WO2024061365A1 - 嘧啶并环类化合物及其制备方法与用途 - Google Patents

嘧啶并环类化合物及其制备方法与用途 Download PDF

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WO2024061365A1
WO2024061365A1 PCT/CN2023/120882 CN2023120882W WO2024061365A1 WO 2024061365 A1 WO2024061365 A1 WO 2024061365A1 CN 2023120882 W CN2023120882 W CN 2023120882W WO 2024061365 A1 WO2024061365 A1 WO 2024061365A1
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compound
alkyl
preparation
formula
hydrogen
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French (fr)
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黄奇
黄维
李升�
谢佳雨
胡海
熊益好
王润凤
吴孝全
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成都奥睿药业有限公司
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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 present invention relates to the field of medical technology, in particular to a pyrimidinocyclic compound and its application as a selective inhibitor of KRAS gene mutation.
  • the murine sarcoma virus oncogene (RAS) protein is an important member of the GTPase family, including NRAS, HRAS and KRAS. These enzymes play important roles in extracellular signal transduction, proliferation, apoptosis and differentiation.
  • KRAS binds to guanine trinucleotide phosphate (GTP) to form an active conformation, and binds to guanine dinucleotide phosphate (GDP) to form an inactive conformation.
  • GTP guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • the mutated KRAS protein binds tightly to GTP, causing the KRAS protein to be in an abnormal continuously activated conformation, resulting in continuous activation of downstream signaling pathways.
  • KRAS inhibitors produce anti-tumor activity by recognizing mutant KRAS, blocking the KRAS/GEF interaction, and inhibiting KRAS downstream effectors.
  • targeting KRAS becomes very difficult due to the high levels of GTP in the body and the strong binding force of KRAS to GTP.
  • the KRAS protein is a narrow, flat pocket, which makes the design of KRAS-based drugs difficult.
  • KRAS G12D mutation regulators In recent years, research on KRAS mutations has mainly focused on KRAS G12C, and there have been fewer studies on KRAS G12D. Recently, Mirati Therapeutics' patent WO2021/041671 reported a class of pyrimidine pyridine compounds with KRAS G12D inhibitory activity, and its representative compounds are as follows (Example 252, MRTX1133). Yifang Bio's patent WO2022/002102 also reported a class of pyrimidine benzene ring compounds with KRAS G12D inhibitory activity, and its representative structure is as follows (Example 145). However, no KRAS G12D inhibitors have yet entered the clinical research stage. Therefore, it is of great significance to develop new KRAS G12D mutation regulators.
  • the present invention provides a pyrimidinocyclic compound with a novel structure and a preparation method thereof.
  • the compound As a selective inhibitor of KRAS mutation, the compound has the advantages of high activity, good selectivity and low toxic and side effects.
  • the present invention provides a compound represented by formula (I) or its tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer Isomers, atropisomers or mixtures thereof, pharmaceutically acceptable salts, solvates or prodrugs thereof:
  • U 1 , U 2 and U 3 are N or CR 4 ;
  • R 1 and R 2 are each independently selected from azacycloalkyl; the azacycloalkyl is optionally substituted by one or more R;
  • L is selected from a single bond, a C 1 -C 6 alkylene chain, or an -OC 1 -C 6 alkylene chain, the hydrogen on the alkylene chain being optionally substituted with one or more deuteriums;
  • R 3 is selected from aryl and heteroaryl groups, which are optionally substituted by one or more R 31 ;
  • the R 31 is selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkenyl or C 1 -C 6 alkynyl;
  • the R on the atom and the carbon atom together form a C 3 -C 6 cycloalkyl group, which is optionally substituted by one or more substituents selected from halogen, C 1 -C 6 alkyl replace;
  • R a and R b are each independently selected from hydrogen or C 1 -C 6 alkyl.
  • R 2 is selected from 5 to 12 membered nitrogen heterocycloalkyl containing 1 or 2 nitrogen atoms; the 5 to 12 membered heterocycloalkyl is optionally substituted by one or more R 21 .
  • two R 21 attached to the same carbon atom together with the carbon atom form a C 3 -C 6 cycloalkyl group , which is optionally replaced by one or more Halogen substitution, the condition is that when two R 21 connected to the same carbon atom together with the carbon atom form a C 3 -C 6 cycloalkyl group and the C 3 -C 6 cycloalkyl group is substituted by halogen, the 5 There is no other substitution to the 12-membered azacycloalkyl group.
  • the R 2 is Wherein, R 21 , R 21 ' and the carbon atoms to which they are connected together form a C 3 -C 6 cycloalkyl group, and the C 3 -C 6 cycloalkyl group is optionally substituted by one or more substituents selected from halogen.
  • the R 21 is selected from
  • the compound represented by formula (I) has a structure represented by formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII):
  • R 1 , L and R 2 each have the same definition as the compound of formula (I).
  • R 42 is halogen; preferably, R 42 is fluorine.
  • R 43 is selected from halogen, hydrogen, and haloalkanes; preferably, R 43 is hydrogen.
  • R 1 is selected from a 5- to 12-membered azacycloalkyl group containing 1 or 2 nitrogen atoms; the azacycloalkyl group is optionally substituted with one or more R 11 .
  • R 1 is selected from described Optionally substituted by one or more R 11 .
  • said Ra and Rb are each independently selected from hydrogen or methyl.
  • the R 11 is selected from hydrogen, hydroxyl, amino, methyl, acetyl or methylamino.
  • R 1 is selected from
  • R 1 is selected from
  • R 1 is selected from
  • R3 is selected from a 5- to 10-membered aryl group or a 5-10-membered heteroaryl group, which is optionally substituted by one or more R 31 replaced.
  • R 3 is selected from naphthyl, phenyl, pyridyl or indazolyl; the naphthyl, phenyl, pyridyl or indazolyl is optionally substituted by one or more R 31 .
  • the R 31 is selected from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkenyl or C 1 - C 6 alkynyl;
  • the R 31 is selected from hydrogen, fluorine, chlorine, hydroxyl, amino, methyl, ethyl, isopropyl, trifluoromethyl, cyclopropyl or ethynyl;
  • R 3 is selected from
  • R 3 is selected from
  • R 3 is selected from
  • L is selected from C 1 -C 6 alkoxy.
  • L is -OCH2- .
  • -LR 2 is
  • -LR 2 is in the form of a mixture or mixture form.
  • the compound represented by formula (II) has the structure represented by formula (IIa):
  • R 1 has the same definition as the compound of formula (I); R 41 , R 42 , and R 43 have the same definitions as before;
  • Ring E 1 and Ring E 2 are each independently selected from a 5- or 6-membered aryl group and a 5- or 6-membered heteroaryl group;
  • R 31 ', R 31 ′′ are each independently selected from hydrogen, halogen, hydroxyl, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkenyl or C 1 -C 6 Alkynyl;
  • R5 is selected from deuterium, F, Cl, Br or I;
  • n 1 , m 2 and m 3 are each independently 1 or 2;
  • the compound represented by formula (III) has the structure represented by formula (IIIa):
  • R 1 and R 3 have the same definitions as for the compound of formula (I); R 41 , R 42 and R 43 have the same definitions as before;
  • R 5 is selected from F, Cl, Br or I
  • the invention provides the following intermediates or mixtures thereof:
  • a method for preparing the above compound which includes one or more selected from the following synthetic routes:
  • the intermediate INT-1-1 reacts with 3-chloro-2-(chloromethyl)prop-1-ene to obtain the intermediate INT-1-2.
  • the intermediate INT-1-2 reacts with (trifluoromethyl)trimethylsilane to obtain the intermediate INT-1-3.
  • the intermediate INT-1-3 reacts with lithium aluminum hydride to obtain the crude intermediate INT-1.
  • the compound of formula (I-1) is substituted with R 1 H to obtain the compound of formula (I-2), and the compound of formula (I-2) is further reacted with LH-R 2 to obtain the compound of formula (I).
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above compound or its tautomer, cis-trans isomer, meso, racemate or enantiomer. , diastereomers, atropisomers or mixtures thereof, their pharmaceutically acceptable salts, solvates or prodrugs and pharmaceutically acceptable excipients.
  • Another aspect of the present invention provides the above compound or its tautomer, cis-trans isomer, meso, racemate, enantiomer, diastereomer, atropisomer Conforms or their mixture forms, their pharmaceutically acceptable salts, solvates or prodrugs, and the use of the above pharmaceutical compositions in the preparation of drugs for the treatment, prevention and/or treatment of KRAS G12D mutation-induced diseases.
  • Another aspect of the present invention provides the use of the above-mentioned compound or its tautomer, cis-trans isomer, meso isomer, racemate, enantiomer, diastereomer, atropisomer or a mixture thereof, its pharmaceutically acceptable salt, solvate, prodrug or the above-mentioned pharmaceutical composition in the preparation of KRAS mutation inhibitors.
  • the KRAS mutation is KRAS G12D mutation.
  • Another aspect of the present invention provides a method for inhibiting KRAS mutations in a patient in need thereof, comprising administering to the patient the above-mentioned compound or its tautomer, cis-trans isomer, mesoform, Racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, pharmaceutically acceptable salts, solvates, prodrugs or pharmaceutical compositions thereof.
  • Another aspect of the present invention provides a method for inhibiting KRAS mutations in a biological sample, which includes mixing the biological sample with the above compound or its tautomer, cis-trans isomer, meso, exo Racemates, enantiomers, diastereomers, atropisomers or mixtures thereof, their pharmaceutically acceptable salts, solvates, prodrugs or the above pharmaceutical compositions.
  • Another aspect of the invention provides a method for treating a disorder mediated by a KRAS mutation in a patient in need thereof, comprising administering to the patient the above-mentioned compound or a tautomer, cis-trans isomer thereof , meso, racemate, enantiomer, diastereomer, atropisomer or mixture thereof, its pharmaceutically acceptable salt, solvate, prodrug or the above Pharmaceutical compositions.
  • the disorders mediated by KRAS mutations include, but are not limited to, gastric cancer, pancreatic cancer, lung cancer, blood cancer, and colorectal cancer.
  • the KRAS mutation-mediated disorders include, but are not limited to, gastric adenocarcinoma, pancreatic cancer, non-small cell lung cancer, acute myelogenous leukemia, and colorectal cancer.
  • nouns and terms involved in the embodiments of the present invention will be described.
  • the nouns and terms involved in the embodiments of the present invention are suitable for the following explanations.
  • the term "pharmaceutically acceptable salt” refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the pharmacological activity of the parent compound.
  • Such salts include: acid addition salts formed with inorganic acids or with organic acids, the inorganic acids such as nitric acid, phosphoric acid, carbonic acid, etc.; the organic acids such as propionic acid, hexanoic acid, cyclopentanoic acid, Glycolic acid, pyruvic acid, gluconic acid, stearic acid, muconic acid, etc.; or salts formed when the acidic protons present on the parent compound are replaced by metal ions, such as alkali metal ions or alkaline earth metal ions; or with organic bases
  • the coordination compound formed, the organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds provided by the invention also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention. In addition, prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • solvate refers to a substance formed by combining a compound of the invention with a pharmaceutically acceptable solvent.
  • Solvent compounds include stoichiometric amounts of solvent compounds and non-stoichiometric amounts of solvent compounds. Certain compounds of the present invention may exist in unsolvated or solvated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention.
  • the compounds described in the present invention may exist in the form of stereoisomers, and therefore encompass all possible stereoisomers, including but not limited to cis-trans isomers, tautomers, enantiomers, non- Enantiomers, atropisomers (or can also be called rotamers), etc.
  • the compounds of the present invention can also be in any combination or any mixture of the aforementioned stereoisomers, such as meso , racemates, and equal mixtures of atropisomers.
  • the atropisomer of the present invention is an axial or planar chiral stereoisomer produced based on restricted intramolecular rotation.
  • the present invention provides compounds represented by the above types of structures, or their tautomers, cis-trans isomers, meso, racemates, enantiomers, and diastereomers. isomers, atropisomers or mixtures thereof, where "mixtures thereof” include any of the aforementioned stereoisomers (e.g.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon group containing 1 to 20 carbon atoms.
  • C 1 -C 6 alkyl refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and Various branched chain isomers, etc.
  • alkoxy refers to a group having the structure -O-alkyl, where alkyl is as defined above.
  • alkenyl refers to an alkyl group as defined above having one or more carbon-carbon double bonds at any point in the chain
  • C 2 -C 6 alkenyl refers to an alkyl group having 2 Alkenyl groups with up to 6 carbon atoms and at least one carbon-carbon double bond.
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, pentenyl, hexenyl, butadienyl, and the like.
  • alkynyl refers to an alkyl group as defined above having one or more carbon-carbon triple bonds at any point in the chain
  • C 2-8 alkynyl refers to an alkyl group having 2 to Alkynyl group with 8 carbon atoms and at least one carbon-carbon triple bond.
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic fused cyclic hydrocarbon group
  • heterocyclyl refers to a cyclic hydrocarbon group having 5 to 12 ring atoms.
  • aryl refers to an all-carbon monocyclic ring having 6 to 14 ring atoms, an all-carbon polycyclic ring (the rings are connected by covalent bonds, not fused) or an all-carbon fused ring.
  • Polycyclic (that is, rings sharing adjacent pairs of carbon atoms) groups at least one ring in the group is aromatic, that is, it has a conjugated ⁇ electron system.
  • Preferred is C 6-10 aryl.
  • C 6-14 aryl groups include monocyclic aryl groups, polycyclic aryl groups and aromatic condensed polycyclic rings. Examples of monocyclic aryl groups include phenyl groups, and examples of polycyclic aryl groups include biphenyl groups.
  • the aromatic fused polycyclic ring may be a polycyclic group formed by the fusion of a single aryl ring and one or more monoaryl rings, Non-limiting examples thereof include naphthyl, anthracenyl, and the like.
  • the above types of aryl groups may be substituted or unsubstituted.
  • the substituent is preferably one or more substituent groups described in this application.
  • heteroaryl refers to a monocyclic or fused polycyclic ring (i.e., a shared pair of adjacent ring atoms, a shared pair of adjacent ring atoms) substituted with at least one heteroatom independently selected from nitrogen, oxygen, or sulfur.
  • the atomic pairs may be C-C or N-C) groups, in which the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen atoms may be optionally quaternized.
  • the heteroaryl group has 6, 10 or 14 shared ⁇ electrons and at least one ring in the group is aromatic.
  • the term "5- to 10-membered heteroaryl” refers to a heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • substituted or “substituted” means that any one or more hydrogen atoms on a particular atom are replaced by a substituent.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • the compounds represented by formulas (I) to (VII) of the present invention can be prepared by using synthetic methods known in the art or by using methods known in the art in combination with the methods described in the present invention.
  • the solvents, temperatures and other reaction conditions given in the present invention are exemplary and may be varied according to methods well known in the art.
  • the compounds described in the examples of the present invention can be synthesized according to the methods described in the examples using appropriate starting materials according to their specific structures, or can also be synthesized using methods similar to those described in the examples.
  • the starting materials used to synthesize the compounds of the embodiments of the present invention can be prepared by known synthesis methods or similar methods documented in the literature or obtained from commercial sources.
  • the compounds in the examples can be further resolved to obtain their stereoisomers as needed by methods well known in the art, such as crystallization, chromatography, etc.
  • the resolution conditions can be easily obtained by those skilled in the art through routine means or limited experiments.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or subject.
  • Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicines. Know.
  • the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explanted reservoir.
  • parenteral administration such as subcutaneous, intravenous, intramuscular , intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or by means of an explanted reservoir.
  • the compounds of the present invention may be formulated in any orally acceptable preparation form, including, but not limited to, tablets, capsules, aqueous solutions or aqueous suspensions.
  • Carriers used in tablets generally include lactose and corn starch, and lubricants such as magnesium stearate may also be added.
  • Diluents used in capsule formulations generally include lactose and dried corn starch.
  • Aqueous suspension formulations usually consist of the active ingredient mixed with suitable emulsifying and suspending agents. If desired, some sweetening, flavoring or coloring agents may be added to the above oral preparation forms.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic amount of a drug or agent sufficient to achieve the desired effect.
  • the amount of a given drug depends on many factors, such as the specific dosage regimen, the type of disease or condition and its severity, and the subject requiring treatment. or host's uniqueness (e.g., body weight), however, dosages administered may be determined by those known in the art, depending on the particular surrounding circumstances, including, for example, the specific drug being employed, the route of administration, the condition being treated, and the subject or host being treated. The method is routinely determined.
  • the dosage administered will typically be in the range of 0.02-5000 mg/day, for example about 1-1500 mg/day.
  • the required dose may conveniently be presented as one dose, or as divided doses administered simultaneously (or within a short period of time) or at appropriate intervals, for example two, three, four or more divided doses per day.
  • the specific effective amount can be appropriately adjusted according to the patient's condition and in conjunction with the physician's diagnosis.
  • the raw materials and equipment used in the specific embodiments of the present disclosure are all known products and can be obtained by purchasing commercially available products.
  • the intermediate INT-1-3 (570 mg, 2.20 mmol) and lithium aluminum hydride (0.17 g, 4.49 mmol) were dissolved in tetrahydrofuran (15 mL), heated to reflux, and stirred for 5 h. The temperature was lowered to 0 ° C, sodium hydroxide solution (0.15 mL, 15% aqueous solution) was added dropwise, and then 0.2 mL of water was added dropwise, dichloromethane was added to dilute, anhydrous sodium sulfate was added to dry, diatomaceous earth was filtered, and concentrated under reduced pressure to obtain the intermediate INT-1 crude product, which was directly used in the next step reaction with a yield of 90%.
  • intermediate INT-3-2 (6g, 24.32mmol) was dissolved in acetonitrile (15mL), and hydrogen chloride-1,4 dioxane solution (45mL, 4mol/L) was added dropwise. Stir at room temperature overnight. Concentrate under reduced pressure, add ethyl acetate to dilute, add saturated potassium carbonate solution under ice bath to adjust the pH to weak alkalinity, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain intermediate INT-3-3 The crude product is used directly in the next step.
  • intermediate INT-6-4 is similar to the preparation of INT-3-6 in step (5) of Preparation Example 3. It is prepared by replacing the raw material intermediate INT-3-5 with the intermediate INT-6-3. The yield is 85%. MS(ESI,positive ion)m/z:423.2[M+H] + .
  • intermediate INT-6-5 is similar to the preparation of INT-3-7 in step (6) of Preparation Example 3.
  • the raw material intermediate INT-3-6 is replaced by the intermediate INT-6-4.
  • the yield is 90%.
  • intermediate INT-6 is similar to the preparation of INT-3 in step (7) of Preparation Example 3, by replacing the raw material intermediate INT-3-7 with the intermediate INT-6-5, and the yield is 88%.
  • intermediate INT-7-2 is similar to the preparation of INT-5-3 in step (2) of Preparation Example 5.
  • the raw material intermediate INT-5-2 is replaced by the intermediate INT-7-1.
  • the yield is 86%.
  • intermediate INT-7-2 The preparation of intermediate INT-7-2 is similar to the step (3) INT-5-4 of Preparation Example 5.
  • the raw material intermediate INT-5-3 is replaced by the intermediate INT-7-2.
  • the yield is 91 %.
  • the intermediate INT-8-1 (5g, 32.01mmol) was dissolved in methanol (64mL), and sodium borohydride (1.27g, 33.57mmol) was added in batches. Stir in ice bath for 1 hour. Add 100 mL of saturated aqueous ammonium chloride solution, extract twice with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude intermediate INT-8-2, which can be used directly in the next step with a yield of 96 %.
  • intermediate INT-8-3 (2g, 14.27mmol) and benzyl(methoxymethyl)[(trimethylsilyl)methyl]amine (4.40g, 18.55mmol) were dissolved in Trifluoroacetic acid (0.24g, 2.10mmol) was added dropwise to dry ethyl acetate (24mL) at 0°C, and the mixture was naturally warmed to room temperature and stirred overnight.
  • Trifluoroacetic acid (0.24g, 2.10mmol) was added dropwise to dry ethyl acetate (24mL) at 0°C, and the mixture was naturally warmed to room temperature and stirred overnight.
  • Add saturated aqueous potassium carbonate solution 100 mL
  • extract with ethyl acetate 100 mL ⁇ 2
  • intermediate INT-9-2 is similar to that of step (2) INT-2-3 in Preparation Example 2, except that the raw material INT-2-3 is replaced by INT-9-1, and the yield is 88%.
  • intermediate INT-9-2 The preparation of intermediate INT-9-2 is similar to step (4) INT-2 in Preparation Example 2, by replacing intermediate INT-4 with intermediate INT-9-2, and the yield is 80%.
  • the intermediate INT-10-1 (2923 mg, 20 mmol) was dissolved in acetonitrile (40 mL), 1-bromobut-2-ene (3.19 g, 24 mmol), potassium carbonate (8292.6 mg, 60 mmol), sodium iodide (600 mg, 4 mmol) were added, and the mixture was reacted at 40°C overnight.
  • the reaction solution was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain the intermediate INT-10-2 with a yield of 77%.
  • Methyl iodide-d 3 (9.32g, 64.29mmol) was dissolved in tetrahydrofuran (96mL), and triphenylphosphine (13.2g, 50.14mmol) was added. Stir at room temperature for 1 hour. Raise the temperature and reflux for 1 hour. Cool to room temperature, filter with suction, and dry the filter cake to obtain the product. Yield 99%.
  • the synthesis method is similar to INT-11-2, except that the raw material methyltriphenylphosphine bromide is replaced by the intermediate INT-15-2. Yield 22%. MS(ESI,positive ion)m/z:244.3[M+H] + .
  • intermediate INT-5b The preparation of intermediate INT-5b is similar to that of INT-5a, using intermediates INT-5-5 and INT-1b as raw materials. MS(ESI,positive ion)m/z:720.25,722.23[M+H]+.
  • intermediate 2-1 was similar to that of intermediate 1-1 in step (1) of Example 1, by replacing intermediate INT-5a with intermediate INT-5b, and the yield was 68%.
  • intermediate 3-2 was similar to the preparation of intermediate 1-2 in step (2) of Example 1, using intermediate 3-1 and intermediate INT-2 as raw materials, with a yield of 53%.
  • intermediate 4-2 is similar to that of intermediate 3-2 in step (2) of Example 3, using intermediate 4-1 and intermediate INT-2 as raw materials, with a yield of 66%.
  • intermediate 5-2 was similar to that of intermediate 3-2 in step (2) of Example 3, using intermediate 5-1 and intermediate INT-2 as raw materials, with a yield of 30%.
  • intermediate 6-1 is similar to the intermediate INT-5-5 in step (4) of Preparation Example 5, by replacing the intermediate INT-5-4 with the intermediate INT-3, and the yield is 82%.
  • intermediate 6-2 is similar to the intermediate INT-5 in step (5) of Preparation Example 5, using intermediate 6-1 and intermediate INT-1 as raw materials, with a yield of 75%.
  • intermediate 6-3 was similar to that of intermediate 3-2 in step (2) of Example 3, using intermediate 6-2 and intermediate INT-2 as raw materials, with a yield of 63%.
  • the intermediate 6-2 (100 mg, 0.17 mmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (0.5 mL) was added in an ice-water bath. The mixture was reacted at room temperature for 2 hours and concentrated under reduced pressure to obtain the crude intermediate 8-1 with a yield of 98%, which was directly used in the next step.
  • intermediate 8-3 was similar to that of intermediate 3-2 in step (2) of Example 3. It was prepared by replacing intermediate 3-1 with intermediate 8-2. The yield was 61%. MS(ESI,positive ion)m/z:901.7[M+H]+.
  • AGS is a human gastric adenocarcinoma cell line with Kras G12D mutation
  • ASPC-1 is a human metastatic pancreatic adenocarcinoma cell line with Kras G12D mutation
  • NCI-H358 is a human non-small cell lung cancer cell line with Kras G12C mutation
  • MOLM13 cells are Kras wild-type cells. human acute myelogenous leukemia cell lines.
  • AGS, AsPC-1, NCI-H358, and MOLM13 cells were cultured in 1640 medium + 10% FBS + 1% penicillin/streptomycin medium in an incubator at 37°C and 5% CO2 for 24 hours.
  • the 96-well plates of AGS, NCI-H358, and MOLM13 cells were placed in a cell culture incubator at 37°C and 5% CO2 for 72 hours, and the 96-well plates of AsPC-1 cells were placed in a cell culture incubator at 37°C and 5% CO2. Culture in a cell culture incubator for 7 days. After the culture, add 20 ⁇ L of MTT solution (5 mg/mL) to each well and place it in a cell culture incubator at 37°C and 5% CO2 for 1.5 h.
  • MTT solution 5 mg/mL
  • C, C0 and X represent the average absorbance values of the normal cell group, blank control group and drug-treated group respectively.
  • Graphpad Prism 5.0 software was used to fit the cell inhibition rate curve and calculate the IC 50 value of the cell growth inhibition rate of the test compound.
  • the example compounds provided by the present invention have a good inhibitory effect on the growth of Kras G12D mutated cell lines AGS and ASPC-1 cells. However, it has a weak inhibitory effect on the growth of Kras G12C mutant cell line NCI-H358 and Kras wild-type cell line MOLM13. Some compounds such as compounds 1, 2, 3, 6, 7, 9, 12, 13, and 14 The IC 50 value for inhibiting the growth of AGS cells is less than 500nM, and the IC 50 value of some compounds such as 6, 7, 12, 13, 14, etc. for inhibiting the growth of ASPC-1 cells is less than 500nM.
  • the KRAS G12D inhibitory effect of small molecule compounds was evaluated using the KRAS G12D and cRAF binding assay and the HTRF method.
  • MAb Anti 6HIS-d2 and MAb Anti GST-Eu cryptate were purchased from Cisbio, KRAS G12D was purchased from Bpsbioscience, c-Raf was purchased from Pharmaron, and GTP was purchased from Sigma.
  • C, C 0 and X represent the average HTRF signal value of the reaction control group, blank control group and drug treatment group respectively.
  • Graphpad Prism software was used to fit the IC 50 value of the compound according to the nonlinear regression equation.
  • the compounds of the present invention have a high inhibitory effect on KRAS G12D protein, with IC 50 values less than 500 nM. Some embodiments such as 4, 5, 6, 7, 9, 11, 14, etc. have IC 50 values less than 500 nM. 100nM.
  • the compounds of the present invention can significantly inhibit the proliferation of KRAS G12D mutated tumor cells AGS and ASPC-1 cells.
  • the IC 50 values for inhibiting the proliferation of AGS and ASPC-1 cells are both less than 1000 nM.
  • Some of the compounds in the embodiments inhibit the proliferation of AGS and ASPC-1 cells.
  • the IC 50 values are less than 500nM or even 100nM.
  • the anti-proliferative activities of Compounds 6, 7, 13 and 14 on AGS and ASPC-1 cells are better than those of MRTX1133 and Example 145 of WO2022/002102.
  • the compound of the present invention has a weak inhibitory effect on the growth of the Kras G12C mutant cell line NCI-H358 and the Kras wild-type cell line MOLM13, indicating that the compound of the present invention has good selectivity.
  • Test Example 3 Compound SD rats, pharmacokinetic properties in vivo
  • SD rats Six male Sprague-Dawley (SD) rats, weighing 200-230 g, were randomly divided into 2 groups, with 3 rats in each group.
  • the test compounds were administered intravenously (i.v.) and intraperitoneally (i.p.) respectively.
  • the subjects were fasted for 12 h before the experiment and had free access to water. Eat at the same time 2 hours after administration.
  • the intravenous and intraperitoneal injection administration solutions are prepared with DMSO/HS15/NaCl (5/3/92, v/v/v). Give 3 mg/kg by intraperitoneal injection and 5 mg/kg by intravenous injection. Record the administration time and record the time at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after administration. Collect blood through the jugular vein or other appropriate methods at the time point. Each sample is collected about 0.20 mL, anticoagulated with sodium heparin, and placed on ice after collection. And centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6800g, 6 minutes, 2-8°C). Plasma samples were stored in a -80°C refrigerator before analysis.

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Abstract

式(I)所示的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，及其作为KRAS突变的选择性抑制剂的用途，其具有活性高，选择性好且毒副作用低等优点。

Description

嘧啶并环类化合物及其制备方法与用途 技术领域
本发明涉及医药技术领域，特别涉及一种嘧啶并环类化合物，及其作为KRAS基因突变的选择性抑制剂的应用。
背景技术
鼠类肉瘤病毒癌基因(RAS)蛋白是GTP酶家族中的一个重要成员，包括NRAS，HRAS和KRAS。这些酶在细胞外信号转导，增殖，凋亡和分化中起重要作用。KRAS与鸟嘌呤三核苷酸磷酸(GTP)结合为活性构象，与鸟嘌呤二核苷酸磷酸(GDP)结合为无活性构象。突变的KRAS蛋白和GTP紧密结合使KRAS蛋白处于异常的持续激活构象，导致下游信号通路持续性激活。KRAS抑制剂通过识别突变KRAS，阻断KRAS/GEF相互作用，抑制KRAS下游效应因子从而产生抗肿瘤活性。然而，由于体内高水平的GTP和KRAS与GTP强有力的结合作用力，导致靶向KRAS变得非常困难。此外，KRAS蛋白是一个狭长的平坦口袋，这导致了基于KRAS药物的设计变得困难。
近年来，针对KRAS突变的研究主要集中在KRAS G12C，针对KRAS G12D的研究较少。最近Mirati Therapeutics的专利WO2021/041671报道了一类嘧啶并吡啶化合物具有KRAS G12D抑制活性，其代表化合物如下(实施例252,MRTX1133)。益方生物专利WO2022/002102也报道了一类具有KRAS G12D抑制活性的嘧啶并苯环化合物，其代表结构如下(实施例145)。但目前仍未有KRAS G12D抑制剂进入临床研究阶段。因此，开发新型的KRAS G12D突变调节剂具有重要的意义。
发明内容
本发明提供一种结构新颖的嘧啶并环类化合物及其制备方法，其作为KRAS突变的选择性抑制剂，具有活性高，选择性好且毒副作用低等优点。
在一方面，本发明提供一种式(I)所示的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药：
式中，
U1、U2、U3为N或CR4；
R1、R2各自独立地选自氮杂环烷基；所述氮杂环烷基任选地被一个或多个R取代；
L选自单键、C1-C6亚烷基链或-O-C1-C6亚烷基链，所述亚烷基链上的氢任选地被一个或多个氘取代；
所述R4选自氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-6炔基、C3-C6环烷基或-N＝S(O)C1-C6烷基，所述C1-C6烷基、C2-C6烯基、C2-6炔基、C3-C6环烷基或-N＝S(O)C1-C6烷基任选地被一个或多个卤素取代；
R3选自芳基、杂芳基，所述芳基、杂芳基任选地被一个或多个R31取代；
所述R31选自氢、卤素、羟基、氨基、C1-C6烷基、C3-C6环烷基、C1-C6烯基或C1-C6炔基；
所述R选自氢、氘、卤素、羟基、C1-C6烷基、-C(＝O)-C1-C6烷基或-NRaRb，或，两个连接在同一碳原子上的R与碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个选自卤素、C1-C6烷基的取代基取代；
其中，Ra、Rb各自独立地选自氢或C1-C6烷基。
在一些具体实施方式中，R2选自含1或2个氮原子的5至12元氮杂环烷基；所述5至12元杂环烷基任选地被一个或多个R21取代。
所述R21选自氢、氘、卤素、羟基、C1-C6烷基、-C(＝O)-C1-C6烷基或-NRaRb，或，两个连接在同一碳原子上的R21与碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个选自卤素、C1-C6烷基的取代基取代。
在一些具体实施方式中，两个连接在同一碳原子上的R21与碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个卤素取代，条件是，当两个连接在同一碳原子上的R21与碳原子共同形成C3-C6环烷基且所述C3-C6环烷基被卤素取代时，所述5至12元氮杂环烷基无其它取代。
在一些具体实施方式中，所述R2为其中，R21、R21’与其连接的碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个选自卤素的取代基取代。
在一些具体实施方式中，所述R21选自
在一些具体实施方式中，式(I)所示的化合物具有式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)所示结构：
式中，R1、L、R2各自定义同式(I)化合物。
其中，R41、R42各自独立地选自氢、卤素、氰基、卤素取代或未取代的C1-C6烷基、C2-C6烯基、C2-6炔基、C3-C6环烷基或-N＝S(＝O)-C1-C6烷基。
优选地，R41、R42、R43各自独立地选自氢、氟、氯、氰基、乙基、三氟甲基、环丙基、乙烯基、乙炔基、或-N＝S(＝O)(CH3)2。
优选地，R41选自氢、氟、氯、氰基、三氟甲基、环丙基、乙烯基或-N＝S(O)(CH3)2。
优选地，R42为卤素；优选地，R42为氟。
优选地，R43选自卤素、氢、卤代烷烃；优选地，R43为氢。
在一些具体实施方式中，R1选自选自含1或2个氮原子的5至12元氮杂环烷基；所述氮杂环烷基任选地被一个或多个R11取代。
优选地，R1选自所述任选地被一个或多个R11取代。
所述R11选自氢、羟基、C1-C6烷基、-C(＝O)-C1-C6烷基或-NRaRb；其中，Ra、Rb各自独立地选自氢或C1-C6烷基。
优选地，所述Ra、Rb各自独立地选自氢或甲基。
优选地，所述R11选自氢、羟基、氨基、甲基、乙酰基或甲氨基。
优选地，R1选自
优选地，R1选自
优选地，R1选自
在一些具体实施方式中，R3选自5至10元芳基或5-10元杂芳基，所述5至10元芳基或5至10元杂芳基任选地被一个或多个R31取代。
优选地，R3选自萘基、苯基、吡啶基或吲唑基；所述萘基、苯基、吡啶基或吲唑基任选地被一个或多个R31取代。
所述R31选自氢、卤素、羟基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烯基或C1-C6炔基；
优选地，所述R31选自氢、氟、氯、羟基、氨基、甲基、乙基、异丙基、三氟甲基、环丙基或乙炔基；
优选地，R3选自
优选地，R3选自
优选地，R3选自
在一些具体实施方式中，L选自C1-C6烷氧基。
优选地，L为-OCH2-。
优选地，-L-R2为
优选地，-L-R2为的混合物形式或的混合物形式。
在一些具体实施方式中，式(II)所示的化合物具有式(IIa)所示结构：
式中，R1定义同式(I)化合物；R41、R42、R43各自定义同前；
环E1、环E2各自独立地选自5或6元芳基、5或6原杂芳基；
R31’、R31”各自独立地选自氢、卤素、羟基、氨基、C1-C6烷基、C3-C6环烷基、C1-C6烯基或C1-C6炔基；
R5选自氘、F、Cl、Br或I；
m1、m2、m3各自独立地为1或2；
优选地，所述选自萘基或更优选地，所述为萘基；
优选地，所述为
在一些具体实施方式中，式(III)所示的化合物具有式(IIIa)所示结构：
式中，R1、R3定义同式(I)化合物；R41、R42、R43各自定义同前；
R5选自F、Cl、Br或I；
优选地，所述为
在一些具体实施方式中，本发明提供以下中间体或其混合物：
在一些具体实施方案中，提供的混合物，其结构任意指定为1H NMR(400MHz,CDCl3)δ3.38(d,1H),3.32(d,1H),3.17–3.04(m,2H),2.80(d,1H),2.72–2.59(m,1H),1.99(dd,1H),1.92–1.80(m,3H),1.79–1.60(m,2H),1.38–1.29(m,1H),1.29–1.17(m,1H).或1H NMR(400MHz,Chloroform-d)δ3.34(d,J＝2.1Hz,2H),3.30–3.16(m,2H),3.14–3.05(m,1H),2.84–2.74(m,2H),2.07(d,J＝13.2Hz,1H),2.01–1.91(m,2H),1.90–1.68(m,3H),1.36–1.26(m,2H).。
在一些具体实施方案中，提供的混合物，其结构任意指定为1H NMR(400MHz,CDCl3)δ3.38(d,1H),3.32(d,1H),3.17–3.04(m,2H),2.80(d,1H),2.72–2.59(m,1H),1.99(dd,1H),1.92–1.80(m,3H),1.79–1.60(m,2H),1.38–1.29(m,1H),1.29–1.17(m,1H).或1H NMR(400MHz,Chloroform-d)δ3.34(d,J＝2.1Hz,2H),3.30–3.16(m,2H),3.14–3.05(m,1H),2.84–2.74(m,2H),2.07(d,J＝13.2Hz,1H),2.01–1.91(m,2H),1.90–1.68(m,3H),1.36–1.26(m,2H).。
以下化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药：



本发明的再一方面，提供一种上述化合物的制备方法，其包括选自以下合成路线中的一个或多个：
合成路线1：
中间体INT-1-1与3-氯-2-(氯甲基)丙-1-烯反应得到中间体INT-1-2，中间体INT-1-2与(三氟甲基)三甲基硅烷反应得到中间体INT-1-3，将中间体INT-1-3与氢化铝锂反应得到中间体INT-1粗品。
合成路线2:
式(I-1)化合物与R1H取代反应得到式(I-2)化合物，式(I-2)化合物进一步与LH-R2反应得到式(I)化合物。
本发明的另一方面，提供一种药物组合物，所述组合物包含上述化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药和药学上可接受的辅料。
本发明的另一方面，提供上述化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药、上述药物组合物在制备治疗制备预防和/或治疗KRAS G12D突变诱导疾病的药物中的用途。
本发明的另一方面，提供上述化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或上述药物组合物在制备KRAS突变抑制剂中的用途。
优选地，所述KRAS突变为KRAS G12D突变。
本发明的另一方面，提供一种抑制有需要的患者中的KRAS突变的方法，其包含向所述患者施用上述化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或上述药物组合物。
本发明的另一方面，提供一种抑制生物样品中的KRAS突变的方法，其包含使所述生物样品与上述化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或上述药物组合物接触。
本发明的另一方面，提供一种用于治疗有需要的患者的由KRAS突变介导的病症的方法，其包含向所述患者施用上述化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或上述药物组合物。
在一些具体实施方式中，所述由KRAS突变介导的病症包括但不限于胃癌、胰腺癌、肺癌、血液癌、结直肠癌。
优选地，所述KRAS突变介导的病症包括但不限于胃腺癌、胰腺癌、非小细胞肺癌、急性髓原白血病细胞、结肠直肠癌。
具体实施方式
为了使本发明的目的、技术方案和优点更加清楚，下面将对本发明作进一步地详细描述，所描述的实施例不应视为对本发明的限制，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其它实施例，都属于本发明保护的范围。
在以下的描述中，涉及到“一些实施例”，其描述了所有可能实施例的子集，但是可以理解，“一些实施例”可以是所有可能实施例的相同子集或不同子集，并且可以在不冲突的情况下相互结合。
对本发明实施例进行进一步详细说明之前，对本发明实施例中涉及的名词和术语进行说明，本发明实施例中涉及的名词和术语适用于如下的解释。
如本文中所使用的，术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括：与无机酸或与有机酸形成的酸加成的盐，所述的无机酸诸如硝酸，磷酸，碳酸等；所述的有机酸诸如丙酸，己酸，环戊丙酸，乙醇酸，丙酮酸，葡糖酸，硬脂酸，粘康酸等；或在母体化合物上存在的酸性质子被金属离子，例如碱金属离子或碱土金属离子取代时形成的盐；或与有机碱形成的配位化合物，所述的有机碱诸如乙醇胺，二乙醇胺，三乙醇胺，N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文中所使用的，术语“溶剂化物”是指本发明化合物与制药上可接受的溶剂结合形成的物质。溶剂化合物包括化学计算量的溶剂化合物和非化学计算量的溶剂化合物。本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体、阻转异构体(或也可以称为旋转异构体)等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。
如前所述，本发明提供了上述各类结构所示化合物，或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其中“其混合物形式”包括前述的任一立体异构体(例如 互变异构体、顺反异构体、对映异构体、非对映异构体、阻转异构体)和/或混合物(内消旋体、外消旋体)之间的任意形式的混合，例如顺反异构体的混合物，对映异构体和非对映异构体的混合物，非对映异构体的混合物，阻转异构体的混合物，或顺反异构体和外消旋体的混合，对映异构体和非对映异构体混合物的混合，阻转异构体与非对映异构体混合物的混合等。
如本文中所使用的，各基团中取代基所含有的“-”符号表示与其他基团或结构连接的键。
如本文中所使用的，术语“烷基”指直链或支链饱和脂肪族烃基基团，其包含1到20个碳原子。术语“C1-C6烷基”指具有1到6个碳原子的直链或支链烷基。烷基具体实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。
如本文中所使用的，术语“烷氧基”指具有-O-烷基结构的基团，其中烷基的定义如上所述。
如本文中所使用的，术语“烯基”指在链的任何位点上具有一个或多个碳-碳双键的如上定义的烷基，术语“C2-C6烯基”指具有2到6个碳原子和至少一个碳-碳双键的烯基。烯基具体实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基、戊烯基、己烯基、丁间二烯基等。
如本文中所使用的，术语“炔基”指在链的任何位点上具有一个或多个碳-碳三键的如上定义的烷基，术语“C2-8炔基”指具有2到8个碳原子和至少一个碳-碳三键的炔基。炔基具体实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。
如本文中所使用的，术语“卤素”指氟、氯、溴和碘。
如本文中所使用的，术语“杂环烷基”指饱和或部分不饱和单环或多环稠合的环状烃基，术语“5至12元杂环基”指具有5到12个环原子的饱和或部分不饱和单环或多环稠合的环状烃基，其中一个或多个(优选为1、2、3或4个)环原子为选自氮杂原子，其余环原子为碳。其中环原子为氮原子时，其可以是被取代的或未取代的。
如本文中所使用的，术语“芳基”，指具有6到14个环原子的全碳单环，全碳多环(环与环通过共价键连接，非稠合)或全碳稠合多环(也就是共享毗邻碳原子对的环)基团，基团中至少一个环为芳香性的，即具有共轭的π电子体系。优选为C6-10芳基。本发明中C6-14芳基包括单环芳基、多环芳基和芳香稠合多环，其中单环芳基的实例包括苯基，多环芳基的实例包括联苯基等。
本发明中，C6-14芳基为芳香稠合多环时，所述的芳香稠合多环可以为单芳基环与一个或多个单芳基环稠合形成的多环基团，其非限制性实例包括萘基，蒽基等。
在本发明中，上述各类芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个本申请中所记载的取代基团。
如本文中所使用的，术语“杂芳基”指环原子被至少一个独立选自氮、氧或硫的杂原子取代的单环或稠合多环(即共享毗邻环原子对，共享的毗邻环原子对可以是C-C或N-C)基团，其中氮和硫原子可任选地被氧化，氮原子可任选地被季铵化。所述杂芳基具有共享的6，10或14个π电子，基团中至少一个环是芳族的。术语“5至10元杂芳基”指具有5到10个环原子，其中1、2、3或4个环原子为杂原子的杂芳基。
如本文中所使用的，术语“取代的”或“取代”是指特定原子上的任意一个或多个氢原子被取代基取代。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
本发明式(I)-式(VII)所示的化合物可使用本领域已知的合成方法或使用本领域已知的方法与本发明记载的方法组合制备得到。本发明给出的溶剂、温度和其它反应条件均为示例性的，可根据本领域熟知的方法而变化。本发明所记载的实施例化合物可根据其具体结构，使用适当的起始原料按照实施例中记载的方法合成，也可以使用与实施例中记载的类似方法合成得到。用于合成本发明实施例化合物的起始原料可通过已知合成方法或文献记载的类似方法制备得到或从商业来源获得。实施例化合物可根据需要，进一步通过本领域熟知的方法，例如结晶、色谱法等拆分得到其立体异构体，其拆分条件是本领域技术人员通过常规手段或有限试验而容易获得的。
术语“药学可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者受试者无毒副作用的任何制剂或载体介质代表性的载体，包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周 知。
在本发明的实施方案中，所述药物组合物可以以下的任意方式施用：口服，喷雾吸入，直肠用药，鼻腔用药，颊部用药，局部用药，非肠道用药，如皮下，静脉，肌内，腹膜内，鞘内，心室内，胸骨内和颅内注射或输入，或借助一种外植储器用药。当口服用药时，本发明的化合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。片剂使用的载体一般包括乳糖和玉米淀粉，另外也可加入润滑剂如硬脂酸镁。胶囊制剂使用的稀释剂一般包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
如本文中所使用的，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。在本发明的实施方式中，在根据本发明对患者进行治疗时，给定药物的量取决于诸多因素，如具体的给药方案、疾病或病症类型及其严重性、需要治疗的受治疗者或宿主的独特性(例如体重)，但是，根据特定的周围情况，包括例如已采用的具体药物、给药途径、治疗的病症、以及治疗的受治疗者或宿主，施用剂量可由本领域已知的方法常规决定。通常，就成人治疗使用的剂量而言，施用剂量典型地在0.02-5000mg/天，例如约1-1500mg/天的范围。该所需剂量可以方便地被表现为一剂、或同时给药的(或在短时间内)或在适当的间隔的分剂量，例如每天二、三、四剂或更多分剂。本领域技术人员可以理解的是，尽管给出了上述剂量范围，但具体的有效量可根据患者的情况并结合医师诊断而适当调节。
实施例与制备例
本公开具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
制备例1:中间体INT-1的制备
(1)中间体INT-1-2：2-亚甲基-5-氧代四氢-1H-吡咯里嗪-7a(5H)-羧酸乙酯的制备
氩气保护下，将中间体INT-1-1(10g,63.63mmol)，3-氯-2-(氯甲基)丙-1-烯(12.73g,101.81mmol)溶于四氢呋喃(48mL)中，降温至-78℃，滴入双三甲基硅基胺基锂(21.29g,127.26mmol)。搅拌下自然升温过夜。降温至0℃，用饱和氯化铵水溶液淬灭，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，硅胶柱分离纯化(石油醚/乙酸乙酯＝1:1)得到中间体INT-1-2，产率64％。MS(ESI,positive ion)m/z:210.3.[M+H]+.
(2)中间体INT-1-3的制备
氩气保护下，在加压釜中，将中间体INT-1-2(1g,4.78mmol)，碘化钠(0.72g,4.78mmol)溶于中四氢呋喃(9.6mL)，滴入(三氟甲基)三甲基硅烷(3.40g,23.9mmol)。完毕后，用氩气缓慢吹扫加压釜，置换除去空气。密封，搅拌下升温至80℃过夜。降温至0℃，用氯化铵水溶液淬灭，用乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，残留物经硅胶色谱柱分离纯化(石油醚/乙酸乙酯＝1:2)得到中间体INT-1-3，MS(ESI,positive ion)m/z:260.3[M+H]+。
(3)中间体INT-1的制备
氩气保护下，将中间体INT-1-3(570mg,2.20mmol)，氢化铝锂(0.17g,4.49mmol)溶于四氢呋喃(15mL)中，升温至回流，搅拌5h。降温至0℃，滴入氢氧化钠溶液(0.15mL,15％水溶液)，再滴入0.2mL水，加入二氯甲烷稀释，加入无水硫酸钠干燥，硅藻土过滤，减压浓缩，得到中间体INT-1粗品直接用于下一步反应，产率为90％。
制备例2:中间体INT-2的制备
(1)中间体INT-2-2：7-氟-8-((三异丙基硅基)乙炔基)萘-1,3-二醇的制备
将中间体INT-2-1(1.2g，6.74mmol)，(2-溴乙炔基)三异丙基硅烷(1.82g，6.93mmol)，二氯双(4-甲基异丙基苯基)钌(II)(0.204g，0.33mmol)，醋酸钾(1.32g，13.48mmol)溶于1,4-二氧六环(12mL)，氮气保护。升温至110℃，搅拌2h。过滤，滤液减压浓缩，上柱纯化(石油醚/乙酸乙酯＝15:1)得到中间体INT-2-2，产率45.5％。MS(ESI,positive ion)m/z:357.1.[M-H]-。
(2)中间体INT-2-3：3-(乙氧甲氧基)-7-氟-8-((三异丙基硅基)乙炔基)萘-1-醇的制备
氩气保护0℃下将中间体INT-2-2(1.2g，3.52mmol)溶于二氯甲烷(12mL)，加入N,N-二异丙基乙胺(1.36g，14.08mmol)和氯甲基乙醚(5.00g，5.28mmol)室温搅拌2h。加入水终止反应，用乙酸乙酯萃取，无水硫酸钠干燥，抽滤，减压浓缩，残留物上硅胶色谱柱分离(石油醚/乙酸乙酯＝50:1)得到中间体INT-2-3，产率51％。MS(ESI,positive ion)m/z:415.0.[M-H]-。
(3)中间体INT-2-4：3-(乙氧甲氧基)-7-氟-8-((三异丙基硅基)乙炔基)萘-1-基三氟甲烷磺酸酯的制备
氩气保护，在-40℃下将中间体INT-2-3(1g，2.4mmol)溶于二氯甲烷(10mL)，加入N,N-二异丙基乙胺(0.93g，7.2mmol)，滴入三氟甲磺酸酐(1.02g，14.08mmol)，-40℃搅拌1h。加水，升温至室温，用乙酸乙酯萃取，无水硫酸钠干燥，抽滤，减压浓缩，残留物上硅胶色谱柱分离(石油醚/乙酸乙酯＝60:1)得到中间体INT-2-4，产率80％。
(4)中间体INT-2：((6-(乙氧甲氧基)-2-氟-8-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)萘-1-基)乙炔基)三异丙基硅烷的制备
氩气保护下，混合中间体2-4(0.072g，0.14mmol)，醋酸钾(0.05g，0.51mmol)，甲苯(1mL)，联硼酸频那醇酯(0.072g，0.28mmol)，1,1'-双(二苯基膦)二茂铁]二氯化钯(0.010g，0.014mmol)。反应液升温至回流，反应12小时，后减压浓缩，经硅胶色谱板分离(石油醚/乙酸乙酯＝15：1)得到中间体INT-2，产率72％。1H NMR(400MHz,CDCl3)δ7.70-7.65(m,1H),7.52(d,J＝2.4Hz,1H),7.40(d,J＝2.4Hz,1H),7.26(t,J＝8.4Hz),5.30(s,2H),3.50-5.40(m,2H),1.46(s,12H),1.20-1.15(m,24H).
制备例3:中间体INT-3的制备
(1)中间体INT-3-2：叔丁基(2-氯-3-氟吡啶-4-基)氨基甲酸酯的制备
氩气保护，混合中间体INT-3-1(9g，51.27mmol)，三乙胺(15.57g，153.8mmol)，叔丁醇(60mL)，甲苯(60mL)，加入4A分子筛(15g)，升温至110℃，搅拌30分钟，后降温至0℃，加入叠氮磷酸二苯酯(21.16g，76.91mmol)，升温至100℃，搅拌约5小时。抽滤，滤液减压浓缩，经硅胶色谱柱纯化(石油醚/乙酸乙酯＝5:1)得到中间体INT-3-2，产率63.3％。MS(ESI,positive ion)m/z:247.2.[M+H]+。
(2)中间体INT-3-3：2-氯-3-氟吡啶-4-胺的制备
室温下，将中间体INT-3-2(6g，24.32mmol)溶于乙腈(15mL),滴入氯化氢-1,4二氧六环溶液(45mL，4mol/L)。室温搅拌过夜。减压浓缩，加入乙酸乙酯稀释，冰浴下加入饱和碳酸钾溶液调节pH至弱碱性，乙酸乙酯萃取，无水硫酸钠干燥，过滤，减压浓缩，得中间体INT-3-3粗品，直接用于下一步。
(3)中间体INT-3-4：2-氯-3-氟-5-碘吡啶-4-胺的制备
氩气氛围保护，室温下混合中间体INT-3-3(2.4g，16.38mmol)，N-碘代丁二酰亚胺(4.42g，19.66mmol)，对甲苯磺酸一水合物(0.16g，0.82mmol)，乙腈(11mL)，升温至70℃搅拌过夜。加入乙酸乙酯稀释，饱和碳酸钾溶液，萃取，盐水洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，得中间体INT-3-4粗品，直接 用于下一步反应。MS(ESI,positive ion)m/z:273.2.[M+H]+。
(4)中间体INT-3-5：乙基4-氨基-6-氯-5-氟烟酸酯的制备
氩气保护下，混合中间体INT-3-4(4.63g，16.99mmol)，六羰基钼(4.49g，16.99mmol)，双(三苯基膦)二氯化钯(0.732g，1.04mmol)，三乙胺(10mL)，乙醇(100mL)。升温至80℃，搅拌过夜。冷却至室温，过滤，加乙酸乙酯稀释，水洗，有机相经饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩，残留物经硅胶色谱柱纯化(石油醚/乙酸乙酯＝1:1)得到中间体INT-3-5，产率65％。MS(ESI,positive ion)m/z:219.3.[M+H]+。
(5)中间体INT-3-6：乙基6-氯-5-氟-4-(3-(2,2,2-三氯乙酰基)脲基)烟酸酯的制备
将中间体INT-3-5(0.15g，0.69mmol)溶于四氢呋喃(2mL)，冰水浴下滴入三氯乙酰异氰酸酯(0.13g，0.69mmol)。自然升温至室温，搅拌1小时。减压浓缩，甲基叔丁基醚打浆，抽滤，得到中间体INT-3-6为白色固体。产率87％。MS(ESI,positive ion)m/z:406.1.[M-H]-。
(6)中间体INT-3-7：7-氯-8-氟吡啶并[4,3-d]嘧啶-2,4(1H,3H)-二酮的制备
冰水浴下，将中间体INT-3-6(0.15g，0.37mmol)溶于于无水甲醇(1.5mL)，滴入氨的甲醇溶液(0.15mL，7mol/L)，室温搅拌过夜。减压浓缩，甲基叔丁基醚打浆，抽滤得到白色固体，即为中间体INT-3-7。产率89％。MS(ESI,positive ion)m/z:214.0.[M-H]-。
(7)中间体INT-3：2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶的制备
氩气保护，混合中间体3-7(83mg，0.39mmol)，N,N-二异丙基乙胺(251.6mg，1.95mmol)，三氯氧磷(0.83ml)，升温至90℃，搅拌1小时。减压浓缩，残留物通过快速硅胶色谱柱纯化(二氯甲烷)，洗脱液直接用稀酸水洗涤，无水硫酸钠干燥，过滤，减压浓缩，得到黄色固体即为中间体INT-3。MS(ESI,positive ion)m/z:252.2.[M+H]+。
制备例4:中间体INT-4的制备
(1)中间体INT-4-2：2-氨基-4-溴-5-氯-3-氟苯甲酸的制备
将化合物INT-4-1(5g，21.37mmol)，N-氯代丁二酰亚胺(4.28g，32.05mmol)溶于N,N-二甲基甲酰胺(40mL)，氩气保护，升温至40℃搅拌4小时，冷却至室温，加入水，用乙酸乙酯萃取，有机相用盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得到中间体INT-4-2，产率75％。MS(ESI,positive ion)m/z:268.3.270.1[M+H]+。
(2)中间体INT-4-3：7-溴-6-氯-8-氟喹唑啉-2,4(1H,3H)-二酮的制备
将中间体INT-4-2(1.1g，4.10mmol)和尿素(8.67g，144.34mmol)放于100mL圆底烧瓶中，氩气保护，升温至180℃反应3小时，降温至80℃，加入水搅拌20分钟，抽滤，滤饼在80℃的水中搅拌20分钟，再次抽滤，滤饼用甲基叔丁基醚打浆一次，抽滤，滤饼烘干得到中间体INT-4-3，产率85％。MS(ESI,positive ion)m/z:291.1.[M-H]-。
(3)中间体INT-4：7-溴-2,4,6-三氯-8-氟喹唑啉的制备
将中间体INT-4-3(3g，10.22mmol)放于圆底烧瓶中，加入三氯氧磷(30mL)，再加入N,N-二异丙基乙胺(2.34g，18.11mmol)，升温至100℃搅拌约2小时，浓缩至干，冰浴下，加入稀盐酸(0.1mol/L)调节pH，二氯甲烷萃取，有机相经饱和氯化钠洗涤，用无水硫酸钠干燥，抽滤，减压浓缩，粗品即为中间体INT-4，直接用于下一步反应。
制备例5:化合物INT-5的制备
(1)中间体INT-5-2：2-氨基-4-溴-3-氟-5-碘苯甲酸的制备
将化合物INT-5-1(20g,85.86mmol)溶于N,N-二甲基甲酰胺(200mL)后加入N-碘代丁二酰亚胺(29g,128mmol)，反应体系在80℃下反应12小时，后反应液倒入冰水中，乙酸乙酯萃取，有机层经饱和食盐水洗涤、硫酸钠干燥，减压浓缩得到棕色粗品中间体INT-5-2,产率90％。MS(ESI,positive ion)m/z:359.96,361.95.[M+H]+.
(2)中间体INT-5-3：7-溴-8-氟-6-碘-喹唑林-2,4(1H,3H)-二酮的制备
将中间体INT-5-2(25g,69.67mmol)和尿素(25.1g,418mmol)混合后在200℃下搅拌3小时。随后将反应体系冷却至室温，加入80℃水打浆两次，固体经多次乙酸乙酯洗涤后最终得灰白色固体为中间体INT-5-3，产率为80％。MS(ESI,negative ion)m/z:383.1[M-H]-.
(3)中间体INT-5-4：7-溴-2,4-二氯-8-氟-6-碘喹唑林的制备
将中间体INT-5-3(5g,13mmol)和N,N-二甲基苯胺(1.6g,13mmol)溶于三氯氧磷(82.5g,538mmol,50mL)后，反应体系在100℃反应1小时。冷却减压浓缩，残留物溶于二氯甲烷中，100mL加入稀盐酸(1mol/L)中，二氯甲烷萃取，有机层经饱和食盐水洗涤,硫酸钠干燥，减压浓缩得中间体INT-5-4,产率为60％。
(4)中间体INT-5-5：叔丁基-(1R,5S)-3-(7-溴-2-氯-8-氟-6-碘喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸酯的制备
将中间体INT-5-4(2g,4.7mmol)和N,N-二异丙基乙胺(0.72g,5.64mmol)溶于N,N-二甲基甲酰胺(20mL)，0℃下加入3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯(1.2g，5.64mmol)，室温搅拌2h，后将反应液经二氯甲烷稀释后加水洗涤，饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，经硅胶柱层析(石油醚/乙酸乙酯＝5：1)纯化得中间体INT-5-5，产率75％。MS(ESI,positive ion)m/z:597.04,599.05[M+H]+.
(5)中间体INT-5：叔丁基-(1R,5S)-3-(7-溴-2-(2,2-二氟二氢-1'H,3'H-螺[环丙基-1，2'-吡咯里嗪]-7a'(5'H)-基)甲氧))-8-氟-6-碘喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸酯的制备
将中间体INT-5-5(2g,3.3mmol),碳酸铯(2.19g,6.6mmol),INT-1(0.6g,3.9mmol)溶于N,N-二甲基甲酰胺(20mL)，反应体系80℃下搅拌12小时，后将反应液冷却至室温，加水稀释后，乙酸乙酯萃取两次，有机层经饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，经硅胶柱(二氯甲烷：甲醇＝15：1)纯化得中间体INT-5，产率73％。MS(ESI,positive ion)m/z:720.25,722.23[M+H]+.
制备例6:化合物INT-6的制备
(1)中间体INT-6-2：3-溴-2,4-二氟-6-碘苯胺的制备
氩气氛围保护下，室温下混合中间体INT-6-1(0.5g，2.4mmol)，碘(0.66g，2.6mmol)，硫酸银(0.78g，2.5mmol)，乙醇(10mL)，室温反应2小时。加入饱和硫代硫酸钠水溶液淬灭反应，加入乙酸乙酯稀释， 水洗，盐水洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析(石油醚：乙酸乙酯＝2：1)分离纯化得中间体INT-6-2，产率87％。MS(ESI,positive ion)m/z:333.9，335.9[M+H]+.
(2)中间体INT-6-3：2-氨基-4溴-3，5-二氟苯甲酸乙酯的制备
将中间体INT-6-2(0.6g，1.8mmol)，六羰基钼(0.475g，1.8mmol)，三乙胺(0.7g，7.21mmol)，双三苯基磷二氯化钯(0.126mg,0.18mmol)，溶于乙醇(10mL)，氮气保护下，80℃下反应5小时。减压浓缩后乙酸乙酯稀释，水洗，盐水洗涤有机相，无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析(石油醚：乙酸乙酯＝3：1)分离纯化得中间体INT-6-3，产率60％。MS(ESI,positive ion)m/z:280.2[M+H]+.
(3)中间体INT-6-4：4-氯-3,5-二氟-2-(3-(2,2,2-三氯乙酰基)脲基)苯甲酸乙酯的制备：
中间体INT-6-4的制备与制备例3步骤(5)INT-3-6的制备类似，将原料中间体INT-3-5替换为中间体INT-6-3制得，产率为85％。MS(ESI,positive ion)m/z:423.2[M+H]+.
(4)中间体INT-6-5：7-溴-6,8-二氟喹唑啉-2,4(1H,3H)-二酮的制备：
中间体INT-6-5的制备与制备例3步骤(6)INT-3-7的制备类似，将原料中间体INT-3-6替换为中间体INT-6-4制得，产率为90％。MS(ESI,positive ion)m/z:423.2[M+H]+.
(5)中间体INT-6：7-溴-2,4-二氯-2,8-二氟喹唑啉的制备：
中间体INT-6的制备与制备例3步骤(7)INT-3的制备类似，将原料中间体INT-3-7替换为中间体INT-6-5制得，产率为88％。MS(ESI,positive ion)m/z:313.1[M+H]+.
制备例7:化合物INT-7的制备
(1)中间体INT-7-2：7-溴-8-氟喹唑啉-2,4(1H,3H)-二酮的制备
中间体INT-7-2的制备与制备例5步骤(2)INT-5-3的制备类似，将原料中间体INT-5-2替换为中间体INT-7-1制得，产率为86％。MS(ESI,positive ion)m/z:259.2[M+H]+.
(2)中间体INT-7：7-溴-2,4-二氯-8-氟喹唑啉的制备
中间体INT-7-2的制备与制备例5步骤(3)INT-5-4的类似，将原料中间体INT-5-3替换为中间体INT-7-2制得，产率为91％。MS(ESI,positive ion)m/z:313.1[M+H]+.
制备例8:中间体INT-8的制备
(1)中间体INT-8-2：2-羟基环戊烷-1-羧酸乙脂的制备
冰浴下，将中间体INT-8-1(5g，32.01mmol)溶于甲醇(64mL)中，分批加入硼氢化钠(1.27g，33.57mmol)。冰浴下搅拌1小时。加入100mL饱和氯化铵水溶液，乙酸乙酯萃取两次，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得中间体INT-8-2粗品，直接用于下一步，产率96％。
(2)中间体INT-8-3：环戊-1-烯-1-羧酸乙酯的制备
在氩气保护下，将中间体INT-8-2(4.2g，26.55mmol)溶于吡啶(26mL)中，加入对甲苯磺酰氯(5.57g，29.21mmol)。80℃下搅拌过夜。冷却至室温，加入水(100mL)，用石油醚萃取，合并有机相，水洗涤一次，无 水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝10:1)得到中间体INT-8-3，产率64％。
(3)中间体INT-8-4：2-苄基六氢环戊基[c]吡咯-3a(1H)-羧酸乙酯的制备
氩气保护下，将中间体INT-8-3(2g，14.27mmol)，苄基(甲氧基甲基)[(三甲基硅基)甲基]胺(4.40g，18.55mmol)溶于干燥的乙酸乙酯(24mL)中，0℃下滴入三氟乙酸(0.24g，2.10mmol)，自然升温至室温，搅拌过夜。向反应体系中加入饱和碳酸钾水溶液(100mL)，乙酸乙酯(100mL×2)萃取，合并有机相，水洗涤一次，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝1:1)得到中间体INT-8-4，产率36％。MS(ESI,positive ion)m/z:274.3.[M+H]+.
(4)中间体INT-8-5：2-苄基六氢环戊基[c]吡咯-3a(1H)-羧酸的制备
将中间体INT-8-4(0.32g，1.17mmol)溶于甲醇(1mL)与四氢呋喃(1mL)的混合溶剂中。将氢氧化钾(0.079g，1.40mmol)的水溶液滴入至反应体系中。室温搅拌过夜。冰浴下稀盐酸(1M)调pH至弱酸性，减压浓缩得中间体INT-8-5的粗品，直接用于下一步。MS(ESI,positive ion)m/z:246.2.[M+H]+。
(5)中间体INT-8-6：(2-苄基六氢环戊基[c]吡咯-3a(1H)-基)氨基甲酸叔丁酯的制备
将中间体INT-8-5(0.33g，1.35mmol)溶于叔丁醇(3mL)中。加入分子筛(330mg)及三乙基胺(0.30g，2.97mmol)，氩气保护下回流30分钟，将反应体系冷却至室温后，将叠氮磷酸二苯酯(0.41g，1.49mmol)滴入反应体系中，继续回流5小时。冷却至室温，加入50mL饱和碳酸钾水溶液，乙酸乙酯萃取两次。合并有机相，无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱层析分离(二氯甲烷/甲醇＝30/1)得到中间体INT-8-6，产率11.7％。MS(ESI,positive ion)m/z:317.2.[M+H]+.
(6)中间体INT-8-7：2-苄基-N-甲基六氢环戊基[c]吡咯-3a(1H)-胺的制备
将中间体INT-8-6(0.25g，0.79mmol)溶于四氢呋喃(5mL)中。0℃下加入氢化铝锂(0.057g，1.50mmol)，后回流4小时。冰浴下加入氢氧化钠水溶液(1mol/L，0.1mL)，再滴加水(0.1mL)，经硅藻土过滤，滤液用硫酸钠干燥，过滤，减压浓缩，得到中间体INT-8-7的粗品，直接用于下一步。MS(ESI,positive ion)m/z:231.3.[M+H]+.
(7)中间体INT-8-8：(2-苄基六氢环戊基[c]吡咯-3a(1H)-基)(甲基)氨基甲酸叔丁基酯的制备
将中间体INT-8-7(0.124g，0.39mmol)，二碳酸二叔丁酯(0.12g，0.57mmol)溶于干燥的二氯甲烷(2mL)中，0℃下加入三乙基胺(0.12g，1.19mmol)，室温搅拌2小时。冰浴下加入20mL水，乙酸乙酯萃取两次，合并有机相，经无水硫酸钠干燥，过滤，减压浓缩，残留物用硅胶柱色谱分离(二氯甲烷/甲醇＝20/1)得到中间体INT-8-8，产率73％。MS(ESI,positive ion)m/z:331.3.[M+H]+.
(8)中间体INT-8：(六氢环戊基[c]吡咯-3a(1H)-基)(甲基)氨基甲酸叔丁酯的制备
将中间体INT-8-8(0.096g，0.29mmol)溶于四氢呋喃(3mL)中。加入氢氧化钯/碳(氢氧化钯含量20％，0.096g)，氢气下室温搅拌过夜。经硅藻土抽滤，滤饼用乙酸乙酯洗涤多次，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，得到中间体INT-8,产率52％。MS(ESI,positive ion)m/z:241.2.[M+H]+.
制备例9:中间体INT-9的制备
(1)中间体INT-9-2：1-溴-3-(乙氧甲氧基)萘的制备
中间体INT-9-2的制备与制备例2步骤(2)INT-2-3类似，将原料INT-2-3替换为INT-9-1制得，产率为88％。
(2)中间体INT-9：2-(3-(一氧甲氧基)萘基-4,4,5,5-四甲基-1,3,2-二氧环硼酯的制备
中间体INT-9-2的制备与制备例2步骤(4)INT-2类似，将中间体INT-4替换为中间体INT-9-2制得，产率为80％。
制备例10:中间体INT-10的制备
(1)中间体INT-10-2：2-(苄基(丁-2-烯-1-基)氨基)乙氰
将中间体INT-10-1(2923mg,20mmol)溶于乙腈(40mL)中，加入1-溴丁-2-烯(3.19g,24mmol)，碳酸钾(8292.6mg,60mmol)，碘化钠(600mg,4mmol)，40℃反应过夜。反应液过滤，减压浓缩后经硅胶柱层析纯化得中间体INT-10-2,产率77％。MS(ESI,positive ion)m/z:201.33.[M+H]+.
(2)中间体INT-10-3：3-苄基-6-甲基-3-氮杂双环[3.1.0]己-1-胺
将钛酸四异丙酯(5.1g,18.13mmol)溶于四氢呋喃中(10mL)中，-78℃下加入环己基氯化镁(5.2g,36mmol)，反应45分钟后，加入中间体INT-10-2(3.3g,16.48mmol),室温反应过夜，加入三氟化硼乙醚(1.7g,36.26mmol),反应2小时。加氢氧化钠水溶液淬灭后过滤，滤液经乙酸乙酯萃取，有机层经食盐水洗，无水硫酸钠干燥后减压浓缩，得中间体INT-10-3粗品，直接用于下一步反应。MS(ESI,positive ion)m/z:203.23.[M+H]+.
(3)中间体INT-10-4：叔丁基(3-苄基-6-甲基-3-氮杂二环[3.1.0]己烷-1-基)氨基甲酯
将中间体INT-10-3(600mg,3.0mmol)溶于乙酸乙酯和水(10mL,4:1)的混合溶剂中，加入碳酸氢钠(756mg,9.0mmol)，二碳酸二叔丁酯(720mg,3.3mmol)，室温反应2小时。反应液加乙酸乙酯稀释，水洗，饱和食盐水洗，滤液减压浓缩，经硅胶柱层析(石油醚/乙酸乙酯＝5：1)得中间体INT-10-4，产率为92％。MS(ESI,positive ion)m/z:303.43.[M+H]+.
(4)中间体INT-10：叔丁基(3-氮杂二环[3.1.0]己烷-1-基)氨基甲酯
将中间体INT-10-4(60mg，0.3mmol)溶于四氢呋喃(3mL)中。加入氢氧化钯/碳(氢氧化钯含量20％，0.096g)，氢气下室温搅拌过夜。经硅藻土抽滤，滤饼用乙酸乙酯洗涤多次，合并有机相，用无水硫酸钠干燥，过滤，减压浓缩，得到中间体INT-10,产率52％。MS(ESI,positive ion)m/z:213.35.[M+H]+.
制备例11:化合物INT-11-4的制备
(1)中间体INT-11-2：1-(叔丁基)2-甲基(S)-4-亚甲基吡咯烷-1,2-二羧酸酯的制备
将甲基三苯基溴化膦(714.44mg,2mmol)，叔丁醇钾(224.42mg,2mmol)加入THF(4mL)中，冰盐浴下反应2h，加入中间体INT-11-1(243.26mg,1mmol)，室温反应1h，TLC监控原料反应完全。加入氯化铵水溶液淬灭，乙酸乙酯萃取，有机相用盐水洗，干燥(硫酸钠)、过滤、浓缩，残留物用硅胶柱色谱柱纯化得到化合物INT-11-2，56mg，产率23％。MS(ESI,positive ion)m/z:242.0[M+H]+.
(2)中间体INT-11-3：5-(叔丁基)6-甲基(6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5,6-二羧酸酯的制备
将中间体INT-11-2(120mg,0.50mmol)，碘化钠(37.47mg,0.25mmol)，(三氟甲基)三甲基硅烷(177.74mg,1.25mmol)加入THF(4mL)中，氩气置换三次，升温60摄氏度，搅拌过夜。加入水，用乙酸乙酯萃取，合并有机相，盐水洗，干燥，浓缩至干，得到粗品化合物INT-11-3，备用。
(3)中间体INT-11-4：5-(叔丁氧羰基)-1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧酸的制备
将中间体INT-11-3溶解在甲醇(2mL)中，加入水(2mL)，加入氢氧化钠(81.6mg,2.04mmol)。室温搅拌1h，TLC监控反应完全。用稀盐酸(1mol/L)调节PH＝4，加入水，用乙酸乙酯萃取两次，合并有机相，盐水洗，干燥，浓缩至干，残留物用硅胶柱色谱柱纯化(乙酸乙酯/甲醇＝0％to 10％)得到化合物INT-11-4。MS(ESI,positive ion)m/z:278.3[M+H]+。
制备例14化合物INT-14的制备
(1)中间体INT-14：(±)-((1R,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1，2'-吡咯里嗪]-7a'(5'H)-基-5',5'-d2)甲烷-d2-醇或(±)-((1S,7a'S)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1，2'-吡咯里嗪]-7a'(5'H)-基-5',5'-d2)甲烷-d2-醇之一的制备
氩气保护下，将中间体INT-1-3(300mg,1.16mmol)溶于干燥的四氢呋喃(15mL)中，分批加入氘代氢化锂铝(0.146g,3.48mmol)，完毕后升温至回流，搅拌5h。降温至0℃，滴入氢氧化钠溶液(0.15mL,15％水溶液)，再滴入0.3mL水，搅拌20min.，加入二氯甲烷稀释，铺硅藻土抽滤，用乙酸乙酯洗涤滤饼，合并滤液，加入无水硫酸钠干燥过滤，减压浓缩，得到中间体INT-14粗品，产率为90％。1H NMR(400MHz,DMSO)δ4.55(s,1H),3.01(dd,J＝11.9,7.2Hz,1H),2.66(d,J＝11.9Hz,1H),1.98(dd,J＝13.2,6.1Hz,1H),1.93–1.82(m,1H),1.79–1.68(m,J＝12.1,7.6Hz,2H),1.67–1.57(m,1H),1.51–1.39(m,J＝17.0,9.4,3.4Hz,3H).。MS(ESI,positive ion)m/z:208.3[M+H]+。
制备例15:化合物INT-15的制备
(1)中间体INT-15-2：(甲基-d3)三苯基碘化膦的制备
将碘甲烷-d3(9.32g,64.29mmol)溶于四氢呋喃(96mL)，加入三苯基膦(13.2g,50.14mmol)。室温搅拌1小时。升温回流1小时。冷却至室温，抽滤，滤饼干燥即得产物。产率99％。
(2)中间体INT-15-3：1-(叔丁基)2-甲基(S)-4-(亚甲基-d2)吡咯烷-1，2-二羧酸酯的制备
合成方法与INT-11-2类似，将原料甲基三苯基溴化膦替换为中间体INT-15-2。产率22％。MS(ESI,positive ion)m/z:244.3[M+H]+.。
(3)中间体INT-15-4：5-(叔丁基)6-甲基(6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5，6-二羧酸酯-2,2-d2的制备
合成方法与INT-11-3类似，将中间体INT-11-2替换为中间体INT-15-3。产率55％。MS(ESI,positive ion)m/z:294.3[M+H]+.。
(4)中间体INT-15-5：(3R,6S)-5-(叔丁氧羰基)-1,1-二氟-5-氮杂螺[2.4]庚烷-6-羧-2,2-d2酸的制备
合成方法与INT-11-4类似，将中间体INT-11-3替换为中间体INT-15-4，硅胶柱色谱纯化产物时，大极性的产物(洗脱剂后冲洗出的产物)即为INT-15-5。产率61％。MS(ESI,positive ion)m/z:280.3[M+H]+.。
(5)中间体INT-15-6：5-(叔丁基)6-甲基(3R,6S)-1,1-二氟-5-氮杂螺[2.4]庚烷-5，6-二羧酸酯-2,2-d2的制备
合成方法与INT-12-1类似，将中间体INT-11-4替换为中间体INT-15-5，产率91％。MS(ESI,positive ion)m/z:294.3[M+H]+.。
(6)中间体INT-15-7：5-(叔丁基)6-甲基(3R)-6-(3-氯丙基)-1,1-二氟-5-氮杂螺[2.4]庚烷-5，6-二羧酸酯-2,2-d2的制备
合成方法与INT-12-2类似，将中间体INT-12-1替换为中间体INT-15-6，产率31％。MS(ESI,positive ion)m/z: 370.3[M+H]+.。
(7)中间体INT-15-8：甲基(1R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1，2'-吡咯利嗪]-7a'(5'H)-羧酸酯-3,3-d2的制备
合成方法与INT-12-3类似，将中间体INT-12-2替换为中间体INT-15-7，产率75％。MS(ESI,positive ion)m/z:234.3[M+H]+.。
(8)中间体INT-15-9：((1R)-2,2-二氟二氢-1'H,3'H-螺[环丙烷-1，2'-吡咯里嗪]-7a'(5'H)-基-3,3-d2)甲醇的制备
合成方法与INT-12-4类似，将中间体INT-12-3替换为中间体INT-15-8，产率100％。MS(ESI,positive ion)m/z:206.3[M+H]+.。
实施例1:化合物1和2的制备
中间体INT-5a和INT-5b的制备
将中间体INT-5-5(2g,3.3mmol),碳酸铯(2.19g,6.6mmol),INT-1a(0.6g,3.9mmol)溶于N,N-二甲基甲酰胺(20mL)，反应体系80℃下搅拌12小时，后将反应液冷却至室温，加水稀释后，乙酸乙酯萃取两次，有机层经饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，经硅胶柱(二氯甲烷：甲醇＝15：1)纯化得中间体INT-5a，产率73％。MS(ESI,positive ion)m/z:720.25,722.23[M+H]+.
中间体INT-5b的制备与INT-5a类似，以中间体INT-5-5和INT-1b为原料制得。MS(ESI,positive ion)m/z:720.25,722.23[M+H]+.

(1)中间体1-1：(1R,5S)-3-(7-溴-6-氰基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体INT-5a(0.1g,0.13mmol),氰化亚酮(24mg,0.26mmol)溶于N,N-二甲基甲酰胺(2mL)，后加入四(三苯基膦)钯(11mg,0.01mmol),反应体系100℃下搅拌5小时，后将反应液冷却至室温，倒入冰水中，乙酸乙酯萃取，有机层经饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，经C-18反向硅胶柱纯化得中间体1-1，产率63％。MS(ESI,positive ion)m/z:663.5[M+H]+.
(2)中间体1-2：(1R,5S)-3-(6-氰基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-7-(3-(乙氧基甲氧基)萘-1-基)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体1-1(21mg,0.033mmol),中间体INT-9(22mg,0.066mmol)溶于四氢呋喃(1.7mL)和水(0.4mL)的混合溶剂，后加入磷酸钾(23mg,0.11mmol)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)(2.8mg,0.0033mmol),反应体系70℃下搅拌3小时，后将反应液冷却至室温，乙酸乙酯萃取，有机层经饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，经C-18反向硅胶柱纯化得中间体1-2，产率52％。MS(ESI,positive ion)m/z:785.6[M+H]+.
(3)化合物1：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟-7-(3-(羟基萘-1-基)喹唑林-6-氰的制备
冰浴下将中间体1-2(13mg,0.017mmol)溶于二氯甲烷(2mL)和三氟乙酸(1.5mL)的混合溶剂，室温下搅拌3小时，后减压浓缩，经C-18反向硅胶柱(0.1％三氟醋酸水溶液/乙腈＝60％)纯化得化合物1，产率13％。MS(ESI,positive ion)m/z:627.5[M+H]+.
(1)中间体2-1：(1R,5S)-3-(7-溴-6-氰基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体2-1的制备与实施例1步骤(1)中间体1-1类似，将中间体INT-5a替换为中间体INT-5b制得，产率68％。MS(ESI,positive ion)m/z:663.5[M+H]+.
(2)中间体2-2：(1R,5S)-3-(6-氰基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-7-(3-(乙氧基甲氧基)萘-1-基)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体2-2的制备与实施例1步骤(2)中间体1-2类似，将中间体1-1替换为中间体2-1制得，产率50％。MS(ESI,positive ion)m/z:785.6[M+H]+.
(3)化合物2：4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟-7-(3-(羟基萘-1-基)喹唑林-6-氰的制备
化合物2的制备与实施例1步骤(3)化合物1类似，将中间体1-2替换为中间体2-2制得，产率20％。MS(ESI,positive ion)m/z:627.5[M+H]+.
得到的两对异构体化合物1和化合物2，其结构为任意指定，结构确认为1H NMR(400MHz,Methanol-d4)δ8.39(s,1H),7.82–7.76(m,1H),7.48–7.42(m,1H),7.34–7.20(m,3H),7.14(dd,J＝4.4,2.4Hz,1H),4.78–4.70(m,2H),4.28–4.17(m,2H),4.05–3.91(m,4H),3.90–3.80(m,1H),3.67–3.58(m,1H),3.51–3.40(m,1H),3.25–3.14(m,1H),2.64(dd,J＝14.1,5.9Hz,1H),2.47–2.34(m,1H),2.32–2.22(m,2H),2.22–2.00(m,5H),1.82–1.68(m,3H).
1H NMR(400MHz,DMSO-d6)δ10.05(br,1H),8.40(s,1H),7.86(d,J＝8.3Hz,1H),7.49(t,J＝7.4Hz,1H),7.40–7.22(m,3H),7.19(t,J＝2.1Hz,1H),4.56–4.33(m,2H),4.15–4.06(m,1H),4.06–3.95(m,1H),3.76–3.63(m,1H),3.62–3.53(m,3H),3.06(d,J＝10.4Hz,1H),3.03–2.91(m,1H),2.80(dd,J＝10.4,5.7Hz,1H),2.74–2.64(m,1H),2.13(d,J＝13.1Hz,1H),2.04–1.87(m,3H),1.87–1.73(m,2H),1.71–1.61(m,2H),1.60–1.50(m,2H),1.37(d,J＝6.0Hz,1H),1.33–1.15(m,2H).
实施例3:化合物3的制备
(1)中间体3-1：(1R,5S)-3-(7-溴-6-环丙基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体INT-5(0.1g,0.13mmol),环丙基硼酸(12mg,0.15mmol)溶于1,4-二氧六环(2mL)和水(0.5mL)的混合溶液，后加入磷酸钾(63mg,0.3mmol)，四(三苯基膦)钯(11mg,0.01mmol),反应体系60℃下搅拌5小时，后将反应液冷却至室温，乙酸乙酯萃取，有机层经饱和食盐水洗涤，经无水硫酸钠干燥后减压浓缩，经C-18反向硅胶柱纯化得中间体3-1，产率72％。MS(ESI,positive ion)m/z:663.5[M+H]+.
(2)中间体3-2：(1R,5S)-3-(6-环丙基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-7-(3-(乙氧基甲氧基)-7-氟-8-((三异丙基硅基)乙炔基萘-1-基)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体3-2的制备与实施例1步骤(2)中间体1-2的制备类似，以中间体3-1和中间体INT-2为原料制得，产率53％。MS(ESI,positive ion)m/z:998.8[M+H]+.
(3)化合物3：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-6-环丙基-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟喹唑林-7-基)-5-乙炔基-6-氟-萘-2-酚的制备
冰浴下将中间体3-2(30mg,0.03mmol)溶于二氯甲烷(2mL)和三氟乙酸(1.5mL)的混合溶剂，室温下搅拌3小时，后减压浓缩，后加N,N-二甲基甲酰胺(1.0mL)溶解后加入氟化铯(109mg,0.72mmol),室温反应1小时后，过滤，经C-18反向硅胶柱纯化得化合物3(产率21％)。1H NMR(400MHz,DMSO-d6)δ7.94(dd,J＝9.1,6.0Hz,1H),7.44(t,J＝9.0Hz,1H),7.34(s,1H),7.24–7.15(m,1H),7.08(s,1H),4.26–4.08(m,8H),3.73(s,1H),3.53-3.50(m,2H),3.17–3.07(m,1H),3.02(s,1H),2.77–2.66(m,1H),2.09(dd,J＝12.9,5.7Hz,2H),2.04–1.96(m,2H),1.90(d,J＝13.2Hz,1H),1.86–1.39(m,11H).、MS(ESI,positive ion)m/z:684.5[M+H]+.
实施例4:化合物4的制备
(1)中间体4-1：(1R,5S)-3-(7-溴--2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟-6-乙烯基喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体INT-5(0.12g,0.16mmol),乙烯三氟硼酸钾(26mg,0.19mmol)溶于1,4-二氧六环(1.5mL)和水(0.3mL)的混合溶液，后加入磷酸钾七水合物(216mg,0.64mmol),1,1'-二(二苯膦基)二茂铁二氯化钯(12mg,0.016mmol)，反应体系50℃下搅拌2小时，后将反应液冷却至室温，过滤，减压浓缩，经硅胶柱层析纯化得中间体4-1，产率65％。MS(ESI,positive ion)m/z:664.5[M+H]+.
(2)中间体4-2：(1R,5S)-3-(-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-7-(3-(乙氧基甲氧基)-7-氟-8-((三异丙基硅基)乙炔基萘-1-基)-8-氟-6-乙烯基喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体4-2的制备与实施例3步骤(2)中间体3-2类似，以中间体4-1和中间体INT-2为原料制得，产率66％。MS(ESI,positive ion)m/z:984.7[M+H]+.
(3)化合物4：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟-6-乙烯基喹唑林-7-基)-5-乙炔基-6-氟-萘-2-酚的制备
化合物4的制备与实施例3步骤(3)化合物3类似，将中间体2-2替换为中间体4-2制得(产率45％)。
1H NMR(400MHz,DMSO)δ11.58(s,1H),8.05-7.84(m,2H),7.44(m,2H),7.12-6.94(m,1H),6.25-6.09(m,1H),5.75(m,1H),5.22-5.12(m,1H),4.70(s,2H),4.62-4.46(m,2H),4.26-4.10(m,3H),3.95-3.85(m,6H),2.39-2.10(m,3H),2.07(s,2H),2.04-1.80(m,7H).、MS(ESI,positive ion)m/z:670.5[M+H]+.
实施例5:化合物5的制备
(1)中间体5-1：(1R,5S)-3-(7-溴--2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-6-(二甲基亚磺酰亚胺)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体INT-5(0.07g,0.092mmol),二甲基亚磺酰亚胺(26mg,0.19mmol)溶于1,4-二氧六环(1.5mL)和水(0.3mL)的混合溶液，后加入磷酸钾七水合物(216mg,0.64mmol),醋酸钯(2m g,0.0092mmol),4,5-双二苯基膦-9,9-二甲基氧杂蒽(11mg,0.019mmol),碳酸铯(60mg,0.18mmol),反应体系60℃下搅拌过夜，后将反应液冷却至室温，过滤，减压浓缩，经硅胶柱层析纯化得中间体5-1，产率75％。MS(ESI,positive ion)m/z:728.5[M+H]+.
(2)中间体5-2：(1R,5S)-3-(-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-7-(3-(乙氧基甲氧基)-7-氟-8-((三异丙基硅基)乙炔基萘-1-基)-6-(二甲基亚磺酰亚胺)-8-氟喹唑林-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体5-2的制备与实施例3步骤(2)中间体3-2类似，以中间体5-1和中间体INT-2为原料制得，产率30％。MS(ESI,positive ion)m/z:1049.8[M+H]+.
(3)化合物5：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-6-(二甲基亚磺酰亚胺)-8-氟喹唑林-7-基)-5-乙炔基-6-氟-萘-2-酚的制备
化合物5的制备与实施例3步骤(3)化合物3类似，将中间体3-2替换为中间体5-2制得(产率28％)。
1H NMR(400MHz,Methanol-d4)δ7.79(dd,J＝9.2,5.8Hz,1H),7.59(d,J＝1.4Hz,1H),7.26(d,J＝8.9Hz,1H),7.24–7.21(m,1H),7.01(d,J＝2.5Hz,1H),4.42–4.26(m,4H),3.66–3.59(m,2H),3.55–3.44(m,2H),3.29–3.26(m,2H),3.19–3.10(m,1H),3.02(s,3H),2.93(s,3H),2.82(d,J＝12.2Hz,1H),2.74–2.62(m,1H),2.33–2.22(m,1H),2.22–2.10(m,2H),2.05–2.00(m,1H),2.00–1.71(m,4H),1.49–1.25(m,4H).、MS(ESI,positive ion)m/z:735.5[M+H]+.
实施例6:化合物6的制备
(1)中间体6-1：(1R,5S)-3-(2,7-二氯-8-氟-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备：
中间体6-1的制备与制备例5步骤(4)中间体INT-5-5类似，将中间体INT-5-4替换为中间体INT-3制得,产率为82％。MS(ESI,positive ion)m/z:428.3,430.3[M+H]+.
(2)中间体6-2：(1R,5S)-3-(7-氯-2-(2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)甲氧))-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体6-2的制备与制备例5步骤(5)中间体INT-5类似，以中间体6-1和中间体INT-1为原料制得,产率为75％。MS(ESI,positive ion)m/z:595.5,597.5[M+H]+.
(3)中间体6-3：(1R,5S)-3-(2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-7-(3-(乙氧基甲氧基)-7-氟-8-((三异丙基硅基)乙炔基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷基-8-羧酸叔丁酯的制备
中间体6-3的制备与实施例3步骤(2)中间体3-2类似，以中间体6-2和中间体INT-2为原料制得，产率63％。MS(ESI,positive ion)m/z:959.8[M+H]+.
(4)化合物6：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙炔基-6-氟-萘-2-酚的制备
化合物6的制备与实施例3步骤(3)化合物3类似，以中间体6-3为原料制得(产率36％)。
1H NMR(400MHz,Methanol-d4)δ9.19(s,1H),7.79–7.65(m,1H),7.38–7.23(m,2H),7.10–7.02(m,1H),4.83–4.71(m,5H),4.30(d,J＝12.2Hz,2H),4.17–3.80(m,4H),3.52–3.42(m,1H),3.25–3.14(m,1H),2.79–2.40(m,2H),2.36–2.07(m,7H),1.81(t,J＝9.0Hz,2H).、MS(ESI,positive ion)m/z:645.5[M+H]+.
实施例7:化合物7的制备
(1)化合物7：4-(4-(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷基)-2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2-吡咯里嗪]-7a'(5'H)-基)-甲氧基)-8-氟吡啶并[4,3-d]嘧啶-7-基)-5-乙基-6-氟-萘-2-酚的制备
将化合物6(30mg,0.047mmol)溶于四氢呋喃(2mL)中，加入钯碳(30mg,10％钯)，在氢气下室温搅拌过夜。后过滤，滤液减压浓缩后经C18反向硅胶柱纯化得化合物7(产率为23)。
1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.10(s,1H),7.77(dd,J＝9.1,6.0Hz,1H),7.40–7.30(m,2H),7.02(d,J＝2.6Hz,1H),4.42(d,J＝12.2Hz,2H),4.27–4.14(m,2H),3.67–3.50(m,4H),3.15–3.05(m,1H),3.05–2.96(m,1H),2.77–2.64(m,1H),2.43–2.31(m,1H),2.22–2.05(m,2H),2.05–1.95(m,1H),1.89(d,J＝13.3Hz,1H),1.87–1.70(m,2H),1.69–1.52(m,5H),1.52–1.41(m,1H),1.23(s,2H),0.72(t,J＝7.4Hz,3H).、MS(ESI,positive ion)m/z:649.5[M+H]+.
实施例8:化合物8的制备
(1)中间体8-1：7a'-((4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基-7-氯-8氟吡啶并[4,3-d]嘧啶-2-基)氧)甲基)-2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]的制备
将中间体6-2(100mg,0.17mmol)溶于二氯甲烷(1mL)，后在冰水浴下加入三氟醋酸(0.5mL),室温反应2小时，减压浓缩得中间体8-1粗品，产率为98％，直接用于下一步反应。MS(ESI,positive ion)m/z:539.4[M+H]+.
(2)中间体8-2：1-(1R,5S)-3-(7-氯-2-(2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)甲氧))-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷基)乙-1-酮的制备
将中间体8-1(130mg,0.18mmol)溶于二氯甲烷(2mL)后，冰浴下加入N,N-二异丙基乙胺(93mg,0.72mmol)和乙酸酐(28mg,0.27mmol)，室温搅拌两小时，加水淬灭反应，二氯甲烷萃取，有机相经无水硫酸钠干燥，过滤，减压浓缩，经硅胶柱层析纯化得中间体8-2，产率为98％。MS(ESI,positive ion)m/z:581.4[M+H]+.
(3)中间体8-3：1-(1R,5S)-3-(7-(3-(乙氧基甲氧基)-7-氟-8-((三异丙基硅基)乙炔基萘-1-基)-2-(2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)甲氧))-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷基)乙-1-酮的制备
中间体8-3的制备与实施例3步骤(2)中间体3-2类似，将中间体3-1替换为中间体8-2制备得到，产率61％。MS(ESI,positive ion)m/z:901.7[M+H]+.
(4)化合物8：1-(1R,5S)-3-(2-((2,2-二氟二氢-1'H,3'H-螺[环丙基-1,2'-吡咯里嗪]-7a'(5'H)-基)甲氧))-7-(8-乙炔基-7-氟-3-羟基萘-1-基)-8-氟吡啶并[4,3-d]嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷基)乙-1-酮的制备化合物8a的制备与实施例3步骤(2)化合物3类似，将中间体3-2替换为中间体8-3制得(产率18％)。
1H NMR(400MHz,Methanol-d4)δ9.02(s,1H),7.85(dd,J＝9.1,5.7Hz,1H),7.37–7.28(m,2H),7.22–7.19(m,1H),4.77–4.46(m,5H),4.40–4.32(m,2H),3.82(d,J＝12.8Hz,1H),3.72(d,J＝12.6Hz,1H),3.37–3.33(m,1H),3.17(s,1H),2.85(d,J＝12.2Hz,1H),2.76–2.65(m,1H),2.32–2.24(m,1H),2.22–1.98(m,6H),1.98–1.71(m,6H),1.51–1.37(m,2H).、MS(ESI,positive ion)m/z:687.5[M+H]+.
实施例9:化合物9的制备
将化合物6(100mg,0.17mmol)溶于二氯甲烷(3mL)后加入叔丁基二甲基氯硅烷(77mg,0.51mmol)，咪唑 (69mg,1.0mmol)，室温反应两小时。加水淬灭反应后，减压浓缩，经C18反向硅胶柱层析分离纯化得到化合物9(产率40％)。
1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.99(dd,J＝9.2,5.9Hz,1H),7.48(t,J＝9.0Hz,1H),7.41(d,J＝2.6Hz,1H),7.19(d,J＝2.5Hz,1H),4.86–4.72(m,5H),4.34(d,J＝12.2Hz,2H),4.15–3.79(m,4H),3.55–3.43(m,1H),3.26–3.17(m,1H),2.80–2.42(m,2H),2.38–2.05(m,7H),1.82(t,J＝9.0Hz,2H),0.86(s,9H),-0.02(s,6H).、MS(ESI,positive ion)m/z:759.55[M+H]+。
实施例10:化合物10的制备
化合物10的制备与实施例6化合物6类似，将步骤(2)中的3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯替换为中间体INT-8，其余步骤相同，制备得到化合物10。
1H NMR测试数据为1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.25(d,J＝4.8Hz,1H),7.98(dd,J＝9.2,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.6Hz,1H),7.17(dd,J＝5.5,2.5Hz,1H),4.31–4.13(m,2H),4.12–4.00(m,1H),3.96(d,J＝4.5Hz,1H),3.93–3.72(m,2H),3.16–3.07(m,1H),3.07–2.99(m,1H),2.72(d,J＝11.8Hz,1H),2.61–2.54(m,2H),2.30(d,J＝4.3Hz,3H),2.13–2.05(m,1H),2.05–1.87(m,3H),1.87–1.71(m,8H),1.69–1.44(m,3H).、MS(ESI,positive ion)m/z:673.58[M+H]+.
实施例11:化合物11的制备
化合物11的制备与实施例化合物6类似，将步骤(2)中的3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯替换为3-甲基哌啶-3-醇，其余步骤相同，制备得到化合物11。
1H NMR测试数据为1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),9.14(s,1H),7.97(dd,J＝9.2,5.9Hz,1H),7.48-7.43(m,1H),7.39(dd,J＝2.6,1.4Hz,1H),7.21(dd,J＝17.8,2.6Hz,1H),4.76(d,J＝22.0Hz,1H),4.43–4.27(m,1H),4.27–4.06(m,3H),4.02–3.94(m,1H),3.59(t,J＝13.7Hz,1H),3.27–3.23(m,1H),3.15–3.06(m,1H),3.06–2.96(m,1H),2.76–2.66(m,1H),2.12–1.94(m,3H),1.90(d,J＝13.3Hz,1H),1.86–1.42(m,7H),1.26–1.11(m,4H).、MS(ESI,positive ion)m/z:648.55[M+H]+.
实施例12:化合物12的制备
化合物12的制备与化合物6类似，将步骤(1)中的中间体INT-3替换为中间体INT-4，其余步骤相同，制备得到化合物12。
1H NMR测试数据为1H NMR(400MHz,Methanol-d4)δ7.88–7.76(m,2H),7.36–7.23(m,2H),7.02(d,J＝2.6Hz,1H),4.53–4.46(m,2H),4.42(d,J＝12.8Hz,1H),4.38–4.26(m,2H),3.70–3.54(m,4H),3.26–3.22(m,1H),3.18–3.10(m,12H),2.82(d,J＝12.2Hz,1H),2.74–2.64(m,1H),2.30–2.22(m,1H),2.21–2.09(m,2H),2.07–1.97(m,3H),1.97–1.71(m,5H),1.64–1.54(m,1H),1.49–1.34(m,2H).
实施例13:化合物13的制备
化合物13的制备与化合物6类似，将步骤(1)中的中间体INT-3替换为中间体INT-6，其余步骤相同，制备得到化合物13。
1H NMR测试数据为1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),8.00(dd,J＝9.2,6.0Hz,1H),7.73–7.63(m,1H),7.56–7.42(m,2H),7.21(d,J＝2.5Hz,1H),4.67(d,J＝3.9Hz,2H),4.48–4.37(m,2H),4.16(d,J＝11.5Hz,2H),4.00(s,1H),3.94(d,J＝13.7Hz,1H),3.85(d,J＝13.7Hz,1H),3.80–3.73(m,1H),3.72–3.62(m,1H),3.42(d,J＝12.6Hz,1H),3.12(d,J＝6.2Hz,1H),2.44(d,J＝5.2Hz,1H),2.35–2.19(m,2H),2.19–2.11(m,1H),2.11–1.93(m,6H),1.88(dt,J＝11.1,6.5Hz,2H).、MS(ESI,positive ion)m/z:662.35[M+H]+.
实施例14:化合物14的制备
化合物14的制备与化合物6类似，将步骤(1)中的中间体INT-3替换为中间体INT-7，其余步骤相同，制备得到化合物14。
1H NMR测试数据为1H NMR(400MHz,DMSO-d6)δ7.95(dd,J＝9.2,6.0Hz,1H),7.74(d,J＝8.7Hz,1H),7.45(t,J＝9.0Hz,1H),7.35(d,J＝2.5Hz,1H),7.18(dd,J＝8.6,6.8Hz,1H),7.08(d,J＝2.5Hz,1H),4.36–4.13(m,4H),3.85(s,1H),3.53(s,2H),3.47(d,J＝11.9Hz,2H),3.17–3.09(m,1H),3.08–3.00(m,1H),2.74(d,J＝11.8Hz,1H),2.59–2.55(m,1H),2.15–2.07(m,1H),2.07–1.98(m,1H),1.92(d,J＝13.3Hz,1H),1.87–1.79(m,1H),1.79–1.43(m,7H).、MS(ESI,positive ion)m/z:644.45[M+H]+.
实施例15:化合物15的制备
化合物15的制备与化合物7类似，将原料化合物6替换为化合物14。
1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),7.81(d,J＝8.6Hz,1H),7.78–7.69(m,1H),7.39–7.19(m,3H),6.92(d,J＝2.4Hz,1H),4.28(d,J＝10.6Hz,2H),4.23–4.10(m,2H),3.57–3.43(m,4H),3.13–3.05(m,1H),3.05–2.96(m,1H),2.70(d,J＝11.8Hz,1H),2.58–2.53(m,1H),2.42–2.28(m,2H),2.12–2.04(m,1H),2.03–1.94(m,2H),1.93–1.85(m,1H),1.85–1.27(m,10H),0.70(t,J＝7.3Hz,3H).MS(ESI,positive ion)m/z:648.46[M+H]+.
实施例16:化合物16的制备
化合物16的制备与化合物6类似，将步骤(2)中的3,8-二氮杂双环[3.2.1]辛烷-3-羧酸叔丁酯替换为中间体INT-10，其余步骤相同，制备得到化合物16。
1H NMR测试数据为1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),9.23(s,1H),8.92(s,1H),8.00(dd,J＝9.2,6.0Hz,1H),7.48(t,J＝9.0Hz,1H),7.42(d,J＝2.5Hz,1H),7.27–7.11(m,1H),4.74–4.56(m,3H),4.55-45(m,1H),4.39-4.05(m,3H),3.88(s,1H),3.80-3.74(m,1H),3.69-3.60(m,1H),3.20-3.10(m,1H),2.45-2.40(m,1H),2.37–2.11(m,3H),2.11–1.94(m,3H),1.92-1.85(m,2H),1.26(d,J＝4.6Hz,3H),1.15-1.10(m,1H).、MS(ESI,positive ion)m/z:645.55[M+H]+.
实施例21:化合物21的制备
与化合物6类似，将原料INT-1替换为中间体INT-14。1H NMR(400MHz,DMSO)δ9.05(s,1H),7.97(dd,J＝9.0,6.0Hz,1H),7.46(t,J＝9.0Hz,1H),7.38(s,1H),7.19(s,1H),4.48(d,J＝12.0Hz,1H),4.33(d,J＝12.4Hz,1H),3.94(s,1H), 3.69–3.53(m,4H),3.16–3.06(m,J＝11.5,6.6Hz,1H),2.73(d,J＝11.8Hz,1H),2.14–2.05(m,J＝12.9,4.7Hz,1H),2.04–1.96(m,1H),1.91(d,J＝13.3Hz,1H),1.86–1.78(m,J＝7.7Hz,1H),1.78–1.71(m,1H),1.71–1.63(m,J＝16.3Hz,4H),1.63–1.53(m,2H),1.53–1.44(m,J＝3.0Hz,1H).。MS(ESI,positive ion)m/z:649.4[M+H]+.
实施例22:化合物22的制备
与化合物6类似，将原料INT-1替换为中间体INT-15-9。1H NMR(400MHz,DMSO)δ10.16(br,1H),9.05(s,1H),7.99(dd,J＝9.1,5.9Hz,1H),7.47(t,J＝9.0Hz,1H),7.40(d,J＝2.5Hz,1H),7.19(d,J＝2.2Hz,1H),4.48(d,J＝11.9Hz,1H),4.33(d,J＝12.2Hz,1H),4.28–4.11(m,J＝8.7Hz,2H),3.94(s,1H),3.64(d,J＝12.3Hz,1H),3.61–3.50(m,3H),3.12(dd,J＝11.8,6.8Hz,1H),3.07–2.98(m,J＝6.3,3.0Hz,1H),2.73(d,J＝11.8Hz,1H),2.60–2.54(m,1H),2.09(dd,J＝13.3,5.5Hz,1H),2.05–1.96(m,J＝10.5,5.0Hz,1H),1.91(d,J＝13.3Hz,1H),1.87–1.72(m,J＝22.1,4.9Hz,2H),1.71–1.64(m,4H),1.64–1.52(m,1H)。MS(ESI,positive ion)m/z:647.4[M+H]+.
测试例1:细胞增殖抑制实验
实验材料
实验方法
AGS为Kras G12D突变的人胃腺癌细胞株，ASPC-1为Kras G12D突变的人转移胰腺腺癌细胞株，NCI-H358为Kras G12C突变的人非小细胞肺癌细胞株，MOLM13细胞为Kras野生型的人急性髓原白血病细胞株。AGS、AsPC-1、NCI-H358、MOLM13细胞采用1640培养基+10％FBS+1％青/链霉素培养基，置于37℃、5％CO2的培养箱中培养24h。实验时，收集处于对数生长期的细胞，接种于96孔板中，置于37℃、5％CO2的细胞培养箱中培养24h。第2天，用培养基稀释待测化合物到相应浓度(0.08-20μM)并加入到96孔板相应孔中，每孔加100μL，使得化合物的终浓度为0.04-10μM，每个样品浓度3个复孔，每块板同时设置3～6个空白对照孔和3～6个正常细胞对照孔。加药后，AGS、NCI-H358、MOLM13细胞的96孔板置于37℃、5％CO2的细胞培养箱中培养72h，AsPC-1细胞的96孔板置于37℃、5％CO2的细胞培养箱中培养7天。培养结束后每孔加20μL的MTT溶液(5mg/mL)，置于37℃、5％CO2的细胞培养箱孵育1.5h。孵育结束后AGS、AsPC-1、NCI-H358细胞去掉孔板中的培养基，每孔加入150μL的DMSO，置于水平振荡仪上中速振荡5min后使用酶标仪测570nm波长下的吸光度；MOLM13细胞每孔加80μL的20％SDS溶液(含0.1％盐酸)，置于37℃、5％CO2的细胞培养箱中孵育4h以上后使用酶标仪测570nm波长下的吸光度。并根据以下公式计算药物对细胞生长的相对抑制率：
细胞抑制率＝[1-(X-C0)/(C-C0)]×100％
其中，C、C0和X分别代表正常细胞组、空白对照组和药物处理组的平均吸光度值。最后，使用Graphpad Prism 5.0软件拟合细胞抑制率曲线并计算出待测化合物的细胞生长抑制率的IC50值。
结果：本发明提供的实施例化合物对Kras G12D突变的细胞系AGS、ASPC-1细胞的生长均具有较好的抑制作 用，而对Kras G12C突变的细胞系NCI-H358和Kras野生型细胞系MOLM13的生长具有较弱的抑制作用，部分化合物如化合物1、2、3、6、7、9、12、13、14等对AGS细胞生长抑制的IC50值小于500nM，部分化合物如6、7、12、13、14等对ASPC-1细胞生长抑制的IC50值小于500nM。
测试例2:KRAS G12D蛋白结合测试
实验方法
使用KRASG12D与cRAF结合试验以及HTRF法，评估小分子化合物的KRASG12D抑制作用。
实验材料
MAb Anti 6HIS-d2、MAb Anti GST-Eu cryptate购于Cisbio公司，KRASG12D购于Bpsbioscience公司，c-Raf购于Pharmaron公司，GTP购于Sigma公司。
实验方法
首先，将3μL参比原液转移至27μL 100％DMSO中，待测化合物原液为第一个稀释点，3倍稀释，共计11个浓度梯度，随后，将2μL稀释化合物分别转移到18μL稀释缓冲液中，进行再次稀释。最后，将最终稀释化合物吸取2μL，转移到384板中，含2个重复，并以1000rpm离心384测定板。离心后，先将4μL KRASG12D&GTP混合物加入每个测定孔中，再将4μL cRAF添加到每个测定孔中，孵育15min。随后，将10uL GST-Tb&His-d2混合物加入每个测定孔中，并在4℃环境下作用3h。最后，使用BMG读取HTRF信号(665/615nm比率)，并用非线性回归方程拟合化合物的IC50，化合物的KRASG12D激酶抑制率计算公式如下：
抑制率(inhibition，％)＝100％-(X-C0)/(C-C0)*100％
其中，C、C0和X分别代表反应对照组、空白对照组和药物处理组的平均HTRF信号值。最后，使用Graphpad Prism软件根据非线性回归方程拟合化合物的IC50值。
综合生物测试结果分析，本发明化合物对KRAS G12D蛋白均具有较高的抑制作用，IC50值均小于500nM，部分实施例如4、5、6、7、9、11、14等IC50值均小于100nM。同时，本发明化合物能够明显抑制KRAS G12D突变的肿瘤细胞AGS、ASPC-1细胞增殖，抑制AGS、ASPC-1细胞增殖的IC50值均小于1000nM，部分实施例化合物抑制AGS、ASPC-1细胞增殖的IC50值均小于500nM甚至100nM。特别地，如实化合物6、7、13、14化合物对AGS、ASPC-1细胞抗增殖活性均优于MRTX1133和WO2022/002102的实施例145。并且本发明化合物对Kras G12C突变的细胞系NCI-H358和Kras野生型细胞系MOLM13的生长均具有较弱的抑制作用，说明本发明化合物具有较好的选择性。
对照化合物MRTX1133结构式如下：
测试例3:化合物SD大鼠,体内药代性质
实验方法
雄性Sprague-Dawley(SD)大鼠6只，体重200-230g，随机分成2组，每组3只。分别静脉注射(i.v.)和腹腔注射(i.p.)给予受试化合物。实验前禁食12h，自由饮水。给药后2h统一进食。
静脉注射和腹腔注射给药溶液以DMSO/HS15/NaCl(5/3/92，v/v/v)配制。按腹腔注射3mg/kg,静脉注射5mg/kg给予，记录给药时间，并在给药后5分钟、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时、24小时的时间点经颈静脉采血或其他合适方式，每个样品采集约0.20mL，肝素钠抗凝，采集后放置冰上。并于1小时之内离心分离血浆(离心条件：6800g，6分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。
实验结果
综合结果分析，化合物6单次给药后能够达到抑制肿瘤细胞生长的药物起效浓度，同时具有较理想的生物利用度，成药性良好，具备进一步针对多种适应症开发新药的潜力。
表1:化合物6的SD大鼠药代动力学数据

以上所述，仅为本发明的实施例而已，并非用于限定本发明的保护范围，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (16)

  1. 式(I)所示的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药：
    式中，
    U1、U2、U3为N或CR4；
    R1、R2各自独立地选自氮杂环烷基；所述氮杂环烷基任选地被一个或多个R取代；
    L选自单键、C1-C6亚烷基链或-O-C1-C6亚烷基链，所述亚烷基链上的氢任选地被一个或多个氘取代；
    所述R4选自氢、卤素、氰基、C1-C6烷基、C2-C6烯基、C2-6炔基、C3-C6环烷基或-N＝S(O)C1-C6烷基，所述C1-C6烷基、C2-C6烯基、C2-6炔基、C3-C6环烷基或-N＝S(O)C1-C6烷基任选地被一个或多个卤素取代；
    R3选自芳基、杂芳基，所述芳基、杂芳基任选地被一个或多个R31取代；
    所述R31选自氢、卤素、羟基、氨基、C1-C6烷基、C3-C6环烷基、C1-C6烯基或C1-C6炔基；
    所述R选自氢、氘、卤素、羟基、C1-C6烷基、-C(＝O)-C1-C6烷基或-NRaRb，或，两个连接在同一碳原子上的R与碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个选自卤素、C1-C6烷基的取代基取代；
    其中，Ra、Rb各自独立地选自氢或C1-C6烷基。
  2. 权利要求1所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，R2选自含1或2个氮原子的5至12元氮杂环烷基，所述5至12元杂环烷基任选地被一个或多个R21取代；
    所述R21选自氢、氘、卤素、羟基、C1-C6烷基、-C(＝O)-C1-C6烷基或-NRaRb，或，两个连接在同一碳原子上的R21与碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个选自卤素、C1-C6烷基的取代基取代；优选地，两个连接在同一碳原子上的R21与碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个卤素取代，条件是，当两个连接在同一碳原子上的R21与碳原子共同形成C3-C6环烷基且所述C3-C6环烷基被卤素取代时，所述5至12元氮杂环烷基无其它取代；
    优选地，所述R2为其中，R21、R21’与其连接的碳原子共同形成C3-C6环烷基，所述C3-C6环烷基任选地被一个或多个选自卤素的取代基取代；
    优选地，所述R21选自
  3. 权利要求1或2所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，式(I)所示的化合物具有式(II)、式(III)、式(IV)、式(V)、式(VI)或式(VII)所示结构：
    式中，R1、L、R2各自定义同式(I)化合物；
    其中，R41、R42各自独立地选自氢、卤素、氰基、卤素取代或未取代的C1-C6烷基、C2-C6烯基、C2-6炔基、C3-C6环烷基或-N＝S(＝O)-C1-C6烷基；优选地，R41、R42、R43各自独立地选自氢、氟、氯、氰基、乙基、三氟甲基、环丙基、乙烯基、乙炔基、或-N＝S(＝O)(CH3)2；
    优选地，R41选自氢、氟、氯、氰基、三氟甲基、环丙基、乙烯基或-N＝S(O)(CH3)2；
    优选地，R42为卤素；优选地，R42为氟；
    优选地，R43选自卤素、氢、卤代烷烃；优选地，R43为氢。
  4. 权利要求1-3任一项所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，R1选自含1或2个氮原子的5至12元氮杂环烷基；所述氮杂环烷基任选地被一个或多个R11取代；
    优选地，R1选自所述任选地被一个或多个R11取代；
    所述R11选自氢、羟基、C1-C6烷基、-C(＝O)-C1-C6烷基或-NRaRb；其中，Ra、Rb各自独立地选自氢或C1-C6烷基；
    优选地，所述Ra、Rb各自独立地选自氢或甲基；
    优选地，所述R11选自氢、羟基、氨基、甲基、乙酰基或甲氨基；
    优选地，R1选自
    优选地，R1选自
    优选地，R1选自
  5. 权利要求1-4任一项所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，R3选自5至10元芳基或5-10元杂芳基，所述5至10元芳基或5至10元杂芳基任选地被一个或多个R31取代；
    优选地，R3选自萘基、苯基、吡啶基或吲唑基；所述萘基、苯基、吡啶基或吲唑基任选地被一个或多个R31取代；
    所述R31选自氢、卤素、羟基、C1-C6烷基、C3-C6环烷基、卤代C1-C6烷基、C1-C6烯基或C1-C6炔基；
    优选地，所述R31选自氢、氟、氯、羟基、氨基、甲基、乙基、异丙基、三氟甲基、环丙基或乙炔基；
    优选地，R3选自
    优选地，R3选自 优选地，R3选自
  6. 权利要求1-5任一项所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，L选自C1-C6烷氧基；
    优选地，L为-OCH2-；
    优选地，-L-R2为
    优选地，-L-R2为的混合物形式或的混合物形式。
  7. 权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，式(II)所示的化合物具有式(IIa)所示结构：
    式中，R1定义同式(I)化合物；R41、R42、R43各自定义同权利要求3；
    环E1、环E2各自独立地选自5或6元芳基、5或6原杂芳基；
    R31’、R31”各自独立地选自氢、卤素、羟基、氨基、C1-C6烷基、C3-C6环烷基、C1-C6烯基或C1-C6炔基；
    R5选自氘、F、Cl、Br或I；
    m1、m2、m3各自独立地为1或2；
    优选地，所述选自萘基或更优选地，所述为萘基；
    优选地，所述为
  8. 权利要求3所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药，其中，式(III)所示的化合物具有式(IIIa)所示结构：
    式中，R1、R3定义同式(I)化合物；R42、R43各自定义同权利要求3；
    R5选自F、Cl、Br或I；
    优选地，所述为
  9. 以下化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构 体或其混合物形式，其药学上可接受的盐、溶剂合物或前药：



  10. 药物组合物，其特征在于，所述组合物包含根据权利要求1-9任一项所述的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物或前药和药学上可接受的辅料。
  11. 权利要求1-9任一项的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或权利要求10的药物组合物在制备治疗制备预防和/或治疗KRAS G12D突变诱导疾病的药物或KRAS突变抑制剂中的用途。
  12. 权利要求1-9任一项的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或权利要求10的药物组合物在制备KRAS突变抑制剂中的用途；
    优选地，所述KRAS突变为KRAS G12D突变。
  13. 一种抑制有需要的患者中的KRAS突变的方法，其包含向所述患者施用根据权利要求1-9任一项的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或权利要求10的药物组合物。
  14. 一种抑制生物样品中的KRAS突变的方法，其包含使所述生物样品与根据权利要求1-9任一项的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或权利要求10的药物组合物接触。
  15. 一种用于治疗有需要的患者的由KRAS突变介导的病症的方法，其包含向所述患者施用根据权利要求1-9任一项的化合物或其互变异构体、顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体或其混合物形式，其药学上可接受的盐、溶剂合物、前药或权利要求10的药物组合物。
  16. 权利要求11或12所述的用途或权利要求13-15任一项的方法，其中，所述由KRAS突变介导的病症包括但不限于胃癌、胰腺癌、肺癌、血液癌、结直肠癌；
    优选地，所述KRAS突变介导的病症包括但不限于胃腺癌、胰腺癌、非小细胞肺癌、急性髓原白血病细胞、结肠直肠癌。
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