WO2024088069A1 - Preparation for aromatic kras mutant protein inhibitor and use thereof - Google Patents

Preparation for aromatic kras mutant protein inhibitor and use thereof Download PDF

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WO2024088069A1
WO2024088069A1 PCT/CN2023/124193 CN2023124193W WO2024088069A1 WO 2024088069 A1 WO2024088069 A1 WO 2024088069A1 CN 2023124193 W CN2023124193 W CN 2023124193W WO 2024088069 A1 WO2024088069 A1 WO 2024088069A1
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mmol
alkyl
membered
esi
methoxy
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PCT/CN2023/124193
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French (fr)
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梁永宏
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药雅科技(上海)有限公司
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65848—Cyclic amide derivatives of acids of phosphorus, in which two nitrogen atoms belong to the ring

Definitions

  • the present invention belongs to the field of drug synthesis, and specifically relates to a novel KRAS inhibitor and a preparation method and use thereof.
  • the present invention generally relates to novel compounds and methods for their preparation and use as KRAS inhibitors, for example for the treatment of cancer.
  • RAS represents a group of tightly related monomeric globular proteins of 189 amino acids (molecular weight 21 kDa) that are associated with the plasma membrane and bind either GDP or GTP.
  • RAS acts as a molecular switch. When RAS contains bound GDP, it is in a quiescent or off state and is in an "inactive state.” In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. After binding to GTP, RAS is "turned on” and is able to interact with and activate other proteins (its "downstream targets”). RAS proteins themselves have a very low intrinsic ability to hydrolyze GTP back to GDP, thus placing themselves in an off state.
  • GAPs GTPase activating proteins
  • the RAS protein contains a G domain, which is responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which allows post-translational modifications and is responsible for targeting the protein to the membrane.
  • the size of the G domain is about 21-25kDa, and it contains a phosphate binding loop (P-loop).
  • the P-loop is the pocket where nucleotides bind in proteins. This is a rigid part of the domain with conserved amino acid residues (glycine 12, threonine 26 and lysine 16) and is essential for nucleotide binding and hydrolysis.
  • the G domain also contains the so-called Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are dynamic parts of the protein and are often referred to as a 'spring-loaded' mechanism due to their ability to switch between resting and loaded states.
  • the key interaction is the hydrogen bond formed by Threonine 35 and Glycine 60, with the ⁇ -phosphate of GTP, which holds the Switch1 and Switch2 regions, respectively, in their active conformations. After GTP hydrolysis and release of the phosphates, the two relax to the inactive GDP conformation.
  • the most well-known members of the RAS subfamily are HRAS, KRAS, and NRAS, primarily because they are associated with multiple types of cancer. Mutations in any of the three major isoforms of RAS (HRAS, NRAS, or KRAS) are the most common in human tumorigenesis. Approximately 30% of human tumors are found to carry mutations in the RAS gene. Of note, KRAS mutations are detected in 25-30% of tumors. In contrast, the rates of oncogenic mutations occurring in NRAS and HRAS family members are much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 of the P-loop and at residue Q61.
  • G12C is a frequent mutation of the KRAS gene (mutation of glycine 12 to cysteine). This mutation has been found in approximately 13% of cancer occurrences, approximately 43% of lung cancer occurrences, and approximately 100% of MYH-associated polyposis (familial colon cancer syndrome).
  • KRAS mutant protein As a cutting-edge target, KRAS mutant protein has received widespread attention. Among them, AMG-510 developed by Amgen was approved for marketing by the FDA last year. In recent years, other companies have applied for a number of patents on KRAS inhibitors, such as W02016164675, W02016168540, WO2021141628, WO2022098625, WO2022087371, WO2020101736, WO2022109485, WO2022109487 and WO2020146613. Therefore, although progress has been made in this field, there is still a need for improved compounds for the treatment of cancer in this field. The present invention satisfies this need and provides other related advantages.
  • the present invention provides compounds capable of inhibiting KRAS mutations, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof.
  • each L 2 at each occurrence is independently selected from a bond, OC 0-6 alkyl, NHC 0-6 alkyl, C 1-6 alkyl, COC 0-6 alkyl or SC 0-6 alkyl;
  • Each R 1 is independently selected at each occurrence from H, D, halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, CN, OC 1-6 alkyl; each R 1 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C 1-6 alkyl;
  • n 1-3
  • Each X 1 , X 2 , X 3 at each occurrence is independently selected from N, CR 3 ;
  • Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
  • Each R 4 is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 3-6 carbocyclyl, 3-10 membered heterocycle, 4-10 membered heterocondensed ring; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 4 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C 1-6 alkyl, -C 1-6 alkoxy, oxo, OC 1-6 alkyl, C 3-6 carbocyclyl, 3-10 membered heterocycle;
  • G is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aromatic or heteroaromatic, each heterocycloalkyl, fused heterocyclyl, spiroheterocyclyl, heteroaromatic independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or P at each occurrence, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiroheterocyclyl, aromatic or heteroaromatic is optionally substituted with one or more G;
  • G1 is each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaromatic, -OR5 , -OC(O) NR5R6 , -C(O) OR5 , -C(O ) NR5R6 , -C(O) R5 , -NR5R6 , -NR5C(O) R6 , -NR5C (O) NR6R7 , -S(O) iR5 or -NR5S (O) iR6 , wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaromatic is optionally substituted by one or more deuterium, cyano, halogen,
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
  • each L 2 at each occurrence is independently selected from a bond, OC 0-6 alkyl, NHC 0-6 alkyl, C 1-6 alkyl, COC 0-6 alkyl or SC 0-6 alkyl;
  • Each R 1 is independently selected at each occurrence from H, D, halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, CN, OC 1-6 alkyl; each R 1 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C 1-6 alkyl;
  • n 1-3
  • Each X 1 at each occurrence is independently selected from N, CR 3 ;
  • Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
  • At most one of Y 1 , Y 2 , Y 3 and Y 4 is selected from heteroatoms N, O and S, and the others are selected from CR 3 ;
  • Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
  • Each R 4 is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 3-6 carbocyclyl, 3-10 membered heterocycle, 4-10 membered heterocondensed ring; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 4 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C 1-6 alkyl, -C 1-6 alkoxy, oxo, OC 1-6 alkyl, C 3-6 carbocyclyl, 3-10 membered heterocycle;
  • G is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aromatic or heteroaromatic, each heterocycloalkyl, fused heterocyclyl, spiroheterocyclyl, heteroaromatic independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or P at each occurrence, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiroheterocyclyl, aromatic or heteroaromatic is optionally substituted with one or more G;
  • G1 is each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaromatic, -OR5 , -OC(O) NR5R6 , -C(O) OR5 , -C(O ) NR5R6, -C(O) R5 , -NR5R6 , -NR5C (O) R6 , -NR5C (O) NR6R7 , -S(O) iR5 or -NR5S (O) iR6 , wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaromatic is optionally substituted by one or more deuterium, cyano, halogen, C1
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
  • the compounds described by formula (I) and formula (II) or their isomers, solvates or precursors, or their pharmaceutically acceptable salts are selected from the following compounds, their isomers, solvates or precursors, or their pharmaceutically acceptable salts:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by formula (I) and formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • the present invention relates to a method for treating diseases related to KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H in mammals, comprising administering a therapeutically effective amount of a compound represented by formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • a mammal preferably a human
  • the present invention relates to the use of compounds represented by formula (I) and formula (II) or pharmaceutically acceptable salts thereof in drugs for preventing or treating KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H related diseases.
  • the present invention relates to compounds represented by formula (I) and formula (II) or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, for preventing or treating KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H related diseases.
  • Cxy used herein has the following meanings and represents a range of carbon atoms, wherein x and y are both integers, for example, C3-8 cycloalkyl represents a cycloalkyl having 3-8 carbon atoms, i.e., a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that “ C3-8 " also includes any sub-ranges therein, such as C3-7 , C3-6 , C4-7 , C4-6 , C5-6 , etc.
  • Alkyl refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • alkyl examples include 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 and 2-ethylbutyl.
  • the alkyl can be substituted or unsubstituted.
  • alkenyl refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • Non-limiting examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1,4-pentadienyl, and 1,4-butadienyl.
  • the alkenyl may be substituted or unsubstituted.
  • Alkynyl refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms.
  • Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl.
  • the alkynyl may be substituted or unsubstituted.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon substituent containing from 3 to 14 carbon ring atoms.
  • a cycloalkyl group can be a single carbon ring, typically containing from 3 to 7 carbon ring atoms.
  • Non-limiting examples of single-ring cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • Cycloalkyl groups can be Alternatively there may be bi- or tricyclic rings fused together, such as decahydronaphthyl. The cycloalkyl groups may be substituted or unsubstituted.
  • Heterocyclyl refers to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur.
  • the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused rings, spirocyclic or bridged ring systems, the nitrogen, carbon or sulfur on the heterocyclyl can be selectively oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclyl can be partially or fully saturated.
  • the heterocyclyl can be connected to the rest of the molecule through a single bond via a carbon atom or heteroatom on the ring.
  • the heterocyclyl containing fused rings can contain one or more aromatic or heteroaromatic rings, as long as the atoms on the non-aromatic rings are connected to the rest of the molecule.
  • the heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
  • “Spiro heterocyclic group” refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated electronic system, preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • spiral cycloalkyl is divided into single spiral heterocyclic group, double spiral heterocyclic group or multi-spiro heterocyclic group, preferably single spiral cycloalkyl and double spiral cycloalkyl. More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl.
  • spiral heterocyclic group include:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated ⁇ electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon.
  • fused heterocyclic groups include:
  • Aryl or “aromatic group” refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring.
  • Heteroaryl or “heteroaromatic” refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be monocyclic, bicyclic, tricyclic or tetracyclic. The heteroaryl group is preferably a stable 4-11 membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 5-8 membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl examples include acridinyl, azepine, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyrone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinuclyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazo
  • heteroaryl is preferably a 5-8 membered heteroaryl group, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridinyl, pyrimidinyl, thiazolyl.
  • the heteroaryl group may be substituted or unsubstituted.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Haldroxy refers to -OH
  • amino refers to -NH 2
  • amide refers to -NHCO-
  • cyano refers to -CN
  • nitro refers to -CN
  • isocyano refers to -NC
  • trifluoromethyl refers to -CF 3 .
  • heteroatom or “hetero” as used herein alone or as part of other components refers to atoms other than carbon and hydrogen, and the heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different.
  • fused or "fused ring,” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
  • spiro or "spirocycle,” as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not.
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
  • Substituted means that one or more atoms, preferably 5, more preferably 1 to 3 atoms in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are in their possible chemical positions and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, a free amine or hydroxyl group may be unstable when combined with a carbon atom with an unsaturated (such as olefin) bond.
  • the substituents include, but are not limited to , hydroxyl, amine, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, etc.
  • “Pharmaceutical composition” refers to a composition containing one or more compounds described herein or their pharmaceutically acceptable salts or prodrugs and other components such as pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thereby exert biological activity.
  • Stereoisomers refer to compounds with the same molecular formula but different properties or sequences of atomic bonding or spatial arrangements of their atoms, and isomers with different atomic spatial arrangements are called “stereoisomers”. Stereoisomers include optical isomers, geometric isomers, and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of substituents around the chiral carbon atom, these optical isomers are "R” or "S” configurations. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
  • the compounds of the present invention may also exist as geometric isomers.
  • the present invention contemplates compounds having carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups or heterocyclic groups.
  • the various geometric isomers and mixtures thereof are generated by the distribution of substituents around the ring. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl or heterocyclic rings are designated as cis or trans configurations.
  • the compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
  • the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof and is not limited to any one tautomeric or stereoisomeric form used in the naming of the compound or chemical formula.
  • isotope refers to all isotopes of atoms that occur in the compounds of the present invention. Isotopes include those atoms with the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to 2H , 3H , 13C , 14C , 15N , 18O , 31P , 32P , 35S , 18F and 36Cl , respectively.
  • the isotope-labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached examples using suitable isotope-labeled reagents instead of non-isotope-labeled agents.
  • Such compounds have various potential uses, such as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to advantageously change biological, pharmacological or pharmacokinetic properties.
  • Prodrug means that the compounds of the present invention can be administered in the form of prodrugs.
  • Prodrugs refer to derivatives that are converted into the biologically active compounds of the present invention under physiological conditions in vivo, such as by oxidation, reduction, hydrolysis, etc. (each of which is carried out using an enzyme or without the participation of an enzyme).
  • prodrugs are compounds in which the amine groups in the compounds of the present invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamide, pivaloyloxymethylamino, or in which the hydroxyl groups are acylated, alkylated, phosphorylated or converted into borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or in which the carboxyl groups are esterified or amidated, or in which the sulfhydryl groups are selectively delivered to the target and/or to the cytosol of the cell.
  • the carrier molecule such as a peptide, forms a disulfide bridge.
  • “Pharmaceutically acceptable salts” or “pharmaceutically acceptable” refer to salts made of pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids.
  • the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compounds of the present invention containing acidic groups can exist in salt form and can be used according to the present invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts.
  • salts include sodium salts, potassium salts, calcium salts, magnesium salts or with amines or organic amines, such as primary amines, secondary amines, tertiary amines, cyclic amines, etc., such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline and caffeine, etc.
  • particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
  • the compounds of the present invention containing basic groups can exist in salt form and can be used according to the present invention in the form of addition with inorganic or organic acids.
  • suitable acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids well known to those skilled in the art.
  • the present invention also comprises inner salt or betaine salt except the salt form mentioned.
  • Each salt is obtained by conventional methods well known to those skilled in the art, for example by making these contact with organic or inorganic acid or base in solvent or dispersant or by anion exchange or cation exchange with other salts.
  • tumor includes benign tumors and malignant tumors (eg, cancer).
  • cancer includes various malignant tumors in which KRAS is involved, including but not limited to pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, multiple eosinophilia syndrome, myeloma and other solid tumors and blood tumors.
  • pancreatic cancer non-small cell lung cancer, small cell lung cancer, lung
  • an "effective amount” for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant relief of the condition. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.
  • polymorph or “polymorphism” used in the present invention means that the compounds of the present invention have multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form. The present invention covers all multiple forms or mixtures thereof.
  • solvate refers to an association of one or more molecules of the compound of the invention with one or more solvent molecules.
  • the solvent may be water, in which case the solvate is a hydrate. It may also be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms.
  • the compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also only accidentally retain water or a mixture of water and some other solvents.
  • the compounds of the present invention may react in a solvent or precipitate or crystallize in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.
  • subject refers to individuals suffering from diseases, disorders or conditions, etc., including mammals and non-mammals
  • mammals include but are not limited to any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc.
  • non-human mammals include but are not limited to birds and fish, etc.
  • the mammal is a human.
  • treatment refers to the treatment of relevant disease conditions in mammals, especially humans, including
  • disease and “disorder” may be used interchangeably or may have different meanings because certain specific diseases or disorders do not yet have a known causative agent (so the cause of the disease is still unclear), and therefore cannot be considered a disease but can only be viewed as an unwanted condition or syndrome, the syndrome of which more or less specific symptoms have been confirmed by clinical researchers.
  • administering refers to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
  • the present invention also provides a method for preparing the compound.
  • the preparation of the compound described in the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered to limit the scope of the present invention in any way.
  • the compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the method described in the present invention.
  • the product obtained in each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc.
  • the starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature (reaxys).
  • temperatures are in degrees Celsius.
  • Reagents were purchased from commercial suppliers such as Chem blocks Inc and 3wpharm and were used directly without further purification unless otherwise stated.
  • column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant;
  • preparative thin layer chromatography used thin layer chromatography silica gel preform plates (HSGF254) produced by Yantai Institute of Chemical Industry; and MS was determined using a Therno LCD Fleet (ESI) liquid chromatography-mass spectrometer.
  • ESI Therno LCD Fleet
  • the nuclear magnetic data (1H NMR) were obtained using a Bruker Avance-400MHz or Varian Oxford-400Hz NMR spectrometer.
  • the solvents used for the nuclear magnetic data included CDCl 3 , CD 3 OD, D 2 O, DMS-d6, etc., with tetramethylsilane (0.000ppm) as the reference or residual solvent as the reference (CDCl 3: 7.26ppm; CD 3 OD: 3.31ppm; D 2 O: 4.79ppm; d6-DMSO: 2.50ppm).
  • peak shape diversity When peak shape diversity is indicated, the following abbreviations represent different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are in Hertz (Hz).
  • reaction mixture was cooled to room temperature, treated with water (50mL), and extracted with ethyl acetate (3x50mL). The combined organic matter was washed with saline solution (50mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain 3-fluoro-2-iodo-6-(cyanomethyl)benzoic acid methyl ester (14.2g).
  • Triisopropylsilyl acetylene (5.47 g, 0.03 mol) and triethylamine (14.4 ml), followed by copper iodide (0.2 g) and bis-(triphenylphosphine)-palladium dichloride (0.73 g) were added to an oxygen-free solution of 7-fluoro-8-iodo-3-methoxy-2H-isoquinolin-1-one (9.6 g, 0.03 mol) in 150 ml of dry THF under argon. The solution was stirred at ambient temperature for 16 hours, then filtered through celite and evaporated.
  • reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3x50 mL). The combined organic matter was washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 2-fluoro-6-(cyanomethyl)benzoate (13.1 g) [M+H] + .
  • the reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3x50 mL). The combined organics were washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 2-chloro-6-(cyanomethyl)benzoate (14.75 g).
  • the reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3x50 mL). The combined organics were washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 2-methyl-6-(cyanomethyl)benzoate (10.96 g).
  • 2,4,7-Trichloropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), 2-oxo-1,3,7-triazaspiro[4.5]decane (1.70 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyrido[2,3-d]pyrimidine (5.50 g, 78%).
  • 2,4,7-trichloropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), (3R)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyrido[2,3-d]pyrimidine (2.81 g).
  • 2,4,7-trichloro-6-fluoropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), (3R)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-6-fluoropyrido[2,3-d]pyrimidine (2.88 g).
  • 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), 8-boc-3,8-diazabicyclo[3.2.1]octane (2.33 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (3.71 g).
  • 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (3R)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (2.82 g).
  • 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (3S)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3S)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (2.88 g).
  • 2,4,7-Trichloro-6-fluoropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), 1,3,7-triazaspiro[4.5]decane-2-one (1.69 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours.
  • 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-2-one (2.08 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours.
  • 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-2-one (2.08 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours.
  • 6-fluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (69.7 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid Compound
  • 2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.29 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours.
  • Embodiment 84 is a diagrammatic representation of Embodiment 84.
  • “++++” indicates IC 50 ⁇ 5 nM; “+++” indicates 5 nM ⁇ IC 50 ⁇ 50 nM; “++” indicates 50 nM ⁇ IC 50 ⁇ 2000 nM; and “+” indicates 2000 nM ⁇ IC 50 .
  • Cells were seeded in a transparent 96-well cell culture plate, with 80 ⁇ L of cell suspension per well, and each well contained 8,000 cells.
  • the cell plate was placed in a carbon dioxide incubator and incubated overnight at 37 degrees. 2 ⁇ L of compound was added to 78 ⁇ L of cell culture medium, mixed, and 20 ⁇ L of compound solution was added to the corresponding well of the cell plate. The cell plate was returned to the carbon dioxide incubator and incubated for 1 hour. After the incubation, the cell supernatant was discarded and 50 ⁇ L of 1X cell lysis buffer was added to each well, and incubated at room temperature for 30 minutes.
  • Phospho-ERK1/2 Eu Cryptate an Dilute tibody and Phospho-ERK1/2 d2 antibody 20 times and take 16 ⁇ L cell lysate supernatant into each well of a new 384 white microplate, then add 2 ⁇ L Phospho-ERK1/2 Eu Cryptate antibody dilution and 2 ⁇ L Phospho-ERK1/2 d2 antibody dilution, incubate at room temperature for at least 4 hours. After the incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm;

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Abstract

Compounds of general formula (I) and formula (II) have good activity for inhibiting tumor growth and have good safety. Provided are preparation for a Kras inhibitor and a use thereof. Specifically, provided are compounds represented by formulae (I) and (II) and pharmaceutically acceptable salts thereof, a pharmaceutical composition containing the compounds and/or the pharmaceutically acceptable salts thereof, and use of the compounds or the pharmaceutically acceptable salts in the treatment or prevention of Kras kinase-related diseases, especially tumors, wherein the compounds are heterocyclic compounds. Also disclosed is a preparation method for the pharmaceutical composition containing the compounds or the pharmaceutically acceptable salts thereof. The definition of each substituent in general formula (I) and formula (II) is the same as that in the description. The feature chemical formulae: formula (I) and formula (II).

