A1 (en) * 2022-07-29 2024-02-01 江苏恒瑞医药股份有限公司 Pharmaceutical composition comprising kras g12d inhibitor
WO2024041573A1 (en) * 2022-08-25 2024-02-29 Zai Lab (Shanghai) Co., Ltd. Fused multi-heterocyclic compounds as kras g12d modulators and uses thereof
WO2024061370A1 (en) * 2022-09-23 2024-03-28 劲方医药科技(上海)有限公司 Pyrimidine-fused ring compound, and preparation method therefor and use thereof

Also Published As

Publication number Publication date
CN117677624A (en) 2024-03-08

Similar Documents

Publication Publication Date Title
WO2023001123A1 (en) New pyridopyrimidine derivative
CN107735399B (en) Chiral diaryl macrocycles as modulators of protein kinases
TWI551595B (en) 2,4-disubstituted benzene-1,5-diamine derivatives and their use, Its preparation of pharmaceutical compositions and pharmaceutical compositions
WO2021218110A1 (en) Benzothiazolyl biaryl compound, and preparation method and use
WO2020156285A1 (en) Benzopyridone heterocyclic compound and use thereof
CN102325752A (en) Carbazole and carboline kinase inhibitors
WO2021190417A1 (en) Novel aminopyrimidine egfr inhibitor
WO2023274383A1 (en) Kras g12d inhibitor and use thereof
WO2021249475A1 (en) Fused quinazoline derivative, preparation method therefor and application thereof in medicine
WO2022247816A1 (en) Nitrogen-containing heterocyclic compound, preparation method therefor, and application thereof in medicines
CN113387962A (en) Pyrazolo [3,4-d ] pyrimidine-3-one derivative, pharmaceutical composition and application thereof
CN117642407A (en) Nitrogen-containing heterocyclic compound, preparation method, intermediate and application thereof
WO2023143312A1 (en) Nitrogen-containing heterocyclic compound, and preparation method therefor and use thereof
CN115427035A (en) ENL/AF9YEATS inhibitors
CN115867346A (en) Kinase inhibitors
TW202346297A (en) Compounds with activity of anti-kras-mutated tumors
WO2022037631A1 (en) Heterocyclic derivative and preparation method therefor and use thereof
WO2022161489A1 (en) Pentaheterocyclic compound, preparation method therefor and use thereof
WO2022033416A1 (en) Fused ring compound as egfr inhibitor, and preparation method therefor and use thereof
WO2022033455A1 (en) Triazine derivative having egfr inhibitory activity, preparation method therefor and use thereof
WO2021197467A1 (en) Multi-target anti-tumor compound, preparation method therefor and use thereof
WO2021249417A1 (en) Heterocyclic compound and derivative thereof
JP2022554385A (en) WDR5 inhibitors and modulators
CN112839931A (en) 1,2,3, 4-tetrahydroquinoxaline derivative and preparation method and application thereof
TW202118756A (en) Heterocyclic compounds as bcr-abl inhibitors

Legal Events

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

Ref document number: 22845288

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE