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WO2022194192A1 - 一类杂芳环化合物、其制备方法及用途 - Google Patents

一类杂芳环化合物、其制备方法及用途 Download PDF

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Publication number
WO2022194192A1
WO2022194192A1 PCT/CN2022/081102 CN2022081102W WO2022194192A1 WO 2022194192 A1 WO2022194192 A1 WO 2022194192A1 CN 2022081102 W CN2022081102 W CN 2022081102W WO 2022194192 A1 WO2022194192 A1 WO 2022194192A1
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Prior art keywords
alkyl
compound
alkylene
cycloalkyl
hydrogen
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PCT/CN2022/081102
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English (en)
French (fr)
Inventor
刘金明
唐建川
任云
何婷
刘谦
田强
宋宏梅
葛均友
王晶翼
Original Assignee
四川科伦博泰生物医药股份有限公司
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Priority to CN202280010512.9A priority Critical patent/CN116801883A/zh
Publication of WO2022194192A1 publication Critical patent/WO2022194192A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 invention belongs to the field of medicinal chemistry, and in particular relates to a class of heteroaromatic compounds, a preparation method thereof, a pharmaceutical composition comprising the same, and uses thereof.
  • the RAS family is a class of guanine nucleotide-binding proteins with GTPase activity. As a molecular switch, RAS can realize the conversion of GDP-bound inactive state and GTP-bound activated state, transmit upstream signals received by cells to downstream various signaling pathways, and regulate protein synthesis, gene transcription, cell growth, differentiation, and apoptosis. and migration, etc.
  • the RAS gene is one of the most prevalent proto-oncogenes in human cancers.
  • RAS mutation can lead to the continuous activation of downstream signaling pathways, which promotes the occurrence and development of tumors.
  • the RAS family includes HRAS, NRAS, and KRAS, and about 85% of RAS mutations in all tumor types occur in KRAS.
  • KRAS-mutated tumors the GTPase activity of KRAS itself decreased, and KRAS remained active.
  • KRAS mutation is closely related to the occurrence of lung cancer, pancreatic cancer and colorectal cancer, and the highest frequency (about 34%) is the mutation of glycine at position 12 on KRAS to aspartic acid (KRAS G12D).
  • KRAS G12D small molecule inhibitors of KRAS G12D has always been one of the difficulties in the field of medicine.
  • Boehringer Ingelheim's BI-2852 uses the principle of molecular glue to induce KRAS G12D to form a dimer and block the interaction between KRAS and downstream proteins;
  • Revolution uses mTOR inhibitors to induce KRAS G12D protein to form a ternary complex, block The interaction of KRAS and downstream effector proteins;
  • Mirati Company disclosed a new class of KRAS G12D inhibitors in WO2021041671A1, but did not disclose its mechanism of action.
  • KRAS has become an excellent tumor therapy target, there are no clinically validated drugs targeting KRAS G12D. Therefore, there is an urgent need in the art to develop KRAS G12D targeting inhibitors with novel structures, good biological activity and high druggability.
  • the present invention provides a class of heteroaromatic compounds, which have a strong inhibitory effect on the target KRAS G12D, and thus have better tumor treatment effects.
  • the compounds of the present invention also possess various excellent properties, such as good physicochemical properties (eg solubility, physical and/or chemical stability) and good safety.
  • the compound is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotopically labeled compound or metabolite thereof Object:
  • X 1 is selected from N and CR 5 ;
  • L is selected from covalent bonds, -O-, -S- and -NR 6 -;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substituted;
  • R 2 is selected from
  • each X 2 is independently selected from N and CR 9 ;
  • R 3 is selected from C 1-6 alkyl and C 1-6 haloalkyl
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more R 10 ;
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 6 is selected from hydrogen and C 1-6 alkyl
  • R 7 is selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -OC(O)-R 11 , -NR 11 R 12 , -NR 12 -C(O)- R 11 , -NR 12 -C(O)-NR 11 R 12 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-OR 12 , -C( O)-NR 11 R 12 , C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, -C 1-6 alkylene -R 13 , -C 1-6 al
  • R 8 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-cyano and C 1-6 haloalkyl;
  • R 9 is selected from hydrogen, hydroxyl and C 1-6 alkyl
  • R 10 is selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl and heteroaryl is optionally selected from one or more of hydrogen, halogen, hydroxy, cyano Substituent substitution of C 1-6 alkyl and C 1-6 haloalkyl;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkyl-OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl , the cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 12 is selected from hydrogen and C 1-6 alkyl
  • R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl optionally being One or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl substituted;
  • R 14 is selected from hydrogen and C 1-6 alkyl
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, or 2;
  • o, p, q, r and s are each independently selected from 0, 1, 2 or 3, provided that o and r are not both 0 and p and q are not both 0.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph thereof , solvates, N-oxides, isotopically-labeled compounds or metabolites, and one or more pharmaceutically acceptable carriers.
  • the present invention provides a kit comprising a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds or metabolites, or pharmaceutical compositions of the invention, and optionally, packaging and/or instructions.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds thereof Or metabolites, or pharmaceutical compositions of the present invention, for inhibiting KRAS G12D.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds thereof Or metabolites, or the pharmaceutical composition of the present invention, which is used for the prevention or treatment of KRAS G12D-mediated related diseases.
  • the present invention provides compounds of the present invention or pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds thereof Or metabolite or use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating KRAS G12D-mediated related diseases.
  • the present invention provides a method of preventing or treating KRAS G12D-mediated related diseases, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, Stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds or metabolites, or pharmaceutical compositions of the invention.
  • the present invention provides methods of preparing the compounds of the present invention.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon group.
  • C 1-6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds.
  • C 2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon double bonds (eg vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexene group, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, etc.), which are optionally separated by one or more (such as 1 to 3) Suitable substituents such as halogen are substituted.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms and one, two or three (preferably one) carbon-carbon triple bonds, such as ethynyl , 1-propynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3 -hexynyl, 4-hexynyl, 5-hexynyl, etc.), optionally substituted with one or more (eg 1 to 3) suitable substituents such as halogen.
  • cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl) , cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic rings, including spirocyclic, fused or bridged systems such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo [3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), optionally substituted with one or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl
  • cyclohexyl cycloheptyl
  • C 3-6 cycloalkyl refers to a saturated or partially unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, cyclopropyl, cyclo) having 3 to 6 ring carbon atoms butyl, cyclopentyl or cyclohexyl) optionally substituted with one or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • halo or halogen group is defined to include fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with one or more, such as 1 to 3, the same or different halogen atoms.
  • C1-6 haloalkyl refers to a haloalkyl group having 1 to 6 carbon atoms, such as -CF3 , -C2F5 , -CHF2, -CH2F , -CH2CF3 , - CH 2 Cl or -CH 2 CH 2 CF 3 etc.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic group, eg, having 2, 3, 4, 5, 6, 7, 8 or 9 carbons in the ring atom and one or more (eg 1, 2, 3 or 4) heteroatoms independently selected from N, O or S(O) t (where t is 0, 1 or 2), eg 3- 12-membered heterocyclyl, 3-7-membered heterocyclyl, 3-6-membered heterocyclyl, 5-6-membered heterocyclyl, etc.
  • the polycyclic group can be a parallel, spiro or bridged ring, such as 5-12 A membered ring, a 5-12 membered spiro ring, or a 5-12 membered bridged ring.
  • Representative examples of heterocyclyl include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, hexahydro- 1H-pyrrolinyl, hexahydropyrrolizinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl , piperazinyl, etc.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated pi electron system.
  • C6-10 aryl or “ C6-10 aromatic ring” refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl (ring) or naphthyl (ring).
  • the aryl group is optionally substituted with one or more (such as 1 to 3) suitable substituents (eg, halogen, -OH, -CN, -NO2 , C1-6 alkyl, etc.).
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic, bicyclic or tricyclic aromatic ring system containing at least one heteroatom selected from N, O and S, for example having 5, 6 , 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and, in addition, in each case may For benzo-fused.
  • a heteroaryl or heteroaryl ring can be selected from thienyl (ring), furyl (ring), pyrrolyl (ring), oxazolyl (ring), thiazolyl (ring), imidazolyl (ring), pyrrolyl (ring) oxazolyl (ring), isoxazolyl (ring), isothiazolyl (ring), oxadiazolyl (ring), triazolyl (ring), thiadiazolyl (ring), etc., and their benzos derivatives; or pyridyl (ring), pyridazinyl (ring), pyrimidinyl (ring), pyrazinyl (ring), triazinyl (ring), etc., and their benzo derivatives.
  • substituted means that one or more (eg, 1, 2, 3, or 4) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is at Normal valences in the present case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently The selected substituents are substituted or unsubstituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected substituents Substitute or not.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass numbers.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, 2 H, 3 H, deuterium D, tritium T); isotopes of carbon (eg, 11 C, 13 C, and 14 C); chlorine isotopes of fluorine (eg 37 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O, 17 O and 18 O); isotopes of phosphorus (eg 32 P); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, 2 H, 3 H, deuterium D, tritium T
  • isotopes of carbon eg, 11 C, 13 C, and 14 C
  • chlorine isotopes of fluorine eg 37
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds having one or more (eg, 1, 2, 3, or 4) asymmetric centers, it may give rise to racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of this application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% %) of isomers or mixtures thereof.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates or metabolites, which, upon administration to a patient in need thereof, can directly or indirectly provide the present invention compounds or their metabolites or residues. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts.
  • suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • Nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; Nitrogen-containing heterocycles. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished by conventional protecting groups, as described, for example, in Protective Groups in Organic Chemistry, ed.J.F.W.McOmie, Plenum Press, 1973; and T.W.Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 those protecting groups, these references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • An object of the present invention is to provide a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N-oxide, isotope thereof Labeled compounds or metabolites:
  • X 1 is selected from N and CR 5 ;
  • L is selected from covalent bonds, -O-, -S- and -NR 6 -;
  • R 1 is selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substituted;
  • R 2 is selected from
  • each X 2 is independently selected from N and CR 9 ;
  • R 3 is selected from C 1-6 alkyl and C 1-6 haloalkyl
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more R 10 ;
  • R 5 is selected from hydrogen, halogen, cyano, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 6 is selected from hydrogen and C 1-6 alkyl
  • R 7 is selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -OC(O)-R 11 , -NR 11 R 12 , -NR 12 -C(O)- R 11 , -NR 12 -C(O)-NR 11 R 12 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-OR 12 , -C( O)-NR 11 R 12 , C 3-10 cycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, said cycloalkyl, aryl, heteroaryl and heterocyclyl are each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl, -C 1-6 alkylene -R 13 , -C 1-6 al
  • R 8 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -C 1-6 alkyl-OH, -C 1-6 alkyl-cyano and C 1-6 haloalkyl;
  • R 9 is selected from hydrogen, hydroxyl and C 1-6 alkyl
  • R 10 is selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl and 5-10 membered heteroaryl, each of said alkyl, cycloalkyl, heterocyclyl and heteroaryl is optionally selected from one or more of hydrogen, halogen, hydroxy, cyano Substituent substitution of C 1-6 alkyl and C 1-6 haloalkyl;
  • R 11 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkyl-OC 1-6 alkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl , the cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, and C 1-6 haloalkyl;
  • R 12 is selected from hydrogen and C 1-6 alkyl
  • R 13 is selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-12 membered heterocyclyl, each of said cycloalkyl and heterocyclyl optionally being One or more substituents selected from hydrogen, halogen, hydroxyl, cyano, C 1-6 alkyl, C 1-6 haloalkyl substituted;
  • R 14 is selected from hydrogen and C 1-6 alkyl
  • n 0, 1, 2, 3 or 4;
  • n 0, 1 or 2;
  • o, p, q, r and s are each independently selected from 0, 1, 2 or 3, provided that o and r are not both 0 and p and q are not both 0.
  • R 7 is selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -OC(O)-R 11 , -NR 11 R 12 , - NR 12 -C(O)-R 11 , -NR 12 -C(O)-NR 11 R 12 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O )-OR 12 , -C(O)-NR 11 R 12 , C 3-10 cycloalkyl and 3-12 membered heterocyclyl, optionally by one or more independent is substituted with a substituent selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C 1-6 alkyl and C 1-6 haloalkyl.
  • X 1 is selected from N and CH. In a preferred embodiment, X 1 is N.
  • X 2 is selected from CR 9 .
  • X 2 is selected from CH.
  • L is selected from covalent bonds, -O-, -S-, -NH- and -N(C 1-3 alkyl)-.
  • L is selected from -O-, -NH- and -N(C 1-3 alkyl)-.
  • L is -O-.
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, and 3-12 membered heterocyclyl, each of which is optional is substituted with one or more R 7 , each R 7 is independently selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-NR 11 R 12 , C 3-10 cycloalkyl, C 6-10 membered aryl, 5-10 membered heteroaryl and 3-12 membered heterocyclyl, each of said cycloalkyl, aryl, heteroaryl and heterocyclyl optionally being independently selected by one or more Substituted from the following substituents: hydrogen, halogen, hydroxy, amino, cyano, C
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more substituted with R 7 , each R 7 is independently selected from hydrogen, halogen, cyano, -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O) -R 11 , -NR 12 -C(O)-OR 11 , -C(O)-R 11 , -C(O)-NR 11 R 12 , C 3-10 cycloalkyl and 3-12 membered heterocycle each of the cycloalkyl and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, C1-6 alkyl, and C1 -6 haloalkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of which is optional is substituted with one or more R 7 , each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 , C 3-6 cycloalkyl, 5-10-membered heteroaryl and 3-12-membered heterocyclyl, the The cycloalkyl, heteroaryl and heterocyclyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, -C 1-6 alkylene -R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substitutions, each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 and 3-12 membered heterocyclyl optionally substituted with one or more substituents independently selected from : hydrogen, halogen, hydroxyl, amino, cyano and C 1-6 alkyl.
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of which is optional is substituted with one or more R 7 , each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 , 5-10-membered heteroaryl and 3-12-membered heterocyclyl, said heteroaryl and heterocyclyl Each is optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, cyano, -C 1-6 alkylene -R 13 , -C 1-3 alkylene -OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O)-R 13
  • R 1 is selected from C 1-6 alkyl, C 3-10 cycloalkyl and 3-12 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being replaced by one or more R 7 substitutions, each R 7 is independently selected from -OR 11 , -OC(O)-NR 11 R 12 , -NR 11 R 12 , -NR 12 -C(O)-R 11 , -NR 12 -C(O)-OR 11 , -C(O)-NR 11 R 12 and 3-12 membered heterocyclyl optionally substituted with one or more substituents independently selected from : hydrogen, halogen, hydroxyl, amino, cyano and C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from C 3-6 cycloalkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl, each of said C 3-6 cycloalkyl, 5-6 membered heteroaryl and 5-8 membered heterocyclyl is optionally independently selected by one or more Substituted from the following substituents: halogen, C 1-6 alkyl, -C 1-6 alkylene-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O)-R 13 and C 1-3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and 5-6 membered heterocyclyl; R 14 is selected From hydrogen and C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from 5-6 membered heteroaryl and 5-8 membered heterocyclyl, each of the 5-6 membered heteroaryl and 5-8 membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -C 1-6 alkylene-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O) -R 13 and C 1-3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and 5-6 membered heterocyclyl; R 14 is selected from hydrogen and C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrole azinyl and imidazolyl, each of said cyclopropyl, pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkane group, -C 1-6 alkylene-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC ( O)-R 13 and C 1-3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and morpholinyl; R 14 is C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from pyrrolidinyl, hexahydropyrrolizinyl, and imidazole each of the pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -C 1-6 alkylene Alkyl-R 13 , -C 1-3 alkylene-OH, -C 1-6 alkylene-NR 13 R 14 , -C 1-6 alkylene-OC(O)-R 13 and C 1 -3 haloalkyl; wherein R 13 is selected from C 1-6 alkyl and morpholinyl; R 14 is C 1-6 alkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from cyclopropyl, pyrrolidinyl, hexahydropyrrole azinyl and imidazolyl, each of said cyclopropyl, pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkane group, -C 1-6 alkylene-morpholinyl, -C 1-3 alkylene-OH, -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1- 6 alkylene-OC(O)-(morpholinyl) and C 1-3 haloalkyl.
  • R 1 is C 1-6 alkyl optionally substituted with one or more R 7 , each R 7 is independently selected from pyrrolidinyl, hexahydropyrrolizinyl, and imidazole each of the pyrrolidinyl, hexahydropyrrolazinyl and imidazolyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C 1-6 alkyl, -C 1-6 alkylene Alkyl-morpholinyl, -C 1-3 alkylene-OH, -C 1-6 alkylene-N(C 1-6 alkyl) 2 , -C 1-6 alkylene-OC(O )-(morpholinyl) and C 1-3 haloalkyl.
  • R 1 is selected from where the wavy line Indicates the point of attachment of this group to the rest of the molecule.
  • R 1 is selected from where the wavy line Indicates the point of attachment of this group to the rest of the molecule.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-6 alkyl, C 1- 6 -alkylene-OH or C 1-6 -haloalkyl-substituted 5-12-membered cycloheterocyclyl and 5-10-membered heteroaryl.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-6 alkyl, C 1- 6 -alkylene-OH or C 1-6 haloalkyl-substituted 5-12-membered cycloheterocyclyl.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8-membered cycloheterocyclyl and 5-10-membered heteroaryl.
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8 membered cycloheterocyclyl.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8-membered nitrogen-containing heterocyclic and 5-10-membered heteroaryl groups.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 -alkylene-OH or C 1-3 haloalkyl-substituted 5-8 membered nitrogen-containing heterocyclic group.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 alkylene-OH or C 1-3 haloalkyl substituted hexahydropyrrolizinyl and imidazole.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-3 alkyl, C 1- 3 alkylene-OH or C 1-3 haloalkyl substituted hexahydropyrrolazinyl.
  • R 1 is C 1-3 alkyl optionally substituted with one R 7 selected from the group consisting of optionally substituted with one or more of F, Cl, methyl, chloromethyl, Fluoromethyl or hydroxymethyl substituted hexahydropyrrolizinyl and imidazole.
  • R 1 is selected from
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more R 10
  • each R 10 is each independently selected from hydrogen, halogen, hydroxyl, cyano, C 1-3 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-3 alkyl, C 3-6 ring Alkyl and 3-8 membered heterocyclyl, each of said alkyl, cycloalkyl and heterocyclyl optionally being selected from the group consisting of one or more hydrogen, halogen, hydroxyl, cyano, C1-3 alkyl and Substituent substitution of C 1-3 haloalkyl.
  • R 4 is selected from C 6-10 aryl and 5-10 membered heteroaryl, optionally substituted with one or more R 10 , each R 10 are each independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 2-4 alkynyl, -OC 1-3 alkyl and C 3-6 cycloalkyl, the alkyl optionally being One or more hydrogen and halogen substitution.
  • R4 is selected from phenyl, naphthyl, and indazolyl, each of which is optionally substituted with one or more R10, each R10 Each is independently selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl, C 2-4 alkynyl, -OC 1-3 alkyl and C 3-6 cycloalkyl.
  • R 4 is selected from
  • R 1 is C 1-6 alkyl optionally substituted with one R 7 selected from the group consisting of optionally one or more halogen, C 1-6 alkyl, C 1- 6 alkylene-OH or C 1-6 haloalkyl substituted 3-6 membered heterocyclic group; and R 4 is selected from C 6-10 aryl, which is optionally substituted with one R 10 , R 10 selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally by one or more selected from halogen, hydroxy, cyano, C 1 Substituent substitution of -6 alkyl and C 1-6 haloalkyl.
  • R 1 is selected from C 1-6 alkyl optionally substituted with one R 7 selected from C 1-6 alkyl optionally substituted with one or more halogens, C 1-6 alkyl, C 1-6 alkylene-OH or C 1-6 haloalkyl substituted 5-6 membered nitrogen-containing heterocyclic group; and R 4 is naphthyl, which is optionally substituted by one R 10 , R 10 selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, optionally by one or more selected from halogen, hydroxy, cyano, C 1 Substituent substitution of -6 alkyl and C 1-6 haloalkyl.
  • R 1 is selected from C 1-6 alkyl optionally substituted with one R 7 selected from tetrahydropyrrolyl optionally substituted with C 1-3 alkyl ; and R 4 is naphthyl optionally substituted with one R 10 selected from halogen, hydroxy, C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, the The alkyl group is optionally substituted with one or more substituents selected from halogen, hydroxy, cyano, C1-6 alkyl and C1-6 haloalkyl.
  • each R 3 is each independently selected from C 1-6 alkyl and C 1-6 haloalkyl, or two R 3 attached to the same carbon atom and said carbon atom together form carbonyl or C 3-6 cycloalkyl.
  • each R3 is independently selected from C1-3 alkyl, or two R3 attached to the same carbon atom and said carbon atom together form a carbonyl or C3-6 ring alkyl.
  • each R3 is independently selected from methyl, or two R3s attached to the same carbon atom and said carbon atom together form carbonyl or cyclopropyl.