Description

芳香类KRAS突变蛋白抑制剂的制备及其应用Preparation and application of aromatic KRAS mutant protein inhibitors 【技术领域】[Technical field]
本发明属于药物合成领域，具体涉及一种新型KRAS抑制剂及其制备方法与用途。The present invention belongs to the field of drug synthesis, and specifically relates to a novel KRAS inhibitor and a preparation method and use thereof.
【先前技术】[Prior Art]
本发明通常涉及新的化合物及其制备方法以及作为KRAS抑制剂(例如用于治疗癌症)的用途。The present invention generally relates to novel compounds and methods for their preparation and use as KRAS inhibitors, for example for the treatment of cancer.
RAS代表一组紧密相关的189个氨基酸(分子量21kDa)的单体球状蛋白，其与质膜相关，并结合GDP或GTPoRAS作为分子开关。当RAS含有结合的GDP时，它处于静止或关闭状态，并且处于“非活动状态”。回应细胞暴露于某些促进生长刺激时，RAS被诱导将其结合的GDP转换成GTP。与GTP结合后，RAS被“打开”，并且能够与其它蛋白(其“下游目标”)相互作用和启动其他蛋白。RAS蛋白本身具有非常低的内在能力，无法将GTP水解回GDP，从而使其自身处于关闭状态。关闭RAS需要称为GTPase启动蛋白(GAPs)的外在蛋白，该蛋白与RAS相互作用并大大加快GTP向GDP的转化。RAS中影响其与GAP相互作用或将GTP转换回GDP的能力的任何突变都将导致蛋白质的活化时间延长，从而导致细胞信号延长，使其继续生长和分裂。因为这些信号导致细胞生长和分裂，所以过度活跃的RAS信号可能最终导致癌症。RAS represents a group of tightly related monomeric globular proteins of 189 amino acids (molecular weight 21 kDa) that are associated with the plasma membrane and bind either GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a quiescent or off state and is in an "inactive state." In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to convert its bound GDP into GTP. After binding to GTP, RAS is "turned on" and is able to interact with and activate other proteins (its "downstream targets"). RAS proteins themselves have a very low intrinsic ability to hydrolyze GTP back to GDP, thus placing themselves in an off state. Turning RAS off requires extrinsic proteins called GTPase activating proteins (GAPs), which interact with RAS and greatly speed up the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAPs or convert GTP back to GDP will result in a prolonged activation of the protein, resulting in prolonged signaling to the cell to continue growing and dividing. Because these signals cause cells to grow and divide, overactive RAS signaling may ultimately lead to cancer.
在结构上，RAS蛋白包含一个G结构域，该结构域负责RAS的酶促活性-鸟喋吟核背酸结合和水解(GTPase反应)。它还包含一个称为CAAX盒的C末端延伸，可进行翻译后修饰，并负责将蛋白质靶向膜。G结构域的大小约为21-25kDa，它包含一个磷酸盐结合环(P-环)。P-环为核昔酸在蛋白质中结合的口袋，这是具有保守氨基酸残基((甘氨酸12、苏氨酸26和赖氨酸16))的结构域的刚性部分，对于核昔酸结合和水解至关重要。G域还包含所谓的Switch I(残基30-40)和Switch II(残基60-76)区域，这两个区域都是蛋白质的动态部分，由于它们在能够在静止和负载状态间转换，其通常被称为“弹簧负载'机制。关键相互作用是苏氨酸35和甘氨酸60形成的氢键，具有GTP的Y-磷酸酯，其分别使Switch1和Switch2区域保持其活性构象。GTP水解并释放出磷酸盐后，这两个松弛为非活性的GDP构象。Structurally, the RAS protein contains a G domain, which is responsible for the enzymatic activity of RAS - guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which allows post-translational modifications and is responsible for targeting the protein to the membrane. The size of the G domain is about 21-25kDa, and it contains a phosphate binding loop (P-loop). The P-loop is the pocket where nucleotides bind in proteins. This is a rigid part of the domain with conserved amino acid residues (glycine 12, threonine 26 and lysine 16) and is essential for nucleotide binding and hydrolysis. The G domain also contains the so-called Switch I (residues 30-40) and Switch II (residues 60-76) regions, both of which are dynamic parts of the protein and are often referred to as a 'spring-loaded' mechanism due to their ability to switch between resting and loaded states. The key interaction is the hydrogen bond formed by Threonine 35 and Glycine 60, with the γ-phosphate of GTP, which holds the Switch1 and Switch2 regions, respectively, in their active conformations. After GTP hydrolysis and release of the phosphates, the two relax to the inactive GDP conformation.
RAS亚家族最著名的成员是HRAS，KRAS和NRAS，主要是因为它们与多种类型的癌症有关。RAS的三个主要同工型(HRAS，NRAS或KRAS)基因中的任何一种突变都是人类肿瘤发生中最常见。发现人类肿瘤中约有30％携带RAS基因突变o值得注意的是，KRAS突变在25-30％的肿瘤中检测到。相比之下，在NRAS和HRAS家族成员中发生的致癌突变率要低得多(分别为8％和3％)。在P环的残基G12和G13以及残基Q61处发现了最常见的KRAS突变。G12C是KRAS基因的频繁突变(甘氨酸12突变为半胱氨酸)。已经在大约13％的癌症发生，大约43％的肺癌发生以及大约100％的MYH相关性息肉病(家族性结肠癌综合征)中发现了这种突变。The most well-known members of the RAS subfamily are HRAS, KRAS, and NRAS, primarily because they are associated with multiple types of cancer. Mutations in any of the three major isoforms of RAS (HRAS, NRAS, or KRAS) are the most common in human tumorigenesis. Approximately 30% of human tumors are found to carry mutations in the RAS gene. Of note, KRAS mutations are detected in 25-30% of tumors. In contrast, the rates of oncogenic mutations occurring in NRAS and HRAS family members are much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 of the P-loop and at residue Q61. G12C is a frequent mutation of the KRAS gene (mutation of glycine 12 to cysteine). This mutation has been found in approximately 13% of cancer occurrences, approximately 43% of lung cancer occurrences, and approximately 100% of MYH-associated polyposis (familial colon cancer syndrome).
作为前沿靶点，KRAS突变蛋白受到了广泛关注。其中Amgen研发的AMG-510于去年被FDA批准上市。近年来，其他公司申请了多项专利关于KRAS抑制剂，例如W02016164675、W02016168540、WO2021141628、WO2022098625、WO2022087371、WO2020101736、WO2022109485、WO2022109487和WO2020146613。因此，尽管已在这个领域中取得进展，但在本领域中仍需要改进的治疗癌症的化合 物和方法，例如通过抑制KRAS、HRAS或NRAS来治疗癌症。本发明满足此需要并提供其他相关优势。As a cutting-edge target, KRAS mutant protein has received widespread attention. Among them, AMG-510 developed by Amgen was approved for marketing by the FDA last year. In recent years, other companies have applied for a number of patents on KRAS inhibitors, such as W02016164675, W02016168540, WO2021141628, WO2022098625, WO2022087371, WO2020101736, WO2022109485, WO2022109487 and WO2020146613. Therefore, although progress has been made in this field, there is still a need for improved compounds for the treatment of cancer in this field. The present invention satisfies this need and provides other related advantages.
简而言之，本发明提供了能够抑制KRAS突变的化合物，包括其立体异构体、药物可接受的盐、互变异构体和前药。In short, the present invention provides compounds capable of inhibiting KRAS mutations, including stereoisomers, pharmaceutically acceptable salts, tautomers and prodrugs thereof.
【发明内容】[Summary of the invention]
一种具有通式(I)所示的化合物、其立体异构体、可药用的盐、或异构体，其中通式(I)所示的化合物结构如下：
A compound represented by general formula (I), its stereoisomers, pharmaceutically acceptable salts, or isomers, wherein the compound represented by general formula (I) has the following structure:
每个L2在每次出现时独立地选自键、OC0-6烷基、NHC0-6烷基、C1-6烷基、COC0-6烷基或SC0-6烷基；each L 2 at each occurrence is independently selected from a bond, OC 0-6 alkyl, NHC 0-6 alkyl, C 1-6 alkyl, COC 0-6 alkyl or SC 0-6 alkyl;
每个R1在每次出现时独立地选自H、D、卤素、C1-6烷基、-C2-6烯基、-C2-6炔基、CN、OC1-6烷基；每个R1独立地可选地被1、2、3、4、5或6个选自氘、卤素、-C1-6烷基的取代基取代或不取代；Each R 1 is independently selected at each occurrence from H, D, halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, CN, OC 1-6 alkyl; each R 1 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C 1-6 alkyl;
n为1-3n is 1-3
每个X1，X2，X3在每次出现时独立地选自N，CR3；Each X 1 , X 2 , X 3 at each occurrence is independently selected from N, CR 3 ;
每个R3独立地选自H、D、氰基、卤素、C1-6烷基、CN；Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
每个R4独立地选自H、D、C1-6烷基、C2-6烯基、C2-6炔基、CN、C3-6碳环基、3-10元杂环、4-10元杂稠环；3-8元杂环在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子；每个R4独立地可选地被1、2、3、4、5或6个选自氘、卤素、C1-6烷基、-C1-6烷氧基、氧代、OC1-6烷基、C3-6碳环基、3-10元杂环的取代基取代或不取代；Each R 4 is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 3-6 carbocyclyl, 3-10 membered heterocycle, 4-10 membered heterocondensed ring; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 4 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C 1-6 alkyl, -C 1-6 alkoxy, oxo, OC 1-6 alkyl, C 3-6 carbocyclyl, 3-10 membered heterocycle;
U选3-8元环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，每个杂环烷基、稠杂环基、螺杂环基、杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、S或P的杂原子，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G1所取代；G is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aromatic or heteroaromatic, each heterocycloalkyl, fused heterocyclyl, spiroheterocyclyl, heteroaromatic independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or P at each occurrence, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiroheterocyclyl, aromatic or heteroaromatic is optionally substituted with one or more G;
G1各自独立选自氘、氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR5、-OC(O)NR5R6、-C(O)OR5、-C(O)NR5R6、-C(O)R5、-NR5R6、-NR5C(O)R6、-NR5C(O)NR6R7、-S(O)iR5或-NR5S(O)iR6，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氘、氰基，卤素、C1-7烷基、C2-7烯基、C2-7炔基、C3-9环烷基或3-9元杂环基、C7-10芳基、6-10元杂芳香基、-OR8、-OC(O)NR8R9、-C(O)OR8、-C(O)NR8R9、-C(O)R8、-NR8R9、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)iR8或-NR8S(O)iR9的取代基所取代； G1 is each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaromatic, -OR5 , -OC(O) NR5R6 , -C(O) OR5 , -C(O ) NR5R6 , -C(O) R5 , -NR5R6 , -NR5C(O) R6 , -NR5C (O) NR6R7 , -S(O) iR5 or -NR5S (O) iR6 , wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaromatic is optionally substituted by one or more deuterium, cyano, halogen, C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C The group is substituted by a 3-9- membered cycloalkyl group or a 3-9-membered heterocyclyl group, a C 7-10 aryl group, a 6-10-membered heteroaryl group, -OR 8 , -OC(O)NR 8 R 9 , -C(O)OR 8 , -C(O)NR 8 R 9 , -C(O)R 8 , -NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 , -S(O) i R 8 or -NR 8 S(O) i R 9 ;
R5、R6、R7、R8、R9和R10各自独立选自氢、氘、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基； R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
且i为1或2。And i is 1 or 2.
一种具有通式(II)所示的化合物、其立体异构体、可药用的盐、或异构体，其中通式(I)所示的化合物结构如下：
A compound represented by general formula (II), its stereoisomers, pharmaceutically acceptable salts, or isomers, wherein the compound represented by general formula (I) has the following structure:
每个L2在每次出现时独立地选自键、OC0-6烷基、NHC0-6烷基、C1-6烷基、COC0-6烷基或SC0-6烷基；each L 2 at each occurrence is independently selected from a bond, OC 0-6 alkyl, NHC 0-6 alkyl, C 1-6 alkyl, COC 0-6 alkyl or SC 0-6 alkyl;
每个R1在每次出现时独立地选自H、D、卤素、C1-6烷基、-C2-6烯基、-C2-6炔基、CN、OC1-6烷基；每个R1独立地可选地被1、2、3、4、5或6个选自氘、卤素、-C1-6烷基的取代基取代或不取代；Each R 1 is independently selected at each occurrence from H, D, halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, CN, OC 1-6 alkyl; each R 1 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C 1-6 alkyl;
n为1-3n is 1-3
每个X1在每次出现时独立地选自N，CR3；Each X 1 at each occurrence is independently selected from N, CR 3 ;
每个R3独立地选自H、D、氰基、卤素、C1-6烷基、CN；Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
Y1、Y2、Y3、Y4最多一个选自杂原子N、O、S，其他选自CR3；At most one of Y 1 , Y 2 , Y 3 and Y 4 is selected from heteroatoms N, O and S, and the others are selected from CR 3 ;
每个R3独立地选自H、D、氰基、卤素、C1-6烷基、CN；Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
每个R4独立地选自H、D、C1-6烷基、C2-6烯基、C2-6炔基、CN、C3-6碳环基、3-10元杂环、4-10元杂稠环；3-8元杂环在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子；每个R4独立地可选地被1、2、3、4、5或6个选自氘、卤素、C1-6烷基、-C1-6烷氧基、氧代、OC1-6烷基、C3-6碳环基、3-10元杂环的取代基取代或不取代；Each R 4 is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 3-6 carbocyclyl, 3-10 membered heterocycle, 4-10 membered heterocondensed ring; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 4 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C 1-6 alkyl, -C 1-6 alkoxy, oxo, OC 1-6 alkyl, C 3-6 carbocyclyl, 3-10 membered heterocycle;
U选3-8元环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，每个杂环烷基、稠杂环基、螺杂环基、杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、S或P的杂原子，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G1所取代；G is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aromatic or heteroaromatic, each heterocycloalkyl, fused heterocyclyl, spiroheterocyclyl, heteroaromatic independently containing 1, 2, 3 or 4 heteroatoms selected from N, O, S or P at each occurrence, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiroheterocyclyl, aromatic or heteroaromatic is optionally substituted with one or more G;
G1各自独立选自氘、氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR5、-OC(O)NR5R6、-C(O)OR5、-C(O)NR5R6、-C(O)R5、-NR5R6、-NR5C(O)R6、-NR5C(O)NR6R7、-S(O)iR5或-NR5S(O)iR6，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氘、氰基，卤素、C1-7烷基、C2-7烯基、C2-7炔基、C3-9环烷基或3-9元杂环基、C7-10芳基、6-10元杂芳香基、-OR8、-OC(O)NR8R9、-C(O)OR8、-C(O)NR8R9、-C(O)R8、-NR8R9、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)iR8或-NR8S(O)iR9的取代基所取代； G1 is each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaromatic, -OR5 , -OC(O) NR5R6 , -C(O) OR5 , -C(O ) NR5R6, -C(O) R5 , -NR5R6 , -NR5C (O) R6 , -NR5C (O) NR6R7 , -S(O) iR5 or -NR5S (O) iR6 , wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaromatic is optionally substituted by one or more deuterium, cyano, halogen, C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C The group is substituted by a 3-9- membered cycloalkyl group or a 3-9-membered heterocyclyl group, a C 7-10 aryl group, a 6-10-membered heteroaryl group, -OR 8 , -OC(O)NR 8 R 9 , -C(O)OR 8 , -C(O)NR 8 R 9 , -C(O)R 8 , -NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 , -S(O) i R 8 or -NR 8 S(O) i R 9 ;
R5、R6、R7、R8、R9和R10各自独立选自氢、氘、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
且i为1或2。 And i is 1 or 2.
在一些实施方式中，式(I)和式(II)所述的化合物或者其异构体、溶剂合物或其前体，或它们的药学上可接受的盐选自以下化合物、其异构体、溶剂合物或其前体，或它们的药学上可接受的盐：



In some embodiments, the compounds described by formula (I) and formula (II) or their isomers, solvates or precursors, or their pharmaceutically acceptable salts are selected from the following compounds, their isomers, solvates or precursors, or their pharmaceutically acceptable salts:



另一方面，本发明还提供药物组合物，其包含式(I)和式(II)所示化合物或其药学可接受的盐和药学上可接受的辅料。On the other hand, the present invention also provides a pharmaceutical composition comprising a compound represented by formula (I) and formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
另一方面，本发明涉及治疗哺乳动物中与KRas,KRas G12A,KRas G12C,KRas G12D,KRas G12R,KRas G12S,KRas G12V,KRas G13D or KRas Q61H查关疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式(I)和式(II)所示化合物或其药学可接受的盐、或其药物组合物。On the other hand, the present invention relates to a method for treating diseases related to KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H in mammals, comprising administering a therapeutically effective amount of a compound represented by formula (I) and formula (II) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
另一方面，本发明涉及式(I)和式(II)所示化合物或其药学可接受的盐预防或治疗KRas,KRas G12A,KRas G12C,KRas G12D,KRas G12R,KRas G12S,KRas G12V,KRas G13D or KRas Q61H相关疾病的药物中的用途。On the other hand, the present invention relates to the use of compounds represented by formula (I) and formula (II) or pharmaceutically acceptable salts thereof in drugs for preventing or treating KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H related diseases.
另一方面，本发明涉及预防或治疗KRas,KRas G12A,KRas G12C,KRas G12D,KRas G12R,KRas G12S,KRas G12V,KRas G13D or KRas Q61H相关疾病的式(I)和式(II)所示化合物或其药学可接受的盐、或其药物组合物。On the other hand, the present invention relates to compounds represented by formula (I) and formula (II) or their pharmaceutically acceptable salts, or pharmaceutical compositions thereof, for preventing or treating KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H related diseases.
某些化学术语Some chemical terms
除非有相反陈述，否则下列用在说明书和权利要求书中的术语。Unless stated to the contrary, the following terms are used in the specification and claims.
具有下述含义在本文中使用的表示方式“Cx-y”表示碳原子数的范围、其中x和y均为整数，例如C3-8环烷基表示具有3-8个碳原子的环烷基，即具有3、4、5、6、7或8个碳原子的环烷基。还应理解，“C3-8”还包含其中的任意亚范围、例如C3-7、C3-6、C4-7、C4-6、C5-6等。The expression " Cxy " used herein has the following meanings and represents a range of carbon atoms, wherein x and y are both integers, for example, C3-8 cycloalkyl represents a cycloalkyl having 3-8 carbon atoms, i.e., a cycloalkyl having 3, 4, 5, 6, 7 or 8 carbon atoms. It should also be understood that " C3-8 " also includes any sub-ranges therein, such as C3-7 , C3-6 , C4-7 , C4-6 , C5-6 , etc.
“烷基”指含有1至20个碳原子，例如1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链或支链的烃基基团。烷基的非限制性实例包括甲基、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、1,3-二甲基丁基和2-乙基丁基。所述烷基可以是取代的或未取代的。"Alkyl" refers to a straight or branched hydrocarbon group containing 1 to 20 carbon atoms, such as 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Non-limiting examples of alkyl include 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 and 2-ethylbutyl. The alkyl can be substituted or unsubstituted.
“烯基”指含有至少一个碳碳双键和通常2至20个碳原子例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。烯基的非限制性实例包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基-2-丙烯基、1，4-戊二烯基和1，4-丁二烯基。所述烯基可以是取代的或未取代的。"Alkenyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon double bond and typically 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkenyl include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1,4-pentadienyl, and 1,4-butadienyl. The alkenyl may be substituted or unsubstituted.
“炔基”指含有至少一个碳碳三键和通常2至20个碳原子，例如2至8个碳原子、2至6个碳原子或2至4个碳原子的直链或支链的烃基基团。炔基的非限制性实例包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基和3-丁炔基。所述炔基可以是取代的或未取代的。"Alkynyl" refers to a straight or branched hydrocarbon group containing at least one carbon-carbon triple bond and typically 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 4 carbon atoms. Non-limiting examples of alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The alkynyl may be substituted or unsubstituted.
“环烷基”指含有3至14个碳环原子的饱和环形烃基取代基。环烷基可以是单碳环，通常含有3至7个碳环原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环己基和环庚基。环烷基可 选择地可以是稠合到一起的双或三环、如十氢萘基、所述环烷基可以是取代的或未取代的。"Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent containing from 3 to 14 carbon ring atoms. A cycloalkyl group can be a single carbon ring, typically containing from 3 to 7 carbon ring atoms. Non-limiting examples of single-ring cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkyl groups can be Alternatively there may be bi- or tricyclic rings fused together, such as decahydronaphthyl. The cycloalkyl groups may be substituted or unsubstituted.
“杂环基”、“杂环烷基”、“杂环”是指稳定的3-18元单价非芳香环，包括2-12个碳原子，1-6个选自氮、氧和硫的杂原子。除非另作说明，杂环基基团可以是单环、双环、三环或四环系统，其可能包含稠环、螺环或桥环系统，杂环基上的氮、碳或硫可选择性的被氧化，氮原子可选择性的被季铵化，杂环基可以部分或完全饱和。杂环基可以通过环上的碳原子或杂原子与分子的其余部分通过一个单键连接。包含稠环的杂环基中可以包含一个或多个芳环或杂芳环，只要与分子的其余部分连接的是非芳香环上的原子。为了本申请，杂环基优选的是一个稳定的4-11元单价非芳香单环或二环，其包含1-3个选自氮、氧和硫的杂原子，更优选的是一个稳定的4-8元单价非芳香单环，其包含1-3个选自氮、氧和硫的杂原子。杂环基的非限制性实例包括氮杂环庚烷基、氮杂环丁基、十氢异喹啉基、二氢呋喃基、二氢吲哚基、二氧戊烷基、1,1-二氧-硫代吗啉基、咪唑烷基、咪唑啉基、异噻唑烷基、异恶唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、恶嗪基、呱嗪基、呱啶基、4-呱啶酮基、吡喃基、吡唑烷基、吡咯烷基、喹嗪基、奎宁环基、四氢呋喃基、四氢吡喃基等。"Heterocyclyl", "heterocycloalkyl", "heterocycle" refers to a stable 3-18 membered monovalent non-aromatic ring, including 2-12 carbon atoms, 1-6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless otherwise specified, the heterocyclyl group can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may contain fused rings, spirocyclic or bridged ring systems, the nitrogen, carbon or sulfur on the heterocyclyl can be selectively oxidized, the nitrogen atom can be selectively quaternized, and the heterocyclyl can be partially or fully saturated. The heterocyclyl can be connected to the rest of the molecule through a single bond via a carbon atom or heteroatom on the ring. The heterocyclyl containing fused rings can contain one or more aromatic or heteroaromatic rings, as long as the atoms on the non-aromatic rings are connected to the rest of the molecule. For the purpose of this application, the heterocyclyl is preferably a stable 4-11 membered monovalent non-aromatic monocyclic or bicyclic ring, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 4-8 membered monovalent non-aromatic monocyclic ring, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heterocyclyl groups include azepanyl, azetidinyl, decahydroisoquinolinyl, dihydrofuranyl, indolinyl, dioxolanyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, imidazolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazinyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyranyl, pyrazolidinyl, pyrrolidinyl, quinolizinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like.
“螺杂环基”指5至20元，单环之间共享一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。这些可以含有一个或多个双键，但没有一个环具有完全共扼的电子系统优选为6至14元，更优选为7至10元。根据环与环之间共享螺原子的数目将螺环烷基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环基。螺杂环基的非限制性实施例包含：
"Spiro heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 yuan, one atom (called spiral atom) shared between monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings has a completely conjugated electronic system, preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiral atoms shared between rings, spiral cycloalkyl is divided into single spiral heterocyclic group, double spiral heterocyclic group or multi-spiro heterocyclic group, preferably single spiral cycloalkyl and double spiral cycloalkyl. More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiral cycloalkyl. Non-limiting examples of spiral heterocyclic group include:
“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实施例包含：
"Fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic alkyl, preferably bicyclic or tricyclic, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:
“芳基”或“芳香基”指含有6至14个碳原子的芳香族单环或稠合多环基团，优选为6至10元，例如苯基和萘基，更优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上、其中与母体结构连接在一起的环为芳基环。"Aryl" or "aromatic group" refers to an aromatic monocyclic or fused polycyclic group containing 6 to 14 carbon atoms, preferably 6 to 10 members, such as phenyl and naphthyl, more preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is the aryl ring.
“杂芳基”或“杂芳香基”是指5-16元环状系统，其包含1-15个碳原子，优选的1-10个碳原子，1-4个选自氮，氧和硫的杂原子，至少一个芳香环。除非另作说明，杂芳基可以是单环、双环、三环或四环 系统，其可能包含稠环或桥环系统，只要与分子其他部分的连接点为芳环原子，杂芳环上的氮原子、碳原子和硫原子可以透择性的被氧化，氮原子可选择性的被季铵化。为了本发明，杂芳基优选的为稳定的4-11元单芳香环，其包含1-3个选自氮、氧和硫的杂原子，更优选的为稳定的5-8元单芳香环，其包含1-3个选自选自氮、氧和硫的杂原子。杂芳基的非限定性实例包括吖啶基、氮杂卓基、苯并咪唑基、苯并吲哚基、苯并二氧芑基、苯并二恶茂基、苯并呋喃酮基、苯并呋喃基、苯并萘并呋喃基、苯并吡喃酮基、苯并吡喃基、苯并吡唑基、苯并噻二唑基、苯并噻唑基、苯并三唑基、呋喃基、咪唑基、吲唑基、吲哚基、恶唑基、嘌呤基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、奎宁基、四唑基，噻二唑基、噻唑基、噻吩基、三嗪基，三唑基等。本申请中，杂芳基优选为5-8元杂芳基，其包含1-3选自选自氮、氧和硫的杂原子，更优选为吡啶基、嘧啶基、噻唑基。所述杂芳基可以是取代的或未取代的。"Heteroaryl" or "heteroaromatic" refers to a 5-16 membered ring system containing 1-15 carbon atoms, preferably 1-10 carbon atoms, 1-4 heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring. Unless otherwise specified, a heteroaryl group can be monocyclic, bicyclic, tricyclic or tetracyclic. The heteroaryl group is preferably a stable 4-11 membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, and more preferably a stable 5-8 membered monoaromatic ring containing 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of heteroaryl include acridinyl, azepine, benzimidazolyl, benzindolyl, benzodioxinyl, benzodioxolyl, benzofuranonyl, benzofuranyl, benzonaphthofuranyl, benzopyrone, benzopyranyl, benzopyrazolyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, furanyl, imidazolyl, indazolyl, indolyl, oxazolyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinuclyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, etc. In the present application, heteroaryl is preferably a 5-8 membered heteroaryl group, which contains 1-3 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably pyridinyl, pyrimidinyl, thiazolyl. The heteroaryl group may be substituted or unsubstituted.
“卤素”指氟、氯、溴或碘。"Halogen" refers to fluorine, chlorine, bromine or iodine.
“羟基”指-OH，“氨基”指-NH2，“酰胺基”指-NHCO-，“氰基”指-CN，“硝基”指-CN，“异氰基”指-NC，“三氟甲基”指-CF3。"Hydroxy" refers to -OH, "amino" refers to -NH 2 , "amide" refers to -NHCO-, "cyano" refers to -CN, "nitro" refers to -CN, "isocyano" refers to -NC, and "trifluoromethyl" refers to -CF 3 .
本文单独或作为其他成分的一部分使用的术语“杂原子”或“杂”是指除碳和氢之外的原子，杂原子独立地选自氧、氮、硫、磷、硅、硒和锡，但不限于这些原子，在出现两个或更多杂原子的实施方案中，所述两个或更多杂原子可彼此相同，或者所述两个或更多杂原子中的一些或全部此不同。The term "heteroatom" or "hetero" as used herein alone or as part of other components refers to atoms other than carbon and hydrogen, and the heteroatoms are independently selected from oxygen, nitrogen, sulfur, phosphorus, silicon, selenium and tin, but are not limited to these atoms. In embodiments where two or more heteroatoms are present, the two or more heteroatoms may be the same as each other, or some or all of the two or more heteroatoms may be different.
本文单独或组合使用的术语“稠”或“稠环”是指两个或更多个环共享一个或更多个键的环状结构。[0063] The term "fused" or "fused ring," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more bonds.
本文单独或组合使用的术语“螺”或“螺环”是指两个或更多个环共享一个或更多个原子的环状结构。[0063] The term "spiro" or "spirocycle," as used herein, alone or in combination, refers to a cyclic structure in which two or more rings share one or more atoms.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.
“取代的”指基团中的一个或多个原子，较佳为5个、更佳为1～3个原子彼此独立地被相应数目的取代基取代。不言而喻，取代基处在它们的可能的化学位置本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离的胺基或羟基与具有不饱和(如烯烃)键的碳原子结合时可能是不稳定的。所述取代基包括但不限于羟基、胺基、卤素、氰基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基等。"Substituted" means that one or more atoms, preferably 5, more preferably 1 to 3 atoms in the group are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are in their possible chemical positions and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, a free amine or hydroxyl group may be unstable when combined with a carbon atom with an unsaturated (such as olefin) bond. The substituents include, but are not limited to , hydroxyl, amine, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, etc.
“药物组合物”指含有一种或多种本文所述的化合物或其可药用的盐或前药以及其他分例如可药用的载体和赋形剂的组合物。药物组合物的目的是促对生物体的给药、利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" refers to a composition containing one or more compounds described herein or their pharmaceutically acceptable salts or prodrugs and other components such as pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thereby exert biological activity.
“异构体”指具有相同分子式但其原子结合的性质或顺序或其原子的空间排列不同的化合物称为“异构体”、其原子空间排列不同的异构体称为“立体异构体”。立体异构体包括光学异构体、几何异构体和构象异构体。本发明的化合物可以以光学异构体形式存在。根据手性碳原子周围取代基的构型，这些光学异构体是“R”或“S”构型。光学异构体包括对映异构体和非对映异构体、制备和分离光学异构体的方法是本领域中已知的。"Isomers" refer to compounds with the same molecular formula but different properties or sequences of atomic bonding or spatial arrangements of their atoms, and isomers with different atomic spatial arrangements are called "stereoisomers". Stereoisomers include optical isomers, geometric isomers, and conformational isomers. The compounds of the present invention may exist in the form of optical isomers. Depending on the configuration of substituents around the chiral carbon atom, these optical isomers are "R" or "S" configurations. Optical isomers include enantiomers and diastereomers, and methods for preparing and separating optical isomers are known in the art.
本发明的化合物也可以存在几何异构体。本发明考虑由碳-碳双键、碳-氮双键、环烷基或杂环基团 周的取代基的分布所产生的各种几何异构体和其混合物。碳-碳双键或碳-氮键周围的取代基指定为Z或E构型、环烷基或杂环周围的取代基指定为顺式或反式构型。The compounds of the present invention may also exist as geometric isomers. The present invention contemplates compounds having carbon-carbon double bonds, carbon-nitrogen double bonds, cycloalkyl groups or heterocyclic groups. The various geometric isomers and mixtures thereof are generated by the distribution of substituents around the ring. Substituents around carbon-carbon double bonds or carbon-nitrogen bonds are designated as Z or E configurations, and substituents around cycloalkyl or heterocyclic rings are designated as cis or trans configurations.
本发明的化合物还可能显示互变异构现象，例如酮-烯醇互变异构。The compounds of the present invention may also exhibit tautomerism, such as keto-enol tautomerism.
应该理解，本发明包括任何互变异构或立体异构形式和其混合物、并且不仅限于化合物的命名或化学结式中所使用的任何一个互变异构或立体异构形式。It should be understood that the present invention includes any tautomeric or stereoisomeric forms and mixtures thereof and is not limited to any one tautomeric or stereoisomeric form used in the naming of the compound or chemical formula.
“同位素”是在本发明化合物中出现的原子的所有同位素。同位素包括具有相同原子序数但不同质量数的那些原子。适合并入本发明化合物中的同位素的实例是氢、碳、氮、氧、磷、氟和氯，分别例如但不限于2H、3H、13C、14C、15N、18O、31P、32P、35S、18F和36Cl。本发明的同位素标记化合物通常可通过本域技术人员已知的传统技术或通过与所附实施例中描的那些类似的方法使用适当的同位素标记的试剂代替非同位素标记的剂制。这样的化合物具有各种潜在用途、例如作为测定生物活性中的标样和试剂。在稳定同位素的情况下，这样的化合物具有有利地改变生物、药理学或药代动力学性质的潜力。"Isotope" refers to all isotopes of atoms that occur in the compounds of the present invention. Isotopes include those atoms with the same atomic number but different mass numbers. Examples of isotopes suitable for incorporation into the compounds of the present invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as but not limited to 2H , 3H , 13C , 14C , 15N , 18O , 31P , 32P , 35S , 18F and 36Cl , respectively. The isotope-labeled compounds of the present invention can be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the attached examples using suitable isotope-labeled reagents instead of non-isotope-labeled agents. Such compounds have various potential uses, such as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds have the potential to advantageously change biological, pharmacological or pharmacokinetic properties.
“前药”是指本发明的化合物可以以前药的形式给予。前药是指在活体内的生理条件下例如通过氧化、还原、水解等(它们各自利用酶或在没有酶参与下进行)转化成本发明的生物活性化合物的衍生物。前药的实例是下述化合物：其中本发明的化合物中的胺基被酰化、烷基化或磷酸化，例如二十烷酰基胺基、丙胺酰胺基、新戊酰氧基甲基胺基、或其中羟基被酰化、烷基化、磷酸化或转化成硼酸盐，例如乙酰氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙胺酰氧基、或其中羧基被酯化或酰胺化，或其中巯基与选择性地向靶和/或向细胞的胞质溶胶递送药物的载体分子，例如肽形成二硫桥键、这些化合物可以由本发明的化合物根据公知方法制备。"Prodrug" means that the compounds of the present invention can be administered in the form of prodrugs. Prodrugs refer to derivatives that are converted into the biologically active compounds of the present invention under physiological conditions in vivo, such as by oxidation, reduction, hydrolysis, etc. (each of which is carried out using an enzyme or without the participation of an enzyme). Examples of prodrugs are compounds in which the amine groups in the compounds of the present invention are acylated, alkylated or phosphorylated, such as eicosanoylamino, alanylamide, pivaloyloxymethylamino, or in which the hydroxyl groups are acylated, alkylated, phosphorylated or converted into borate, such as acetoxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, or in which the carboxyl groups are esterified or amidated, or in which the sulfhydryl groups are selectively delivered to the target and/or to the cytosol of the cell. The carrier molecule, such as a peptide, forms a disulfide bridge. These compounds can be prepared by the compounds of the present invention according to known methods.
“可药用的盐”或者“药学上可接受的”是指由可药用的碱或酸，包括无机碱或酸和有机碱或酸制成的。在本发明的化合物含有一个或多个酸性或碱性基团的情况下，本发明还包含它们相应的可药用盐。因此，含有酸性基团的本发明的化合物可以以盐形式存在并可根据本发明使用，例如作为碱金属盐、碱土金属盐或作为铵盐。这样的盐的更确切实例包括钠盐、钾盐、钙盐、镁盐或与胺或有机胺，例如伯胺、仲胺、叔胺、环胺等，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、乙醇胺、二环己胺、乙二胺、嘌呤、呱嗪、呱啶、胆碱和咖啡因等特别优选的有机碱为异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因的盐。含有碱性基团的本发明的化合物可以盐形式存在并可根据本发明以它们与无机或有机酸的加成的形式使用。合适的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、磷酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、特戊酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、胺基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和本领域技术人员已知的其他酸。如果本发明的化合物在分子中同时含有酸性和碱性基团，本发明除所提到的盐形式外还包括内盐或内铵盐。各盐通过本领域技术人员已知的常规方法获得，例如通过在溶剂或分散剂中使这些与有机或无机酸或碱接触或通过与其它盐阴离子交换或阳离子交换。"Pharmaceutically acceptable salts" or "pharmaceutically acceptable" refer to salts made of pharmaceutically acceptable bases or acids, including inorganic bases or acids and organic bases or acids. In the case where the compounds of the present invention contain one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Therefore, the compounds of the present invention containing acidic groups can exist in salt form and can be used according to the present invention, for example as alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or with amines or organic amines, such as primary amines, secondary amines, tertiary amines, cyclic amines, etc., such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, ethanolamine, dicyclohexylamine, ethylenediamine, purines, piperazine, piperidine, choline and caffeine, etc., particularly preferred organic bases are salts of isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. The compounds of the present invention containing basic groups can exist in salt form and can be used according to the present invention in the form of addition with inorganic or organic acids. The example of suitable acid comprises hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid and other acids well known to those skilled in the art. If the compound of the present invention contains acidic and basic groups in the molecule simultaneously, the present invention also comprises inner salt or betaine salt except the salt form mentioned. Each salt is obtained by conventional methods well known to those skilled in the art, for example by making these contact with organic or inorganic acid or base in solvent or dispersant or by anion exchange or cation exchange with other salts.
因此，在本申请中当提及“化合物”、“本发明化合物”或“本发明所化合物”时，包括所有所述化合物形式、例如其前药、稳定同位素衍生物、可药用的盐、异构体、内消旋体、外消旋体、对映异构体、非对映异体及其混合物。 Therefore, when referring to "compound", "compound of the present invention" or "compound of the present invention" in this application, all forms of the compound, such as prodrugs, stable isotope derivatives, pharmaceutically acceptable salts, isomers, mesoforms, racemates, enantiomers, diastereomers and mixtures thereof are included.
在本文中、术语“肿瘤”包括良性肿瘤和恶性肿瘤(例如癌症)。As used herein, the term "tumor" includes benign tumors and malignant tumors (eg, cancer).
在本文中，术语“癌症”包括KRAS参与其发生的各种恶性肿瘤、包括但不限胰腺癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、结肠癌、结直肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。In this article, the term "cancer" includes various malignant tumors in which KRAS is involved, including but not limited to pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, multiple eosinophilia syndrome, myeloma and other solid tumors and blood tumors.
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解或生物系统的任何其他所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。As used herein, the term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refers to an amount of at least one agent or compound sufficient to relieve to some extent one or more symptoms of the disease or condition being treated after administration. The result can be a reduction and/or alleviation of signs, symptoms or causes of disease or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant relief of the condition. Techniques such as dose escalation trials can be used to determine the effective amount appropriate for any individual case.
本发明使用的术语“多晶型物”或“多晶型(现象)”是指本发明的化合物具有多种晶型格形态，本发明的一些化合物可能有一个以上的晶体形式，本发明涵盖所有的多品型态或其混合物。The term "polymorph" or "polymorphism" used in the present invention means that the compounds of the present invention have multiple crystal lattice forms. Some compounds of the present invention may have more than one crystal form. The present invention covers all multiple forms or mixtures thereof.
本发明化合物的中间体化合物及其多品形物也在本发明的范围内。Intermediate compounds of the compounds of the present invention and their multiple forms are also within the scope of the present invention.
结晶经常产生本发明化合物的溶剂化物，本文所用术语“溶剂化物”是指由一个或多个本发明化合物分子和一个或多个溶剂分子组合成的合体。Crystallization often produces a solvate of the compound of the invention. The term "solvate" as used herein refers to an association of one or more molecules of the compound of the invention with one or more solvent molecules.
溶剂可以是水，这种情况下，溶剂化物是水合物。另外还可以是有机溶剂。因此，本发明化合物可作为水合物存在，包括一水合物、二水合物、半水合物、三水合物、四水合物等，以及相应的溶剂化形态。本发明化合物可以是真溶剂化物，但在其他一些情况下，本发明化合物也可能只是偶然保留了水或水跟一些其他溶剂的混合物本发明化合物可在一种溶剂中反应或在一种溶剂中沉淀或结晶。本发明化合物的溶剂化物也包括在本发明的范围内。The solvent may be water, in which case the solvate is a hydrate. It may also be an organic solvent. Therefore, the compounds of the present invention may exist as hydrates, including monohydrates, dihydrates, hemihydrates, trihydrates, tetrahydrates, etc., and the corresponding solvated forms. The compounds of the present invention may be true solvates, but in other cases, the compounds of the present invention may also only accidentally retain water or a mixture of water and some other solvents. The compounds of the present invention may react in a solvent or precipitate or crystallize in a solvent. Solvates of the compounds of the present invention are also included within the scope of the present invention.