  • R 2 is selected from
  • R 2 is selected from
  • the present invention encompasses compounds of formula (I) resulting from any combination of the above preferred groups.
  • the compounds of the present invention have the structure of formula (II-A), formula (II-B) or formula (II-C):
  • each of the groups L, R1, R3 , R4 , R8 , m, n , o, p, q, r and s are as defined above.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein L is selected from covalent bonds, -O-, -S- and -NH-; preferably Typically, L is selected from -O- and -S-; more preferably, L is selected from -O-.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein o, p, q, r and s are each independently selected from 0, 1 or 2; Preferably, o, p, q and r are each independently selected from 0 or 1, and s is selected from 1 or 2; preferably, o and p are selected from 0 or 1, q and r are selected from 1, and s is selected from 1 or 2; preferably, o and p are selected from 0, q and r are selected from 1, and s is selected from 2.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein n is 0 or 1; preferably 0.
  • the compounds of the present invention have the structure of formula (II-A) or formula (II-C), wherein m is 0, 1 or 2.
  • the compounds of the present invention are of formula (II-A-1), (II-A-2), (II-C-1), (II-C-2) or (II-C -3) structure:
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the compounds of the present invention are selected from:
  • Another object of the present invention is to provide a process for the preparation of the compounds of the present invention.
  • the present invention provides a method for preparing a compound of formula (II-A) comprising the steps of:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 , LG 2 and X represent leaving groups, which include but are not limited to halogen atoms, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;
  • PG 1 , PG 2 and PG 3 represent protective groups for hydroxyl or amino groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), methyl, benzyl and the like.
  • Step (1) reacting compound II-A-1 with compound II-A-2 to obtain compound II-A-3;
  • the reaction is preferably carried out in a suitable organic solvent, which can be selected from methanol, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably methanol.
  • a suitable organic solvent which can be selected from methanol, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably methanol.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base, which can be selected from diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • a suitable organic or inorganic base which can be selected from diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • the reaction is carried out at a suitable temperature, preferably 0-80°C.
  • the reaction is carried out for a suitable time, eg, 2-24 hours.
  • Step (2) coupling reaction of compound II-A-3 and compound II-A-4 to obtain compound II-A-5;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.
  • the base is an organic or inorganic base, such as diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) deprotecting compound II-A-5 to obtain compound II-A-6;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl.
  • the base is an organic or inorganic base, such as sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (5) deprotecting compound II-A-8 to obtain compound II-A-9;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcohol-based protic solvents, tetrahydrofuran, N,N-dimethylformamide and any combination thereof, preferably N,N-dimethylformamide.
  • the deprotection reaction is preferably carried out in the presence of sodium ethanethiolate.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 50-100°C.
  • the reaction is carried out for a suitable time, eg, 1-12 hours.
  • step (6) compound II-A-9 is subjected to condensation reaction with compound II-A-10 to obtain compound II-A-11;
  • the condensation reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from tetrahydrofuran, N,N-dimethylformamide, dichloromethane and any combination thereof, preferably N,N-dimethylformamide.
  • the condensation reaction is preferably carried out in the presence of a suitable organic base, which can be selected from diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec -7-ene, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • a suitable organic base which can be selected from diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec -7-ene, preferably 1,8-diazabicyclo[5.4.0]undec-7-ene.
  • the condensation reaction is carried out in the presence of a suitable condensing agent, and the condensing agent can be selected from Carter condensing agent, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N ,N',N'-tetramethylurea hexafluorophosphate, preferably Carter condensing agent.
  • a suitable condensing agent can be selected from Carter condensing agent, 1-hydroxybenzotriazole, 2-(7-azobenzotriazole)-N,N ,N',N'-tetramethylurea hexafluorophosphate, preferably Carter condensing agent.
  • the deprotection reaction is carried out at a suitable temperature, preferably 20-100°C.
  • the reaction is carried out for a suitable time, eg, 2-24 hours.
  • Step (7) deprotecting compound II-A-11 to obtain compound II-A;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • the present invention provides a second method for preparing the compound of formula (II-A), which comprises the following steps:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 , LG 2 and X represent leaving groups, which include but are not limited to halogen atoms, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, and the like;
  • PG 1 and PG 3 represent amino protecting groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • Step (1) reacting compound II-A-1 with compound II-A-10 to obtain compound IIa-A-2;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N,N-dimethylformamide formamide.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base, which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • a suitable organic or inorganic base which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • the reaction is carried out at a suitable temperature, preferably 20-100°C.
  • the reaction is carried out for a suitable time, eg, 1-12 hours.
  • Step (2) coupling reaction of compound IIa-A-2 and compound II-A-4 to obtain compound IIa-A-3;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.
  • the base is an organic or inorganic base, such as diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) deprotecting compound IIa-A-3 to obtain compound IIa-A-4;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, 1,1'-bis(diphenylphosphino)ferrocene, preferably 1,1'-bis(diphenylphosphino)ferrocene.
  • the base is an organic or inorganic base, such as sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane and toluene.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane and toluene.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (5) deprotecting compound II-A-11 to obtain compound II-A;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a suitable deprotection reagent.
  • the deprotection reagent can be selected from trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid, preferably trimethyliodosilane or hydrobromic acid acetic acid solution.
  • the deprotection reaction is carried out at a suitable temperature, preferably 0-100°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • the present invention provides a third method for preparing the compound of formula (II-A), which comprises the following steps:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 and X represent a leaving group, and the leaving group includes but is not limited to halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl, etc.;
  • PG 1 and PG 3 represent amino protecting groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • Step (1) subjecting compound IIb-A-1 to a ring closure reaction to obtain compound IIb-A-2;
  • the ring closure reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from methanol, ethanol, tetrahydrofuran and any combination thereof, preferably methanol.
  • the reaction is preferably carried out in the presence of a suitable organic base, which can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • a suitable organic base which can be selected from sodium ethoxide, sodium methoxide, sodium tert-butoxide, preferably sodium methoxide.
  • the reaction is carried out at a suitable temperature, preferably 20-60°C.
  • the reaction is carried out for a suitable time, eg, 12-36 hours.
  • Step (2) subjecting compound IIb-A-2 to a substitution reaction to obtain compound IIb-A-3;
  • the reaction is carried out in the presence of a suitable substitution reagent, which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxybromide, a Carter condensing agent, preferably trifluoromethanesulfonic anhydride.
  • a suitable substitution reagent which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxybromide, a Carter condensing agent, preferably trifluoromethanesulfonic anhydride.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, toluene, tetrahydrofuran and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • the reaction is carried out at a suitable temperature, preferably 0°C to 120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) reacting compound IIb-A-3 with compound II-A-10 to obtain compound IIb-A-4;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from N,N-dimethylformamide, N,N-dimethylacetamide, toluene, tetrahydrofuran, 1,4-dioxane and any combination thereof, preferably N,N-dioxane Methylformamide.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base, which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • a suitable organic or inorganic base which can be selected from N,N-diisopropylethylamine, triethylamine, sodium methoxide, sodium tert-butoxide, N,N-diisopropylethylamine is preferred.
  • the reaction is carried out at a suitable temperature, preferably 20-100°C.
  • the reaction is carried out for a suitable time, eg, 1-12 hours.
  • Step (4) deprotecting compound IIb-A-4 to obtain compound IIb-A-5;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the deprotection reaction is preferably carried out in the presence of a suitable acid.
  • the acid may be selected from hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 2-12 hours.
  • Step (5) coupling reaction of compound IIb-A-5 and compound II-A-7 to obtain compound IIb-A-6;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) Phenylphosphine) palladium, palladium acetate, methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino) -1,1'-biphenyl-2-yl)palladium(II), preferably methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1' -
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (6) subjecting compound IIb-A-6 to oxidation reaction to obtain compound IIb-A-7;
  • the oxidation reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from ethyl acetate, methanol, 1,4-dioxane, dichloromethane and any combination thereof, preferably dichloromethane.
  • the oxidation reaction is carried out in the presence of a suitable oxidizing agent.
  • the oxidant can be selected from hydrogen peroxide, m-chloroperoxybenzoic acid, potassium hydrogen persulfate. Meta-chloroperoxybenzoic acid is preferred.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-40°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • step (7) compound IIb-A-7 is subjected to substitution reaction with compound II-A-4 to obtain compound II-A-11;
  • the substitution reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, toluene, tetrahydrofuran and any combination thereof, preferably toluene.
  • substitution reaction is preferably carried out in the presence of a suitable organic or inorganic base, such as sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, preferably potassium tert-butoxide.
  • a suitable organic or inorganic base such as sodium tert-butoxide, potassium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydride, preferably potassium tert-butoxide.
  • the substitution reaction is carried out at a suitable temperature, preferably 0°C to 40°C.
  • the reaction is carried out for a suitable time, eg, 0.5-16 hours.
  • Step (8) deprotecting compound II-A-11 to obtain compound II-A;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a suitable deprotection reagent.
  • the deprotection reagent can be selected from trimethylsilyl iodide, hydrobromic acid acetic acid solution, and trifluoroacetic acid. Preference is given to trimethylsilyl iodide or hydrobromic acid in acetic acid.
  • the deprotection reaction is carried out at a suitable temperature, preferably 0-100°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • the present invention provides a method for the preparation of a compound of formula (II-C), comprising the steps of:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 represents a leaving group, which includes but is not limited to halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl, methylsulfonyl, etc.;
  • PG 3 represents a protecting group for amino, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • the reaction is carried out in the presence of a suitable halogenated or pseudohalogenated reagent, which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxytribromide, preferably trifluoromethanesulfonic anhydride.
  • a suitable halogenated or pseudohalogenated reagent which is trifluoromethanesulfonic anhydride, phosphorus oxychloride, phosphorus oxytribromide, preferably trifluoromethanesulfonic anhydride.
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from dichloromethane, toluene, tetrahydrofuran and any combination thereof, preferably dichloromethane.
  • the reaction is preferably carried out in the presence of a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • a suitable organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, N,N-dimethylaniline, preferably N,N - Diisopropylethylamine.
  • the reaction is carried out at a suitable temperature, preferably -70°C to 100°C.
  • the reaction is carried out for a suitable time, eg, 1-16 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'
  • the base is an organic base or an inorganic base, such as N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably sodium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • the reduction reaction is preferably carried out in the presence of a metal catalyst.
  • the metal catalyst is a palladium metal catalyst or a platinum metal catalyst, such as palladium on carbon, palladium hydroxide, platinum dioxide, preferably palladium on carbon.
  • the reduction reaction is preferably carried out in the presence of hydrogen.
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent can be selected from methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and any combination thereof, preferably methanol.
  • the reaction is carried out at a suitable temperature, preferably 20-60°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out under suitable deprotection reagents.
  • the deprotection reagent can be selected from trimethylsilyl iodide, hydrobromic acid acetic acid solution, and trifluoroacetic acid. A solution of hydrobromic acid in acetic acid is preferred.
  • the deprotection reaction is carried out at a suitable temperature, preferably 0-100°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • the present invention provides a second method for the preparation of compounds of formula (II-C) comprising the steps of:
  • L, R 1 , R 3 , R 4 , R 8 , m, n, o, p, q, r and s are as defined above;
  • LG 1 , LG 2 and X represent a leaving group, and the leaving group includes but is not limited to halogen atom, trifluoromethanesulfonate, methylthio, methylsulfinyl and methylsulfonyl, etc.;
  • PG 1 and PG 3 represent amino protecting groups, including but not limited to benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc) and benzyl, etc.;
  • Step (1) coupling reaction of compound II-A-1 and compound II-C-2 to obtain compound IIa-C-3;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium dichloromethane complex.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex compound, tetrakis(triphenylphosphine) palladium, palladium acetate, preferably [1,1'
  • the base is an organic or inorganic base, such as N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, potassium acetate, sodium carbonate, preferably potassium acetate.
  • organic or inorganic base such as N,N-diisopropylethylamine, triethylamine, sodium tert-butoxide, potassium carbonate, cesium carbonate, potassium acetate, sodium carbonate, preferably potassium acetate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably a combination of 1,4-dioxane and water.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (2) coupling reaction of compound IIa-C-3 and compound II-A-4 to obtain compound IIa-C-4;
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, (2-dicyclohexylphosphino-2',6'-diisopropoxy-1, methanesulfonic acid) 1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II), [1,1'-bis(diphenylphosphino)ferrocene]dichloride Palladium, tetrakis(triphenylphosphine)palladium, palladium acetate, preferably methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) (2 -Amino-1,1'-biphenyl-2-yl)palla
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably toluene.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (3) deprotecting compound IIa-C-4 to obtain compound IIa-C-5;
  • the reaction is preferably carried out in the presence of a metal catalyst.
  • the metal catalyst is a palladium metal catalyst or a platinum metal catalyst, such as palladium on carbon, palladium hydroxide, platinum dioxide, preferably palladium on carbon.
  • the reaction is preferably carried out in the presence of hydrogen.
  • the reaction is preferably carried out in a suitable organic solvent, and the organic solvent can be selected from ammonia methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and any combination thereof, preferably ammonia methanol.
  • the reaction is carried out at a suitable temperature, preferably 20-60°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst, a ligand and a base.
  • the metal catalyst is a palladium metal catalyst, such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium acetate, preferably tris(dibenzylideneacetone)dipalladium.
  • a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]dichloride palladium, tetrakis(tris(triphenylphosphino)ferrocene) phenylphosphine) palladium, palladium
  • the ligands are phosphorus ligands such as 4,5-bisdiphenylphosphine-9,9-dimethylxanthene, 2-dicyclohexylphosphorus-2',6'-diisopropoxy- 1,1'-biphenyl, 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl Benzene, preferably 2-dicyclohexylphosphorus-2',6'-diisopropoxy-1,1'-biphenyl.
  • the base is an organic or inorganic base, such as sodium tert-butoxide, potassium carbonate, cesium carbonate, sodium carbonate, preferably cesium carbonate.
  • the reaction is preferably carried out in a suitable solvent, which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • a suitable solvent which can be selected from N,N-dimethylformamide, N-methylpyrrolidone, toluene, ethanol, ethylene glycol dimethyl ether, water, 1,4- Dioxane and any combination thereof, preferably 1,4-dioxane.
  • the reaction is carried out at a suitable temperature, preferably 50-120°C.
  • the reaction is carried out for a suitable time, eg, 2-16 hours.
  • Step (5) deprotecting compound II-C-4 to obtain compound II-C;
  • the deprotection reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent can be selected from alcoholic protic solvents, tetrahydrofuran, dichloromethane, N,N-dimethylformamide and any combination thereof, preferably dichloromethane.
  • the reaction is carried out in the presence of a suitable deprotection reagent.
  • the deprotection reagent can be selected from trimethyliodosilane, hydrobromic acid acetic acid solution, trifluoroacetic acid, preferably trifluoroacetic acid.
  • the deprotection reaction is carried out at a suitable temperature, and the temperature is preferably 0-80°C.
  • the reaction is carried out for a suitable time, eg, 0.5-12 hours.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or polymorph thereof , solvates, N-oxides, isotopically-labeled compounds or metabolites, and one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide a kit comprising the compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph, solvate, N- Oxides, isotopically-labeled compounds or metabolites, or pharmaceutical compositions of the invention, and optionally, packaging and/or instructions.
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions or formulations of the present invention include, but are not limited to, sterile liquids such as water and oils.
  • the pharmaceutical composition may, for example, be in the form of a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation and the like.
  • compositions of the present invention may act systemically and/or locally.
  • they may be administered by a suitable route, eg by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally or by oral administration.
  • a suitable route eg by injection (eg intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally or by oral administration.
  • the compound of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.001 mg to about 1000 mg.
  • the present invention provides a method of preparing a pharmaceutical composition of the present invention, the method comprising combining a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph
  • a pharmaceutically acceptable salt e.g., a pharmaceutically acceptable salt, stereoisomer, tautomer, polymorph
  • the form, solvate, N-oxide, isotopically-labeled compound or metabolite is combined with one or more pharmaceutically acceptable carriers.
  • Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds Or metabolites, or pharmaceutical compositions of the present invention, for inhibiting KRAS G12D.
  • Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds Or metabolites, or the pharmaceutical composition of the present invention, which is used for the prevention or treatment of KRAS G12D-mediated related diseases.
  • Another object of the present invention is to provide the compounds of the present invention or their pharmaceutically acceptable salts, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds Or metabolite or use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating KRAS G12D-mediated related diseases.
  • Another object of the present invention is to provide a method for preventing or treating KRAS G12D-mediated related diseases, which comprises administering to an individual in need thereof a prophylactically or therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, Stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled compounds or metabolites, or pharmaceutical compositions of the invention.
  • the KRAS G12D-mediated related disease is a tumor, preferably, the KRAS G12D-mediated related disease is cancer.
  • an effective amount refers to an amount sufficient to achieve the desired prophylactic or therapeutic effect, eg, an amount to achieve relief of one or more symptoms associated with the disease to be treated.
  • Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg body weight per day. In some cases, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.
  • treating means reversing, alleviating the progression of a disorder or condition to which such term is applied or one or more symptoms of such a disorder or condition, or preventing such disorder or A condition or one or more symptoms of such a disorder or condition.
  • prevention includes inhibiting and delaying the onset of the disease, and includes not only prevention before the disease develops, but also prevention of the recurrence of the disease after treatment.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • the structures of the compounds were determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
  • the measuring instrument of 1 H NMR is JEOL Eclipse 400 nuclear magnetic instrument, and the measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ), and the internal standard is is tetramethylsilane (TMS) and chemical shifts ([delta]) are given in parts per million (ppm).
  • the MS measuring instrument was an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • Instrument model Agilent 1260, chromatographic column: Waters SunFire Prep C18OBD (19mm ⁇ 150mm ⁇ 5.0 ⁇ m); column temperature: 25°C; flow rate: 20.0mL/min; detection wavelength: 214nm; elution gradient: (0min: 10% A, 90% B; 16.0 min: 90% A, 10% B); mobile phase A: acetonitrile; mobile phase B: 0.05% formic acid in water.
  • the thin-layer chromatography silica gel plate used an aluminum plate (20 ⁇ 20cm) produced by Merck, and the specification adopted for the separation and purification of thin-layer chromatography was GF 254 (1mm) produced in Yantai.
  • the monitoring of the reaction adopts thin layer chromatography (TLC) or LC-MS;
  • the used developing solvent systems include: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system, the volume of solvent The ratio is adjusted according to the polarity of the compound or by adding triethylamine or the like.
  • Microwave reactions were performed using a Biotage Initiator+ (400W, RT ⁇ 300°C) microwave reactor.
  • the eluent system includes: dichloromethane and methanol system, and petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine can also be added for adjustment.
  • the temperature of the reaction is room temperature (20 °C ⁇ 35 °C);
  • the reagents used in the present invention were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Teber Chemical.
  • the first step Preparation of 8-benzyl-3-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate
  • Step 2 Preparation of benzyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-((hexahydro-1H-pyrrolazine- Preparation of 7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tert-butyl ester
  • the third step 3-(2-((Hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-4 -yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester
  • the first step the preparation of 4-hydroxy-2-(methylthio)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylate tert-butyl ester
  • methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1 ,1'-biphenyl-2-yl)palladium(II) (160.82 mg, 0.19 mmol), and stirred at 100°C for 12 hours.
  • the sixth step 3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(methylsulfinyl)-5,6,7,8-tetrahydropyrido[3, Preparation of 4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the fourth step the preparation of (2S,7aR)-2-fluorotetrahydro-1H-pyrroleazine-7a(5H)-carboxylate methyl ester
  • the fifth step the preparation of ((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol
  • the first step 4-(8-((benzyloxy)carbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2S,7aR)-2 -Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate tert-butyl ester preparation
  • the second step 3-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydro Preparation of pyrid[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the second step 3-(7-benzyl-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetra Preparation of Hydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester
  • the third step 3-(2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3 Preparation of ,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • the first step the preparation of 2-(4,5-dibromo-2-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
  • 1,8-Dibromonaphthalene (1 g, 3.46 mmol), bis(1,5-cyclooctadiene)bis-M-methoxydiiridium (I) (114.49 mg, 173.10 ⁇ mol), 4,4' -Di-tert-butyl-2,2'-bipyridine (56.31 mg, 207.72 ⁇ mol) was dissolved in tetrahydrofuran (15.0 mL), replaced with nitrogen three times, and 4,4,5,5-tetramethyl was added by injection under stirring -1,3,2-dioxaborolane (4.48 g, 34.62 mmol), the system was stirred at 70°C for 10 hours.
  • the third step preparation of 1,8-dibromo-3-(methoxymethoxy)naphthalene
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8 - Preparation of tert-butyl tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate
  • Example 2 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-( Preparation of ((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 2)
  • the second step 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-( Preparation of ((S)-1-methylpyrrolidin-2-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 2)
  • Example 3 4-(4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrole Preparation of oxazin-7a(5H)-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol (Compound 29)
  • the first step 3-(7-(3-benzyloxy-1-naphthyl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H))-yl )methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Preparation of benzyl carboxylate
  • reaction system was stirred at 0°C for 2 hours.
  • Step 2 4-(4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrole Preparation of oxazin-7a(5H)-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl)naphthalen-2-ol
  • the first step 3-(7-(3-(benzyloxy)naphthalen-1-yl)-2-(hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7 Preparation of ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • Step 2 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy) Preparation of -5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol
  • the first step 3-(7-(8-Bromonaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8- Preparation of benzyl tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((hexahydro-1H - Preparation of pyrrozin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 6 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 31)
  • the first step 3-(7-(8-bromonaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • esters 3-(7-(8-bromonaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 7 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 30)
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • esters 3-(7-(8-chloronaphthalen-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrroazin-7a(5H)-yl)methoxy benzyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • Step 2 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((((2S,7aR) - Preparation of 2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 8 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 33)
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-(hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydro
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • the first step 3-[7-(3-benzyloxy-1-naphthyl)-2-[2-(2-methylimidazol-1-yl)ethoxy]-5,6,7,8 - Preparation of benzyl tetrahydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
  • the second step 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(2-(2-methyl-1H-imidazol-1-yl)ethyl Preparation of oxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol
  • Example 10 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidine Preparation of -2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol (Compound 35A or 35B)
  • Step 1 Preparation of 7-benzyl-2-chloro-4-methoxy-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • the seventh step 3-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5, Preparation of 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylic acid tert-butyl ester
  • the eighth step 3-(7-(3-(benzyloxy)naphthalene-1-yl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-5, Preparation of 6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
  • Step 9 4-(4-(8-azabicyclo[3.2.1]octan-3-yl)-2-((S)-1-methylpyrrolidin-2-yl)methoxy) Preparation of -5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol (Compound 35)
  • Step 10 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-(((S)-1-methylpyrrolidine Preparation of -2-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)naphthalen-2-ol (Compound 35A or 35B)
  • the crude product of the ninth step was purified by high performance liquid chromatography to obtain the title compound 35A (2.10 mg, yield: 4.58%) and compound 35B (2.56 mg, yield: 5.58%).
  • Compound 35A retention time is 7.0 minutes
  • Compound 35B retention time is 7.8 minutes
  • Example 11 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 37)
  • the first step 3-(7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetra
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-fluoronaphthalen-1-yl)-2-((hexahydro-1H- Preparation of pyrrolizin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • Example 12 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((hexa Preparation of Hydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 36)
  • the first step 3-(7-(8-Chloro-7-fluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7 Preparation of ,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-chloro-7-fluoronaphthalen-1-yl)-2-((hexa Preparation of Hydrogen-1H-Pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrazin[3,4-d]pyrimidine
  • Example 13 4-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro Preparation of -1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 38)
  • the first step 3-(7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7, Preparation of 8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid benzyl ester
  • the second step 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro Preparation of -1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine
  • the reaction raw material of the second step 3-(7-(8-bromonaphthalen-1-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy )-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester Replaced with 3-(7-(7,8-difluoronaphthalen-1-yl)-2-((hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8- Benzyl tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate to give the title compound (22 mg, yield: 42.1%).
  • Example 14 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 86A or 86B ) preparation
  • the first step 3-(7-(8-chloronaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5
  • Step 2 4-(-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-((2R,7aS)-2- Preparation of fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 86)
  • reaction solution was concentrated, the residue was diluted with ethyl acetate (3 mL), washed three times with sodium bicarbonate solution (10 mL), the organic phases were combined, backwashed twice with saturated brine (10 mL), dried over anhydrous sodium sulfate, and then reduced The solvent was removed by rotary evaporation to give the title compound (40.0 mg, crude).
  • the third step 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-chloronaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 86A or 86B ) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 86A (18.0 mg, yield: 21.82%) and compound 86B (10.0 mg, yield: 11.85%).
  • Example 15 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (compound 89A or 89B) preparation
  • the first step 3-(7-(8-Fluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroleazine -7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8 - Preparation of tert-butyl carboxylate
  • Step 2 4-(4-(-8-Azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroleazine-7a Preparation of -yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (Compound 89)
  • the third step 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (compound 89A or 89B) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 89A (5.0 mg, yield: 9.6%) and compound 89B (6.1 mg, yield: 11.5%).
  • Example 16 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5,6-difluoronaphthalene-2- Preparation of alcohols (compounds 90A or 90B)
  • the first step 3-(7-(7,8-difluoro-3-(methoxymethoxy)naphthalene-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H -Pyrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane
  • Step 2 4-(4-(8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazine-7a- Preparation of yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5,6-difluoronaphthalen-2-ol (Compound 90)
  • the third step 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5,6-difluoronaphthalene-2- Preparation of alcohols (compounds 90A or 90B)
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 90A (3.0 mg, yield: 4.1%) and compound 90B (1.6 mg, yield: 2.3%).
  • Compound 90A retention time is 5.15 minutes
  • Compound 90B retention time is 5.53 minutes
  • Example 17 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 87A or 87B ) preparation
  • the first step 3-(7-(8-bromonaphthalen-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5
  • Example 14 Using the synthetic route of Example 14, the first reaction raw material 1-bromo-8-chloronaphthalene was replaced with 1,8-dibromonaphthalene to obtain the title compound (272 mg, yield: 58.1%).
  • Step 2 4-(8-azabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-((2R,7aS)-2-fluoro Preparation of hexahydro-1H-pyrrolazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 87)
  • the third step 4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-7-(8-bromonaphthalen-1-yl)-2-(( 2R,7aS)-2-fluorohexahydro-1H-pyrroazin-7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (Compound 87A or 87B ) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 87A (8.2 mg, yield: 17.5%) and compound 87B (7.0 mg, yield: 15.3%).
  • Example 18 4-(4-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy) Preparation of -5,6-dihydropyrid[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol (Compound 40)
  • the first step 3-(7-(8-Fluoro-3-(methoxymethoxy)naphthalen-1-yl)-2-(hexahydro-1H-pyrroazin-7a-yl)methoxy) -5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate benzyl ester preparation
  • Step 2 4-(4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-((hexahydro-1H-pyrroazin-7a-yl)methoxy) Preparation of -5,6-dihydropyridine[3,4-d]pyrimidin-7(8H)-yl)-5-fluoronaphthalen-2-ol
  • Example 19 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-bromonaphthalen-2-ol (compound 88A or 88B) preparation
  • the first step 3-(7-(8-bromo-3-(methoxymethoxy)naphthalene-1-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrroleazine -7a-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octane-8 - Preparation of tert-butyl carboxylate
  • Step 2 4-(4-(8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro-1H-pyrrolazine-7a- Preparation of yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-bromonaphthalen-2-ol (Compound 88)
  • the third step 4-(4-((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)-2-((2R,7aS)-2-fluorohexahydro -1H-Pyrrolazin-7a-yl)methoxy)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-5-bromonaphthalen-2-ol (compound 88A or 88B) preparation
  • the crude product of the second step was purified by high performance liquid chromatography to obtain the title compound 88A (3.0 mg, yield: 10.09%) and compound 88B (2.5 mg, yield: 8.41%).
  • Compound 88A retention time is 6 minutes
  • Proteins Tag1-SOS1 and Tag2-KRAS G12D
  • Buffer Diluent Buffer and Detection Buffer
  • KRAS-G12D/SOS1 binding assay kit components Tag1-SOS1, Tag2-KRAS G12D, Anti tag1 tb 3+ and Anti tag2 XL665 are all 1x
  • Protein and label reaction time Incubate at 4°C for 3 hours or extend to overnight
  • Microplate reader parameters BMG PHERAstar Fluorescence, Homogeneous Time Resolved Fluorescence (HTRF) method, excitation wavelength 337nm, emission wavelengths 620nm and 665nm
  • the compounds to be tested were incubated with a mixture of Tag1-SOS1 and Tag2-KRAS G12D and GTP in Diluent Buffer system for 15 minutes at room temperature for protein binding. Add the label diluted in Detection Buffer to the reaction plate, incubate at 4°C for 3 hours or extend to overnight, put the reaction plate in a microplate reader, and use the HTRF method to read the signal value of each well in the plate.
  • the curve was fitted according to a four parameter model and the median inhibitory concentration ( IC50 ) of the compound was calculated.
  • the compounds of the present invention showed strong inhibitory activity.
  • Protein immobilization buffer 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP
  • Running buffer A 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP
  • Running buffer B 10mM HEPES, 150mM NaCl, 0.05% Tween-20 and 10 ⁇ M GDP, 1% DMSO
  • Binding and dissociation time 120s on/200s off
  • Chip surface activation select flow cell 2, automatically inject 10mM NiCl2, the flow rate is 4 ⁇ L/min, and the injection time is 500s.
  • the binding and dissociation signals of the compound and the protein were recorded in real time, and the signal values of the reference channel and the built-in blank control were subtracted (double subtraction) during data processing (Biacore T200 evaluation software).
  • the sensorgrams of the double-subtracted signal values of the reference channel and the built-in blank were fitted with Kinetics or steady-state Affinity (1:1) mode.
  • the affinity of the compound with the protein was characterized by K D value (K d /K a ) , where K d is the dissociation constant and Ka is the binding constant.
  • the compound of the present invention showed a strong affinity.

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Abstract

本发明涉及式I的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，包含其的药物组合物和药盒，其制备方法及其在制备用于预防或治疗KRAS G12D介导的相关疾病的药物中的用途。

Description

一类杂芳环化合物、其制备方法及用途 技术领域
本发明属于药物化学领域，具体涉及一类杂芳环化合物、其制备方法、包含其的药物组合物及其用途。
背景技术
RAS家族是一类具有GTP酶活性的鸟嘌呤核苷酸结合蛋白。作为分子开关，RAS可以实现GDP结合的非激活状态和GTP结合的激活状态的转换，传递细胞接收到的上游信号到下游多种信号通路，调控蛋白质合成、基因转录、细胞生长、分化、凋亡和迁移等。
在癌症研究领域，RAS基因是人类癌症中最普遍的原癌基因之一。RAS突变会导致下游信号通路的持续性激活，促进肿瘤的发生发展。RAS家族包括HRAS、NRAS和KRAS，所有肿瘤类型中约85％的RAS突变发生在KRAS。KRAS突变肿瘤中，KRAS本身的GTP酶活性下降，KRAS持续维持活性状态。KRAS突变与肺癌、胰腺癌和结直肠癌的发生有着密切的关系，且发生在KRAS上12位甘氨酸突变为天冬氨酸(KRAS G12D)的频率最高(约34％)。
针对KRAS G12D小分子抑制剂的研发一直是医药领域的难点之一。勃林格殷格翰公司的BI-2852利用分子胶原理，诱导KRAS G12D形成二聚体，阻断KRAS与下游蛋白的相互作用；Revolution公司利用mTOR抑制剂诱导KRAS G12D蛋白形成三元复合物，阻断KRAS与下游效应蛋白的相互作用；Mirati公司在WO2021041671A1中公开了一类新的KRAS G12D抑制剂，未披露其作用机制。
虽然KRAS已经成为极佳的肿瘤治疗靶点，但尚无以KRAS G12D为靶点的临床验证药物。因此，本领域急需开发结构新颖，生物活性好、成药性高的KRAS G12D靶向抑制剂。
发明概述
一方面，本发明提供了一类杂芳环化合物，这类化合物对靶点KRAS G12D具有很强的抑制作用，因此具有更好的肿瘤治疗效果。本发明的化合物还具有多种优异性质，例如良好的物理化学性质(例如溶解度、物理和/或化学稳定性)和良好的安全性。
所述化合物为式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物：
Figure PCTCN2022081102-appb-000001
其中，
X 1选自N和CR 5；
L选自共价键、-O-、-S-和-NR 6-；
R 1选自氢、C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代；
R 2选自
Figure PCTCN2022081102-appb-000002
每一个X 2各自独立选自N和CR 9；
R 3选自C 1-6烷基和C 1-6卤代烷基；或者
与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基；
R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基各自任选地被一个或多个R 10取代；
R 5选自氢、卤素、氰基、C 1-6烷基和C 1-6卤代烷基；
R 6选自氢和C 1-6烷基；
R 7选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-O-C(O)-R 11、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-NR 11R 12、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-OR 12、-C(O)-NR 11R 12、C 3-10环烷基、C 6-10芳基、5-10元杂芳基和3-12元杂环基，所述环烷基、芳基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1- 6亚烷基-OR 13、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-6卤代烷基；
R 8选自卤素、羟基、氰基、C 1-6烷基、-C 1-6烷基-OH、-C 1-6烷基-氰基和C 1-6卤代烷基；
R 9选自氢、羟基和C 1-6烷基；
R 10选自氢、卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-C 1-6烷基、C 3-10环烷基、3-12元杂环基和5-10元杂芳基，所述烷基、环烷基、杂环基和杂芳基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基和C 1-6卤代烷基的取代基取代；
R 11选自氢、C 1-6烷基、C 1-6卤代烷基、-C 1-6烷基-O-C 1-6烷基、C 3-10环烷基、3-12元杂环基，所述环烷基和杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基的取代基取代；
R 12选自氢和C 1-6烷基；
R 13选自氢、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、3-12元杂环基，所述环烷基和杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基的取代基取代；
R 14选自氢和C 1-6烷基；
m为0、1、2、3或4；
n为0、1或2；并且
o、p、q、r和s各自独立地选自0、1、2或3，条件是o和r不同时为0，且p和q不同时为0。
另一方面，本发明提供了一种药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，以及一种或多种药学上可接受的载体。
另一方面，本发明提供了一种药盒，其包含本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物，以及任选存在的包装和/或说明书。
另一方面，本发明提供了本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物，其用于抑制KRAS G12D。
另一方面，本发明提供了本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物，其用于预防或治疗KRAS G12D介导的相关疾病。
另一方面，本发明提供了本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物或者本发明的药物组合物在制备用于预防或治疗KRAS G12D介导的相关疾病的药物中的用途。
另一方面，本发明提供了预防或治疗KRAS G12D介导的相关疾病的方法，其包括向有此需要的个体给药预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物。
另一方面，本发明提供了制备本发明的化合物的方法。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好 理解，但仍然阐述以下定义以更好地解释本发明。
如本文中所使用，术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，术语“烷基”定义为直链或支链的饱和脂肪族烃基。例如，如本文中所使用，术语“C 1-6烷基”指具有1至6个碳原子的直链或支链的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被一个或多个(诸如1至3个)适合的取代基如卤素取代。
如本文中所使用，术语“烯基”是指具有一个或多个碳-碳双键的直链或支链的脂肪族烃基。例如，本文中所使用的术语“C 2-6烯基”是指具有2至6个碳原子以及一个、两个或三个(优选一个)碳-碳双键的烯基(如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基等)，其任选地被一个或多个(如1至3个)合适的取代基如卤素取代。
如本文中所使用，术语“炔基”是指具有一个或多个碳-碳三键的直链或支链的脂肪族烃基。例如，如本文中所使用的术语“C 2-6炔基”是指具有2至6个碳原子以及一个、两个或三个(优选一个)碳-碳三键的炔基(如乙炔基、1-丙炔基、2-丙炔基、2-丁炔基、3-丁炔基、2-戊炔基、3-戊炔基、4-戊炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基等)，其任选地被一个或多个(如1至3个)合适的取代基如卤素取代。
如本文中所使用，术语“环烷基”指饱和或部分不饱和的非芳族单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统，诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被一个或多个(诸如1至3个)适合的取代基取代。例如，术语“C 3-6环烷基”指具有3至6个成环碳原子的饱和或部分不饱和的非芳族单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被一个或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括氟、氯、溴或碘。
如本文中所使用，术语“卤代烷基”是指被一个或多个(诸如1至3个)相同或不同的卤素原子取代的烷基。例如，术语“C 1-6卤代烷基”指具有1至6个碳原子的卤代烷基，例如-CF 3、-C 2F 5、-CHF 2、-CH 2F、-CH 2CF 3、-CH 2Cl或-CH 2CH 2CF 3等。
如本文中所使用，术语“杂环基”指饱和或部分不饱和的单环或多环基团，例如其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如1个、2个、3个或4个)独立地选自N、O或S(O) t(其中t是0、1或2)的杂原子，例如3-12元杂环基、3-7元杂环基、3-6元杂环基、5-6元杂环基等，多环基团可以为并环、螺环或桥环，例如5-12元并环、5-12元螺环或5-12元桥环。杂环基的代表性实例包括但不限于环氧乙烷基、氮丙啶基、氮杂环丁基(azetidinyl)、氧杂环丁基(oxetanyl)、四氢呋喃基、吡咯烷基、六氢-1H-吡咯啉基、六氢吡咯嗪基、吡咯烷酮基、咪唑烷基、吡唑烷基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基等。
如本文中所使用，术语“芳基”或“芳环”指具有共轭π电子系统的全碳单环或稠合多环芳族基团。例如，术语“C 6-10芳基”或“C 6-10芳环”指含有6至10个碳原子的芳族基团，诸如苯基(环)或萘基(环)。芳基任选地被一个或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。
如本文中所使用，术语“杂芳基”或“杂芳环”指含有至少一个选自N、O和S的杂原子的单环、双环或三环芳族环系，例如具有5、6、8、9、10、11、12、13或14个环原子，特别是含有1或2或3或4或5或6或9或10个碳原子，并且，另外在每一种情况下可为苯并稠合的。例如，杂芳基或杂芳环可选自噻吩基(环)、呋喃基(环)、吡咯基(环)、噁唑基(环)、噻唑基(环)、咪唑基(环)、吡唑基(环)、异噁唑基(环)、异噻唑基(环)、噁二唑基(环)、三唑基(环)、噻二唑基(环)等，以及它们的苯并衍生物；或吡啶基(环)、哒嗪基(环)、嘧啶基(环)、吡嗪基(环)、三嗪基(环)等，以及它们的苯并衍生物。
术语“取代”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被….取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的取代基替代或未替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的取代基替代或未替代。
如果取代基被描述为“独立地选自”一组基团，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括但不限于氢的同位素(例如 2H、 3H、氘D、氚T)；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 37Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。
术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本发明的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于：药学上可接受的盐、溶剂合物或代谢物，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。适合的酸加成盐由形成药学上可接受盐的酸来形成。适合的碱加成盐由形成药学上可接受盐的碱来形成。适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky 和A.J.Boulton,Eds.,Academic Press。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley & Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，可以在适当的后续阶段移除保护基。
术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
化合物
本发明的一个目的在于提供一种式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物：
Figure PCTCN2022081102-appb-000003
其中，
X 1选自N和CR 5；
L选自共价键、-O-、-S-和-NR 6-；
R 1选自氢、C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代；
R 2选自
Figure PCTCN2022081102-appb-000004
每一个X 2各自独立选自N和CR 9；
R 3选自C 1-6烷基和C 1-6卤代烷基；或者
与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基；
R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基各自任选地被一个或多个R 10取代；
R 5选自氢、卤素、氰基、C 1-6烷基和C 1-6卤代烷基；
R 6选自氢和C 1-6烷基；
R 7选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-O-C(O)-R 11、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-NR 11R 12、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-OR 12、-C(O)-NR 11R 12、C 3-10环烷基、C 6-10芳基、5-10元杂芳基和3-12元杂环基，所述环烷基、芳基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1- 6亚烷基-OR 13、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-6卤代烷基；
R 8选自卤素、羟基、氰基、C 1-6烷基、-C 1-6烷基-OH、-C 1-6烷基-氰基和C 1-6卤代烷基；
R 9选自氢、羟基和C 1-6烷基；
R 10选自氢、卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-C 1-6烷基、C 3-10环烷基、3-12元杂环基和5-10元杂芳基，所述烷基、环烷基、杂环基和杂芳基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基和C 1-6卤代烷基的取代基取代；
R 11选自氢、C 1-6烷基、C 1-6卤代烷基、-C 1-6烷基-O-C 1-6烷基、C 3-10环烷基、3-12元杂环基，所述环烷基和杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基的取代基取代；
R 12选自氢和C 1-6烷基；
R 13选自氢、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、3-12元杂环基，所述环烷基和杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基的取代基取代；
R 14选自氢和C 1-6烷基；
m为0、1、2、3或4；
n为0、1或2；
o、p、q、r和s各自独立地选自0、1、2或3，条件是o和r不同时为0，且p和q不同时为0。
根据本发明的一些实施方案，R 7选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-O-C(O)-R 11、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-NR 11R 12、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-OR 12、-C(O)-NR 11R 12、C 3-10环烷基和3-12元杂环基，所述环烷基和杂环基任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基和C 1-6卤代烷基。
根据本发明的一些实施方案，X 1选自选自N和CH。在优选的实施方案中，X 1为N。
根据本发明的一些实施方案，X 2选自CR 9。在优选地实施方案中，X 2选自CH。
根据本发明的一些实施方案，L选自共价键、-O-、-S-、-NH-和-N(C 1-3烷基)-。在优选的实施方案中，L选自-O-、-NH-和-N(C 1-3烷基)-。在特别优选的实施方案中，L为-O-。
根据本发明的一些实施方案，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-NR 11R 12、C 3-10环烷基、C 6-10芳基、5-10元杂芳基和3-12元杂环基，所述环烷基、芳基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-6亚烷基-OR 13、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-6卤代烷基。优选地，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-NR 11R 12、C 3-10环烷基和3-12元杂环基，所述环烷基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基和C 1-6卤代烷基。
在一些优选的实施方案中，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-NR 11R 12、C 3-6环烷基、5-10元杂芳基和3-12元杂环基，所述环烷基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13、C 1-3卤代烷基和C 1-6烷基。优选地，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-NR 11R 12和3-12元杂环基，所述杂环基任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基和C 1-6烷基。
在一些优选的实施方案中，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-NR 11R 12、5-10元杂芳基和3-12元杂环基，所述杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13、C 1-3卤代烷基和C 1-6烷基。优选地，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-NR 11R 12和3-12元杂环基，所述杂环基任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基和C 1-6烷基。
在一些优选的实施方案中，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自C 3-6环烷基、5-6元杂芳基和5-8元杂环基，所述C 3-6环烷基、5-6元杂芳基和5-8元杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-3亚 烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-3卤代烷基；其中R 13选自C 1-6烷基和5-6元杂环基；R 14选自氢和C 1-6烷基。
在一些优选的实施方案中，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自5-6元杂芳基和5-8元杂环基，所述5-6元杂芳基和5-8元杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-3卤代烷基；其中R 13选自C 1-6烷基和5-6元杂环基；R 14选自氢和C 1-6烷基。
在一些优选的实施方案中，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基，所述环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-3卤代烷基；其中R 13选自C 1-6烷基和吗啉基；R 14为C 1-6烷基。
在一些优选的实施方案中，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自吡咯烷基、六氢吡咯嗪基和咪唑基，所述吡咯烷基、六氢吡咯嗪基和咪唑基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-3卤代烷基；其中R 13选自C 1-6烷基和吗啉基；R 14为C 1-6烷基。
在一些优选的实施方案中，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基，所述环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-吗啉基、-C 1-3亚烷基-OH、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1-6亚烷基-O-C(O)-(吗啉基)和C 1-3卤代烷基。
在一些优选的实施方案中，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自吡咯烷基、六氢吡咯嗪基和咪唑基，所述吡咯烷基、六氢吡咯嗪基和咪唑基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-吗啉基、-C 1-3亚烷基-OH、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1-6亚烷基-O-C(O)-(吗啉基)和C 1-3卤代烷基。
在一些优选的实施方案中，R 1选自
Figure PCTCN2022081102-appb-000005
Figure PCTCN2022081102-appb-000006
Figure PCTCN2022081102-appb-000007
其中波浪线
Figure PCTCN2022081102-appb-000008
表示该基团与分子其余部分的连接点。
在一些优选的实施方案中，R 1选自
Figure PCTCN2022081102-appb-000009
Figure PCTCN2022081102-appb-000010
Figure PCTCN2022081102-appb-000011
其中波浪线
Figure PCTCN2022081102-appb-000012
表示该基团与分子其余部分的连接点。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-6烷基、C 1-6亚烷基-OH或C 1-6卤代烷基取代的5-12元并环杂环基和5-10元杂芳基。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-6烷基、C 1-6亚烷基-OH或C 1-6卤代烷基取代的5-12元并环杂环基。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的5-8元并环杂环基和5-10元杂芳基。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的5-8元并环杂环基。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的5-8元含氮并环杂环基和5-10元杂芳基。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的5-8元含氮并环杂环基。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的六氢吡咯嗪基和咪唑。
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的六氢吡咯嗪基。在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个F、Cl、甲基、氯代甲基、氟代甲基或羟甲基取代的六氢吡咯嗪基和咪唑。
在一些优选的实施方案中，R 1选自
Figure PCTCN2022081102-appb-000013
Figure PCTCN2022081102-appb-000014
根据本发明的一些实施方案，R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基各自任选地被一个或多个R 10取代，每个R 10各自独立地选自氢、卤素、羟基、氰基、C 1-3烷基、C 2-4烯基、C 2-4炔基、-O-C 1-3烷基、C 3-6环烷基和3-8元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-3烷基和C 1-3卤代烷基的取代基取代。
在一些优选的实施方案中，R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基任选地被一个或多个R 10取代，每个R 10各自独立地选自氢、卤素、羟基、C 1-3烷基、C 2-4炔基、-O-C 1-3烷基和C 3-6环烷基，所述烷基任选地被一个或多个氢和卤素取代。
在一些优选的实施方案中，R 4选自苯基、萘基和吲唑基，所述苯基、萘基和吲唑基各自任选地被一个或多个R 10取代，每个R 10各自独立地选自氢、卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 2-4炔基、-O-C 1-3烷基和C 3-6环烷基。
在一些优选的实施方案中，R 4选自
Figure PCTCN2022081102-appb-000015
Figure PCTCN2022081102-appb-000016
在一些优选的实施方案中，R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-6烷基、C 1-6亚烷基-OH或C 1-6卤代烷基取代的3-6元杂环基；且R 4选自C 6-10芳基，所述芳基任选地被一个R 10取代，R 10选自卤素、羟基、C 1-6烷基、C 2-6烯基和C 2-6炔基，所述烷基任选地被一个或多个选自卤素、羟基、氰基、C 1-6烷基和C 1-6卤代烷基的取代基取代。
在一些优选的实施方案中，R 1选自任选地被一个R 7取代的C 1-6烷基，R 7选自任选地被一个或多个卤素、C 1-6烷基、C 1-6亚烷基-OH或C 1-6卤代烷基取代的含5-6元含氮杂环基；且R 4为萘基，所述萘基任选地被一个R 10取代，R 10选自卤素、羟基、C 1-6烷基、C 2-6烯基和C 2-6炔基，所述烷基任选地被一个或多个选自卤素、羟基、氰基、C 1-6烷基和C 1-6卤代烷基的取代基取代。
在一些优选的实施方案中，R 1选自任选地被一个R 7取代的C 1-6烷基，R 7选自任选地被C 1-3烷基取代的四氢吡咯基；且R 4为萘基，所述萘基任选地被一个R 10取代，R 10选自卤素、羟基、C 1-6烷基、C 2-6烯基和C 2-6炔基，所述烷基任选地被一个或多个选自卤素、羟基、氰基、C 1-6烷基和C 1-6卤代烷基的取代基取代。
根据本发明的一些实施方案，每个R 3各自独立地选自C 1-6烷基和C 1-6卤代烷基，或者与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基或C 3-6环烷基。
在一些优选的实施方案中，每个R 3各自独立地选自C 1-3烷基，或者与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基或C 3-6环烷基。
在特别优选的实施方案中，每个R 3各自独立地选自甲基，或者与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基或环丙基。
根据本发明的一些实施方案，R 2选自
Figure PCTCN2022081102-appb-000017
在本发明的一些实施方案中，R 2选自
Figure PCTCN2022081102-appb-000018
本发明涵盖对上述优选基团进行任意组合所得的式(I)的化合物。
根据本发明的一些实施方案，本发明的化合物具有式(II-A)、式(II-B)或式(II-C)的结构：
Figure PCTCN2022081102-appb-000019
其中，各基团L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如上文所定义。
根据本发明的一些实施方案，本发明的化合物具有式(II-A)或式(II-C)的结构，其中L选自共价键、-O-、-S-和-NH-；优选地，L选自-O-和-S-；更优选地，L选自-O-。
根据本发明的一些实施方案，本发明的化合物具有式(II-A)或式(II-C)的结构，其中o、p、q、r和s各自独立地选自0、1或2；优选地，o、p、q和r各自独立地选自0或1，s选自1或2；优选地，o和p选自0或1，q和r选自1，s选自1或2；优选地，o和p选自0，q和r选自1，s选自2。
根据本发明的一些实施方案，本发明的化合物具有式(II-A)或式(II-C)的结构，其中n为0或1；优选为0。
根据本发明的一些实施方案，本发明的化合物具有式(II-A)或式(II-C)的结构，其中m为0、1或2。
在一些优选的实施方案中，本发明的化合物具有式(II-A-1)、(II-A-2)、(II-C-1)、(II-C-2)或(II-C-3)的结构：
Figure PCTCN2022081102-appb-000020
其中，各基团L、R 1、R 3、R 4和m如上文所定义。
本发明的上述式(I)、式(II-A)、式(II-B)、式(II-C)、式(II-A-1)、(II-A-2)、(II-C-1)、(II-C-2)或(II-C-3)中，所有实施方案的基团可以适宜地选择任意组合，从而得到不同的通式范围或具体方案。这些范围和方案均属于本发明。
本发明涵盖对各个实施方案进行任意组合所得的化合物。
根据本发明的一些实施方案，本发明的化合物选自：
Figure PCTCN2022081102-appb-000021
Figure PCTCN2022081102-appb-000022
Figure PCTCN2022081102-appb-000023
Figure PCTCN2022081102-appb-000024
Figure PCTCN2022081102-appb-000025
Figure PCTCN2022081102-appb-000026
Figure PCTCN2022081102-appb-000027
Figure PCTCN2022081102-appb-000028
Figure PCTCN2022081102-appb-000029
Figure PCTCN2022081102-appb-000030
Figure PCTCN2022081102-appb-000031
制备方法
本发明的另一目的在于提供制备本发明的化合物的方法。例如，本发明提供了一种制备式(II-A)的化合物的方法，其包括以下步骤：
路线1
Figure PCTCN2022081102-appb-000032
其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如上文所定义；
LG 1、LG 2和X表示离去基团，所述离去基团包括但不限于卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基等；
PG 1、PG 2和PG 3表示羟基或氨基的保护基团，包括但不限于苄氧羰基(Cbz)、叔丁氧羰基(Boc)、甲基和苄基等。
步骤(1)使化合物II-A-1与化合物II-A-2反应以得到化合物II-A-3；
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自甲醇、甲苯、四氢呋喃、1,4-二氧六环及其任意组合，优选甲醇。
所述反应优选在适合的有机碱或无机碱的存在下进行，所述有机碱或无机碱可选自二异丙基乙胺、三乙胺、甲醇钠、叔丁醇钠，优选甲醇钠。
所述反应在适合的温度下进行，所述温度优选为0-80℃。
所述反应进行合适的时间，例如2-24小时。
步骤(2)使化合物II-A-3与化合物II-A-4进行偶联反应以得到化合物II-A-5；
所述偶联反应优选在金属催化剂、配体和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述配体是磷配体，例如4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、2-二环己基膦-2′,6′-二甲氧基-联苯，优选4,5-双二苯基膦-9,9-二甲基氧杂蒽。所述碱是有机碱或无机碱，例如二异丙基乙胺、三乙胺、叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(3)使化合物II-A-5进行脱保护反应以得到化合物II-A-6；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自乙酸乙酯、甲醇、1,4-二氧六环、二氯甲烷及其任意组合，优选二氯甲烷。
所述脱保护反应优选在适合的酸的存在下进行。所述酸可选自盐酸、氢溴酸、对甲苯磺酸、甲 烷磺酸、三氟乙酸，优选三氟乙酸。
所述脱保护反应在适合的温度下进行，所述温度优选为0-40℃。
所述反应进行合适的时间，例如2-12小时。
步骤(4)使化合物II-A-6与化合物II-A-7进行偶联反应以得到化合物II-A-8；
所述偶联反应优选在金属催化剂、配体和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯，优选三(二亚苄基丙酮)二钯。所述配体是磷配体，例如4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、2-二环己基膦-2′,6′-二甲氧基-联苯，优选2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯。所述碱是有机碱或无机碱，例如叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(5)使化合物II-A-8进行脱保护反应以得到化合物II-A-9；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自醇类质子溶剂、四氢呋喃、N,N-二甲基甲酰胺及其任意组合，优选N,N-二甲基甲酰胺。
所述脱保护反应优选在乙硫醇钠的存在下进行。
所述脱保护反应在适合的温度下进行，所述温度优选为50-100℃。
所述反应进行合适的时间，例如1-12小时。
步骤(6)使化合物II-A-9与化合物II-A-10进行缩合反应以得到化合物II-A-11；
所述缩合反应优选在适合的有机溶剂中进行。所述有机溶剂可选自四氢呋喃、N,N-二甲基甲酰胺、二氯甲烷及其任意组合，优选N,N-二甲基甲酰胺。
所述缩合反应优选在适合的有机碱的存在下进行，所述有机碱可选自二异丙基乙胺、三乙胺、1,8-二氮杂二环[5.4.0]十一碳-7-烯，优选1,8-二氮杂二环[5.4.0]十一碳-7-烯。
所述缩合反应在适合的缩合剂的存在下进行，所述缩合剂可选自卡特缩合剂、1-羟基苯并三唑、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯，优选卡特缩合剂。
所述脱保护反应在适合的温度下进行，所述温度优选为20-100℃。
所述反应进行合适的时间，例如2-24小时。
步骤(7)使化合物II-A-11进行脱保护反应以得到化合物II-A；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自乙酸乙酯、甲醇、1,4-二氧六环、二氯甲烷及其任意组合，优选二氯甲烷。
所述脱保护反应优选在适合的酸的存在下进行。所述酸可选自盐酸、氢溴酸、对甲苯磺酸、甲烷磺酸、三氟乙酸，优选三氟乙酸。
所述脱保护反应在适合的温度下进行，所述温度优选为0-40℃。
所述反应进行合适的时间，例如2-12小时。
本发明提供了第二种制备式(II-A)的化合物的方法，其包括以下步骤：
路线2
Figure PCTCN2022081102-appb-000033
其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如上文所定义；
LG 1、LG 2和X表示离去基团，所述离去基团包括但不限于卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基等；
PG 1和PG 3表示氨基的保护基团，包括但不限于苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基等；
步骤(1)使化合物II-A-1与化合物II-A-10反应以得到化合物IIa-A-2；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯、四氢呋喃、1,4-二氧六环及其任意组合，优选N,N-二甲基甲酰胺。
所述反应优选在适合的有机碱或无机碱的存在下进行，所述有机碱或无机碱可选自N,N-二异丙基乙胺、三乙胺、甲醇钠、叔丁醇钠，优选N,N-二异丙基乙胺。
所述反应在适合的温度下进行，所述温度优选为20-100℃。
所述反应进行合适的时间，例如1-12小时。
步骤(2)使化合物IIa-A-2与化合物II-A-4进行偶联反应以得到化合物IIa-A-3；
所述偶联反应优选在金属催化剂、配体和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述配体是磷配体，例如4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、2-二环己基膦-2′,6′-二甲氧基-联苯，优选4,5-双二苯基膦-9,9-二甲基氧杂蒽。所述碱是有机碱或无机碱，例如二异丙基乙胺、三乙胺、叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(3)使化合物IIa-A-3进行脱保护反应以得到化合物IIa-A-4；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自乙酸乙酯、甲醇、1,4-二氧六环、二氯甲烷及其任意组合，优选二氯甲烷。
所述脱保护反应优选在适合的酸的存在下进行。所述酸可选自盐酸、氢溴酸、对甲苯磺酸、甲烷磺酸、三氟乙酸，优选三氟乙酸。
所述脱保护反应在适合的温度下进行，所述温度优选为0-40℃。
所述反应进行合适的时间，例如2-12小时。
步骤(4)使化合物IIa-A-4与化合物II-A-7进行偶联反应以得到化合物II-A-11；
所述偶联反应优选在金属催化剂、配体和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯，优选三(二亚苄基丙酮)二钯。所述配体是磷配体，例如4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、2-二环己基膦-2′,6′-二甲氧基-联苯、1,1'-双(二苯基膦)二茂铁，优选1,1'-双(二苯基膦)二茂铁。所述碱是有机碱或无机碱，例如叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和甲苯。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(5)使化合物II-A-11进行脱保护反应以得到化合物II-A；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自醇类质子溶剂、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺及其任意组合，优选二氯甲烷。
所述反应在适合的脱保护试剂的存在下进行。所述脱保护试剂可选自三甲基碘硅烷、氢溴酸乙酸溶液、三氟醋酸，优选三甲基碘硅烷或氢溴酸乙酸溶液。
所述脱保护反应在适合的温度下进行，所述温度优选为0-100℃。
所述反应进行合适的时间，例如0.5-12小时。
本发明提供了第三种制备式(II-A)的化合物的方法，其包括以下步骤：
路线3
Figure PCTCN2022081102-appb-000034
其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如上文所定义；
LG 1和X表示离去基团，所述离去基团包括但不限于卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基等；
PG 1和PG 3表示氨基的保护基团，包括但不限于苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基等；
步骤(1)使化合物IIb-A-1进行关环反应以得到化合物IIb-A-2；
所述关环反应优选在适合的有机溶剂中进行。所述有机溶剂可选甲醇、乙醇、四氢呋喃及其任意组合，优选甲醇。
所述反应优选在适合的有机碱的存在下进行，所述有机碱可选自乙醇钠、甲醇钠、叔丁醇钠，优选甲醇钠。
所述反应在适合的温度下进行，所述温度优选为20-60℃。
所述反应进行合适的时间，例如12-36小时。
步骤(2)使化合物IIb-A-2进行取代反应以得到化合物IIb-A-3；
所述反应在适合的取代试剂的存在下进行，所述试剂是三氟甲磺酸酐、三氯氧磷、三溴氧磷、卡特缩合剂，优选三氟甲磺酸酐。
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选二氯甲烷、甲苯、四氢呋喃及其任意组合，优选二氯甲烷。
所述反应优选在适合的有机碱或无机碱的存在下进行，所述有机碱例如N,N-二异丙基乙胺、三乙胺、N,N-二甲基苯胺，优选N,N-二异丙基乙胺。
所述反应在适合的温度下进行，所述温度优选为0℃-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(3)使化合物IIb-A-3与化合物II-A-10反应以得到化合物IIb-A-4；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选自N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯、四氢呋喃、1,4-二氧六环及其任意组合，优选N,N-二甲基甲酰胺。
所述反应优选在适合的有机碱或无机碱的存在下进行，所述有机碱或无机碱可选自N,N-二异丙基乙胺、三乙胺、甲醇钠、叔丁醇钠，优选N,N-二异丙基乙胺。
所述反应在适合的温度下进行，所述温度优选为20-100℃。
所述反应进行合适的时间，例如1-12小时。
步骤(4)使化合物IIb-A-4进行脱保护反应以得到化合物IIb-A-5；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自乙酸乙酯、甲醇、1,4-二氧六环、二氯甲烷及其任意组合，优选二氯甲烷。
所述脱保护反应优选在适合的酸的存在下进行。所述酸可选自盐酸、氢溴酸、对甲苯磺酸、甲烷磺酸、三氟乙酸，优选三氟乙酸。
所述脱保护反应在适合的温度下进行，所述温度优选为0-40℃。
所述反应进行合适的时间，例如2-12小时。
步骤(5)使化合物IIb-A-5与化合物II-A-7进行偶联反应以得到化合物IIb-A-6；
所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯、甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)，优选甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)。所述碱是有机碱或无机碱，例如叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选甲苯。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(6)使化合物IIb-A-6进行氧化反应以得到化合物IIb-A-7；
所述氧化反应优选在适合的有机溶剂中进行。所述有机溶剂可选自乙酸乙酯、甲醇、1,4-二氧六环、二氯甲烷及其任意组合，优选二氯甲烷。
所述氧化反应在适合的氧化剂的存在下进行。所述氧化剂可选自双氧水、间氯过氧苯甲酸、过硫酸氢钾。优选间氯过氧苯甲酸。
所述脱保护反应在适合的温度下进行，所述温度优选为0-40℃。
所述反应进行合适的时间，例如0.5-12小时。
步骤(7)使化合物IIb-A-7与化合物II-A-4进行取代反应以得到化合物II-A-11；
所述取代反应优选在适合的有机溶剂中进行。所述有机溶剂可选二氯甲烷、甲苯、四氢呋喃及其任意组合，优选甲苯。
所述取代反应优选在适合的有机碱或无机碱的存在下进行，例如叔丁醇钠、叔丁醇钾、碳酸钾、碳酸铯、碳酸钠、氢化钠，优选叔丁醇钾。
所述取代反应在适合的温度下进行，所述温度优选为0℃-40℃。
所述反应进行合适的时间，例如0.5-16小时。
步骤(8)使化合物II-A-11进行脱保护反应以得到化合物II-A；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自醇类质子溶剂、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺及其任意组合，优选二氯甲烷。
所述反应在适合的脱保护试剂的存在下进行。所述脱保护试剂可选自三甲基碘硅烷、氢溴酸乙酸溶液、三氟醋酸。优选三甲基碘硅烷或氢溴酸乙酸溶液。
所述脱保护反应在适合的温度下进行，所述温度优选为0-100℃。
所述反应进行合适的时间，例如0.5-12小时。
本发明提供了制备式(II-C)的化合物的方法，其包括以下步骤：
路线4
Figure PCTCN2022081102-appb-000035
其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如上文所定义；
LG 1表示离去基团，所述离去基团包括但不限于卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基等；
PG 3表示氨基的保护基团，包括但不限于苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基等；
(1)使化合物II-A-9进行反应以得到化合物II-C-1；
所述反应在适合的卤代或拟卤代试剂的存在下进行，所述试剂是三氟甲磺酸酐、三氯氧磷、三溴氧磷，优选三氟甲磺酸酐。
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选二氯甲烷、甲苯、四氢呋喃及其任意组合，优选二氯甲烷。
所述反应优选在适合的有机碱或无机碱的存在下进行，所述有机碱例如N,N-二异丙基乙胺、三乙胺、N,N-二甲基苯胺，优选N,N-二异丙基乙胺。
所述反应在适合的温度下进行，所述温度优选为-70℃-100℃。
所述反应进行合适的时间，例如1-16小时。
(2)使化合物II-C-1与化合物II-C-2进行偶联反应以得到化合物II-C-3；
所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂， 例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、四(三苯基膦)钯、醋酸钯，优选[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。所述碱是有机碱或无机碱，例如N,N-二异丙基乙胺、三乙胺、叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸钠。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的组合。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
(3)使化合物II-C-3进行还原反应以得到化合物II-C-4；
所述还原反应优选在金属催化剂的存在下进行。优选地，所述金属催化剂是钯金属催化剂或铂金属催化剂，例如钯碳、氢氧化钯、二氧化铂，优选钯碳。
所述还原反应优选在氢气的存在下进行。
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃及其任意组合，优选甲醇。
所述反应在适合的温度下进行，所述温度优选为20-60℃。
所述反应进行合适的时间，例如2-16小时。
(4)使化合物II-C-4进行脱保护反应以得到化合物II-C；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自醇类质子溶剂、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺及其任意组合，优选二氯甲烷。
所述反应在适合的脱保护试剂下进行。所述脱保护试剂可选自三甲基碘硅烷、氢溴酸乙酸溶液、三氟醋酸。优选氢溴酸乙酸溶液。
所述脱保护反应在适合的温度下进行，所述温度优选为0-100℃。
所述反应进行合适的时间，例如0.5-12小时。
本发明提供了制备式(II-C)的化合物的第二种方法，其包括以下步骤：
路线5
Figure PCTCN2022081102-appb-000036
其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如上文所定义；
LG 1、LG 2和X表示离去基团，所述的离去基团包括但不限于卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基等；
PG 1和PG 3表示氨基的保护基团，包括但不限于苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基等；
步骤(1)使化合物II-A-1与化合物II-C-2进行偶联反应以得到化合物IIa-C-3；
所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、四(三苯基膦)钯、醋酸钯，优选[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。所述碱是有机碱或无机碱，例如 N,N-二异丙基乙胺、三乙胺、叔丁醇钠、碳酸钾、碳酸铯、醋酸钾、碳酸钠，优选醋酸钾。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环和水的组合。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(2)使化合物IIa-C-3与化合物II-A-4进行偶联反应以得到化合物IIa-C-4；
所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯，优选甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)。所述碱是有机碱或无机碱，例如二异丙基乙胺、三乙胺、叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选甲苯。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(3)使化合物IIa-C-4进行脱保护反应以得到化合物IIa-C-5；
所述反应优选在金属催化剂的存在下进行。优选地，所述金属催化剂是钯金属催化剂或铂金属催化剂，例如钯碳、氢氧化钯、二氧化铂，优选钯碳。
所述反应优选在氢气的存在下进行。
所述反应优选在适合的有机溶剂中进行，所述有机溶剂可选自氨甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃及其任意组合，优选氨甲醇。
所述反应在适合的温度下进行，所述温度优选为20-60℃。
所述反应进行合适的时间，例如2-16小时。
步骤(4)使化合物IIa-C-5与化合物II-A-7进行偶联反应以得到化合物II-C-4；
所述偶联反应优选在金属催化剂、配体和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯、醋酸钯，优选三(二亚苄基丙酮)二钯。所述配体是磷配体，例如4,5-双二苯基膦-9,9-二甲基氧杂蒽、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、2-二环己基膦-2′,6′-二甲氧基-联苯，优选2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯。所述碱是有机碱或无机碱，例如叔丁醇钠、碳酸钾、碳酸铯、碳酸钠，优选碳酸铯。
所述反应优选在适合的溶剂中进行，所述溶剂可选自N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲苯、乙醇、乙二醇二甲醚、水、1,4-二氧六环及其任意组合，优选1,4-二氧六环。
所述反应在适合的温度下进行，所述温度优选为50-120℃。
所述反应进行合适的时间，例如2-16小时。
步骤(5)使化合物II-C-4进行脱保护反应以得到化合物II-C；
所述脱保护反应优选在适合的有机溶剂中进行。所述有机溶剂可选自醇类质子溶剂、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺及其任意组合，优选二氯甲烷。
所述反应在适合的脱保护试剂的存在下进行。所述脱保护试剂可选自三甲基碘硅烷、氢溴酸乙酸溶液、三氟乙酸，优选三氟乙酸。
所述脱保护反应在适合的温度下进行，所述温度优选为0-80℃。
所述反应进行合适的时间，例如0.5-12小时。
上述各反应步骤的具体条件为本领域公知，对此本发明不作具体限定。根据本发明的教导结合本领域公知常识，本领域技术人员可以对通式中的各取代基进行选择替换以制备得到不同的化合物，这些选择和替换均在本发明的保护范围之内。
药物组合物和药盒
本发明的另一目的在于提供一种药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，以及一种或多种药学上可接受的载体。
本发明的另一目的在于提供一种药盒，其包含本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的 药物组合物，以及任选存在的包装和/或说明书。
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物或药物制剂中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油。
所述药物组合物可以例如是固体制剂、半固体制剂、液体制剂或气态制剂等的形式。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药或者通过口服给药。
本发明的化合物在药物组合物中的含量或用量可以是约0.001mg至约1000mg。
在一些实施方案中，本发明提供制备本发明的药物组合物的方法，所述方法包括将本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物与一种或多种药学上可接受的载体组合。
治疗方法和用途
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物，其用于抑制KRAS G12D。
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物，其用于预防或治疗KRAS G12D介导的相关疾病。
本发明的另一目的在于提供本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物或者本发明的药物组合物在制备用于预防或治疗KRAS G12D介导的相关疾病的药物中的用途。
本发明的另一目的在于提供预防或治疗KRAS G12D介导的相关疾病的方法，其包括向有此需要的个体给药预防或治疗有效量的本发明的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者本发明的药物组合物。
根据本发明的一些实施方案，所述KRAS G12D介导的相关疾病为肿瘤，优选地，所述KRAS G12D介导的相关疾病为癌症。
如本文中所使用的术语“有效量”是指足以实现所需预防或治疗效果的量，例如，实现减轻与待治疗疾病相关的一或多种症状的量。
可调整给药方案以提供最佳所需响应。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其它情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文中所使用，术语“预防”包括抑制和延迟疾病的发作，并且不仅包括在发展疾病之前的预防，还包括在治疗后预防疾病的复发。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合实施例对本发明的实施方案进行详细描述。但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，均按照常规条件或制造商建议的条件进行。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。
化合物的结构是通过核磁共振( 1H NMR)或质谱(MS)来确定的。 1H NMR的测定仪器为JEOL Eclipse 400核磁仪，测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)或六氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)，化学位移(δ)以百万分之一(ppm)的单位给出。
MS的测定仪器为Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。
制备高效液相色谱仪的制备方法：
仪器型号：Agilent 1260，色谱柱：Waters SunFire Prep C18OBD(19mm×150mm×5.0μm)；色谱柱温：25℃；流速：20.0mL/min；检测波长：214nm；洗脱梯度：(0min：10％A，90％B；16.0min：90％A，10％B)；流动相A：乙腈；流动相B：0.05％甲酸水溶液。
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的规格是烟台产GF 254(1mm)。
反应的监测采用薄层色谱法(TLC)或LC-MS；使用的展开剂体系包括：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、以及石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。
微波反应使用Biotage Initiator+(400W,RT～300℃)微波反应器。
柱层析一般使用200～300目硅胶为载体。洗脱剂体系包括：二氯甲烷和甲醇体系、以及石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。
实施例中无特殊说明，反应的温度为室温(20℃～35℃)；
本发明所使用的试剂购自Acros Organics、Aldrich Chemical Company、特伯化学等公司。
在常规的合成法以及实施例和中间体合成例中，各缩写的意思如以下所示。
缩写 含义
TLC 薄层色谱法
LC-MS 液相色谱-质谱联用
DMF N,N-二甲基甲酰胺
Pd(dppf)Cl 2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯
CD 3OD 氘代甲醇
CDCl 3 氘代氯仿
DMSO-d 6 六氘代二甲基亚砜
TMS 四甲基硅烷
NMR 核磁共振
MS 质谱
Boc 叔丁氧羰基
Cbz 苄氧羰基
s 单峰(singlet)
d 二重峰(doublet)
t 三重峰(triplet)
q 四重峰(quartet)
dd 双二重峰(double doublet)
m 多重峰(multiplet)
br 宽峰(broad)
J 偶合常数
Hz 赫兹
中间体制备例
中间体制备例1：(S)-7-(8-氯萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇的制备
Figure PCTCN2022081102-appb-000037
第一步：2-氯-4-甲氧基-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将钠(175.6mg,7.64mmol)溶于甲醇(20mL)中，完全溶解后，冷却体系到0℃，加入2,4-二氯-5,6-二氢吡啶并[3,4-d]嘧啶-7(6H)-甲酸叔丁酯(2.11g,6.94mmol)的甲醇(20mL)溶液，于15℃搅拌4小时，浓缩，用乙酸乙酯(50mL)稀释，用水(30mL)洗两次，干燥，浓缩，得到本步的标题化合物(1.95g，收率：94％)。
MS m/z(ESI):300.0[M+H] +。
第二步：(S)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将2-氯-4-甲氧基-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(1.95g,6.52mmol)和N-甲基-L-脯氨醇(1.58g,13.04mmol)溶于1,4-二氧六环(30mL)中，加入碳酸铯(6.44g,19.56mmol)，氮气置换三次，加入Pd(dppf)Cl 2(486.71mg,0.65mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(794.07mg,1.30mmol)，于100℃搅拌12小时，冷却到室温，加水(40mL)，用乙酸乙酯(30mL)萃取三次，干燥，浓缩，经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到本步的标题化合物(2.3g，收率：93％)。
MS m/z(ESI):379.1[M+H] +。
第三步：(S)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶三氟乙酸盐的制备
将(S)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(2.3g,6.60mmol)溶于二氯甲烷(20mL)中，滴加三氟乙酸(10mL)，于室温搅拌2小时，浓缩，得到本步的标题化合物(3.9g，收率：94％)。
MS m/z(ESI):279.1[M+H] +。
第四步：(S)-7-(8-氯萘-1-基)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将(S)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶三氟乙酸盐(3.9g, 7.7mmol)和1-溴-8-氯萘(2.42g,10.02mmol)溶于干燥的1,4-二氧六环(80mL)中，加入碳酸铯(17.68g,54.21mmol)，氮气保护下，加入三(二亚苄基丙酮)二钯(1.06g,1.15mmol)和2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(718mg,1.54mmol)，于95℃搅拌10小时，加水(50mL)，用乙酸乙酯(40mL)萃取三次，浓缩，经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到本步的标题化合物(1.70g，收率：96.5％)。
MS m/z(ESI):439.0[M+H] +。
第五步：(S)-7-(8-氯萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇的制备
将(S)-7-(8-氯萘-1-基)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(1.70g,3.87mmol)溶于DMF(25mL)中，加入乙硫醇钠(1.30g,15.49mmol)，于100℃搅拌1小时，加入氯化铵的水溶液(50mL)，用乙酸乙酯(25mL)萃取三次，然后用氯仿(30mL)萃取两次，干燥，浓缩得到本步的标题化合物(1.5g，收率：91.1％)。
MS m/z(ESI):425.1[M+H] +。
中间体制备例2：3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
Figure PCTCN2022081102-appb-000038
第一步：8-苄基-3-叔丁基3,8-二氮杂双环[3.2.1]辛烷-3,8-二羧酸酯的制备
将3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(5.0g,23.55mmol)溶于二氯甲烷(50mL)中。在氮气保护下，加入N,N-二异丙基乙胺(9.22g,70.66mmol)。将体系冷却至0℃，向其中滴加氯甲酸苄酯(6.34g,35.33mmol)，并在25℃下搅拌4小时，然后水洗、干燥并浓缩，得到标题化合物(8.16g，收率：100％)。
MS m/z(ESI):347.2[M+H] +。
第二步：3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将8-苄基-3-叔丁基3,8-二氮杂双环[3.2.1]辛烷-3,8-二羧酸酯(8.16g,23.52mmol)溶于三氟乙酸(40mL)和二氯甲烷(80mL)中。将体系在20℃下搅拌2小时，浓缩，并加入碳酸氢钠溶液使水相pH>8。用乙酸乙酯(50mL)萃取三次、干燥有机相、浓缩并打浆(洗脱剂：石油醚/乙酸乙酯＝10/1，体积比)12小时，然后过滤并干燥滤饼，得到标题化合物(4.6g，收率：79％)。
MS m/z(ESI):247.1[M+H] +。
中间体制备例3：3-(2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
Figure PCTCN2022081102-appb-000039
第一步：4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-氯-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将2,4-二氯-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(1.0g,3.29mmol)和N,N-二异丙基乙胺(1.29g,9.87mmol)溶于DMF(10mL)中，并加入3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(0.85g,3.29mmol)。将体系在80℃下搅拌2小时，用乙酸乙酯(30mL)稀释，然后水洗、干燥、浓缩并通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1，体积比)，得到标题化合物(1.2g，收率：67％)。
MS m/z(ESI):514.2[M+H] +。
第二步：4-8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-氯-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(1.3g,2.53mmol)和(六氢-1H-吡咯嗪-7a-基)甲醇(0.714g,5.06mmol)溶于1.4-二氧六环(20mL)中，并加入碳酸铯(2.5g,7.59mmol)。用氮气置换三次，然后加入[1,1'-双(二苯基膦基) 二茂铁]二氯化钯(188.83mg,0.25mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(308.08mg,0.51mmol)，并在100℃下搅拌12小时。将体系冷却到室温，加水(40mL)，并用乙酸乙酯(30mL)萃取三次，将有机层干燥、浓缩并通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(430mg，收率：53.5％)。
MS m/z(ESI):619.4[M+H] +。
第三步：3-(2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(430mg,0.70mmol)溶于二氯甲烷(10mL)中，滴加三氟乙酸(5mL)，并在室温下搅拌2小时。将体系浓缩，并加入碳酸氢钠溶液使水相pH>8，然后用乙酸乙酯(30mL)萃取三次，干燥有机相，浓缩，得到标题化合物(220mg，收率：60.9％)。
MS m/z(ESI):519.4[M+H] +。
中间体制备例4：3-(7-(3-(苄氧基)萘-1-基)-2-(甲基亚磺酰基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
Figure PCTCN2022081102-appb-000040
第一步：4-羟基-2-(甲硫基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将甲醇钠(29.26g,531mmol)溶于甲醇(500mL)中，加入1-N-叔丁氧羰基-3-氧代哌啶-4-羧酸乙酯(25.0g,88.46mmol)，然后加入S-甲基异硫脲硫酸盐(46.66g,159.23mmol)。将体系在室温下搅拌16小时，用2摩尔的盐酸调pH>5，浓缩，然后加水剧烈搅拌，形成固体，过滤，用乙酸乙酯(100mL)冲洗固体，收集滤饼，干燥，得到标题化合物(22.67g，收率：77％)。
MS m/z(ESI):298.1[M+H] +。
第二步：2-(甲硫基)-4-((三氟甲基)磺酰基)氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将4-羟基-2-(甲硫基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(22.67g,76.33mmol)溶于二氯甲烷(300mL)中，加入N,N-二异丙基乙胺(19.7g,152.66mmol)，冷却体系到0℃，滴加三氟甲磺酸酐(32.53g,114.5mmol)，滴加完毕后，将体系在室温下搅拌2小时，浓缩并通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1，体积比)，得到标题化合物(20.4g，收率：62％)。
MS m/z(ESI):430.1[M+H] +。
第三步：4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(甲硫基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯的制备
将2-(甲硫基)-4-((三氟甲基)磺酰基)氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(1.0g,2.33mmol)和N,N-二异丙基乙胺(0.9g,6.99mmol)溶于DMF(10mL)中，并加入3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(0.57g,2.33mmol)。将体系在100℃下搅拌2小时，用乙酸乙酯(30mL)稀释，然后水洗、干燥、浓缩并通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1，体积比)，得到标题化合物(1.0g，收率：82％)。
MS m/z(ESI):526.2[M+H] +。
第四步：3-(2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(甲硫基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-羧酸叔丁酯(1.0g,1.9mmol)溶于二氯甲烷(10mL)中，滴加三氟乙酸(5mL)，并在室温下搅拌2小时。将体系浓缩，并加入碳酸氢钠溶液使水相pH>8，然后用乙酸乙酯(30mL)萃取三次，干燥有机相，浓缩，得到标题化合物(810mg，收率：100％)。
MS m/z(ESI):426.1[M+H] +。
第五步：3-(7-(3-(苄氧基)萘-1-基)-2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将3-(2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(0.81g,1.9mmol)和3-苄氧基-1-溴萘(0.89g,2.86mmol)溶于甲苯(10mL)中，并加入碳酸铯(1.86g,5.7mmol)。用氮气置换三次，然后加入甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(160.82mg,0.19mmol)，并在100℃下搅拌12小时。将体系冷却到室温，加水(40mL)，并用乙酸乙酯(30mL)萃取三次，将有机层干燥、浓缩并通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1，体积比)，得到标题化合物(750mg，收率：60％)。
MS m/z(ESI):658.2[M+H] +。
第六步：3-(7-(3-(苄氧基)萘-1-基)-2-(甲基亚磺酰基基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将3-(7-(3-(苄氧基)萘-1-基)-2-(甲硫基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(0.75g,1.14mmol)溶于二氯甲烷(10mL)中，冷却体系到0℃，加入间氯过氧苯甲酸(0.23g,1.14mmol)，并在0℃搅拌0.5小时。加入硫代硫酸钠溶液搅拌0.5小时，加水(10mL)，然后用乙酸乙酯(30mL)萃取三次，干燥有机相，浓缩并通过硅胶柱层析纯化(洗脱剂：乙酸乙酯)，得到标题化合物(400mg，收率：52％)。
MS m/z(ESI):674.2[M+H] +。
中间体制备例5：((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇的制备
Figure PCTCN2022081102-appb-000041
第一步：(2R,4S)-1-(叔丁基)2-甲基4-氟吡咯烷-1,2-二羧酸酯的制备
将(2R,4R)-1-(叔丁基)2-甲基4-羟基吡咯烷-1,2-二羧酸酯(4.0g,16.31mmol)溶于二氯甲烷(50mL)中，在-78℃下加入二乙胺基三氟化硫(5.0g,30.99mmol)，将反应液在-78℃下搅拌2小时后，缓慢升至室温，继续搅拌12小时。经TLC监控反应完全后,在冰浴下加入碳酸氢钠水溶液，将有机相用分液漏斗分出干燥浓缩，得到标题化合物(4.0g,收率:99％)。
LCMS:248.1[M+H] +。
第二步：(2R,4S)-1-(叔丁基)2-甲基2-(3-氯丙基)-4-氟吡咯烷-1,2-二羧酸酯的制备
将(2R,4S)-1-(叔丁基)2-甲基4-氟吡咯烷-1,2-二羧酸酯(4g,16.18mmol)溶解在四氢呋喃(16mL)中，加入六甲基磷酰三胺(3.77g,21.03mmol)，降温至-70℃，缓慢滴加双三甲基硅基胺基锂(21mL,21.03mmol)。于-70℃搅拌1小时后，缓慢滴加1-溴-3-氯丙烷(12.74g,80.9mmol)，将反应升至室温，继续搅拌1小时。用饱和氯化铵水溶液(50mL)淬灭反应，用乙酸乙酯(30mL)萃取三次，合并有机相并用无水硫酸钠干燥，浓缩并通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1，体积比)，得到标题化合物(1.90g,收率:36.3％)。
LCMS:324.1[M+H] +。
第三步：(2R,4S)-2-(3-氯丙基)-4-氟吡咯烷-2-羧酸甲酯盐酸盐的制备
将(2R,4S)-1-(叔丁基)2-甲基2-(3-氯丙基)-4-氟吡咯烷-1,2-二羧酸酯(2g,6.18mmol)溶解在乙酸乙酯(30mL)中，加入盐酸乙酸乙酯溶液(15mL)，将反应液室温搅拌12小时。将反应液减压浓缩，得到标题化合物(1.608g,粗品)。
LCMS:224.1[M+H] +。
第四步：(2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-羧酸甲酯的制备
将(2R,4S)-2-(3-氯丙基)-4-氟吡咯烷-2-羧酸甲酯盐酸盐(1.608g,16.18mmol)溶解在乙腈(20mL)中，加入碳酸氢钠(2.6g,30.9mmol)和碘化钾(103mg,0.618mmol)，将反应在50℃下搅拌12小时。过滤后，将滤液减压浓缩并通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1，体积比)，得到标题化合物(933mg,收率:80.4％)。
LCMS:188.2[M+H] +。
第五步：((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇的制备
将(2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-羧酸甲酯(933mg,4.98mmol)溶解在四氢呋喃(25mL)中，在-40℃下加入氢化铝锂(567mg,14.94mmol)，将反应液在-40℃下搅拌1小时。用硫酸钠水溶液在0℃下淬灭反应，加四氢呋喃稀释，过滤浓缩，得到标题化合物(716mg,收率:90.2％)。
LCMS:160.1[M+H] +。
1H NMR(400MHz,CDCl 3)δ5.32-5.16(m,1H),4.13-3.67(m,1H),3.49-3.32(m,3H),3.05-2.99(m,1H),2.91-2.78(m,1H),2.71-2.65(m,1H),2.26-2.17(m,2H),1.95-1.78(m,4H),1.65-1.59(m,1H)。
中间体制备例6：3-(2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
Figure PCTCN2022081102-appb-000042
第一步：4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔丁酯的制备
将4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-氯-5,6-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔丁酯(400mg,0.74mmol)、((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(123.89mg,0.74mmol)、碳酸铯(608.26mg,1.85mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(43.21mg,0.074mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(27.32mg,0.037mmol)依次加入1,4-二氧六环(10mL)中，用氮气置换三次，将反应体系在100℃下搅拌12小时。将体系冷却至室温，减压旋蒸除掉溶剂，并通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(278mg，收率：56.10％)。
MS m/z(ESI):637.4[M+H] +。
第二步：3-(2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将4-(8-((苄氧基)羰基)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(6H)-羧酸叔丁酯(278mg,414.76μmol)溶于二氯甲烷(10mL)中，用冰水浴降温，于0℃时滴加盐酸/1,4-二氧六环溶液(3mL)，滴毕，将反应体系在室温下搅拌4小时。将反应体系浓缩除掉溶剂，将残余物溶于冰水中(10mL)，用碳酸氢钠溶液调节pH＝7，有固体析出，抽滤并将滤液旋干，得到标题化合物(184mg,收率：78.53％)。
MS m/z(ESI):537.3[M+H] +。
中间体制备例7：3-(2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
Figure PCTCN2022081102-appb-000043
第一步：3-(7-苄基-2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯的制备
将7-苄基-2,4-二氯-5,6,7,8-四氢吡啶并[3,4-D]嘧啶(5.0g,17.0mmol)、8-叔丁氧羰基-8-氮杂双环[3.2.1]辛-2-烯-3-硼酸频哪醇酯(8.5g,25.5mmol)、醋酸钾(5.0g,51mmol)和[1,1'-双(二苯基膦)二茂铁] 二氯化钯二氯甲烷络合物(1.24g,1.7mmol)加入1,4-二氧六环(50mL)和水(10mL)中，用氮气置换三次，将反应体系在90℃下搅拌12小时。待体系冷却至室温，减压旋蒸除掉溶剂，并通过薄层色谱纯化(洗脱剂：石油醚/乙酸乙酯＝2/1，体积比)，得到标题化合物(4.96g,收率：62.5％)。
MS m/z(ESI):467.2[M+H] +。
第二步：3-(7-苄基-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯的制备
将3-(7-苄基-2-氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(4.96g,10.6mmol),((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲醇(3.38g,21.2mmol)、碳酸铯(10.36g,31.8mmol)、甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(0.89g,1.06mmol)依次加入甲苯(80mL)中，用氮气置换三次，将反应体系在110℃下搅拌4小时。将体系冷却至室温，减压旋蒸除掉溶剂，并通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(3.2g，收率：51.0％)。
MS m/z(ESI):590.3[M+H] +。
第三步：3-(2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
将3-(7-苄基-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(3.2g,5.42mmol)溶于氨甲醇溶液(50mL)中，加入10％钯/碳(0.8g)，用氢气置换三次，于45℃下将反应体系在氢气氛围中搅拌24小时。将体系冷却至室温，过滤，浓缩，得到标题化合物(2.58g，收率：94.8％)。
MS m/z(ESI):502.3[M+H] +。
中间体制备例8：1,8-二溴-3-(甲氧基甲氧基)萘的制备
Figure PCTCN2022081102-appb-000044
第一步：2-(4,5-二溴-2-萘基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷的制备
将1,8-二溴萘(1g,3.46mmol)、二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(114.49mg,173.10μmol)、4,4’-二叔丁基-2,2’-联吡啶(56.31mg,207.72μmol)溶于四氢呋喃(15.0mL)，用氮气置换三次，在搅拌状态下注射加入4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(4.48g,34.62mmol)，将体系在70℃下搅拌10小时。待反应液冷却至室温，向反应液中滴入水(30mL)淬灭反应，用乙酸乙酯(30mL)萃取两次，合并有机相，用无水硫酸钠干燥，减压旋蒸除掉溶剂，将残留物通过硅胶柱层析纯化(洗脱剂：石油醚),得到标题化合物(648mg,收率：22.72％)。
MS m/z(ESI):413.0[M+H] +。
第二步：4,5-二溴萘-2-醇的制备
将2-(4,5-二溴-2-萘基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(654mg,1.11mmol)溶于四氢呋喃(5.08mL)，再加入水(17mL)，于10℃搅拌下加乙酸(5.17g,71.35mmol)和30％过氧化氢(2.41g,21.22mmol)，将反应体系在10℃下反应15小时。向反应液中加入亚硫酸氢钠溶液(20mL)，用乙酸乙酯(30mL)萃取两次，合并有机相，用无水硫酸钠干燥，减压旋蒸除掉溶剂，将残留物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝4/1,体积比)，得到标题化合物(268mg,收率：75.87％)。
MS m/z(ESI):303.1[M+H] +。
第三步：1,8-二溴-3-(甲氧基甲氧基)萘的制备
将4,5-二溴萘-2-醇(162mg,509.67μmol)溶于二氯甲烷(3.5mL)，于0℃搅拌下加溴(甲氧基)甲烷(193.69mg,1.53mmol)和N,N-二异丙基乙胺(333.14mg,2.55mmol)，在0℃温度下反应1小时。向反应液中加水(10mL)，用二氯甲烷(20mL)萃取，用水(20mL)洗涤有机相两次，合并有机相，用无水硫酸钠干燥，减压旋蒸除掉溶剂，将残留物通过硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝9/1,体积比)，得到标题化合物(160mg,收率：81.65％)。
MS m/z(ESI):347.1[M+H] +。
1H-NMR(400MHz,CDCl 3)δ7.72(dd,J＝8.0Hz,J＝4.0Hz,1H),7.64(dd,J＝8.0Hz,J＝4.0Hz,2H),7.32(d,J＝4.0Hz,1H),7.16-7.11(m,1H),5.20(s,2H),3.44(s,3H)。
制备例
实施例1：3-(7-(8-氯萘-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,6-二氮杂二环[3.1.1]庚烷(化合物1)的制备
Figure PCTCN2022081102-appb-000045
第一步：3-(7-(8-氯萘-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羧酸叔丁酯的制备
将(S)-7-(8-氯萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(200mg,0.47mmol)溶于DMF(6mL)中，氮气保护下，加入6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷(280.56mg,1.42mmol)、卡特缩合剂(415.74mg,0.94mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(216.18mg,1.42mmol)，于90℃搅拌2小时，冷却到室温，加水(30mL)，用乙酸乙酯(20mL)萃取三次，干燥，浓缩，经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝8/1，体积比)，得到本步标题化合物(120mg，收率：42.1％)。
MS m/z(ESI):605.1[M+H] +。
第二步：3-(7-(8-氯萘-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,6-二氮杂二环[3.1.1]庚烷(化合物1)的制备
将3-(7-(8-氯萘-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羧酸叔丁酯(120mg,0.29mmol)溶于三氟乙酸(1mL)和二氯甲烷(2mL)中，于室温下搅拌2小时后，浓缩反应液，用乙酸乙酯(20mL)稀释，用饱和碳酸氢钠溶液(10mL)调节PH＝8，用乙酸乙酯(10mL)萃取两次，合并有机相，干燥有机相，浓缩，经制备高效液相色谱仪纯化，得到标题化合物(8mg，收率：8.0％)。
MS m/z(ESI):505.2[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ7.93(dd,J＝7.2Hz,8.0Hz,1H),7.75(d,J＝7.6Hz,1H),7.60-7.53(m,2H),7.46(t,J＝8.0Hz,1H),7.35(d,J＝7.2Hz,1H),4.32(d,J＝8.8Hz,1H),4.28-4.24(m,1H),4.18-3.89(m,8H),3.75-3.71(m,1H),3.53-3.50(m,1H),3.38-3.30(m,2H),3.09-3.03(m,1H),2.99-2.94(m,2H),2.63-2.57(m,1H),2.35(s,3H),2.22-2.16(m,1H),1.95-1.89(m,1H),1.72-1.56(m,4H)。
实施例2：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物2)的制备
Figure PCTCN2022081102-appb-000046
第一步：(1R,5S)-3-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8羧酸叔丁酯的制备
采用实施例1的合成路线，将第一步的反应原料6-(叔丁氧羰基)-3,6-二氮杂双环[3.1.1]庚烷替换为(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯，得到标题化合物(108mg，收率：45.4％)。
MS m/z(ESI):619.3[M+H] +。
第二步：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物2)的制备
采用实施例1的合成路线，将第二步的反应原料3-(7-(8-氯萘-1-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,6-二氮杂二环[3.1.1]庚烷-6-羧酸叔丁酯替换为(1R,5S)-3-(7-(8-氯萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯，得到标题化合物(12mg，收率：13.5％)。
MS m/z(ESI):519.2[M+H] +
1H-NMR(400MHz,CD 3OD):δ8.50(br,1H),7.84-7.82(m,1H),7.70-7.68(m,1H),7.54-7.48(m,2H),7.40-7.32(m,2H),4.59-4.55(m,1H),4.49-4.44(m,1H),4.39-4.30(m,2H),4.05(s,2H),3.94-3.90(m,1H),3.74-3.69(m,1H),3.63-3.47(m,4H),3.25-3.12(m,3H),2.96-2.94(m,1H),2.86(s,3H),2.68-2.64(m,1H),2.29-2.23(m,2H),2.08-1.86(m,6H)。
实施例3：4-(4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(6H)-基)萘-2-醇(化合物29)的制备
Figure PCTCN2022081102-appb-000047
第一步：3-(7-(3-苄氧基-1-萘基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将3-(7-(3-苄氧基-1-萘基)-2-(甲基亚磺酰基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4–基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(50mg,70.49μmol)和((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇(17.72mg,105.74μmol)溶于甲苯(5mL)中，用冰水浴降温，于0℃时分批加入叔丁醇钾(13.69mg,140.99μmol)，加毕，将反应体系在0℃下搅拌2小时。将反应体系减压旋蒸除掉溶剂，并通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(25mg,收率：43.82％)。
MS m/z(ESI):769.4[M+H] +
1H-NMR(400MHz,CD 3OD):δ8.11(d,J＝12Hz,1H),7.75(d,J＝8Hz,1H),7.50(d,J＝8Hz,2H),7.42-7.30(m,10H),7.08(s,1H),6.90(s,1H),5.19(s,4H),4.62(s,4H),4.41-4.36(m,2H),4.14-4.10(m,2H),3.48-3.46(m,1H),3.14-3.12(m,1H),2.99-2.92(m,3H),2.01-1.94(m,9H),1.37-1.22(m,7H)。
第二步：4-(4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(6H)-基)萘-2-醇的制备
将3-(7-(3-苄氧基-1-萘基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(25mg,29.26μmol)溶于二氯甲烷(4mL)中，用冰水浴降温，于0℃时滴加氢溴酸/乙酸溶液(39.46mg,146.31μmol)，滴毕，将反应体系在0℃下搅拌0.5小时。将反应体系分离除掉上清液，将固体用碳酸氢钠溶液调pH＝7，并通过高效液相色谱法纯化，得到标题化合物(3.5mg,收率：19.24％)。
MS m/z(ESI):545.3[M+H] +
1H-NMR(400MHz,CD 3OD):δ8.40-8.38(m,1H),8.07(d,J＝8Hz,1H),7.64(d,J＝8Hz,1H),7.37(t,J＝8Hz,1H),7.26(t,J＝8Hz,1H),6.88(d,J＝4Hz,1H),6.79(d,J＝4Hz,1H),5.49-5.36(m,1H),4.50-4.36(m,2H),4.26-4.12(m,6H),3.76-3.68(m,1H),3.45-3.41(m,4H),3.16-2.98(m,4H),2.60-2.52(m,1H),2.25-1.98(m,10H)。
实施例4：4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物28)的制备
Figure PCTCN2022081102-appb-000048
第一步：3-(7-(3-(苄基氧基)萘-1-基)-2-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例3的合成路线，将第一步的反应原料((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇替换为(六氢-1H-吡咯嗪-7a-基)甲醇，得到本步标题化合物(61mg，收率：45.9％)。
MS m/z(ESI):752.3[M+H] +。
第二步：4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇的制备
采用实施例3的合成路线，将第二步的反应原料3-(7-(3-苄氧基-1-萘基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(3-(苄基氧基)萘-1-基)-2-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(10mg，收率：30.1％)。
MS m/z(ESI):527.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)δ8.30(s,1H),7.99(d,J＝8.4Hz,1H),7.66(d,J＝8.0Hz,1H),7.43-7.21(m,2H),6.81(dd,J＝8.0,2.0Hz,2H),4.07(d,J＝6.4Hz,4H),3.97(d,J＝12.0Hz,2H),3.87(s,2H),3.40-2.62(m,10H),2.03-1.54(m,12H)。
实施例5：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴代萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物32)的制备
Figure PCTCN2022081102-appb-000049
第一步：3-(7-(8-溴代萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将3-(2-(2-氟-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(100mg,0.19mmol)和1,8-二溴萘(108.68mg,0.38mmol)溶于干燥的1,4-二氧六环(5mL)中，加入碳酸铯(188mg,0.57mmol)，氮气保护下，加入三(二亚苄基丙酮)二钯(17mg,0.019mmol)和1,1'-双(二苯基膦)二茂铁(21mg,0.038mmol)，于95℃搅拌10小时，加水(20mL)，用乙酸乙酯(10mL)萃取三次，浓缩，经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到本步的标题化合物(40mg，收率：28.6％)。
MS m/z(ESI):725.2[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴代萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将3-(7-(8-溴代萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(40mg,0.055mmol)溶于二氯甲烷(5mL)中，滴加三甲基碘硅烷(110mg,0.55mmol)，于室温下搅拌1小时后，过滤，收集滤饼并将滤饼悬着于乙酸乙酯(10mL)中，加入亚硫酸钠(5mL)搅拌5分钟，加水(10mL)，分液，然后用乙酸乙酯(10mL)萃取两次，合并有机相，干燥有机相，浓缩，经制备高效液相色谱仪纯化，得到标题化合物(15mg，收率：46.1％)。
MS m/z(ESI):589.2[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ7.97(dd,J＝7.2Hz,8.0Hz,1H),7.83-7.81(m,1H),7.75(d,J＝8.0Hz,1H),7.55(t,J＝8.0Hz,1H),7.37-7.34(m,2H),4.10(d,J＝10Hz,1H),4.00(d,J＝12Hz,1H),3.86(t,J＝12Hz,1H),3.62-3.44(m,6H),3.35-3.19(m,7H),3.10(d,J＝4.0Hz,2H),2.95-2.89(m,2H),2.51-2.49(m,1H),1.86-1.67(m,8H),1.57-1.50(m,2H)。
实施例6：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物31)的制备
Figure PCTCN2022081102-appb-000050
第一步：3-(7-(8-溴萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
将3-(2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a((5H)-基)甲氧基))-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(60mg,100.63μmol)、1,8-二溴萘(43.60mg,150.94μmol)、叔丁醇钾(28.51mg,251.57μmol)、1,1'-双(二苯基膦)二茂铁(5.63mg,10.06μmol)和三(二亚苄基丙酮)二钯(4.65mg,5.03μmol)加入甲苯(5mL)中，用氮气置换三次，将反应体系在90℃下搅拌9小时。将体系冷却至室温，减压旋蒸除掉溶剂，并通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(43mg,收率：54.7％)。
MS m/z(ESI):741.1[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将3-(7-(8-溴萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯(43mg,52.18μmol)溶于二氯甲烷(5mL)中，用冰水浴降温，于0℃时滴加氢溴酸/乙酸溶液(68.70mg,254.73μmol)，将反应体系在0℃下搅拌0.5小时。将反应体系分离除掉上清液，将固体用碳酸氢钠溶液调pH＝7，并通过高效液相色谱法纯化，得到标题化合物(16.8mg,收率：46.8％)。
MS m/z(ESI):607.2[M+H] +
1H-NMR(400MHz,CD 3OD):δ7.88(dd,J＝8.0Hz,J＝4.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.38(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,1H),5.41-5.27(m,1H),4.37-4.18(m,4H),3.96-3.87(m,3H),3.66-3.51(m,4H),3.24-3.17(m,4H),3.11-2.83(m,2H),2.66-2.42(m,2H),2.27-1.83(m,9H)。
实施例7：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物30)的制备
Figure PCTCN2022081102-appb-000051
第一步：3-(7-(8-氯萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例6的合成路线，将第一步的反应原料1,8-二溴萘替换为1-溴-8-氯萘，得到标题化合物(48mg,收率：65％)。
MS m/z(ESI):697.3[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
采用实施例6的合成路线，将第二步的反应原料3-(7-(8-溴萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(8-氯萘-1-基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(11.0mg,收率：27.7％)。
MS m/z(ESI):563.2[M+H] +
1H-NMR(400MHz,CD 3OD):δ7.84(d,J＝8Hz,1H),7.69(d,J＝8Hz,1H),7.54-7.49(m,2H),7.39-7.31(m,2H),5.39-5.25(m,1H),4.36-4.09(m,4H),3.85-3.42(m,7H),3.22-3.07(m,4H),3.00-2.76(m,2H),2.64-2.41(m,2H),2.22-1.79(m,9H)。
实施例8：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物33)的制备
Figure PCTCN2022081102-appb-000052
第一步：3-(7-(8-氯萘-1-基)-2-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例5的合成路线，将第一步的反应原料1,8-二溴萘替换为1-溴-8-氯萘，得到本步标题化合物(40mg，收率：33.9％)。
MS m/z(ESI):679.2[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
采用实施例5的合成路线，将第二步的反应原料3-(7-(8-溴代萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(8-氯萘-1-基)-2-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(18mg，收率：47.6％)。
MS m/z(ESI):545.3[M+H] +
1H-NMR(400MHz,DMSO-d 6):δ7.92(dd,J＝8.0Hz,2.0Hz,1H),7.79-7.76(m,1H),7.74(d,J＝8.0Hz,1H),7.53(t,J＝7.6Hz,1H),7.40-7.36(m,2H),4.12(d,J＝12Hz,1H),3.91(d,J＝10Hz,1H),3.77(t,J＝10Hz,1H),3.55-3.41(m,6H),3.30-3.16(m,7H),3.08(d,J＝5.6Hz,2H),2.98-2.87(m,2H),2.62-2.56(m,1H),1.90-1.67(m,8H),1.57-1.52(m,2H)。
实施例9：4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-2-(2-(2-甲基-1H-咪唑-1-基)乙氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物34)的制备
Figure PCTCN2022081102-appb-000053
第一步：3-[7-(3-苄氧基-1-萘基)-2-[2-(2-甲基咪唑-1-基)乙氧基]-5,6,7,8-四氢-5H-吡啶并[3,4-d]嘧啶-4-基]-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例3的合成路线，将第一步的反应原料((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H)-基)甲醇替换为2-(2-甲基咪唑-1-基)乙醇，得到本步标题化合物(90mg，收率：36.2％)。
MS m/z(ESI):737.3[M+H] +。
第二步：4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-2-(2-(2-甲基-1H-咪唑-1-基)乙氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇的制备
采用实施例3的合成路线，将第二步的反应原料3-(7-(3-苄氧基-1-萘基)-2-(((2S,7aR)-2-氟四氢-1H-吡咯嗪-7a(5H))-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧 酸苄酯替换为3-[7-(3-苄氧基-1-萘基)-2-[2-(2-甲基咪唑-1-基)乙氧基]-5,6,7,8-四氢-5H-吡啶并[3,4-d]嘧啶-4-基]-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(23mg，收率：44.5％)。
MS m/z(ESI):512.3[M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.99(d,J＝8.4Hz,1H),7.66(d,J＝8.0Hz,1H),7.40-7.36(m,1H),7.28-7.24(m,1H),7.09(d,J＝4.0Hz,1H),6.85(d,J＝2.4Hz,1H),6.74-6.72(m,2H),4.48(t,J＝6.4Hz,2H),4.26(t,J＝5.6Hz,2H),4.15-3.65(m,8H),3.25-3.22(m,4H),2.84(s,1H),2.31(s,3H),1.87-1.84(m,4H)。
实施例10：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物35A或35B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物35A或35B)的制备
Figure PCTCN2022081102-appb-000054
第一步：7-苄基-2-氯-4-甲氧基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将7-苄基-2,4-二氯-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(2.0g,6.73mmol)溶于无水甲醇(30mL)中，用冰盐浴降温，于0℃分批加入甲醇钠(385.65mg,7.07mmol)，加毕，将反应体系在0℃下搅拌3小时。滴加冰水(50mL)淬灭反应体系，用乙酸乙酯(20mL)萃取三次，合并有机相，用饱和食盐水(20mL)反洗两次，用无水硫酸钠干燥，减压旋蒸除掉溶剂，得到标题化合物(1.91g,收率：93％)。
MS m/z(ESI):290.1[M+H] +。
第二步：(S)-7-苄基-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将7-苄基-2-氯-4-甲氧基-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(1.9g,6.23mmol)、(S)-(1-甲基吡咯烷-2-基)甲醇(942.10mg,8.10mmol)、碳酸铯(5.13g,15.57mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(364.08mg,622.93μmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(230.20mg,311.47μmol)加入 1,4-二氧六环(30mL)中，用氮气置换三次，将反应体系在100℃下搅拌1小时。待体系冷却至室温，减压旋蒸除掉溶剂，将残留物通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比),得到标题化合物(2.1g,收率：86.9％)。
MS m/z(ESI):369.3[M+H] +。
第三步：(S)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将10％钯/碳(0.5g)、(S)-7-苄基-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(2.0g,5.16mmol)加入无水甲醇(30mL)中，用氢气置换三次，将反应体系在室温下搅拌5小时。抽滤，用甲醇(50mL)洗涤滤饼，将滤液减压旋蒸除掉溶剂，得到标题化合物(1.15g,收率：76.12％)。
MS m/z(ESI):279.3[M+H] +。
第四步：(S)-7-(3-(苄氧基)萘-1-基)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
将(S)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(1.1g,3.75mmol)、3-(苄氧基)-1-溴萘(1.78g,5.63mmol)、碳酸铯(3.09g,9.39mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(177mg,0.375mmol)和三(二亚苄基丙酮)二钯(173mg,0.187mmol)加入1,4-二氧六环(15mL)中，用氮气置换三次，将反应体系在100℃下搅拌8小时。待体系冷却至室温，减压旋蒸除掉溶剂，将残留物通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(910mg,收率：45.1％)。
MS m/z(ESI):511.3[M+H] +。
第五步：(S)-7-(3-(苄氧基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇的制备
将(S)-7-(3-(苄氧基)萘-1-基)-4-甲氧基-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(900mg,1.67mmol)和乙硫醇钠(569.10mg,6.70mmol)加入N,N-二甲基甲酰胺(5mL)中，用氮气置换三次，将反应体系在100℃下搅拌2小时。待体系冷却至室温，并通过高效液相色谱法纯化，得到标题化合物(370mg,收率：42.27％)。
MS m/z(ESI):497.2[M+H] +
1H-NMR(400MHz,CD 3OD):δ8.05(t,J＝8.0Hz,1H),7.80-7.74(m,1H),7.51-7.44(m,3H),7.41-7.31(m,4H),7.18-7.11(m,1H),7.02-6.91(m,1H),5.20(s,2H),4.61-4.56(m,1H),4.21(m,1H),3.95-3.70(m,3H),3.50-3.48(m,1H),3.27-3.21(m,1H),3.07(s,3H),3.02-2.95(m,1H),2.78-2.60(m,2H),2.44-2.36(m,1H),2.25-1.95(m,4H)。
第六步：(S)-7-(3-(苄氧基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基三氟甲磺酸酯的制备
将(S)-7-(3-(苄氧基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-醇(150mg,267.83μmol)和N,N-二异丙基乙胺(0.1g,803.49μmol)溶于二氯甲烷(5mL)中，降温至-40℃，于-40℃下滴加三氟甲磺酸酐(114.49mg,401.75μmol)，将反应体系在-40℃下搅拌1小时。于-40℃下滴加1滴氯化铵溶液淬灭，减压旋蒸除掉溶剂，经薄层色谱纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(103mg,收率：58.1％)。
MS m/z(ESI):629.2[M+H] +。
第七步：3-(7-(3-(苄氧基)萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯的制备
将(S)-7-(3-(苄氧基)萘-1-基)-2-((1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基三氟甲磺酸酯(113mg,170.76μmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(115.65mg,341.52μmol)、碳酸钠(45.70mg,426.90μmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(10.10mg,13.66μmol)加入1,4-二氧六环(5mL)和水(0.5mL)中，用氮气置换三次，将反应体系在100℃下搅拌12小时。待体系冷却至室温，减压旋蒸除掉溶剂，并通过薄层色谱纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(108mg,收率：87.3％)。
MS m/z(ESI):688.3[M+H] +。
第八步：3-(7-(3-(苄氧基)萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
将10％钯碳(15mg,89.77μmol)和3-(7-(3-(苄氧基)萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛-2-烯-8-羧酸叔丁酯(65mg,89.77μmol)加入无水甲醇(4mL)中，用氢气置换三次，将反应体系在室温下搅拌2小时，抽滤，用甲醇(10mL)洗涤滤饼，减压旋蒸除掉溶剂，得到标题化合物(58mg,收率：89.0％)。
MS m/z(ESI):690.4[M+H] +。
第九步：4-(4-(8-氮杂双环[3.2.1]辛烷-3-基)-2-((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物35)的制备
将3-(7-(3-(苄氧基)萘-1-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(58mg,79.87μmol)溶于二氯甲烷(3mL)中，用冰水浴降温，于0℃温度下滴加氢溴酸/乙酸(107.71mg,399.34μmol)，将反应体系在0℃下搅拌0.5小时。将反应体系分离除掉上清液，将固体用碳酸氢钠溶液调pH＝7，用乙酸乙酯(10mL)萃取三次，合并有机相，用饱和食盐水(10mL)反洗两次，用无水硫酸钠干燥，减压旋蒸除掉溶剂，得到标题化合物(30mg,粗品)。
MS m/z(ESI):500.3[M+H] +。
第十步：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物35A或35B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-(((S)-1-甲基吡咯烷-2-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)萘-2-醇(化合物35A或35B)的制备
将第九步的粗品通过高效液相色谱法纯化，得到标题化合物35A(2.10mg,收率：4.58％)和化合物35B(2.56mg,收率：5.58％)。
化合物35A：保留时间为7.0分钟；
MS m/z(ESI):500.3[M+H] +；
1H-NMR(400MHz,CD 3OD):δ8.54(br,1H),8.03(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.37(dt,J＝8.0Hz,J＝4.0Hz,1H),7.25(dt,J＝8.0Hz,J＝4.0Hz,1H),6.87(d,J＝4.0Hz,1H),6.79(d,J＝4.0Hz,1H),4.42(d,J＝8.0Hz,1H),4.22(s,2H),4.04(s,2H),3.53-3.44(m,3H),3.14-3.09(m,2H),2.99-2.97(m,2H),2.83-2.81(m,1H),2.54-2.43(m,5H),2.43-2.29(m,5H),2.15-2.10(m,1H),2.06-2.00(m,2H),1.86-1.82(m,2H),1.77-1.69(m,1H)。
化合物35B：保留时间为7.8分钟；
MS m/z(ESI):500.3[M+H] +；
1H-NMR(400MHz,CD 3OD):δ8.52(br,1H),8.03(d,J＝8.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.37(dt,J＝8.0Hz,J＝4.0Hz,1H),7.25(dt,J＝8.0Hz,J＝4.0Hz,1H),6.87(d,J＝4.0Hz,1H),6.79(d,J＝4.0Hz,1H),4.51-4.42(m,2H),4.22(s,2H),4.16(s,2H),3.58-3.50(m,3H)3.15-3.03(m,4H),2.65-2.60(m,4H),2.34-2.15(m,7H),1.97-1.89(m,4H),1.83-1.74(m,1H)。
实施例11：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物37)的制备
Figure PCTCN2022081102-appb-000055
第一步：3-(7-(8-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例5的合成路线，将第一步的反应原料1,8-二溴萘替换为1-溴-8-氟萘，得到本步标题化合物(80mg，收率：59.5％)。
MS m/z(ESI):663.4[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
采用实施例5的合成路线，将第二步的反应原料3-(7-(8-溴萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基) 甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(8-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(23mg，收率：37.9％)。
MS m/z(ESI):529.3[M+H] +
1H NMR(400MHz,DMSO-d 6):δ7.76(d,J＝7.6Hz,1H),7.66(d,J＝8.0Hz,1H),7.55-7.45(m,2H),7.32-7.16(m,2H),4.11-4.01(m,4H),4.01(s,2H),3.81(s,2H),3.65-3.38(m,4H),3.08-3.03(m,2H),2.72-2.66(m,4H),1.95-1.73(m,10H),1.68-1.61(m,2H)。
实施例12：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯-7-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物36)的制备
Figure PCTCN2022081102-appb-000056
第一步：3-(7-(8-氯-7-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例5的合成路线，将第一步的反应原料1,8-二溴萘替换为(8-氯-7-氟-1-萘)三氟甲烷磺酸酯，得到本步标题化合物(40mg，收率：26.78％)。
MS m/z(ESI):697.3[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯-7-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡并啶[3,4-d]嘧啶的制备
采用实施例5的合成路线，将第二步的反应原料3-(7-(8-溴萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(8-氯-7-氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(15mg，收率：42.9％)。
MS m/z(ESI):563.2[M+H] +
1H NMR(400MHz,DMSO-d 6):δ8.04-8.00(m,1H),7.78(d,J＝7.6Hz,1H),7.62-7.51(m,2H),7.40(d,J＝7.6Hz,1H),4.14-4.02(m,4H),3.89(s,2H),3.75-3.71(m,2H),3.60(s,2H),3.09-2.92(m,4H),2.60-2.54(m,2H),2.50-2.48(m,2H),1.89-1.67(m,10H),1.59-1.52(m,2H)。
实施例13：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(7,8-二氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物38)的制备
Figure PCTCN2022081102-appb-000057
第一步：3-(7-(7,8-二氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例5的合成路线，将第一步的反应原料1,8-二溴萘替换为(7,8-二氟-1-萘基)三氟甲基磺酸酯，得到本步标题化合物(60mg，收率：40.1％)。
MS m/z(ESI):681.3[M+H] +。
第二步：4-(3,8-二氮杂双环[3.2.1]辛烷-3-基)-7-(7,8-二氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶的制备
采用实施例5的合成路线，将第二步的反应原料3-(7-(8-溴萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(7,8-二氟萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(22mg，收率：42.1％)。
MS m/z(ESI):547.3[M+H] +
1H NMR(400MHz,DMSO-d 6):δ7.85-7.82(m,1H),7.70-7.61(m,2H),7.50-7.46(m,1H),7.29(d,J＝7.6Hz,1H),4.09-3.93(m,4H),3.93(s,2H),3.63(s,2H),3.40-3.08(m,4H),2.99-2.85(m,4H),2.62-2.56(m,2H),1.91-1.69(m,10H),1.61-1.54(m,2H)。
实施例14：4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物86A或86B)的制备
4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物86A或86B)的制备
Figure PCTCN2022081102-appb-000058
第一步：3-(7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
将3-(2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(100mg,0.19mmol)、1-溴-8-氯萘(96.29mg,0.38mmol)、碳酸铯(194.85mg,0.57mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(22.10mg,38.77μmol)和三(二亚苄基丙酮)二钯(26.54mg,28.41μmol)加入1,4-二氧六环(3mL)中，用氮气置换三次，将反应体系在95℃下搅拌8小时。待体系冷却至室温，减压旋蒸除掉溶剂，将残留物通过硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝10/1，体积比)，得到标题化合物(97mg,收率：69.61％)。
MS m/z(ESI):662.4[M+H] +。
第二步：4-(-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物86)的制备
将3-(7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(97.0mg,131.83μmol)溶于二氯甲烷(3mL)中，于25℃温度下滴加三氟乙酸(1mL)，将反应体系在25℃下搅拌1.5小时。浓缩反应液，用乙酸乙酯(3mL)稀释残留物，用碳酸氢钠溶液(10mL)洗涤三次，合并有机相，用饱和食盐水(10mL)反洗两次，用无水硫酸钠干燥，减压旋蒸除掉溶剂，得到标题化合物(40.0mg,粗品)。
MS m/z(ESI):563.3[M+H] +。
第三步：4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物86A或86B)的制备
4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物86A或86B)的制备
将第二步的粗品通过高效液相色谱法纯化，得到标题化合物86A(18.0mg,收率：21.82％)和化合物86B(10.0mg,收率：11.85％)。
化合物86A：保留时间为5.72分钟；
MS m/z(ESI):563.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.93(d,J＝8.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.60-7.51(m,2H),7.45(t,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),5.27(d,J＝4.0Hz,2H),4.19-3.95(m,5H),3.89(s,1H),3.56(d,J＝10Hz,1H),3.42(s,1H),3.17-2.98(m,5H),2.82(dd,J＝12Hz,J＝8.4Hz,1H),2.68(d,J＝14.4Hz,1H),2.12-1.71(m,13H)。
化合物86B：保留时间为6.11分钟；
MS m/z(ESI):563.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.93(dd,J＝8.0Hz,J＝1.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.56(dd,J＝16.4Hz,J＝8.0Hz,2H),7.45(t,J＝7.6Hz,1H),7.37(d,J＝7.6Hz,1H),5.27(d,J＝12.0Hz,2H),4.21-3.88(m,7H),3.57(d,J＝7.2Hz,1H),3.43-3.29(m,2H),3.19-3.11(m,2H),3.01(d,J＝5.0Hz,1H),2.91-2.78(m,2H),2.22-1.90(m,9H),1.86-1.73(m,4H)。
实施例15：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇(化合物89A或89B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇(化合物89A或89B)的制备
Figure PCTCN2022081102-appb-000059
第一步：3-(7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
采用实施例14的合成路线，将第一步反应原料1-溴-8-氯萘替换为8-氟-3-(甲氧基甲氧基)萘-1-基三氟甲烷磺酸酯，得到标题化合物(60mg,收率：44.41％)。
MS m/z(ESI):706.4[M+H] +。
第二步：4-(4-(-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇(化合物89)的制备
采用实施例14的合成路线，将第二步的反应原料3-(7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯替换为3-(7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯，得到标题化合物(42.1mg,粗品)。
MS m/z(ESI):562.3[M+H] +。
第三步：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇(化合物89A或89B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇(化合物89A或89B)的制备
将第二步的粗品通过高效液相色谱法纯化，得到标题化合物89A(5.0mg,收率：9.6％)和化合物89B(6.1mg,收率：11.5％)。
化合物89A：保留时间为4.65分钟；
MS m/z(ESI):562.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.49(d,J＝8.0Hz,1H),7.36-7.31(m,1H),6.99-6.94(m,1H),6.88(s,1H),6.76(d,J＝4.0Hz,1H),5.35(s,1H),5.21(s,1H),4.13-3.98(m,5H),3.62-3.41(m,3H),3.08-2.67(m,9H),2.33-1.94(m,8H),1.87-1.74(m,5H)。
化合物89B：保留时间为5.31分钟；
MS m/z(ESI):562.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.49(d,J＝8.0Hz,1H),7.36-7.31(m,1H),6.99-6.94(m,1H),6.88(s,1H),6.76(d,J＝4.0Hz,1H),5.35(s,1H),5.21(s,1H),4.12-3.93(m,7H),3.08-2.82(m,8H),2.13-1.98(m,10H),1.88-1.76(m,5H)。
实施例16：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5,6-二氟萘-2-醇(化合物90A或90B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5,6-二氟萘-2-醇(化合物90A或90B)的制备
Figure PCTCN2022081102-appb-000060
第一步：3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
采用实施例14的合成路线，将第一步的反应原料1-溴-8-氯萘替换为7,8-二氟-3-(甲氧基甲氧基)萘-1-基三氟甲烷磺酸酯，得到标题化合物(55mg,收率：38.3％)。
MS m/z(ESI):724.4[M+H] +。
第二步：4-(4-(8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5,6-二氟萘-2-醇(化合物90)的制备
采用实施例14的合成路线，将第二步的反应原料3-(7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯替换为3-(7-(7,8-二氟-3-(甲氧基甲氧基)萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯，得到标题化合物(37mg,粗品)。
MS m/z(ESI):580.3[M+H] +
第三步：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5,6-二氟萘-2-醇(化合物90A或90B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5,6-二氟萘-2-醇(化合物90A或90B)的制备
将第二步的粗品通过高效液相色谱法纯化，得到标题化合物90A(3.0mg,收率：4.1％)和化合物90B(1.6mg,收率：2.3％)。
化合物90A：保留时间为5.15分钟；
MS m/z(ESI):580.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.58-7.45(m,2H),6.91(s,1H),6.85(s,1H),5.38(s,1H),5.21(s,1H),4.14-4.04(m,4H),3.63-3.44(m,3H),3.13-2.67(m,8H),2.33-2.08(m,10H),1.90-1.80(m,5H)。
化合物90B：保留时间为5.53分钟；
MS m/z(ESI):580.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.58-7.45(m,2H),6.91(s,1H),6.85(s,1H),5.38(s,1H),5.21(s,1H),4.13-3.83(m,7H),3.03-2.74(m,8H),2.11-1.95(m,10H),1.89-1.78(m,5H)。
实施例17：4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物87A或87B)的制备
4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物87A或87B)的制备
Figure PCTCN2022081102-appb-000061
第一步：3-(7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
采用实施例14的合成路线，将第一步反应原料1-溴-8-氯萘替换为1,8-二溴萘，得到标题化合物(272mg,收率：58.1％)。
MS m/z(ESI):706.3[M+H] +。
第二步：4-(8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物87)的制备
采用实施例14的合成路线，将第二步反应原料3-(7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯替换为3-(7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯，得到标题化合物(37mg,粗品)。
MS m/z(ESI):580.3[M+H] +。
第三步：4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物87A或87B)的制备
4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-7-(8-溴萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶(化合物87A或87B)的制备
将第二步的粗品通过高效液相色谱法纯化，得到标题化合物87A(8.2mg,收率：17.5％)和化合物87B(7.0mg,收率：15.3％)。
化合物87A：保留时间为6.05分钟；