本文所用的跟制剂，组合物或成分相关的术语“可接受的”是指对治疗主体的总体健康没有持续的有害影响。The term "acceptable" with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。The term "pharmaceutically acceptable" as used herein refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, that is, the substance can be administered to a subject without causing adverse biological reactions or interacting in an adverse manner with any components contained in the composition.
“药学上可接受的载体”包括但不限于已经被相关政府行政部门批准的可以被用于人类和驯养动物的佐剂、载体、赋形剂、助剂、脱臭剂、稀释剂、保鲜剂、染料/着色剂、风味增强剂、表面活性剂和润湿剂、分散剂、悬浮剂、稳定剂等渗剂、溶剂、或乳化剂。"Pharmaceutically acceptable carrier" includes, but is not limited to, adjuvants, carriers, excipients, auxiliary agents, deodorants, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants and wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that have been approved by relevant government administrative departments for use in humans and domesticated animals.
文所用术语“主体”、“患者”、“对象”或“个体”是指患有疾病、紊乱或病症等的个体，包括哺乳动物和非哺乳动物，哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其他猿类和猴)；家畜，例如牛，马、绵羊，山羊，猪；家养动物，例如兔，狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠等。非人哺乳动物的实例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方案中，所述哺乳动物为人。 The terms "subject", "patient", "subject" or "individual" as used herein refer to individuals suffering from diseases, disorders or conditions, etc., including mammals and non-mammals, examples of mammals include but are not limited to any member of the class mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-human mammals include but are not limited to birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human.
本文所用术语“治疗”是指对哺乳动物特别是人类的相关疾病病症的治疗，包括The term "treatment" as used herein refers to the treatment of relevant disease conditions in mammals, especially humans, including
(i)预防哺乳动物，特别是之前已经暴露在某个疾病或病症下但尚未被诊断患有该疾病或病症的哺乳动物，产生相应的疾病或病症；(i) preventing the development of a disease or condition in a mammal, particularly a mammal that has been previously exposed to the disease or condition but has not yet been diagnosed with the disease or condition;
(ii)抑制疾病或病症，即，控制其发展；(ii) inhibiting the disease or condition, i.e., controlling its development;
(iii)缓解疾病或病症，即，使疾病或病症消退缓；(iii) alleviate a disease or condition, i.e., cause the disease or condition to regress;
(iv)缓解疾病或病症引起的症状。(iv) Alleviate symptoms caused by a disease or condition.
本文所用术语“疾病”和“病症”可以互相替代，也可以是不同意思，因为某些特定疾病或病症还没有已知的致病因子(所以发病原因尚不清楚)，所以还不能被认作疾病而只能被看做不想要的状况或综合症，所述综合症或多或少有一些具体症状已经被临床研究人员证实。As used herein, the terms "disease" and "disorder" may be used interchangeably or may have different meanings because certain specific diseases or disorders do not yet have a known causative agent (so the cause of the disease is still unclear), and therefore cannot be considered a disease but can only be viewed as an unwanted condition or syndrome, the syndrome of which more or less specific symptoms have been confirmed by clinical researchers.
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法这些方法。包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。The terms "administering", "administering", "administering", etc. used herein refer to methods that can deliver a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
具体实施方法Specific implementation methods
本发明还提供制备所述化合物的方法。本发明通式(I)所述化合物的制备，可通过以下示例性方法和实施例完成，但这些方法和实施例不应以任何方式被认为是对本发明范围的限制。也可地本领域技术人员所知的合成技术合成本发明所述的化合物，或者综合使用本领域已知方法和本发明所述的方法。每步应所得的产物用本领域已知的分离技术得到，包括但不限于萃取、过滤、蒸馏、结晶、色谱分离等。合成所需要的起始原料和化学试剂可以根据文献(reaxys)常规合成或购买。The present invention also provides a method for preparing the compound. The preparation of the compound described in the general formula (I) of the present invention can be completed by the following exemplary methods and examples, but these methods and examples should not be considered to limit the scope of the present invention in any way. The compound described in the present invention can also be synthesized by synthetic techniques known to those skilled in the art, or a combination of methods known in the art and the method described in the present invention. The product obtained in each step is obtained by separation techniques known in the art, including but not limited to extraction, filtration, distillation, crystallization, chromatographic separation, etc. The starting materials and chemical reagents required for the synthesis can be conventionally synthesized or purchased according to the literature (reaxys).
除非另有说明，温度是摄氏温度。试剂购自Chem blocks Inc和3wpharm等商业供应商，并且这些试剂可直接使用无需进一步纯化，除非另有说明。Unless otherwise stated, temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Chem blocks Inc and 3wpharm and were used directly without further purification unless otherwise stated.
除非另有说明，下列反应在室温、无水溶剂中、氮气或气的正压下或使用干燥管进行；玻璃器皿烘干和/或加热干燥。Unless otherwise stated, the following reactions were performed at room temperature, in anhydrous solvents, under a positive pressure of nitrogen or gas, or using a drying tube; glassware was oven-dried and/or heat-dried.
除非另有说明，柱色谱纯化使用青岛海洋化工厂的200-300目硅胶；制备薄层色谱使用烟台市化学工业研究所生产的薄层色谱硅胶预制板(HSGF254)；MS的测定用Therno LCD Fleet型(ESI)液相色谱-质谱联用仪。Unless otherwise stated, column chromatography purification used 200-300 mesh silica gel from Qingdao Ocean Chemical Plant; preparative thin layer chromatography used thin layer chromatography silica gel preform plates (HSGF254) produced by Yantai Institute of Chemical Industry; and MS was determined using a Therno LCD Fleet (ESI) liquid chromatography-mass spectrometer.
核磁数据(1H NMR)使用Bruker Avance-400MHz或Varian Oxford-400Hz核磁仪，核磁数据使用的溶剂有CDCl3、CD3OD、D2O、DMS-d6等，以四甲基硅烷(0.000ppm)为基准或以残留溶剂为基准(CDCl3:7.26ppm；CD3OD:3.31ppm；D2O:4.79ppm；d6-DMSO:2.50ppm)当标明峰形多样性时，以下简写表示不同峰形：s(单峰)、d(双重峰)、t(三重峰)、q(四重峰)、m(多重峰)、br(宽峰)、dd(双双重峰)、dt(双三重峰)。如果给出了耦合常数，则以Hertz(Hz)为单位。The nuclear magnetic data (1H NMR) were obtained using a Bruker Avance-400MHz or Varian Oxford-400Hz NMR spectrometer. The solvents used for the nuclear magnetic data included CDCl 3 , CD 3 OD, D 2 O, DMS-d6, etc., with tetramethylsilane (0.000ppm) as the reference or residual solvent as the reference (CDCl 3: 7.26ppm; CD 3 OD: 3.31ppm; D 2 O: 4.79ppm; d6-DMSO: 2.50ppm). When peak shape diversity is indicated, the following abbreviations represent different peak shapes: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad peak), dd (double doublet), dt (double triplet). If coupling constants are given, they are in Hertz (Hz).
中间体的制备Preparation of intermediates
3-甲氧基异喹啉-1-频哪硼酸酯
3-Methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向3-甲氧基-2H-异喹啉-l-酮(6.16g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干。残留物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化，得到1-三氟甲磺酸氧基-3-甲氧基异喹啉(5.89g，96％产率)。To a solution of 3-methoxy-2H-isoquinolin-1-one (6.16 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give 1-trifluoromethanesulfonyloxy-3-methoxyisoquinoline (5.89 g, 96% yield).
LC-MS(ESI)：m/z 308[M+H]+。LC-MS (ESI): m/z 308 [M+H] + .
步骤B：Step B:
向1-三氟甲磺酸氧基-3-甲氧基异喹啉(5.83g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到3-甲氧基异喹啉-1-频哪硼酸酯(3.68g，产率68％)。To a mixture of 1-trifluoromethanesulfonyloxy-3-methoxyisoquinoline (5.83 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) eluting with 30-40% ethyl acetate in petroleum ether to give 3-methoxyisoquinoline-1-pinacolborate (3.68 g, 68% yield).
LC-MS(ESI)：m/z 286[M+H]+。LC-MS (ESI): m/z 286 [M+H] + .
(2-氟-6-甲氧基-8-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)异喹啉-1-基)乙炔基)三异丙基硅烷
(2-Fluoro-6-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)isoquinolin-1-yl)ethynyl)triisopropylsilane
步骤A：Step A:
在室温下向5-氟-2-甲基苯甲酸(38.4g)在DMF(450ml)中的搅拌溶液中添加NIS(61.7g)和乙酸钯(II)(5.6g)。将所得反应混合物在110℃下加热15h。将反应混合物冷却至室温并倒入水(1000ml)中。用EtOAc(2x400ml)提取所得混合物。合并的有机相用盐水(300ml)洗涤，用Na2SO4干燥，过滤并减压浓缩，得到3-氟-2-碘-6-甲基苯甲酸(49.6g)。该材料直接用于下一步，无需进一步纯化。To a stirred solution of 5-fluoro-2-methylbenzoic acid (38.4 g) in DMF (450 ml) was added NIS (61.7 g) and palladium (II) acetate (5.6 g) at room temperature. The resulting reaction mixture was heated at 110 ° C for 15 h. The reaction mixture was cooled to room temperature and poured into water (1000 ml). The resulting mixture was extracted with EtOAc (2x400 ml). The combined organic phases were washed with brine (300 ml), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give 3-fluoro-2-iodo-6-methylbenzoic acid (49.6 g). The material was used directly in the next step without further purification.
步骤B：Step B:
加热3-氟-2-碘-6-甲基苯甲酸(42g，0.15mol)、SOCl2(120mL)和DMF(6mL)的溶液，直到混合物变得均匀(15min)。将溶液在23℃下再保持30分钟，然后浓缩溶液。向粗残留物中加入MeOH(240mL)，并将溶液保持在23℃下30分钟。浓缩溶液，得到3-氟-2-碘-6-甲基苯甲酸甲酯(43g)。该材料直接用于下一步，无需进一步纯化。 A solution of 3-fluoro-2-iodo-6-methylbenzoic acid (42 g, 0.15 mol), SOCl2 (120 mL) and DMF (6 mL) was heated until the mixture became homogeneous (15 min). The solution was kept at 23 °C for another 30 min and then the solution was concentrated. MeOH (240 mL) was added to the crude residue and the solution was kept at 23 °C for 30 min. The solution was concentrated to give methyl 3-fluoro-2-iodo-6-methylbenzoate (43 g). The material was used directly in the next step without further purification.
步骤C：Step C:
向3-氟-2-碘-6-甲基苯甲酸甲酯(22g，75mmol)在CCl4(130mL)中的溶液中添加N-溴代琥珀酰亚胺(22g、123mmol)和过氧化苯甲酰(1.46g，7.8mmol)。将反应混合物在85℃氮气气氛下搅拌3小时。过滤粗产物并用甲苯洗涤。蒸发挥发物，将残留物溶解在DMF(150mL)中，加入氰化钠(7.50g)。将所得混合物在60℃下加热5小时。将反应混合物冷却至室温，用水(50mL)处理，并用乙酸乙酯(3x50mL)萃取。合并的有机物用盐水溶液(50mL)洗涤并用无水硫酸钠干燥。将溶液过滤并减压浓缩，得到粗产物。用30-40％乙酸乙酯在石油醚中洗脱，得到3-氟-2-碘-6-(氰甲基)苯甲酸甲酯(14.2g)。To a solution of 3-fluoro-2-iodo-6-methylbenzoic acid methyl ester (22g, 75mmol) in CCl 4 (130mL) was added N-bromosuccinimide (22g, 123mmol) and benzoyl peroxide (1.46g, 7.8mmol). The reaction mixture was stirred for 3 hours at 85°C under a nitrogen atmosphere. The crude product was filtered and washed with toluene. The volatiles were evaporated, the residue was dissolved in DMF (150mL), and sodium cyanide (7.50g) was added. The resulting mixture was heated at 60°C for 5 hours. The reaction mixture was cooled to room temperature, treated with water (50mL), and extracted with ethyl acetate (3x50mL). The combined organic matter was washed with saline solution (50mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain 3-fluoro-2-iodo-6-(cyanomethyl)benzoic acid methyl ester (14.2g).
LC-MS(ESI)：m/z 320[M+H]+。LC-MS (ESI): m/z 320 [M+H] + .
步骤D：Step D:
向3-氟-2-碘-6-(氰甲基)苯甲酸甲酯(10.24g，32mmol)在甲醇(95mL)中的溶液中添加甲醇钠(25％在甲醇中，34.6g，35.7mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到7-氟-8-碘-3-甲氧基-2H-异喹啉-l-酮(10.55g，103％产率)，黄色固体。To a solution of methyl 3-fluoro-2-iodo-6-(cyanomethyl)benzoate (10.24 g, 32 mmol) in methanol (95 mL) was added sodium methoxide (25% in methanol, 34.6 g, 35.7 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 7-fluoro-8-iodo-3-methoxy-2H-isoquinolin-l-one (10.55 g, 103% yield) as a yellow solid.
LC-MS(ESI)：m/z 320[M+H]+。LC-MS (ESI): m/z 320 [M+H] + .
步骤E：Step E:
在氩气下，将三异丙基硅烷基乙炔(5.47g，0.03mol)和三乙胺(14.4ml)，然后将碘化铜(0.2g)和双-(三苯基膦)-二氯化钯(0.73g)加入到7-氟-8-碘-3-甲氧基-2H-异喹啉-l-酮(9.6g，0.03mol)在150ml干燥THF中的无氧溶液中。将溶液在环境温度下搅拌16小时，然后通过硅藻土过滤并蒸发。残余物通过快速色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到7-氟-8-((三异丙基甲硅基)乙炔基)-3-甲氧基-2H-异喹啉-l-酮(8.7g，78％产率)。Triisopropylsilyl acetylene (5.47 g, 0.03 mol) and triethylamine (14.4 ml), followed by copper iodide (0.2 g) and bis-(triphenylphosphine)-palladium dichloride (0.73 g) were added to an oxygen-free solution of 7-fluoro-8-iodo-3-methoxy-2H-isoquinolin-1-one (9.6 g, 0.03 mol) in 150 ml of dry THF under argon. The solution was stirred at ambient temperature for 16 hours, then filtered through celite and evaporated. The residue was purified by flash chromatography (SiO 2 ) eluting with 30-40% ethyl acetate in petroleum ether to give 7-fluoro-8-((triisopropylmethylsilyl)ethynyl)-3-methoxy-2H-isoquinolin-1-one (8.7 g, 78% yield).
LC-MS(ESI)：m/z 374[M+H]+。LC-MS (ESI): m/z 374 [M+H] + .
步骤F：Step F:
向7-氟-8-((三异丙基甲硅基)乙炔基)-3-甲氧基-2H-异喹啉-l-酮(7.4g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干。残留物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化，得到1-三氟甲磺酸基-7-氟-3-甲氧基-8-((三异丙基甲硅基)乙炔基)异喹啉(9.9g，98％产率)。To a solution of 7-fluoro-8-((triisopropylsilyl)ethynyl)-3-methoxy-2H-isoquinolin-1-one (7.4 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate = 1/0 to 60/1) to give 1-trifluoromethanesulfonyl-7-fluoro-3-methoxy-8-((triisopropylsilyl)ethynyl)isoquinoline (9.9 g, 98% yield).
LC-MS(ESI)：m/z 506[M+H]+。LC-MS (ESI): m/z 506 [M+H] + .
步骤G：Step G:
向1-三氟甲磺酸基-7-氟-3-甲氧基-8-((三异丙基甲硅基)乙炔基)异喹啉(9.6g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到(2-氟-6-甲氧基-8-(4,4,5,5-四甲基-1,3,2-二氧代硼烷-2-基)异喹啉-1-基)乙 炔基)三异丙基硅烷(4.4g，产率48％)。To a mixture of 1-trifluoromethanesulfonyl-7-fluoro-3-methoxy-8-((triisopropylsilyl)ethynyl)isoquinoline (9.6 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography ( SiO2 ) eluting with 30-40% ethyl acetate in petroleum ether to afford (2-fluoro-6-methoxy-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-yl)ethyl alkynyl)triisopropylsilane (4.4 g, yield 48%).
LC-MS(ESI)：m/z 484[M+H]+。LC-MS (ESI): m/z 484 [M+H] + .
8-氟-3-甲氧基异喹啉-1-频哪硼酸酯
8-Fluoro-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2-氟-6-甲基苯甲酸甲酯(16.8g，100mmol)在CCl4(130mL)中的溶液中添加NBS(26.7g、150mmol)和过氧化苯甲酰(1.46g，7.8mmol)。将反应混合物在85℃氮气气氛下搅拌3小时。过滤粗产物并用甲苯洗涤。蒸发挥发物，将残留物溶解在DMF(150mL)中，加入氰化钠(9.80g)。将所得混合物在60℃下加热5小时。将反应混合物冷却至室温，用水(50mL)处理，并用乙酸乙酯(3x50mL)萃取。合并的有机物用盐水溶液(50mL)洗涤并用无水硫酸钠干燥。将溶液过滤并减压浓缩，得到粗产物。用30-40％乙酸乙酯在石油醚中洗脱，得到2-氟-6-(氰甲基)苯甲酸甲酯(13.1g)[M+H]+。To a solution of methyl 2-fluoro-6-methylbenzoate (16.8 g, 100 mmol) in CCl 4 (130 mL) was added NBS (26.7 g, 150 mmol) and benzoyl peroxide (1.46 g, 7.8 mmol). The reaction mixture was stirred for 3 hours at 85 ° C under a nitrogen atmosphere. The crude product was filtered and washed with toluene. The volatiles were evaporated, the residue was dissolved in DMF (150 mL), and sodium cyanide (9.80 g) was added. The resulting mixture was heated at 60 ° C for 5 hours. The reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3x50 mL). The combined organic matter was washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 2-fluoro-6-(cyanomethyl)benzoate (13.1 g) [M+H] + .
LC-MS(ESI)：m/z 194。LC-MS(ESI): m/z 194.
步骤B：Step B:
向2-氟-6-(氰甲基)苯甲酸甲酯(9.7g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-氟-3-甲氧基-2H-异喹啉-l-酮(9.74g，101％产率)。To a solution of methyl 2-fluoro-6-(cyanomethyl)benzoate (9.7 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-fluoro-3-methoxy-2H-isoquinolin-l-one (9.74 g, 101% yield).
LC-MS(ESI)：m/z 194[M+H]+。LC-MS (ESI): m/z 194 [M+H] + .
步骤C：Step C:
向8-氟-3-甲氧基-2H-异喹啉-l-酮(3.86g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干。残留物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化，得到1-三氟甲磺酸氧基-8-氟-3-甲氧基异喹啉(6.24g，96％产率)。To a solution of 8-fluoro-3-methoxy-2H-isoquinolin-1-one (3.86 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give 1-trifluoromethanesulfonyloxy-8-fluoro-3-methoxyisoquinoline (6.24 g, 96% yield).
LC-MS(ESI)：m/z 326[M+H]+。LC-MS (ESI): m/z 326 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-氟-3-甲氧基异喹啉(6.19g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油 醚中洗脱，得到8-氟-3-甲氧基异喹啉-1-频哪硼酸酯(3.57g，产率62％)[M+H]+。To a mixture of 1-trifluoromethanesulfonyloxy-8-fluoro-3-methoxyisoquinoline (6.19 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) using 30-40% ethyl acetate in petroleum. Elution with ether afforded 8-fluoro-3-methoxyisoquinoline-1-pinacol borate (3.57 g, 62% yield) [M+H] + .
LC-MS(ESI)：m/z 304。LC-MS(ESI): m/z 304.
8-氯-3-甲氧基异喹啉-1-频哪硼酸酯
8-Chloro-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2-氯-6-甲基苯甲酸甲酯(18.4g，100mmol)在CCl4(130mL)中的溶液中添加NBS(26.7g、150mmol)和过氧化苯甲酰(1.46g，7.8mmol)。将反应混合物在85℃氮气气氛下搅拌3小时。过滤粗产物并用甲苯洗涤。蒸发挥发物，将残留物溶解在DMF(150mL)中，加入氰化钠(9.80g)。将所得混合物在60℃下加热5小时。将反应混合物冷却至室温，用水(50mL)处理，并用乙酸乙酯(3x50mL)萃取。合并的有机物用盐水溶液(50mL)洗涤并用无水硫酸钠干燥。将溶液过滤并减压浓缩，得到粗产物。用30-40％乙酸乙酯在石油醚中洗脱，得到2-氯-6-(氰甲基)苯甲酸甲酯(14.0g)。To a solution of 2-chloro-6-methylbenzoic acid methyl ester (18.4g, 100mmol) in CCl 4 (130mL) was added NBS (26.7g, 150mmol) and benzoyl peroxide (1.46g, 7.8mmol). The reaction mixture was stirred for 3 hours at 85°C under a nitrogen atmosphere. The crude product was filtered and washed with toluene. The volatiles were evaporated, the residue was dissolved in DMF (150mL), and sodium cyanide (9.80g) was added. The resulting mixture was heated at 60°C for 5 hours. The reaction mixture was cooled to room temperature, treated with water (50mL), and extracted with ethyl acetate (3x50mL). The combined organic matter was washed with saline solution (50mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain 2-chloro-6-(cyanomethyl)benzoic acid methyl ester (14.0g).
LC-MS(ESI)：m/z 210[M+H]+。LC-MS (ESI): m/z 210 [M+H] + .
步骤B：Step B:
向2-氯-6-(氰甲基)苯甲酸甲酯(9.7g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-氯-3-甲氧基-2H-异喹啉-l-酮(10.76g，103％产率)。To a solution of methyl 2-chloro-6-(cyanomethyl)benzoate (9.7 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-chloro-3-methoxy-2H-isoquinolin-l-one (10.76 g, 103% yield).
LC-MS(ESI)：m/z 210[M+H]+。LC-MS (ESI): m/z 210 [M+H] + .
步骤C：Step C:
向8-氯-3-甲氧基-2H-异喹啉-l-酮(4.18g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干。残留物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化，得到1-三氟甲磺酸氧基-8-氯-3-甲氧基异喹啉(6.61g，97％产率)。To a solution of 8-chloro-3-methoxy-2H-isoquinolin-1-one (4.18 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give 1-trifluoromethanesulfonyloxy-8-chloro-3-methoxyisoquinoline (6.61 g, 97% yield).
LC-MS(ESI)：m/z 342[M+H]+。LC-MS (ESI): m/z 342 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-氯-3-甲氧基异喹啉(6.48g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油 醚中洗脱，得到8-氯-3-甲氧基异喹啉-1-频哪硼酸酯(4.6g，产率76％)。To a mixture of 1-trifluoromethanesulfonyloxy-8-chloro-3-methoxyisoquinoline (6.48 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxoborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) using 30-40% ethyl acetate in petroleum. Elution with ether gave 8-chloro-3-methoxyisoquinoline-1-pinacol borate (4.6 g, 76% yield).
LC-MS(ESI)：m/z 320[M+H]+。LC-MS (ESI): m/z 320 [M+H] + .
7-氟-8-氯-3-甲氧基异喹啉-1-频哪硼酸酯
7-Fluoro-8-chloro-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2-氯-6-甲基苯甲酸甲酯(20.2g，100mmol)在CCl4(130mL)中的溶液中添加NBS(26.7g,150mmol)和过氧化苯甲酰(1.46g,7.8mmol)。将反应混合物在85℃氮气气氛下搅拌3小时。过滤粗产物并用甲苯洗涤。蒸发挥发物，将残留物溶解在DMF(150mL)中，加入氰化钠(9.80g)。将所得混合物在60℃下加热5小时。将反应混合物冷却至室温，用水(50mL)处理，并用乙酸乙酯(3x50mL)萃取。合并的有机物用盐水溶液(50mL)洗涤并用无水硫酸钠干燥。将溶液过滤并减压浓缩，得到粗产物。用30-40％乙酸乙酯在石油醚中洗脱，得到2-氯-6-(氰甲基)苯甲酸甲酯(14.75g)。To a solution of methyl 2-chloro-6-methylbenzoate (20.2 g, 100 mmol) in CCl 4 (130 mL) was added NBS (26.7 g, 150 mmol) and benzoyl peroxide (1.46 g, 7.8 mmol). The reaction mixture was stirred at 85 ° C for 3 hours under a nitrogen atmosphere. The crude product was filtered and washed with toluene. The volatiles were evaporated, the residue was dissolved in DMF (150 mL), and sodium cyanide (9.80 g) was added. The resulting mixture was heated at 60 ° C for 5 hours. The reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3x50 mL). The combined organics were washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 2-chloro-6-(cyanomethyl)benzoate (14.75 g).
LC-MS(ESI)：m/z 228[M+H]+。LC-MS (ESI): m/z 228 [M+H] + .
步骤B：Step B:
向2-氯-6-(氰甲基)苯甲酸甲酯(11.35g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-氯-3-甲氧基-2H-异喹啉-l-酮(11.58g，102％产率)。To a solution of methyl 2-chloro-6-(cyanomethyl)benzoate (11.35 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-chloro-3-methoxy-2H-isoquinolin-l-one (11.58 g, 102% yield).
LC-MS(ESI)：m/z 228[M+H]+。LC-MS (ESI): m/z 228 [M+H] + .
步骤C：Step C:
向8-氯-7-氟-3-甲氧基-2H-异喹啉-l-酮(4.54g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干。残留物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化，得到1-三氟甲磺酸氧基-8-氯-7-氟-3-甲氧基异喹啉(6.82g，95％产率)。To a solution of 8-chloro-7-fluoro-3-methoxy-2H-isoquinolin-1-one (4.54 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness. The residue was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give 1-trifluoromethanesulfonyloxy-8-chloro-7-fluoro-3-methoxyisoquinoline (6.82 g, 95% yield).
LC-MS(ESI)：m/z 360[M+H]+。LC-MS (ESI): m/z 360 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-氯-7-氟-3-甲氧基异喹啉(6.82g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用 无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到8-氯-7-氟-3-甲氧基异喹啉-1-频哪硼酸酯(4.74g，产率74％)。To a mixture of 1-trifluoromethanesulfonyloxy-8-chloro-7-fluoro-3-methoxyisoquinoline (6.82 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130 °C for 3 hours. The reaction mixture was filtered and concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL) and washed with Drying over anhydrous sodium sulfate, filtration and concentration gave a residue. The residue was purified by column chromatography ( SiO2 ) eluting with 30-40% ethyl acetate in petroleum ether to give 8-chloro-7-fluoro-3-methoxyisoquinoline-1-pinacol borate (4.74 g, 74% yield).
LC-MS(ESI)：m/z 338[M+H]+。LC-MS (ESI): m/z 338 [M+H] + .
8-甲基-3-甲氧基异喹啉-1-频哪硼酸酯
8-Methyl-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2,6-甲基苯甲酸甲酯(16.4g，100mmol)在CCl4(130mL)中的溶液中添加NBS(26.7g、150mmol)和过氧化苯甲酰(1.46g，7.8mmol)。将反应混合物在85℃氮气气氛下搅拌3小时。过滤粗产物并用甲苯洗涤。蒸发挥发物，将残留物溶解在DMF(150mL)中，加入氰化钠(9.80g)。将所得混合物在60℃下加热5小时。将反应混合物冷却至室温，用水(50mL)处理，并用乙酸乙酯(3x50mL)萃取。合并的有机物用盐水溶液(50mL)洗涤并用无水硫酸钠干燥。将溶液过滤并减压浓缩，得到粗产物。用30-40％乙酸乙酯在石油醚中洗脱，得到2-甲基-6-(氰甲基)苯甲酸甲酯(10.96g)。To a solution of methyl 2,6-methylbenzoate (16.4 g, 100 mmol) in CCl 4 (130 mL) was added NBS (26.7 g, 150 mmol) and benzoyl peroxide (1.46 g, 7.8 mmol). The reaction mixture was stirred at 85 ° C for 3 hours under a nitrogen atmosphere. The crude product was filtered and washed with toluene. The volatiles were evaporated, the residue was dissolved in DMF (150 mL), and sodium cyanide (9.80 g) was added. The resulting mixture was heated at 60 ° C for 5 hours. The reaction mixture was cooled to room temperature, treated with water (50 mL), and extracted with ethyl acetate (3x50 mL). The combined organics were washed with saline solution (50 mL) and dried over anhydrous sodium sulfate. The solution was filtered and concentrated under reduced pressure to obtain a crude product. Eluted with 30-40% ethyl acetate in petroleum ether to obtain methyl 2-methyl-6-(cyanomethyl)benzoate (10.96 g).
LC-MS(ESI)：m/z 190[M+H]+。LC-MS (ESI): m/z 190 [M+H] + .
步骤B：Step B:
向2-甲基-6-(氰甲基)苯甲酸甲酯(9.45g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-氯-3-甲氧基-2H-异喹啉-l-酮(9.83g，104％产率)。To a solution of methyl 2-methyl-6-(cyanomethyl)benzoate (9.45 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-chloro-3-methoxy-2H-isoquinolin-l-one (9.83 g, 104% yield).
LC-MS(ESI)：m/z 190[M+H]+。LC-MS (ESI): m/z 190 [M+H] + .
步骤C：Step C:
向8-甲基-3-甲氧基-2H-异喹啉-l-酮(3.78g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干，得到1-三氟甲磺酸氧基-8-氟-3-甲氧基异喹啉(6.16g，96％产率)。To a solution of 8-methyl-3-methoxy-2H-isoquinolin-l-one (3.78 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness to give 1-trifluoromethanesulfonyloxy-8-fluoro-3-methoxyisoquinoline (6.16 g, 96% yield).
LC-MS(ESI)：m/z 322[M+H]+。LC-MS (ESI): m/z 322 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-甲基-3-甲氧基异喹啉(6.06g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混合物 并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到8-甲基-3-甲氧基异喹啉-1-频哪硼酸酯(4.2g，产率74％)。To a mixture of 1-trifluoromethanesulfonyloxy-8-methyl-3-methoxyisoquinoline (6.06 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 h. The reaction mixture was filtered. and concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) eluting with 30-40% ethyl acetate in petroleum ether to give 8-methyl-3-methoxyisoquinoline-1-pinacol borate (4.2 g, 74% yield).
LC-MS(ESI)：m/z 300[M+H]+。LC-MS (ESI): m/z 300 [M+H] + .
7-氟-8-乙基-3-甲氧基异喹啉-1-频哪硼酸酯
7-Fluoro-8-ethyl-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2-碘-3-氟-6-(氰甲基)苯甲酸甲酯(44.5g，139.5mmol)在甲苯(240mL)和水(60mL)中的搅拌溶液中加入乙基硼酸(15.4g，209mmol)、磷酸钾(59.2g，279mmol)和三环己基膦(3.9g，13.9mmol)，并将反应混合物在100℃下搅拌3小时。反应完成后，将反应冷却至室温，用水淬灭并用乙酸乙酯(2*500mL)萃取。合并有机物并用盐水溶液(300mL)洗涤，用Na2SO4干燥，过滤，减压浓缩，得到粗产物。粗产物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化得到2-乙基-3-氟-6-(氰甲基)苯甲酸甲酯(20.79g，65％)。To a stirred solution of methyl 2-iodo-3-fluoro-6-(cyanomethyl)benzoate (44.5 g, 139.5 mmol) in toluene (240 mL) and water (60 mL) was added ethylboric acid (15.4 g, 209 mmol), potassium phosphate (59.2 g, 279 mmol) and tricyclohexylphosphine (3.9 g, 13.9 mmol), and the reaction mixture was stirred at 100 ° C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate (2*500 mL). The organics were combined and washed with brine solution (300 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give methyl 2-ethyl-3-fluoro-6-(cyanomethyl)benzoate (20.79 g, 65%).
LC-MS(ESI)：m/z 221[M+H]+。LC-MS (ESI): m/z 221 [M+H] + .
步骤B：Step B:
向2-乙基-3-氟-6-(氰甲基)苯甲酸甲酯(11.05g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-乙基-7-氟-3-甲氧基-2H-异喹啉-l-酮(11.27g，102％产率)。To a solution of methyl 2-ethyl-3-fluoro-6-(cyanomethyl)benzoate (11.05 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-ethyl-7-fluoro-3-methoxy-2H-isoquinolin-l-one (11.27 g, 102% yield).
LC-MS(ESI)：m/z 221[M+H]+。LC-MS (ESI): m/z 221 [M+H] + .
步骤C：Step C:
向8-乙基-7-氟-3-甲氧基-2H-异喹啉-l-酮(4.4g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干，得到1-三氟甲磺酸氧基-8-乙基-7-氟-3-甲氧基异喹啉(6.84g，97％)。To a solution of 8-ethyl-7-fluoro-3-methoxy-2H-isoquinolin-1-one (4.4 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness to give 1-trifluoromethanesulfonyloxy-8-ethyl-7-fluoro-3-methoxyisoquinoline (6.84 g, 97%).
LC-MS(ESI)：m/z 354[M+H]+。LC-MS (ESI): m/z 354 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-乙基-7-氟-3-甲氧基异喹啉(6.7g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混 合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到7-氟-8-乙基-3-甲氧基异喹啉-1-频哪硼酸酯(3.52g，产率56％)。To a mixture of 1-trifluoromethanesulfonyloxy-8-ethyl-7-fluoro-3-methoxyisoquinoline (6.7 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered. The mixture was concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) eluting with 30-40% ethyl acetate in petroleum ether to give 7-fluoro-8-ethyl-3-methoxyisoquinoline-1-pinacol borate (3.52 g, 56% yield).
LC-MS(ESI)：m/z 332[M+H]+。LC-MS (ESI): m/z 332 [M+H] + .
7-氟-8-异丙基-3-甲氧基异喹啉-1-频哪硼酸酯
7-Fluoro-8-isopropyl-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2-碘-3-氟-6-(氰甲基)苯甲酸甲酯(44.5g，139.5mmol)在甲苯(240mL)和水(60mL)中的搅拌溶液中加入异丙基硼酸(18.3g，209mmol)、磷酸钾(59.2g，279mmol)和三环己基膦(3.9g，13.9mmol)，并将反应混合物在100℃下搅拌3小时。反应完成后，将反应冷却至室温，用水淬灭并用乙酸乙酯(2*500mL)萃取。合并有机物并用盐水溶液(300mL)洗涤，用Na2SO4干燥，过滤，减压浓缩，得到粗产物。粗产物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化得到2-异丙基-3-氟-6-(氰甲基)苯甲酸甲酯(24.01g，52％)。Isopropylboric acid (18.3 g, 209 mmol), potassium phosphate (59.2 g, 279 mmol) and tricyclohexylphosphine (3.9 g, 13.9 mmol) were added to a stirred solution of methyl 2-iodo-3-fluoro-6-(cyanomethyl)benzoate (44.5 g, 139.5 mmol) in toluene (240 mL) and water (60 mL), and the reaction mixture was stirred at 100 ° C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate (2*500 mL). The organics were combined and washed with brine solution (300 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give methyl 2-isopropyl-3-fluoro-6-(cyanomethyl)benzoate (24.01 g, 52%).
LC-MS(ESI)：m/z 236[M+H]+。LC-MS (ESI): m/z 236 [M+H] + .
步骤B：Step B:
向2-异丙基-3-氟-6-(氰甲基)苯甲酸甲酯(11.75g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-异丙基-7-氟-3-甲氧基-2H-异喹啉-l-酮(11.98g，102％产率)。To a solution of methyl 2-isopropyl-3-fluoro-6-(cyanomethyl)benzoate (11.75 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-isopropyl-7-fluoro-3-methoxy-2H-isoquinolin-l-one (11.98 g, 102% yield).
LC-MS(ESI)：m/z 320[M+H]+。LC-MS (ESI): m/z 320 [M+H] + .
步骤C：Step C:
向8-异丙基-7-氟-3-甲氧基-2H-异喹啉-l-酮(7.4g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干，得到1-三氟甲磺酸氧基-8-异丙基-7-氟-3-甲氧基异喹啉(6.32g，99％产率)。To a solution of 8-isopropyl-7-fluoro-3-methoxy-2H-isoquinolin-1-one (7.4 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness to give 1-trifluoromethanesulfonyloxy-8-isopropyl-7-fluoro-3-methoxyisoquinoline (6.32 g, 99% yield).
LC-MS(ESI)：m/z 320[M+H]+。LC-MS (ESI): m/z 320 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-异丙基-7-氟-3-甲氧基异喹啉(6.06g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混 合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到7-氟-8-异丙基-3-甲氧基异喹啉-1-频哪硼酸酯(3.14g，产率48％)。To a mixture of 1-trifluoromethanesulfonyloxy-8-isopropyl-7-fluoro-3-methoxyisoquinoline (6.06 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered. The mixture was concentrated to give a residue. To the residue was added EtOAc (100 mL) and water (80 mL). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO 2 ) eluting with 30-40% ethyl acetate in petroleum ether to give 7-fluoro-8-isopropyl-3-methoxyisoquinoline-1-pinacol borate (3.14 g, 48% yield).
LC-MS(ESI)：m/z 346[M+H]+。LC-MS (ESI): m/z 346 [M+H] + .
7-氟-8-环丙基-3-甲氧基异喹啉-1-频哪硼酸酯
7-Fluoro-8-cyclopropyl-3-methoxyisoquinoline-1-pinacol borate
步骤A：Step A:
向2-碘-3-氟-6-(氰甲基)苯甲酸甲酯(44.5g，139.5mmol)在甲苯(240mL)和水(60mL)中的搅拌溶液中加入异丙基硼酸(18.3g，209mmol)、磷酸钾(59.2g，279mmol)和三环己基膦(3.9g，13.9mmol)，并将反应混合物在100℃下搅拌3小时。反应完成后，将反应冷却至室温，用水淬灭并用乙酸乙酯(2*500mL)萃取。合并有机物并用盐水溶液(300mL)洗涤，用Na2SO4干燥，过滤，减压浓缩，得到粗产物。粗产物通过柱色谱(SiO2，石油醚/乙酸乙酯＝1/0至60/1)纯化得到2-环丙基-3-氟-6-(氰甲基)苯甲酸甲酯(14.95g，46％)。Isopropylboric acid (18.3 g, 209 mmol), potassium phosphate (59.2 g, 279 mmol) and tricyclohexylphosphine (3.9 g, 13.9 mmol) were added to a stirred solution of methyl 2-iodo-3-fluoro-6-(cyanomethyl)benzoate (44.5 g, 139.5 mmol) in toluene (240 mL) and water (60 mL), and the reaction mixture was stirred at 100 ° C for 3 hours. After the reaction was completed, the reaction was cooled to room temperature, quenched with water and extracted with ethyl acetate (2*500 mL). The organics were combined and washed with brine solution (300 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (SiO 2 , petroleum ether/ethyl acetate=1/0 to 60/1) to give methyl 2-cyclopropyl-3-fluoro-6-(cyanomethyl)benzoate (14.95 g, 46%).
LC-MS(ESI)：m/z 234[M+H]+。LC-MS (ESI): m/z 234 [M+H] + .
步骤B：Step B:
向2-环丙基-3-氟-6-(氰甲基)苯甲酸甲酯(11.65g，50mmol)在甲醇(140mL)中的溶液中添加甲醇钠(25％在甲醇中，50mL)。将所得混合物在70℃下加热4小时。将反应混合物冷却至室温并使用1N HC1酸化。过滤沉淀的固体，用水洗涤并在真空下干燥，得到8-环丙基-7-氟-3-甲氧基-2H-异喹啉-l-酮((11.76g，101％产率)。To a solution of methyl 2-cyclopropyl-3-fluoro-6-(cyanomethyl)benzoate (11.65 g, 50 mmol) in methanol (140 mL) was added sodium methoxide (25% in methanol, 50 mL). The resulting mixture was heated at 70 °C for 4 h. The reaction mixture was cooled to room temperature and acidified using 1N HCl. The precipitated solid was filtered, washed with water and dried under vacuum to give 8-cyclopropyl-7-fluoro-3-methoxy-2H-isoquinolin-l-one ((11.76 g, 101% yield).
LC-MS(ESI)：m/z 234[M+H]+。LC-MS (ESI): m/z 234 [M+H] + .
步骤C：Step C:
向8-环丙基-7-氟-3-甲氧基-2H-异喹啉-l-酮(4.66g，20mmol)、DIEA(7.7g，60mmol)在DCM(120mL)中的溶液中加入Tf2O(8.41g，30mmol)，并在-40℃下搅拌混合物0.5h。用冰水(50mL)稀释反应混合物，然后用DCM(30mL)萃取。合并的有机相用Na2SO4干燥并浓缩至干，得到1-三氟甲磺酸氧基-8-环丙基-7-氟-3-甲氧基异喹啉(7.08g，97％产率)。To a solution of 8-cyclopropyl-7-fluoro-3-methoxy-2H-isoquinolin-1-one (4.66 g, 20 mmol), DIEA (7.7 g, 60 mmol) in DCM (120 mL) was added Tf 2 O (8.41 g, 30 mmol), and the mixture was stirred at -40°C for 0.5 h. The reaction mixture was diluted with ice water (50 mL) and then extracted with DCM (30 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated to dryness to give 1-trifluoromethanesulfonyloxy-8-cyclopropyl-7-fluoro-3-methoxyisoquinoline (7.08 g, 97% yield).
LC-MS(ESI)：m/z 366[M+H]+。LC-MS (ESI): m/z 366 [M+H] + .
步骤D：Step D:
向1-三氟甲磺酸氧基-8-环丙基-7-氟-3-甲氧基异喹啉(6.93g，19mmol)、4,4,5,5-四甲基-2-(4,4,1,5,5-四甲基-1,3,2-二氧代硼烷-2-基)-1,2,2-二氧基硼烷(10g，20mmol)、AcOK(5.78g，60mmol)在甲苯(110mL)中的混合物中添加Pd(dppf)Cl2(1.44g，2mmol)。将混合物脱气并在130℃下搅拌3小时。过滤反应混 合物并浓缩，得到残留物。向残余物中加入EtOAc(100mL)和水(80mL)。用盐水(50mL)洗涤有机相，用无水硫酸钠干燥，过滤并浓缩，得到残留物。残余物通过柱色谱法(SiO2)纯化，用30-40％乙酸乙酯在石油醚中洗脱，得到7-氟-8-环丙基-3-甲氧基异喹啉-1-频哪硼酸酯(2.87g，产率44％)。To a mixture of 1-trifluoromethanesulfonyloxy-8-cyclopropyl-7-fluoro-3-methoxyisoquinoline (6.93 g, 19 mmol), 4,4,5,5-tetramethyl-2-(4,4,1,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-1,2,2-dioxyborane (10 g, 20 mmol), AcOK (5.78 g, 60 mmol) in toluene (110 mL) was added Pd(dppf)Cl 2 (1.44 g, 2 mmol). The mixture was degassed and stirred at 130° C. for 3 hours. The reaction mixture was filtered. The mixture was concentrated to give a residue. EtOAc (100 mL) and water (80 mL) were added to the residue. The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2) eluting with 30-40% ethyl acetate in petroleum ether to give 7-fluoro-8-cyclopropyl-3-methoxyisoquinoline-1-pinacol borate (2.87 g, 44% yield).
LC-MS(ESI)：m/z 344[M+H]+。LC-MS (ESI): m/z 344 [M+H] + .
1,3,7-三氮杂螺[4.5]癸烷-2-酮
1,3,7-Triazaspiro[4.5]decan-2-one
步骤A：Step A:
在0℃下，向7-Cbz-2,4-二氧代-1,3,7-三氮螺[4.5]癸烷(2.00g6.6mmol)THF(40mL)的溶液中添加BH3.THF(1M，39.6mL)，将反应物在80℃下搅拌2小时。然后在0℃下缓慢加入MeOH(40mL)使混合物，并在20℃下搅拌0.5小时，然后浓缩。残留物经反相快速色谱纯化，得到黄色固体状7-Cbz-2-氧代-1,3,7-三氮螺[4.5]癸烷(1.57g，80％)To a solution of 7-Cbz-2,4-dioxo-1,3,7-triazaspiro[4.5]decane (2.00 g 6.6 mmol) in THF (40 mL) was added BH 3 .THF (1 M, 39.6 mL) at 0°C and the reaction was stirred at 80°C for 2 hours. MeOH (40 mL) was then slowly added at 0°C to allow the mixture to stir at 20°C for 0.5 hours and then concentrated. The residue was purified by reverse phase flash chromatography to give 7-Cbz-2-oxo-1,3,7-triazaspiro[4.5]decane (1.57 g, 80%) as a yellow solid.
LC-MS(ESI)：m/z 290[M+H]+。LC-MS (ESI): m/z 290 [M+H] + .
步骤B：Step B:
加入7-Cbz-2-氧代-1,3,7-三氮螺[4.5]癸烷(1.63g,5mmol)在MeOH(100mL)中的混合物Pd/C(330mg，10％纯度)，在25℃下在H2(15psi)下搅拌反应1小时。然后将反应物过滤并减压浓缩，通过柱色谱法(SiO2)纯化得到2-氧代-1,3,7-三氮螺[4.5]癸烷(0.728g,94％)。A mixture of 7-Cbz-2-oxo-1,3,7-triazaspiro[4.5]decane (1.63 g, 5 mmol) and Pd/C (330 mg, 10% purity) in MeOH (100 mL) was added, and the reaction was stirred at 25° C. under H 2 (15 psi) for 1 hour. The reaction was then filtered and concentrated under reduced pressure, and purified by column chromatography (SiO 2 ) to give 2-oxo-1,3,7-triazaspiro[4.5]decane (0.728 g, 94%).
LC-MS(ESI)：m/z 156[M+H]+。LC-MS (ESI): m/z 156 [M+H] + .
2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮
2-Thia-1,3,7-triazaspiro[4.5]decane-2,2-one
步骤A：Step A:
在120℃下将磺胺(4.2g，44mmol)在吡啶(100mL)中的溶液搅拌10分钟，然后将N-Cbz-3-氨基-3-(氨基甲基)呱啶(5g，22mmol)添加到溶液中，并将混合物在120℃下搅拌16小时。真空浓缩混合物，然后将混合物倒入200mL H2O中，并用EA(100mL×3)萃取。用水(80mL×2)和盐水(80mL x2)洗涤合并的有机层，用Na2SO4干燥并真空浓缩，过柱色谱法(SiO2)纯化得到黄色固体7-Cbz-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(3.21g,45％)A solution of sulfonamide (4.2 g, 44 mmol) in pyridine (100 mL) was stirred at 120°C for 10 minutes, then N-Cbz-3-amino-3-(aminomethyl)piperidine (5 g, 22 mmol) was added to the solution, and the mixture was stirred at 120°C for 16 hours. The mixture was concentrated in vacuo, then poured into 200 mL of H 2 O and extracted with EA (100 mL×3). The combined organic layers were washed with water (80 mL×2) and brine (80 mL x2), dried over Na 2 SO 4 and concentrated in vacuo, and purified by column chromatography (SiO 2 ) to give 7-Cbz-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (3.21 g, 45%) as a yellow solid.
LC-MS(ESI)：m/z 326[M+H]+。LC-MS (ESI): m/z 326 [M+H] + .
步骤B：Step B:
加入7-Cbz-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(1.63g,5mmol)在MeOH(100mL)中的混合物Pd/C(330mg，10％纯度)，在25℃下在H2(15psi)下搅拌反应1小时。然后将反应物过滤并减压浓缩，通过柱色谱法(SiO2)纯化得到2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(0.908g,95％)。 A mixture of 7-Cbz-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (1.63 g, 5 mmol) in MeOH (100 mL) and Pd/C (330 mg, 10% purity) were added, and the reaction was stirred at 25° C. under H 2 (15 psi) for 1 hour. The reaction was then filtered and concentrated under reduced pressure, and purified by column chromatography (SiO 2 ) to give 2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (0.908 g, 95%).
LC-MS(ESI)：m/z 192[M+H]+。LC-MS (ESI): m/z 192 [M+H] + .
(R)-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮
(R)-2-Thia-1,3,7-triazaspiro[4.5]decan-2,2-one
步骤A：Step A:
在120℃下将磺胺(4.2g，44mmol)在吡啶(100mL)中的溶液搅拌10分钟，然后将(3R)-N-Cbz-3-氨基-3-(氨基甲基)呱啶(5g，22mmol)添加到溶液中，并将混合物在120℃下搅拌16小时。真空浓缩混合物，然后将混合物倒入200mL H2O中，并用EA(100mL×3)萃取。用水(80mL×2)和盐水(80mL x2)洗涤合并的有机层，用Na2SO4干燥并真空浓缩，过柱色谱法(SiO2)纯化得到黄色固体(R)-7-Cbz-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(3.0g,42％)A solution of sulfonamide (4.2 g, 44 mmol) in pyridine (100 mL) was stirred at 120°C for 10 minutes, then (3R)-N-Cbz-3-amino-3-(aminomethyl)piperidine (5 g, 22 mmol) was added to the solution, and the mixture was stirred at 120°C for 16 hours. The mixture was concentrated in vacuo, then poured into 200 mL of H 2 O and extracted with EA (100 mL×3). The combined organic layers were washed with water (80 mL×2) and brine (80 mL x2), dried over Na 2 SO 4 and concentrated in vacuo, and purified by column chromatography (SiO 2 ) to give (R)-7-Cbz-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (3.0 g, 42%) as a yellow solid.
LC-MS(ESI)：m/z 326[M+H]+。LC-MS (ESI): m/z 326 [M+H] + .
步骤B：Step B:
加入(R)-7-Cbz-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(1.63g,5mmol)在MeOH(100mL)中的混合物Pd/C(330mg，10％纯度)，在25℃下在H2(15psi)下搅拌反应1小时。然后将反应物过滤并减压浓缩，通过柱色谱法(SiO2)纯化得到(R)-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(0.888g,93％)。A mixture of (R)-7-Cbz-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (1.63 g, 5 mmol) in MeOH (100 mL) and Pd/C (330 mg, 10% purity) were added, and the reaction was stirred at 25° C. under H 2 (15 psi) for 1 hour. The reaction was then filtered and concentrated under reduced pressure, and purified by column chromatography (SiO 2 ) to give (R)-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (0.888 g, 93%).
LC-MS(ESI)：m/z 192[M+H]+。LC-MS (ESI): m/z 192 [M+H] + .
(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷2-酮
(5R)-2-Methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-2-one
步骤A：Step A:
在120℃下将甲基膦酰双胺(4.14g，44mmol)在溴苯(100mL)中的溶液搅拌10分钟，然后将(3R)-N-Cbz-3-氨基-3-(氨基甲基)呱啶(5g，22mmol)添加到溶液中，并将混合物在120℃下搅拌16小时。真空浓缩混合物，然后将混合物倒入200mL H2O中，并用EA(100mL×3)萃取。用水(80mL×2)和盐水(80mL x2)洗涤合并的有机层，用Na2SO4干燥并真空浓缩，过柱色谱法(SiO2)纯化得到黄色固体1-Cbz-(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷2-酮(2.7g,38％)A solution of methylphosphonic acid diamide (4.14 g, 44 mmol) in bromobenzene (100 mL) was stirred at 120°C for 10 minutes, then (3R)-N-Cbz-3-amino-3-(aminomethyl)piperidinium (5 g, 22 mmol) was added to the solution, and the mixture was stirred at 120°C for 16 hours. The mixture was concentrated in vacuo, then poured into 200 mL of H 2 O and extracted with EA (100 mL×3). The combined organic layers were washed with water (80 mL×2) and brine (80 mL x2), dried over Na 2 SO 4 and concentrated in vacuo, and purified by column chromatography (SiO 2 ) to give 1-Cbz-(5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-2-one (2.7 g, 38%) as a yellow solid.
LC-MS(ESI)：m/z 324[M+H]+。LC-MS (ESI): m/z 324 [M+H] + .
步骤B：Step B:
加入1-Cbz-(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷2-酮(1.63g,5mmol)在MeOH(100mL)中的混合物Pd/C(330mg，10％纯度)，在25℃下在H2(15psi)下搅拌反应1小时。然后将反应物过滤并减压浓缩，通过柱色谱法(SiO2)纯化得到(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷2-酮(0.917g,96％)。A mixture of 1-Cbz-(5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan2-one (1.63 g, 5 mmol) in MeOH (100 mL) and Pd/C (330 mg, 10% purity) were added, and the reaction was stirred at 25° C. under H 2 (15 psi) for 1 hour. The reaction was then filtered and concentrated under reduced pressure, and purified by column chromatography (SiO 2 ) to give (5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan2-one (0.917 g, 96%).
LC-MS(ESI)：m/z 192[M+H]+。LC-MS (ESI): m/z 192 [M+H] + .
N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺
N,N-Dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide
向5-(叔-丁氧羰基)-5,6,7,8-四氢-4H-吡唑并[1,5-A][1,4]二氮杂卓-2-羧酸(10g)和二甲胺(35。5mL)在DCM(100mL)中的溶液中添加HATU(20.3g)和N,N-二异丙基乙胺(13.8g，18.6mL)。将混合物在20℃下搅拌1小时。将混合物在真空下浓缩。残留物通过乙醇重结晶得到N-Boc-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(9.17g)。To a solution of 5-(tert-butyloxycarbonyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (10 g) and dimethylamine (35.5 mL) in DCM (100 mL) was added HATU (20.3 g) and N,N-diisopropylethylamine (13.8 g, 18.6 mL). The mixture was stirred at 20° C. for 1 hour. The mixture was concentrated under vacuum. The residue was recrystallized from ethanol to give N-Boc-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (9.17 g).
LC-MS(ESI)：m/z 309[M+H]+。LC-MS (ESI): m/z 309 [M+H] + .
将N-Boc-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(9g)和HCl/二氧六环(95mL)在MeCN(95mL)中的混合物在0℃下搅拌1小时。将混合物在真空下浓缩。用饱和碳酸氢钠(4mL)将残余物的pH调节至8。过滤得到N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(5.13g)。A mixture of N-Boc-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (9 g) and HCl/dioxane (95 mL) in MeCN (95 mL) was stirred at 0°C for 1 hour. The mixture was concentrated under vacuum. The pH of the residue was adjusted to 8 with saturated sodium bicarbonate (4 mL). Filtration gave N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (5.13 g).
LC-MS(ESI)：m/z 209[M+H]+。LC-MS (ESI): m/z 209 [M+H] + .
实施例1
Example 1
步骤A：Step A:
将2,4,7-三氯吡啶并[2,3-d]嘧啶(2.52g，10mmol)、2-氧代-1,3,7-三氮螺[4.5]癸烷(1.70g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体2,7-二氯-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(5.50g,78％)，2,4,7-Trichloropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), 2-oxo-1,3,7-triazaspiro[4.5]decane (1.70 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyrido[2,3-d]pyrimidine (5.50 g, 78%).
LC/MS(ESI):m/z＝354[M+H]+。LC/MS (ESI): m/z=354 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(353mg，1mmol)、1,2,3,5,6,7- 六氢吡咯嗪-7-基]甲醇(155mg，1.1mmol)、碳酸钾(0.12mg，1.4mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2((四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(0.375g,82％)。2,7-Dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (353 mg, 1 mmol), 1,2,3,5,6,7- The mixture was mixed with 1,4-dihydropyrrolizine-7-yl]methanol (155 mg, 1.1 mmol), potassium carbonate (0.12 mg, 1.4 mmol), a catalytic amount of potassium iodide and DMF (8 mL), heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-2-((tetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (0.375 g, 82%).
LC/MS(ESI):m/z＝458[M+H]+。LC/MS (ESI): m/z=458 [M+H] + .
步骤C：Step C:
将7-氯-2((四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(92mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-((2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(72mg，产率58％)。7-Chloro-2((tetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (92 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to give 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-((2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (72 mg, yield 58%).
LC/MS(ESI):m/z＝627.3[M+H]+.LC/MS (ESI): m/z = 627.3 [M+H] + .
步骤D：Step D:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-((四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(63mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到化合物1(32mg，产率56％)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-((tetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (63 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give Compound 1 (32 mg, yield 56%).
LC/MS(ESI):m/z＝613.3[M+H]+.LC/MS (ESI): m/z = 613.3 [M+H] + .
实施例2
Example 2
步骤A：Step A:
将2,7-二氯-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(250mg，1mmol)、N-甲基-L-脯氨醇(127mg，1.1mmol)、碳酸钾(0.12mg，1.4mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶黄色固体7-氯-2(N-甲基吡咯烷-2-甲氧基)-4-(2-氧代-1,3,7-三氮 螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(367mg)。2,7-Dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (250 mg, 1 mmol), N-methyl-L-prolinol (127 mg, 1.1 mmol), potassium carbonate (0.12 mg, 1.4 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. After cooling to room temperature, the yellow solid 7-chloro-2(N-methylpyrrolidine-2-methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine was dissolved under reduced pressure. Spiro[4.5]decan-7-yl)pyridin[2,3-d]pyrimidine (367 mg).
LC/MS(ESI):m/z＝433.2[M+H]+。LC/MS (ESI): m/z = 433.2 [M+H] + .
步骤B：Step B:
将7-氯-2(N-甲基吡咯烷-2-甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物用柱层析得到7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-((N-甲基吡咯烷-2-甲氧基)吡啶[2,3-d]并嘧啶(89mg)。7-Chloro-2(N-methylpyrrolidin-2-methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to give 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-((N-methylpyrrolidin-2-methoxy)pyridin[2,3-d]pyrimidine (89 mg).
LC/MS(ESI):m/z＝600.3[M+H]+.LC/MS (ESI): m/z = 600.3 [M + H] + .
步骤C：Step C:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-((N-甲基吡咯烷-2-甲氧基)吡啶[2,3-d]并嘧啶(60mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到化合物2(39mg，产率67％)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-((N-methylpyrrolidin-2-methoxy)pyridin[2,3-d]pyrimidine (60 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and then the mixture was warmed to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give compound 2 (39 mg, yield 67%).
LC/MS(ESI):m/z＝587.3[M+H]+.LC/MS (ESI): m/z = 587.3 [M+H] + .
实施例3
Example 3
步骤A：Step A:
将2,7-二氯-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(250mg，1mmol)、1-(((二甲基氨基)环丙基)甲醇(148mg，1.1mmol)、碳酸钾(0.12mg，1.4mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(1-(((二甲基氨基)环丙基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(337mg)。2,7-Dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyrido[2,3-d]pyrimidine (250 mg, 1 mmol), 1-(((dimethylamino)cyclopropyl)methanol (148 mg, 1.1 mmol), potassium carbonate (0.12 mg, 1.4 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain 7-chloro-2(1-(((dimethylamino)cyclopropyl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyrido[2,3-d]pyrimidine (337 mg) as a yellow solid.
LC/MS(ESI):m/z＝433.2[M+H]+。LC/MS (ESI): m/z = 433.2 [M+H] + .
步骤B： Step B:
将7-氯-2(1-((二甲基氨基)环丙基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物用甲醇柱层析得到7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(1-((二甲基氨基)环丙基)甲氧基)吡啶[2,3-d]并嘧啶(69mg，产率58％)。7-Chloro-2(1-((dimethylamino)cyclopropyl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by methanol column chromatography to give 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(1-((dimethylamino)cyclopropyl)methoxy)pyrido[2,3-d]pyrimidine (69 mg, yield 58%).
LC/MS(ESI):m/z＝600.3[M+H]+.LC/MS (ESI): m/z = 600.3 [M + H] + .
步骤C：Step C:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(1-((二甲基氨基)环丙基)甲氧基)吡啶[2,3-d]并嘧啶(60mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到化合物3(34mg，产率58％)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(1-((dimethylamino)cyclopropyl)methoxy)pyrido[2,3-d]pyrimidine (60 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give compound 3 (34 mg, yield 58%).
LC/MS(ESI):m/z＝587.2[M+H]+.LC/MS (ESI): m/z = 587.2 [M+H] + .
实施例4
Example 4
步骤A：Step A:
将2,7-二氯-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(250mg，1mmol)、1-(吡咯-1-基)环丙基)甲醇(155mg，1.1mmol)、碳酸钾(0.12mg，1.4mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(1-(吡咯-1-基)环丙基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(357mg)。2,7-dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (250 mg, 1 mmol), 1-(pyrrol-1-yl)cyclopropyl)methanol (155 mg, 1.1 mmol), potassium carbonate (0.12 mg, 1.4 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-2(1-(pyrrol-1-yl)cyclopropyl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (357 mg).
LC/MS(ESI):m/z＝459[M+H]+。LC/MS (ESI): m/z=459 [M+H] + .
步骤B：Step B:
将7-氯-2(1-(吡咯-1-基)环丙基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(91.8mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二 (1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物用甲醇柱层析得到7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(1-(吡咯-1-基)环丙基)甲氧基)吡啶[2,3-d]并嘧啶(74mg，产率59％)。7-Chloro-2(1-(pyrrol-1-yl)cyclopropyl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (91.8 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldimethoxy] (1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60°C and stirred for 16 hours. The reactants were cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by methanol column chromatography to give 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(1-(pyrrol-1-yl)cyclopropyl)methoxy)pyridin[2,3-d]pyrimidine (74 mg, yield 59%).
LC/MS(ESI):m/z＝627[M+H]+.LC/MS (ESI): m/z = 627 [M+H] + .
步骤C：Step C:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(1-(吡咯-1-基)环丙基)甲氧基)吡啶[2,3-d]并嘧啶(62.7mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到化合物4(34mg，产率55％)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(1-(pyrrol-1-yl)cyclopropyl)methoxy)pyridin[2,3-d]pyrimidine (62.7 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give compound 4 (34 mg, yield 55%).
LC/MS(ESI):m/z＝613[M+H]+.LC/MS (ESI): m/z = 613 [M+H] + .
实施例5
Example 5
步骤A：Step A:
将2,7-二氯-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(250mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(148mg，1.1mmol)、碳酸钾(0.12mg，1.4mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(0.387g,72％)。2,7-Dichloro-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (250 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (148 mg, 1.1 mmol), potassium carbonate (0.12 mg, 1.4 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (0.387 g, 72%).
LC/MS(ESI):m/z＝538.2[M+H]+。LC/MS (ESI): m/z = 538.2 [M+H] + .
步骤B：Step B:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(107mg，0.2mmol)、3-甲氧基-8-氯-7-氟异喹啉硼酸频哪醇酯(67.6mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL) 和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到米黄色固体7-(3-甲氧基-8-氯-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(94mg，产率58％)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (107 mg, 0.2 mmol), 3-methoxy-8-chloro-7-fluoroisoquinolinylboronic acid pinacol ester (67.6 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) were added. After mixing with water (1 mL), the mixture was refluxed and heated to 60 ° C and stirred for 16 hours. The reactants were cooled to room temperature and stirred overnight to give a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. Column chromatography of the crude product gave a beige solid 7-(3-methoxy-8-chloro-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)pyridine[2,3-d]pyrimidine (94 mg, 58% yield).
LC/MS(ESI):m/z＝809.3[M+H]+.LC/MS (ESI): m/z = 809.3 [M + H] + .
步骤C：Step C:
在-78℃下，7-(3-甲氧基-8-氯-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(81mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物5(32mg，产率56％)。At -78°C, 7-(3-methoxy-8-chloro-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (81 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid Compound 5 (32 mg, yield 56%).
LC/MS(ESI):m/z＝579.2[M+H]+.LC/MS (ESI): m/z = 579.2 [M+H] + .
实施例6
Example 6
步骤A：Step A:
将2,4,7-三氯吡啶并[2,3-d]嘧啶(2.52g，10mmol)、2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮(2.37g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)吡啶[2,3-d]并嘧啶(3.61g)。2,4,7-trichloropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), 2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one (2.37 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)pyrido[2,3-d]pyrimidine (3.61 g).
LC/MS(ESI):m/z＝390[M+H]+。LC/MS (ESI): m/z = 390 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)吡啶[2,3-d]并嘧啶(390mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)吡啶 [2,3-d]并嘧啶(0.417g)。2,7-Dichloro-4-2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)pyridin[2,3-d]pyrimidine (390 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, stirred and reacted for 4 hours. Cooled to room temperature, evaporated under reduced pressure to obtain a yellow solid 7-chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridine-7a(5H)-yl)methoxy)-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)pyridine [2,3-d]pyrimidine (0.417 g).
LC/MS(ESI):m/z＝513[M+H]+。LC/MS (ESI): m/z = 513 [M+H] + .
步骤C：Step C:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)吡啶[2,3-d]并嘧啶(126mg，0.2mmol)、3-甲氧基-8-氯-7-氟异喹啉硼酸频哪醇酯(67.6mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-氯-7-氟异喹啉-1-基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(98mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)pyridin[2,3-d]pyrimidine (126 mg, 0.2 mmol), 3-methoxy-8-chloro-7-fluoroisoquinolineboronic acid pinacol ester (67.6 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was subjected to column chromatography to obtain 7-(3-methoxy-8-chloro-7-fluoroisoquinolin-1-yl)-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (98 mg) as a beige solid.
LC/MS(ESI):m/z＝688[M+H]+.LC/MS (ESI): m/z = 688 [M+H] + .
步骤D：Step D:
在-78℃下，7-(3-甲氧基-8-氯-7-氟异喹啉-1-基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(69mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物6(29mg)。At -78°C, 7-(3-methoxy-8-chloro-7-fluoroisoquinolin-1-yl)-4-(2-thia-1,3,7-triazaspiro[4.5]decan-2,2-one-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (69 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid compound 6 (29 mg).
LC/MS(ESI):m/z＝674[M+H]+.LC/MS (ESI): m/z = 674 [M+H] + .
实施例7
Example 7
步骤A：Step A:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)吡啶[2,3-d]并嘧啶(126mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(92mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)pyridin[2,3-d]pyrimidine (126 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (92 mg) as a beige solid.
LC/MS(ESI):m/z＝645[M+H]+.LC/MS (ESI): m/z = 645 [M+H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-氧代-1,3,7-三氮螺[4.5]癸烷-7- 基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(64.5mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物7(28mg)。At -78 ° C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-oxo-1,3,7-triazaspiro[4.5]decane-7- To the mixture was dissolved 2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (64.5 mg, 0.1 mmol) in DCM (2 mL), and BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added. The mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C and adjusted to pH = 7 with 1N NaOH. The mixture was extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a light yellow solid compound 7 (28 mg).
LC/MS(ESI):m/z＝631[M+H]+.LC/MS (ESI): m/z = 631 [M+H] + .
实施例8
Example 8
步骤A：Step A:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)吡啶[2,3-d]并嘧啶(102mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(94mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)pyridin[2,3-d]pyrimidine (102 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was subjected to column chromatography to obtain 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (94 mg) as a beige solid.
LC/MS(ESI):m/z＝681[M+H]+.LC/MS (ESI): m/z = 681 [M+H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(68mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物7(32mg)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-(2-thia-1,3,7-triazaspiro[4.5]decan-2,2-one-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (68 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid Compound 7 (32 mg).
LC/MS(ESI):m/z＝667[M+H]+.LC/MS (ESI): m/z = 667 [M+H] + .
实施例9
Example 9
步骤A：Step A:
将2,4,7-三氯吡啶并[2,3-d]嘧啶(2.52g，10mmol)、(3R)-3-甲基呱啶-3-醇盐酸盐(1.66g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(2.81g)。2,4,7-trichloropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), (3R)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyrido[2,3-d]pyrimidine (2.81 g).
LC/MS(ESI):m/z＝314[M+H]+。LC/MS (ESI): m/z = 314 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(314mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(0.289g)。2,7-Dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (314 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (0.289 g).
LC/MS(ESI):m/z＝436[M+H]+。LC/MS (ESI): m/z=436 [M+H] + .
步骤C：Step C:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-甲基异喹啉硼酸频哪醇酯(60mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-甲基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(96mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-methylisoquinolineboronic acid pinacol ester (60 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-methylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (96 mg) as a beige solid.
LC/MS(ESI):m/z＝573[M+H]+.LC/MS (ESI): m/z = 573 [M + H] + .
步骤D：Step D:
在-78℃下，7-(3-甲氧基-8-甲基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(57.3mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物9(31mg)。 At -78°C, 7-(3-methoxy-8-methylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (57.3 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid compound 9 (31 mg).
LC/MS(ESI):m/z＝559[M+H]+.LC/MS (ESI): m/z = 559 [M + H] + .
实施例10
Example 10
步骤A：Step A:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-氟异喹啉硼酸频哪醇酯(60.8mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(98mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-fluoroisoquinolineboronic acid pinacol ester (60.8 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (98 mg) as a beige solid.
LC/MS(ESI):m/z＝577[M+H]+.LC/MS (ESI): m/z = 577 [M + H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(57.3mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物10(30mg)。At -78°C, 7-(3-methoxy-8-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (57.3 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 10 (30 mg).
LC/MS(ESI):m/z＝563[M+H]+.LC/MS (ESI): m/z = 563 [M + H] + .
实施例11
Embodiment 11
步骤A：Step A:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基异喹啉硼酸频哪醇酯(57mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧 啶(94mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxyisoquinolineboronic acid pinacol ester (57 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain a beige solid 7-(3-methoxyisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine Pyridine (94 mg).
LC/MS(ESI):m/z＝559[M+H]+.LC/MS (ESI): m/z = 559 [M + H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(55.9mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物11(32mg)。At -78°C, 7-(3-methoxyisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (55.9 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 11 (32 mg).
LC/MS(ESI):m/z＝544[M+H]+.LC/MS (ESI): m/z = 544 [M + H] + .
实施例12
Example 12
步骤A：Step A:
将2,4,7-三氯-6-氟吡啶并[2,3-d]嘧啶(2.52g，10mmol)、(3R)-3-甲基呱啶-3-醇盐酸盐(1.66g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)-6-氟吡啶[2,3-d]并嘧啶(2.88g)。2,4,7-trichloro-6-fluoropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), (3R)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-6-fluoropyrido[2,3-d]pyrimidine (2.88 g).
LC/MS(ESI):m/z＝332[M+H]+。LC/MS (ESI): m/z = 332 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)-6-氟吡啶[2,3-d]并嘧啶(332mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-6-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(0.369g)。2,7-Dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-6-fluoropyrido[2,3-d]pyrimidine (332 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-6-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyrido[2,3-d]pyrimidine (0.369 g).
LC/MS(ESI):m/z＝453[M+H]+。LC/MS (ESI): m/z=453 [M+H] + .
步骤C：Step C:
将7-氯-6-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-氯异喹啉硼酸频哪醇酯(64mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体6-氟-7-(3- 甲氧基-8-氯异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(92mg)。7-Chloro-6-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-chloroisoquinolineboronic acid pinacol ester (64 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain a beige solid 6-fluoro-7-(3- methoxy-8-chloroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (92 mg).
LC/MS(ESI):m/z＝612[M+H]+.LC/MS (ESI): m/z = 612 [M+H] + .
步骤D：Step D:
在-78℃下，6-氟-7-(3-甲氧基-8-氯异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶61.2mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物12(31mg)。At -78°C, 6-fluoro-7-(3-methoxy-8-chloroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (61.2 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 12 (31 mg).
LC/MS(ESI):m/z＝598[M+H]+.LC/MS (ESI): m/z = 598 [M+H] + .
实施例13
Example 13
步骤A：Step A:
将7-氯-6-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-7-氟-8-((三异丙基甲硅基)乙炔基)异喹啉硼酸频哪醇酯(96.6mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体6-氟-7-(3-甲氧基8-((三异丙基甲硅基)乙炔基)异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(122mg)。7-Chloro-6-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-7-fluoro-8-((triisopropylmethylsilyl)ethynyl)isoquinolineboronic acid pinacol ester (96.6 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, and then heated under reflux at 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was subjected to column chromatography to give 6-fluoro-7-(3-methoxy 8-((triisopropylmethylsilyl)ethynyl)isoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (122 mg) as a beige solid.
LC/MS(ESI):m/z＝776[M+H]+.LC/MS (ESI): m/z = 776 [M + H] + .
步骤B：Step B:
在-78℃下，6-氟-7-(3-甲氧基-8-((三异丙基甲硅基)乙炔基)异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(77.6mg，0.1mmol)溶于DMF(5mL)中，在N2-保护下加入CsF(152mg，1mmol)，在20℃下搅拌1小时，然后倒入水中，用EA萃取，无水硫酸钠干燥，过滤减压浓缩。将残余物溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物12(27mg)。At -78°C, 6-fluoro-7-(3-methoxy-8-((triisopropylmethylsilyl)ethynyl)isoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (77.6 mg, 0.1 mmol) was dissolved in DMF (5 mL), and CsF (152 mg, 1 mmol) was added under N2- protection. The mixture was stirred at 20°C for 1 hour, then poured into water, extracted with EA, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL), and BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, then the temperature was raised to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a light yellow solid compound 12 (27 mg).
LC/MS(ESI):m/z＝605[M+H]+.LC/MS (ESI): m/z = 605 [M+H] + .
实施例14
Embodiment 14
步骤A：Step A:
将7-氯-6-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.2mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体6-氟-7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(94mg)。7-Chloro-6-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.2 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 6-fluoro-7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (94 mg) as a beige solid.
LC/MS(ESI):m/z＝623[M+H]+.LC/MS (ESI): m/z = 623 [M+H] + .
步骤B：Step B:
在-78℃下，6-氟-7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶62.3mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物14(32mg)。At -78°C, 6-fluoro-7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (62.3 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 14 (32 mg).
LC/MS(ESI):m/z＝609[M+H]+.LC/MS (ESI): m/z = 609 [M + H] + .
实施例14
Embodiment 14
步骤A：Step A:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(96.3mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(112mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (96.3 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (112 mg) as a beige solid.
LC/MS(ESI):m/z＝758[M+H]+. LC/MS (ESI): m/z = 758 [M+H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶75.8mg，0.1mmol)溶于DMF(5mL)中，在N2-保护下加入CsF(152mg，1mmol)，在20℃下搅拌1小时，然后倒入水中，用EA萃取，无水硫酸钠干燥，过滤减压浓缩。将残余物溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物15(24mg)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine 75.8 mg, 0.1 mmol) was dissolved in DMF (5 mL), and CsF (152 mg, 1 mmol) was added under N2- protection. The mixture was stirred at 20°C for 1 hour, then poured into water, extracted with EA, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL), and BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, then warmed to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a light yellow solid compound 15 (24 mg).
LC/MS(ESI):m/z＝587[M+H]+.LC/MS (ESI): m/z = 587 [M + H] + .
实施例16
Example 16
步骤A：Step A:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基-7-氟异喹啉硼酸频哪醇酯(66.2mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶(91mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[2,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethyl-7-fluoroisoquinolineboronic acid pinacol ester (66.2 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (91 mg) as a beige solid.
LC/MS(ESI):m/z＝605[M+H]+.LC/MS (ESI): m/z = 605 [M+H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-乙基-7-氟异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[2,3-d]并嘧啶60.4mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物16(34mg)。At -78°C, 7-(3-methoxy-8-ethyl-7-fluoroisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[2,3-d]pyrimidine (60.4 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 16 (34 mg).
LC/MS(ESI):m/z＝591[M+H]+.LC/MS (ESI): m/z = 591 [M + H] + .
实施例17
Embodiment 17
步骤A：Step A:
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(2.52g，10mmol)、8-boc-3,8-二氮杂双环[3.2.1]辛烷(2.33g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(3.71g)。2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), 8-boc-3,8-diazabicyclo[3.2.1]octane (2.33 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (3.71 g).
LC/MS(ESI):m/z＝428[M+H]+。LC/MS (ESI): m/z = 428 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[2,3-d]并嘧啶(428mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(469mg)。2,7-Dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyrido[2,3-d]pyrimidine (428 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (469 mg).
LC/MS(ESI):m/z＝552[M+H]+。LC/MS (ESI): m/z = 552 [M+H] + .
步骤C：Step C:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(110.4mg，0.2mmol)、3-甲氧基-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-乙基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶(98mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (110.4 mg, 0.2 mmol), 3-methoxy-8-ethylisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-ethylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine (98 mg) as a beige solid.
LC/MS(ESI):m/z＝720[M+H]+.LC/MS (ESI): m/z = 720 [M + H] + .
步骤D：Step D:
在-78℃下，7-(3-甲氧基-8-甲基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-8-氟吡啶并[4,3-d]嘧啶(72.0mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物17(29mg)。At -78°C, 7-(3-methoxy-8-methylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-8-fluoropyrido[4,3-d]pyrimidine (72.0 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 17 (29 mg).
LC/MS(ESI):m/z＝606[M+H]+. LC/MS (ESI): m/z = 606 [M + H] + .
实施例18
Embodiment 18
用与实施例17相似的方法得到化合物18(28mg)。LC/MS(ESI):m/z＝613[M+H]+.Compound 18 (28 mg) was obtained in a similar manner to Example 17. LC/MS (ESI): m/z = 613 [M+H] + .
实施例19
Embodiment 19
步骤A：Step A:
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(2.52g，10mmol)、(3R)-3-甲基呱啶-3-醇盐酸盐(1.66g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(2.82g)。2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (3R)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (2.82 g).
LC/MS(ESI):m/z＝332[M+H]+。LC/MS (ESI): m/z = 332 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((3R)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(332mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-8-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶并[4,3-d]嘧啶(0.368g)。2,7-Dichloro-4-((3R)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (332 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyrido[4,3-d]pyrimidine (0.368 g).
LC/MS(ESI):m/z＝453[M+H]+。LC/MS (ESI): m/z = 453 [M+H] + .
步骤C：Step C:
将7-氯-8-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)吡啶[4,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体8-氟-7-(3-甲氧基-8-乙基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基) 甲氧基)吡啶[4,3-d]并嘧啶(92mg)。7-Chloro-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)pyridin[4,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethylisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain a beige solid 8-fluoro-7-(3-methoxy-8-ethylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a(5H)-yl) 4-(4-(2-methoxy)pyridin[4,3-d]pyrimidine (92 mg).
LC/MS(ESI):m/z＝623[M+H]+.LC/MS (ESI): m/z = 623 [M+H] + .
步骤D：Step D:
在-78℃下，8-氟-7-(3-甲氧基-8-乙基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶61.2mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物19(30mg)。At -78°C, 8-fluoro-7-(3-methoxy-8-ethylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (61.2 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid compound 19 (30 mg).
LC/MS(ESI):m/z＝609[M+H]+.LC/MS (ESI): m/z = 609 [M + H] + .
实施例20
Embodiment 20
步骤A：Step A:
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(2.52g，10mmol)、(3S)-3-甲基呱啶-3-醇盐酸盐(1.66g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((3S)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(2.88g)。2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (3S)-3-methylpiperidin-3-ol hydrochloride (1.66 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((3S)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (2.88 g).
LC/MS(ESI):m/z＝332[M+H]+。LC/MS (ESI): m/z = 332 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((3S)-3-甲基-3-羟基呱啶基)-8-氟吡啶并[4,3-d]嘧啶(332mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-8-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3S)-3-甲基-3-羟基呱啶基)吡啶并[4,3-d]嘧啶(0.378g)。2,7-Dichloro-4-((3S)-3-methyl-3-hydroxypiperidinyl)-8-fluoropyrido[4,3-d]pyrimidine (332 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridinyl-7a(5H)-yl)methoxy)-4-((3S)-3-methyl-3-hydroxypiperidinyl)pyrido[4,3-d]pyrimidine (0.378 g).
LC/MS(ESI):m/z＝453[M+H]+。LC/MS (ESI): m/z=453 [M+H] + .
步骤C：Step C:
将7-氯-8-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3S)-3-甲基-3-羟基呱啶基)吡啶[4,3-d]并嘧啶(87mg，0.2mmol)、3-甲氧基-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体8-氟-7-(3- 甲氧基-8-乙基异喹啉-1-基)-4-((3S)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶(90mg)。7-Chloro-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3S)-3-methyl-3-hydroxypiperidinyl)pyridin[4,3-d]pyrimidine (87 mg, 0.2 mmol), 3-methoxy-8-ethylisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain a beige solid 8-fluoro-7-(3- methoxy-8-ethylisoquinolin-1-yl)-4-((3S)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (90 mg).
LC/MS(ESI):m/z＝623[M+H]+.LC/MS (ESI): m/z = 623 [M+H] + .
步骤D：Step D:
在-78℃下，8-氟-7-(3-甲氧基-8-乙基异喹啉-1-基)-4-((3S)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶61.2mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物20(26mg)。At -78°C, 8-fluoro-7-(3-methoxy-8-ethylisoquinolin-1-yl)-4-((3S)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (61.2 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give a pale yellow solid Compound 20 (26 mg).