MS m/z(ESI):580.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.97(d,J＝8.0Hz,1H),7.82(d,J＝4.0Hz,1H),7.77(d,J＝8.0 Hz,1H),7.58-7.54(m,1H),7.41-7.38(m,2H),5.33(s,1H),5.20(s,1H),4.14-3.81(m,7H),3.56(d,J＝10Hz,1H),3.20-3.00(m,6H),2.82(dd,J＝12.4Hz,J＝8.4Hz,1H),2.68(d,J＝14.4Hz,1H),2.38-2.25(m,3H),2.10-1.75(m,9H)。
化合物87B：保留时间为6.81分钟；
MS m/z(ESI):580.3[M+H] +
1H-NMR(400MHz,DMSO-d 6)：δ7.97(d,J＝8.0Hz,1H),7.81(d,J＝4.0Hz,1H),7.77(d,J＝8.0Hz,1H),7.60-7.52(m,1H),7.41-7.36(m,2H),5.33(s,1H),5.21(s,1H),4.14-3.96(m,4H),3.84-3.79(m,3H),3.56(d,J＝10Hz,1H),3.23-3.00(m,6H),2.82(dd,J＝12.4Hz,J＝8.4Hz,1H),2.68(d,J＝14.4Hz,1H),2.11-1.75(m,12H)。
实施例18：4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇(化合物40)的制备
Figure PCTCN2022081102-appb-000062
第一步：3-(7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯的制备
采用实施例5的合成路线，将第一步的反应原料1,8-二溴萘替换为1-溴-8-氟-3-(甲氧基甲氧基)萘，得到标题化合物(17mg,收率：8.6％)。
MS m/z(ESI):723.3[M+H] +。
第二步：4-(4-(3,8-二氮杂双环[3.2.1]辛-3-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶[3,4-d]嘧啶-7(8H)-基)-5-氟萘-2-醇的制备
采用实施例5的合成路线，将第二步的反应原料3-(7-(8-溴萘-1-基)-2-((六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯替换为3-(7-(8-氟-3-(甲氧基甲氧基)萘-1-基)-2-(六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸苄酯，得到标题化合物(2.3mg,收率：21.22％)。
MS m/z(ESI):545.3[M+H] +
1H-NMR(400MHz,DMSO)：δ7.49(d,J＝8.0Hz,1H),7.36-7.30(m,1H),6.96(dd,J＝16.0Hz,J＝8.0Hz,1H),6.87(s,1H),6.74(d,J＝4.0Hz,1H),4.00(d,J＝6.0Hz,6H),3.62(s,3H),3.01-2.92(m,3H),2.83(s,2H),2.70-2.55(m,3H),1.93-1.53(m,14H)。
实施例19：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-溴萘-2-醇(化合物88A或88B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-溴萘-2-醇(化合物88A或88B)的制备
Figure PCTCN2022081102-appb-000063
第一步：3-(7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯的制备
采用实施例14的合成路线，将第一步的反应原料1-溴-8-氯萘替换为1,8-二溴-3-(甲氧基甲氧基)萘，得到标题化合物(36mg,收率：22.31％)。
MS m/z(ESI):766.3[M+H] +。
第二步：4-(4-(8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-溴萘-2-醇(化合物88)的制备
采用实施例14的合成路线，将第二步的反应原料3-(7-(8-氯萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯替换为3-(7-(8-溴-3-(甲氧基甲氧基)萘-1-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]嘧啶-4-基)-8-氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯，得到标题化合物(10.0mg,粗品)。
MS m/z(ESI):625.3[M+H] +。
第三步：4-(4-((1R,3s,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-溴萘-2-醇(化合物88A或88B)的制备
4-(4-((1R,3r,5S)-8-氮杂双环[3.2.1]辛烷-3-基)-2-((2R,7aS)-2-氟六氢-1H-吡咯嗪-7a-基)甲氧基)-5,6-二氢吡啶并[3,4-d]嘧啶-7(8H)-基)-5-溴萘-2-醇(化合物88A或88B)的制备
将第二步的粗品通过高效液相色谱法纯化，得到标题化合物88A(3.0mg,收率：10.09％)和化合物88B(2.5mg,收率：8.41％)。
化合物88A：保留时间为6分钟；
MS m/z(ESI):625.3[M+H] +
1H-NMR(400MHz,DMSO)：δ7.70(d,J＝8.0Hz,1H),7.53(d,J＝8.0Hz,1H),7.42-7.38(m,1H),7.22-7.17(m,1H),6.98-6.91(m,1H),5.33(s,1H),5.20(s,1H),4.14-3.72(m,10H),3.03(d,J＝32.0Hz,4H),2.84(d,J＝12.0Hz,2H),2.12-1.73(m,13H)。
化合物88B：保留时间为7.4分钟；
MS m/z(ESI):625.3[M+H] +
1H-NMR(400MHz,DMSO)：δ7.69(s,1H),7.53(d,J＝8.0Hz,1H),7.22-7.17(m,1H),6.95(d,J＝16.0Hz,2H),5.33(s,1H),5.20(s,1H),4.13-3.77(m,10H),3.07(s,2H),3.00(s,2H),2.83(s,2H),2.11-1.69(m,13H)。
采用与上述实施例1-19的方法相类似的方法，制备了下表1中的化合物：
表1.化合物表征数据
Figure PCTCN2022081102-appb-000064
Figure PCTCN2022081102-appb-000065
Figure PCTCN2022081102-appb-000066
Figure PCTCN2022081102-appb-000067
Figure PCTCN2022081102-appb-000068
Figure PCTCN2022081102-appb-000069
Figure PCTCN2022081102-appb-000070
Figure PCTCN2022081102-appb-000071
Figure PCTCN2022081102-appb-000072
Figure PCTCN2022081102-appb-000073
Figure PCTCN2022081102-appb-000074
Figure PCTCN2022081102-appb-000075
Figure PCTCN2022081102-appb-000076
Figure PCTCN2022081102-appb-000077
Figure PCTCN2022081102-appb-000078
Figure PCTCN2022081102-appb-000079
Figure PCTCN2022081102-appb-000080
Figure PCTCN2022081102-appb-000081
Figure PCTCN2022081102-appb-000082
Figure PCTCN2022081102-appb-000083
Figure PCTCN2022081102-appb-000084
Figure PCTCN2022081102-appb-000085
Figure PCTCN2022081102-appb-000086
Figure PCTCN2022081102-appb-000087
Figure PCTCN2022081102-appb-000088
Figure PCTCN2022081102-appb-000089
Figure PCTCN2022081102-appb-000090
Figure PCTCN2022081102-appb-000091
Figure PCTCN2022081102-appb-000092
Figure PCTCN2022081102-appb-000093
生物学测试
实验例1：KRAS-G12D(鸟嘌呤-5'-三磷酸(GTP)水解酶G12D突变型)/SOS1体外酶学结合抑制活性实验
实验系统：
KRAS-G12D/SOS1 binding assay kit(厂家：Cisbio)
蛋白：Tag1-SOS1和Tag2-KRAS G12D
标签：Anti tag1 tb 3+和Anti tag2 XL665
缓冲液：Diluent Buffer和Detection Buffer
激活核苷酸：GTP(厂家Sigma)
实验参数：
KRAS-G12D/SOS1 binding assay kit组分：Tag1-SOS1、Tag2-KRAS G12D、Anti tag1 tb 3+和Anti tag2 XL665均为1ⅹ
GTP：10000nM
化合物和KRAS-G12D/SOS1蛋白预孵育结合时间：室温15分钟
蛋白与标签反应时间：4℃密封孵育3小时或延长至过夜
酶标仪参数：BMG PHERAstar Fluorescence，均相时间分辨荧光(HTRF)方法，激发波长337nm，发射波长620nm和665nm
实验步骤：
将待测化合物与Tag1-SOS1和Tag2-KRAS G12D与GTP的混合物在Diluent Buffer体系下室温孵育15分钟进行蛋白结合。向反应板中加入Detection Buffer稀释的标签，于4℃孵育3小时或延长至过夜，将反应板放入酶标仪中，采用HTRF法读取板中各孔的信号值。
数据处理：
以溶媒组(含1ⅹTag1-SOS1、1ⅹTag2-KRAS G12D、Anti tag1 tb 3+和Anti tag2 XL665,1％DMSO)为阴性对照，反应缓冲液组(含1ⅹTag1-SOS1、Anti Tag1 tb 3+和Anti tag2 XL665,1％DMSO)为空白对照，计算各浓度组的相对抑制活性，抑制率＝100％-(测试组-空白组)/(溶媒组-空白组)*100％。按照四参数模型拟合曲线，计算化合物的半数抑制浓度(IC 50)。
实验结果：
按照上述方法测定化合物对KRAS-G12D/SOS1体外酶学结合抑制活性，结果如表2中所示。
表2.KRAS-G12D/SOS1体外酶学结合抑制活性实验结果
化合物 IC 50(nM)
1 340
28 26
29 50
31 115
32 7
33 31
34 35
35A 26
35B 6
40 7
86A 20
86B 627
87A 20
88B 180
89A 10
89B 164
90A 17
结论：
在KRAS-G12D/SOS1体外酶学结合抑制活性实验中，本发明的化合物表现出较强的抑制活性。
实验例2：化合物与His-KRAS(G12D&Q61H)蛋白的表面等离子共振(SPR)结合实验
实验系统：
蛋白：His-KRAS(G12D&Q61H)
实验参数：
His-KRAS(G12D&Q61H)浓度：0.04mg/mL
缓冲液体系：
1)Protein immobilization buffer:10mM HEPES,150mM NaCl,0.05％Tween-20and 10μM GDP
2)Running buffer A:10mM HEPES,150mM NaCl,0.05％Tween-20and 10μM GDP
3)Running buffer B:10mM HEPES,150mM NaCl,0.05％Tween-20and 10μM GDP,1％DMSO
化合物浓度：50μM～0.781μM,两倍梯度稀释，DMSO终浓度为1％
结合解离时间：120s on/200s off
流速：50μL/min
仪器参数：Biacore T200(GE Healthcare)
芯片：S系列NTA传感器芯片
实验步骤：
(1)蛋白固定
1)温度设置：将仪器温度设置到25℃。
2)插入S系列NTA传感器芯片，然后执行“Prime”命令。
3)开始手动程序，设置流速为10uL/min.
4)选择flow cell 2，然后自动进样350mM EDTA(pH 8.0)and 50mM NaOH(1v:1v)混合液以冲洗芯片表面，进样速度为60μL/min，进样时间为60s，重复两次。
5)芯片表面活化：选择flow cell 2,自动进样10mM NiCl2，流速为4μL/min,进样时间为500s.
6)用Protein immobilization buffer稀释His-KRAS(G12D&Q61H)到40μg/mL.自动进样120uL His-KRAS(G12D&Q61H)，将His-KRAS(G12D&Q61H)蛋白固定在流通池2表面，进样速度为4μL/min，进样时间为1150s。
7)将流速调回10uL/min，平衡芯片表面至基线基本稳定(基线下降速度<2RU/min)。
(2)样品检测
在Biacore T200 Control Software中利用method模式编写程序。温度设为25℃，流速设为50uL/min。程序开始先进行8次Running buffer B进样，然后化合物顺序设为浓度从小到大自动进样，化合物流过芯片上固定的蛋白表面，与芯片结合。设置Flow cell 1为参比通道，并且设置0浓度作为内置空白对照。每一个循环均用50％DMSO的清洗进样针。DMSO的信号值影响用1％的DMSO标准曲线校正。
数据处理：
对化合物与蛋白的结合信号和解离信号进行实时记录，并在数据处理(Biacore T200评价软件)时扣除参比通道与内置空白对照的信号值(双扣除)。将参比通道和内置空白对照的信号值双扣除的传感图用Kinetics或者稳态Affinity(1:1)模式拟合。用K D值(K d/K a)表征化合物与蛋白的亲和力，其中K d为解离常数，K a为结合常数。
实验结果：
按照上述方法测定化合物与His-KRAS(G12D&Q61H)蛋白的亲和力，结果如表3所示：
表3.化合物与His-KRAS(G12D&Q61H)亲和力测试结果
化合物 K D(nM)
2 556
结论：
在化合物与His-KRAS(G12D&Q61H)的结合试验中，本发明的化合物表现出较强的亲和力。
上述实施例不以任何方式限定本申请的方案。除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (14)

  1. 式(I)的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物：
    Figure PCTCN2022081102-appb-100001
    其中，
    X 1选自N和CR 5；
    L选自共价键、-O-、-S-和-NR 6-；
    R 1选自氢、C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代；
    R 2选自
    Figure PCTCN2022081102-appb-100002
    每一个X 2各自独立选自N和CR 9；
    R 3选自C 1-6烷基和C 1-6卤代烷基；或者
    与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基、C 3-6环烷基或3-6元杂环基；
    R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基各自任选地被一个或多个R 10取代；
    R 5选自氢、卤素、氰基、C 1-6烷基和C 1-6卤代烷基；
    R 6选自氢和C 1-6烷基；
    R 7选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-O-C(O)-R 11、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-NR 11R 12、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-OR 12、-C(O)-NR 11R 12、C 3-10环烷基、C 6-10芳基、5-10元杂芳基和3-12元杂环基，所述环烷基、芳基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1- 6亚烷基-OR 13、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-6卤代烷基；
    R 8选自卤素、羟基、氰基、C 1-6烷基、-C 1-6烷基-OH、-C 1-6烷基-氰基和C 1-6卤代烷基；
    R 9选自氢、羟基和C 1-6烷基；
    R 10选自氢、卤素、羟基、氰基、C 1-6烷基、C 2-6烯基、C 2-6炔基、-O-C 1-6烷基、C 3-10环烷基、3-12元杂环基和5-10元杂芳基，所述烷基、环烷基、杂环基或杂芳基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基和C 1-6卤代烷基的取代基取代；
    R 11选自氢、C 1-6烷基、C 1-6卤代烷基、-C 1-6烷基-O-C 1-6烷基、C 3-10环烷基、3-12元杂环基，所述环烷基或杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基的取代基取代；
    R 12选自氢和C 1-6烷基；
    R 13选自氢、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、3-12元杂环基，所述环烷基或杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-6烷基、C 1-6卤代烷基的取代基取代；
    R 14选自氢和C 1-6烷基；
    m为0、1、2、3或4；
    n为0、1或2；并且
    o、p、q、r和s各自独立地选自0、1、2或3，条件是o和r不同时为0，且p和q不同时为0。
  2. 权利要求1所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    R 7选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-O-C(O)-R 11、-NR 11R 12、-NR 12-C(O)-R 11、- NR 12-C(O)-NR 11R 12、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-OR 12、-C(O)-NR 11R 12、C 3-10环烷基和3-12元杂环基，所述环烷基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基和C 1-6卤代烷基。
  3. 权利要求1或2所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    X 1选自N和CH；
    优选地，X 1为N。
  4. 权利要求1-3中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    L选自共价键、-O-、-S-、-NH-和-N(C 1-3烷基)-；
    优选地，L选自-O-、-NH-和-N(C 1-3烷基)-；
    更优选地，L为-O-。
  5. 权利要求1-4中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自氢、卤素、氰基、-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-R 11、-C(O)-NR 11R 12、C 3-10环烷基、C 6-10芳基、5-10元杂芳基和3-12元杂环基，所述环烷基、芳基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-6亚烷基-OR 13、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-6卤代烷基；
    优选地，R 1选自C 1-6烷基、C 3-10环烷基和3-12元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个R 7取代，每个R 7各自独立地选自-OR 11、-O-C(O)-NR 11R 12、-NR 11R 12、-NR 12-C(O)-R 11、-NR 12-C(O)-OR 11、-C(O)-NR 11R 12、C 3-6环烷基、5-10元杂芳基和3-12元杂环基，所述环烷基、杂芳基和杂环基各自任选地被一个或多个独立地选自下列的取代基取代：氢、卤素、羟基、氨基、氰基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13、C 1-3卤代烷基和C 1-6烷基；
    更优选地，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自C 3-6环烷基、5-6元杂芳基和5-8元杂环基，所述C 3-6环烷基、5-6元杂芳基和5-8元杂环基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1-6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-3卤代烷基；其中R 13选自C 1-6烷基和5-6元杂环基；R 14选自氢和C 1-6烷基；
    更优选地，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基，所述环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-R 13、-C 1-3亚烷基-OH、-C 1- 6亚烷基-NR 13R 14、-C 1-6亚烷基-O-C(O)-R 13和C 1-3卤代烷基；其中R 13选自C 1-6烷基和吗啉基；R 14为C 1-6烷基；
    更优选地，R 1为任选地被一个或多个R 7取代的C 1-6烷基，每个R 7各自独立地选自环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基，所述环丙基、吡咯烷基、六氢吡咯嗪基和咪唑基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、C 1-6烷基、-C 1-6亚烷基-吗啉基、-C 1-3亚烷基-OH、-C 1-6亚烷基-N(C 1-6烷基) 2、-C 1-6亚烷基-O-C(O)-(吗啉基)和C 1-3卤代烷基；
    更优选地，R 1选自：
    Figure PCTCN2022081102-appb-100003
    Figure PCTCN2022081102-appb-100004
    Figure PCTCN2022081102-appb-100005
    其中波浪线
    Figure PCTCN2022081102-appb-100006
    表示该基团与分子其余部分的连接点。
  6. 权利要求1-5中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-6烷基、C 1-6亚烷基-OH或C 1-6卤代烷基取代的5-12元并环杂环基；
    优选地，R 1为任选地被一个R 7取代的C 1-6烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1- 3亚烷基-OH或C 1-3卤代烷基取代的5-8元并环杂环基；
    更优选地，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的5-8元含氮并环杂环基；
    更优选地，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个卤素、C 1-3烷基、C 1-3亚烷基-OH或C 1-3卤代烷基取代的六氢吡咯嗪基；
    更优选地，R 1为任选地被一个R 7取代的C 1-3烷基，R 7选自任选被一个或多个F、Cl、甲基、氯代甲基、氟代甲基或羟甲基取代的六氢吡咯嗪基；
    更优选地，R 1选自
    Figure PCTCN2022081102-appb-100007
    Figure PCTCN2022081102-appb-100008
  7. 权利要求1-6中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基各自任选地被一个或多个R 10取代，每个R 10各自独立地选自氢、卤素、羟基、氰基、C 1-3烷基、C 2-4烯基、C 2-4炔基、-O-C 1-3烷基、C 3-6环烷基和3-8元杂环基，所述烷基、环烷基和杂环基各自任选地被一个或多个选自氢、卤素、羟基、氰基、C 1-3烷基和C 1-3卤代烷基的取代基取代；
    优选地，R 4选自C 6-10芳基和5-10元杂芳基，所述芳基和杂芳基各自任选地被一个或多个R 10取代，每个R 10各自独立地选自氢、卤素、羟基、C 1-3烷基、C 2-4炔基、-O-C 1-3烷基和C 3-6环烷基，所述烷基任选地被一个或多个氢和卤素取代；
    更优选地，R 4选自苯基、萘基和吲唑基，所述苯基、萘基和吲唑基各自任选地被一个或多个R 10取代，每个R 10各自独立地选自氢、卤素、羟基、C 1-3烷基、C 1-3卤代烷基、C 2-4炔基、-O-C 1-3烷基和C 3-6环烷基。
  8. 权利要求1-7中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中：
    每个R 3各自独立地选自C 1-6烷基和C 1-6卤代烷基，或者与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基或C 3-6环烷基；
    优选地，每个R 3各自独立地选自C 1-3烷基，或者与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基或C 3-6环烷基；
    更优选地，每个R 3各自独立地选自甲基，或者与同一个碳原子连接的两个R 3和所述碳原子一起形成羰基或环丙基。
  9. 权利要求1-8中任一项所述的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，其中所述化合物具有式(II-A)或式(II-B)或式(II-C)的结构：
    Figure PCTCN2022081102-appb-100009
    其中，各基团L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s权利要求1-8中任一项所定义；
    优选地，所述化合物具有式(II-A-1)、(II-A-2)、(II-C-1)、(II-C-2)或(II-C-3)的结构：
    Figure PCTCN2022081102-appb-100010
  10. 化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，所述化合物具有如下结构：
    Figure PCTCN2022081102-appb-100011
    Figure PCTCN2022081102-appb-100012
    Figure PCTCN2022081102-appb-100013
    Figure PCTCN2022081102-appb-100014
    Figure PCTCN2022081102-appb-100015
    Figure PCTCN2022081102-appb-100016
    Figure PCTCN2022081102-appb-100017
    Figure PCTCN2022081102-appb-100018
    Figure PCTCN2022081102-appb-100019
    Figure PCTCN2022081102-appb-100020
    Figure PCTCN2022081102-appb-100021
  11. 药物组合物，其包含预防或治疗有效量的权利要求1-10中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，以及一种或多种药学上可接受的载体。
  12. 药盒，其包据权利要求1-10中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物，或者权利要求11的药物组合物。
  13. 权利要求1-10中任一项的化合物或其药学上可接受的盐、立体异构体、互变异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物或代谢物或者权利要求11的药物组合物在制备用于预防或治疗KRAS G12D介导的相关疾病的药物中的用途，其中所述药物优选通过口服、静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药，其中所述KRAS G12D介导的相关疾病优选为肿瘤。
  14. 制备权利要求9的式(II-A)或式(II-C)化合物的方法，其包括以下方法：
    制备式(II-A)化合物的方法一，其包括以下步骤：
    路线1
    Figure PCTCN2022081102-appb-100022
    其中，
    L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如权利要求1-8中任一项所定义；
    LG 1、LG 2和X表示离去基团，所述离去基团优选地选自卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基；
    PG 1、PG 2和PG 3表示羟基或氨基的保护基团，所述保护基团优选地选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)、甲基和苄基；或者
    制备式(II-A)化合物的方法二，其包括以下步骤：
    路线2
    Figure PCTCN2022081102-appb-100023
    其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如权利要求1-8中任一项所定义；
    LG 1、LG 2和X表示离去基团，所述离去基团优选地选自卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基；
    PG 1和PG 3表示氨基的保护基团，所述保护基团优选地选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基；或者
    制备式(II-A)化合物的方法三，其包括以下步骤：
    路线3
    Figure PCTCN2022081102-appb-100024
    其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如权利要求1-8中任一项所定义；
    LG 1和X表示离去基团，所述离去基团优选地选自卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基；
    PG 1和PG 3表示氨基的保护基团，所述保护基团优选地选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基；
    制备式(II-C)化合物的方法一，其包括以下步骤：
    路线4
    Figure PCTCN2022081102-appb-100025
    其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如权利要求1-8中任一项所定义；
    LG 1表示离去基团，所述离去基团优选地选自卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基；
    PG 3表示氨基的保护基团，所述保护基团优选地选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基；或者
    制备式(II-C)的化合物的方法二，其包括以下步骤：
    路线5
    Figure PCTCN2022081102-appb-100026
    其中，L、R 1、R 3、R 4、R 8、m、n、o、p、q、r和s如权利要求1-8中任一项所定义；
    LG 1、LG 2和X表示离去基团，所述离去基团优选地选自卤素原子、三氟甲烷磺酸酯、甲硫基、甲基亚磺酰基和甲基磺酰基；
    PG 1和PG 3表示氨基的保护基团，所述保护基团优选地选自苄氧羰基(Cbz)、叔丁氧羰基(Boc)和苄基。
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