LC/MS(ESI):m/z＝609[M+H]+.LC/MS (ESI): m/z = 609 [M + H] + .
实施例21
Embodiment 21
用与实施例19相似的方法得到化合物21(28mg)。LC/MS(ESI):m/z＝605[M+H]+.Compound 21 (28 mg) was obtained in a similar manner to Example 19. LC/MS (ESI): m/z = 605 [M+H] + .
实施例22
Embodiment 22
用与实施例20相似的方法得到化合物22(29mg)。LC/MS(ESI):m/z＝605[M+H]+.Compound 22 (29 mg) was obtained by a method similar to Example 20. LC/MS (ESI): m/z = 605 [M+H] + .
实施例23
Embodiment 23
用与实施例19相似的方法得到化合物23(32mg)。LC/MS(ESI):m/z＝609[M+H]+.Compound 23 (32 mg) was obtained by a method similar to Example 19. LC/MS (ESI): m/z = 609 [M+H] + .
实施例24
Embodiment 24
用与实施例20相似的方法得到化合物24(28mg)。LC/MS(ESI):m/z＝605[M+H]+.Compound 24 (28 mg) was obtained by a method similar to Example 20. LC/MS (ESI): m/z = 605 [M+H] + .
实施例25
Embodiment 25
用与实施例19相似的方法得到化合物25(29mg)。LC/MS(ESI):m/z＝604[M+H]+.Compound 25 (29 mg) was obtained in a similar manner to Example 19. LC/MS (ESI): m/z = 604 [M+H] + .
实施例26
Embodiment 26
用与实施例20相似的方法得到化合物26(29mg)。LC/MS(ESI):m/z＝604[M+H]+.Compound 26 (29 mg) was obtained by a method similar to Example 20. LC/MS (ESI): m/z = 604 [M+H] + .
实施例27
Embodiment 27
用与实施例20相似的方法得到化合物27(24mg)。LC/MS(ESI):m/z＝615[M+H]+.Compound 27 (24 mg) was obtained by a method similar to Example 20. LC/MS (ESI): m/z = 615 [M+H] + .
实施例28
Embodiment 28
用与实施例19相似的方法得到化合物28(31mg)。LC/MS(ESI):m/z＝615[M+H]+.Compound 28 (31 mg) was obtained by a method similar to Example 19. LC/MS (ESI): m/z = 615 [M+H] + .
实施例29
Embodiment 29
用与实施例17相似的方法得到化合物29(32mg)。LC/MS(ESI):m/z＝605[M+H]+.Compound 29 (32 mg) was obtained by a method similar to Example 17. LC/MS (ESI): m/z = 605 [M+H] + .
实施例30
Embodiment 30
用与实施例18相似的方法得到化合物30(27mg)。LC/MS(ESI):m/z＝612[M+H]+.Compound 30 (27 mg) was obtained by a method similar to Example 18. LC/MS (ESI): m/z = 612 [M+H] + .
实施例31
Embodiment 31
用与实施例18相似的方法得到化合物31(38mg)。LC/MS(ESI):m/z＝608[M+H]+.Compound 31 (38 mg) was obtained in a similar manner to Example 18. LC/MS (ESI): m/z = 608 [M+H] + .
实施例32
Embodiment 32
用与实施例20相似的方法得到化合物32(31mg)。LC/MS(ESI):m/z＝608[M+H]+.Compound 32 (31 mg) was obtained by a method similar to Example 20. LC/MS (ESI): m/z = 608 [M+H] + .
实施例33
Embodiment 33
用与实施例14相似的方法得到化合物33(24mg)。LC/MS(ESI):m/z＝616[M+H]+.Compound 33 (24 mg) was obtained by a method similar to Example 14. LC/MS (ESI): m/z = 616 [M+H] + .
实施例34
Embodiment 34
用与实施例9相似的方法得到化合物34(31mg)。LC/MS(ESI):m/z＝598[M+H]+.Compound 34 (31 mg) was obtained by a method similar to Example 9. LC/MS (ESI): m/z = 598 [M+H] + .
实施例35
Embodiment 35
步骤A：Step A:
将7-溴-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((3R)-3-甲基-3-羟基呱啶基)-6,8-二氟喹唑啉(100.2mg，0.2mmol)、3-甲氧基-8-乙基异喹啉硼酸频哪醇酯(67.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-乙基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-6,8-二氟喹唑啉(92mg)。7-Bromo-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-6,8-difluoroquinazoline (100.2 mg, 0.2 mmol), 3-methoxy-8-ethylisoquinolineboronic acid pinacol ester (67.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 7-(3-methoxy-8-ethylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-6,8-difluoroquinazoline (92 mg) as a beige solid.
LC/MS(ESI):m/z＝647[M+H]+.LC/MS (ESI): m/z = 647 [M+H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-甲基异喹啉-1-基)-4-((3R)-3-甲基-3-羟基呱啶基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-6,8-二氟喹唑啉(64.7mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物17(29mg)。得到化合物35(34mg)。LC/MS(ESI):m/z＝633[M+H]+.At -78°C, 7-(3-methoxy-8-methylisoquinolin-1-yl)-4-((3R)-3-methyl-3-hydroxypiperidinyl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-6,8-difluoroquinazoline (64.7 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and then the mixture was warmed to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a light yellow solid compound 17 (29 mg). Compound 35 (34 mg) was obtained. LC/MS (ESI): m/z=633[M+H] + .
实施例36
Embodiment 36
用与实施例36相似的方法得到化合物36(27mg)。LC/MS(ESI):m/z＝649[M+H]+.Compound 36 (27 mg) was obtained by a method similar to Example 36. LC/MS (ESI): m/z = 649 [M+H] + .
实施例37
Embodiment 37
用与实施例36相似的方法得到化合物37(29mg)。LC/MS(ESI):m/z＝626[M+H]+.Compound 37 (29 mg) was obtained by a method similar to Example 36. LC/MS (ESI): m/z = 626 [M+H] + .
实施例38
Embodiment 38
用与实施例36相似的方法得到化合物38(28mg)。LC/MS(ESI):m/z＝643[M+H]+.Compound 38 (28 mg) was obtained by a method similar to Example 36. LC/MS (ESI): m/z = 643 [M+H] + .
实施例39
Embodiment 39
用与实施例36相似的方法得到化合物39(28mg)。LC/MS(ESI):m/z＝622[M+H]+.Compound 39 (28 mg) was obtained by a method similar to Example 36. LC/MS (ESI): m/z = 622 [M+H] + .
实施例40
Embodiment 40
用与实施例36相似的方法得到化合物40(32mg)。LC/MS(ESI):m/z＝639[M+H]+.Compound 40 (32 mg) was obtained by a method similar to Example 36. LC/MS (ESI): m/z = 639 [M+H] + .
实施例41
Embodiment 41
步骤A：Step A:
将2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(8-boc-3,8-二氮杂双环[3.2.1]辛烷-3- 基)-5,6,7,8-四氢吡啶并[3,4-d]并嘧啶(100mg，0.2mmol)、1-三氟甲磺酸基-7-氟-3-甲氧基-8-((三异丙基甲硅基)乙炔基)异喹啉(100.8mg，0.2mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(16mg，0.022mmol)、Cs2CO3、二氧六环(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到7-(3-甲氧基8-((三异丙基甲硅基)乙炔基)异喹啉-1-基)-4-(8-boc-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-5,6,7,8-四氢吡啶并[3,4-d]并嘧啶(132mg)。2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(8-boc-3,8-diazabicyclo[3.2.1]octane-3- After mixing 1-trifluoromethanesulfonyl-7-fluoro-3-methoxy-8-((triisopropylmethylsilyl)ethynyl)isoquinoline (100.8 mg, 0.2 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (16 mg, 0.022 mmol), Cs 2 CO 3 , dioxane (5 mL) and water (1 mL), the mixture was heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to give 7-(3-methoxy-8-((triisopropylmethylsilyl)ethynyl)isoquinolin-1-yl)-4-(8-boc-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrin-7a(5H)-yl)methoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (132 mg).
LC/MS(ESI):m/z＝845[M+H]+.LC/MS (ESI): m/z = 845 [M + H] + .
步骤B：Step B:
在-78℃下，7-(3-甲氧基-8-((三异丙基甲硅基)乙炔基)异喹啉-1-基)-4-(8-boc-3,8-二氮杂双环[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)5,6,7,8-四氢吡啶并[3,4-d]并嘧啶(126.6mg，0.15mmol)溶于DMF(5mL)中，在N2-保护下加入CsF(152mg，1mmol)，在20℃下搅拌1小时，然后倒入水中，用EA萃取，无水硫酸钠干燥，过滤减压浓缩。将残余物溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物41(48mg)。At -78°C, 7-(3-methoxy-8-((triisopropylmethylsilyl)ethynyl)isoquinolin-1-yl)-4-(8-boc-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (126.6 mg, 0.15 mmol) was dissolved in DMF (5 mL), and CsF (152 mg, 1 mmol) was added under N2- protection. The mixture was stirred at 20°C for 1 hour, then poured into water, extracted with EA, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL), and BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, then the temperature was raised to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a light yellow solid compound 41 (48 mg).
LC/MS(ESI):m/z＝605[M+H]+.LC/MS (ESI): m/z = 605 [M+H] + .
实施例42
Embodiment 42
用与实施例41相似的方法得到化合物42(43mg)。LC/MS(ESI):m/z＝591[M+H]+。Compound 42 (43 mg) was obtained in a similar manner to Example 41. LC/MS (ESI): m/z = 591 [M+H] + .
实施例43
Embodiment 43
用与实施例41相似的方法得到化合物43(41mg)。LC/MS(ESI):m/z＝602[M+H]+。Compound 43 (41 mg) was obtained in a similar manner to Example 41. LC/MS (ESI): m/z = 602 [M+H] + .
实施例44
Embodiment 44
用与实施例41相似的方法得到化合物44(47mg)。LC/MS(ESI):m/z＝595[M+H]+。Compound 44 (47 mg) was obtained in a similar manner to Example 41. LC/MS (ESI): m/z = 595 [M+H] + .
实施例45
Embodiment 45
步骤A：Step A:
将2,4,7-三氯-6-氟吡啶并[2,3-d]嘧啶(2.52g，10mmol)、1,3,7-三氮螺[4.5]癸烷-2-酮(1.69g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-6-氟吡啶[2,3-d]并嘧啶(3.41g)。2,4,7-Trichloro-6-fluoropyrido[2,3-d]pyrimidine (2.52 g, 10 mmol), 1,3,7-triazaspiro[4.5]decane-2-one (1.69 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)-6-fluoropyrido[2,3-d]pyrimidine (3.41 g).
LC/MS(ESI):m/z＝372[M+H]+。LC/MS (ESI): m/z = 372 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-6-氟吡啶[2,3-d]并嘧啶(371mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-6-氟吡啶[2,3-d]并嘧啶(0.387g)。2,7-Dichloro-4-((2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)-6-fluoropyrido[2,3-d]pyrimidine (371 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol) and iodine were added in a catalytic amount. Potassium chloride and DMF (8 mL) were mixed, heated to 120°C, stirred and reacted for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 7-chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)-6-fluoropyrido[2,3-d]pyrimidine (0.387 g).
LC/MS(ESI):m/z＝493[M+H]+。LC/MS (ESI): m/z = 493 [M+H] + .
步骤C：Step C:
将7-氯-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(2-硫杂-1,3,7-三氮螺[4.5]癸烷-2,2-酮-7-基)-6-氟吡啶[2,3-d]并嘧啶(98mg，0.2mmol)、3-甲氧基-8-氯-7-氟异喹啉硼酸频哪醇酯(67.6mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到米黄色固体7-(3-甲氧基-8-氯-7-氟异喹啉-1-基)-4-((2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-6-氟吡啶[2,3-d]并嘧啶(92mg)。7-Chloro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(2-thia-1,3,7-triazaspiro[4.5]decane-2,2-one-7-yl)-6-fluoropyrido[2,3-d]pyrimidine (98 mg, 0.2 mmol), 3-methoxy-8-chloro-7-fluoroisoquinolineboronic acid pinacol ester (67.6 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was subjected to column chromatography to give 7-(3-methoxy-8-chloro-7-fluoroisoquinolin-1-yl)-4-((2-oxo-1,3,7-triazaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine-7a(5H)-yl)methoxy)-6-fluoropyridin[2,3-d]pyrimidine (92 mg) as a beige solid.
LC/MS(ESI):m/z＝670[M+H]+。LC/MS (ESI): m/z = 670 [M+H] + .
步骤D： Step D:
在-78℃下，7-(3-甲氧基-8-氯-7-氟异喹啉-1-基)-4-((2-氧代-1,3,7-三氮螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-6-氟吡啶[2,3-d]并嘧啶(67mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物45(23mg)。At -78°C, 7-(3-methoxy-8-chloro-7-fluoroisoquinolin-1-yl)-4-((2-oxo-1,3,7-triazaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-6-fluoropyrido[2,3-d]pyrimidine (67 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure, and purified by preparative HPLC to give Compound 45 (23 mg) as a pale yellow solid.
LC/MS(ESI):m/z＝656[M+H]+。LC/MS (ESI): m/z = 656 [M+H] + .
实施例46
Embodiment 46
用与实施例45相似的方法得到化合物46(32mg)。LC/MS(ESI):m/z＝692[M+H]+。Compound 46 (32 mg) was obtained in a similar manner to Example 45. LC/MS (ESI): m/z = 692 [M+H] + .
实施例47
Embodiment 47
用与实施例45相似的方法得到化合物47(25mg)。LC/MS(ESI):m/z＝685[M+H]+。Compound 47 (25 mg) was obtained in a similar manner to Example 45. LC/MS (ESI): m/z = 685 [M+H] + .
实施例48
Embodiment 48
用与实施例45相似的方法得到化合物48(22mg)。LC/MS(ESI):m/z＝683[M+H]+。Compound 48 (22 mg) was obtained in a similar manner to Example 45. LC/MS (ESI): m/z = 683 [M+H] + .
实施例49
Embodiment 49
用与实施例45相似的方法得到化合物49(21mg)。LC/MS(ESI):m/z＝702[M+H]+。Compound 49 (21 mg) was obtained in a similar manner to Example 45. LC/MS (ESI): m/z = 702 [M+H] + .
实施例50
Embodiment 50
用与实施例45相似的方法得到化合物50(16mg)。LC/MS(ESI):m/z＝715[M+H]+。Compound 50 (16 mg) was obtained in a similar manner to Example 45. LC/MS (ESI): m/z = 715 [M+H] + .
实施例51
Embodiment 51
用与实施例32相似的方法得到化合物51(22mg)。LC/MS(ESI):m/z＝620[M+H]+。Compound 51 (22 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 620 [M+H] + .
实施例52
Embodiment 52
用与实施例32相似的方法得到化合物52(21mg)。LC/MS(ESI):m/z＝620[M+H]+。Compound 52 (21 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 620 [M+H] + .
实施例53
Embodiment 53
用与实施例32相似的方法得到化合物53(21mg)。LC/MS(ESI):m/z＝619[M+H]+。Compound 53 (21 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 619 [M+H] + .
实施例54
Embodiment 54
用与实施例32相似的方法得到化合物54(18mg)。LC/MS(ESI):m/z＝637[M+H]+。Compound 54 (18 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 637 [M+H] + .
实施例55
Embodiment 55
用与实施例32相似的方法得到化合物55(16mg)。LC/MS(ESI):m/z＝640[M+H]+。Compound 55 (16 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 640 [M+H] + .
实施例56
Embodiment 56
用与实施例32相似的方法得到化合物56(27mg)。LC/MS(ESI):m/z＝623[M+H]+。Compound 56 (27 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 623 [M+H] + .
实施例57
Embodiment 57
用与实施例32相似的方法得到化合物57(29mg)。LC/MS(ESI):m/z＝623[M+H]+。Compound 57 (29 mg) was obtained in a similar manner to Example 32. LC/MS (ESI): m/z = 623 [M+H] + .
实施例58
Embodiment 58
步骤A：Step A:
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(2.52g，10mmol)、(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-2-酮(2.08g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-8-氟吡啶并[4,3-d]嘧啶(3.42g)。2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-2-one (2.08 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-8-fluoropyrido[4,3-d]pyrimidine (3.42 g).
LC/MS(ESI):m/z＝406[M+H]+。LC/MS (ESI): m/z=406 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-8-氟吡啶并[4,3-d]嘧啶(406mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-氯-8-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)吡啶并[4,3-d]嘧啶(387mg)。2,7-Dichloro-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-8-fluoropyrido[4,3-d]pyrimidine (406 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for reaction for 4 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to give 7-chloro-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidine (387 mg) as a yellow solid.
LC/MS(ESI):m/z＝528[M+H]+。LC/MS (ESI): m/z=528 [M+H] + .
步骤C：Step C:
将7-氯-8-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)吡啶[4,3-d]并嘧啶(105.4mg，0.2mmol)、3-甲氧基-7-氟-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到8-氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶(91mg)。7-Chloro-8-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]dec-7-yl)pyridin[4,3-d]pyrimidine (105.4 mg, 0.2 mmol), 3-methoxy-7-fluoro-8-ethylisoquinolinylboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, then heated under reflux to 60° C. and stirred for reaction for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL), and the solid was collected by filtration. The crude product was column chromatographed to obtain 8-fluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinoline-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (91 mg).
LC/MS(ESI):m/z＝697[M+H]+.LC/MS (ESI): m/z = 697 [M+H] + .
步骤D：Step D:
在-78℃下，8-氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺 [4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶(69.7mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物58(28mg)。At -78 °C, 8-fluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro [4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (69.7 mg, 0.1 mmol) was dissolved in DCM (2 mL), and BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and then the temperature was raised to room temperature and stirred for 5 h, then cooled to -78°C, adjusted to Ph=7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a light yellow solid Compound 58 (28 mg).
LC/MS(ESI):m/z＝683[M+H]+.LC/MS (ESI): m/z = 683 [M + H] + .
实施例59
Embodiment 59
用与实施例58相似的方法得到化合物59(24mg)。LC/MS(ESI):m/z＝690[M+H]+。Compound 59 (24 mg) was obtained in a similar manner to Example 58. LC/MS (ESI): m/z = 690 [M+H] + .
实施例60
Embodiment 60
用与实施例58相似的方法得到化合物60(22mg)。LC/MS(ESI):m/z＝697[M+H]+。Compound 60 (22 mg) was obtained in a similar manner to Example 58. LC/MS (ESI): m/z = 697 [M+H] + .
实施例61
Embodiment 61
用与实施例58相似的方法得到化合物61(20mg)。LC/MS(ESI):m/z＝695[M+H]+。Compound 61 (20 mg) was obtained in a similar manner to Example 58. LC/MS (ESI): m/z = 695 [M+H] + .
实施例62
Embodiment 62
步骤A：Step A:
将7-溴-2,4-二氯-6,8-二氟喹唑啉(3.13g，10mmol)、(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-2-酮(2.08g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体7-溴-2-氯-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-6,8-二氟喹唑啉(3.52g)。7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (3.13 g, 10 mmol), (5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-2-one (2.08 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain 7-bromo-2-chloro-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-6,8-difluoroquinazoline (3.52 g) as a yellow solid.
LC/MS(ESI):m/z＝467[M+H]+。LC/MS (ESI): m/z=467 [M+H] + .
步骤B：Step B:
将7-溴-2-氯-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-6,8-二氟喹唑啉(467mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-溴-6,8-二氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)喹唑啉(384mg)。Mix 7-bromo-2-chloro-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-6,8-difluoroquinazoline (467 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL), heat to 120°C, and stir to react for 4 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure to give 7-bromo-6,8-difluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-7-yl)quinazoline (384 mg) as a yellow solid.
LC/MS(ESI):m/z＝590[M+H]+。LC/MS (ESI): m/z = 590 [M+H] + .
步骤C：Step C:
将7-溴-6,8-二氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)喹唑啉(118mg，0.2mmol)、3-甲氧基-7-氟-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到6,8-二氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)喹唑啉(78mg)。7-Bromo-6,8-difluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)quinazoline (118 mg, 0.2 mmol), 3-methoxy-7-fluoro-8-ethylisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, and then heated under reflux to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was subjected to column chromatography to give 6,8-difluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)quinazoline (78 mg).
LC/MS(ESI):m/z＝714[M+H]+.LC/MS (ESI): m/z = 714 [M+H] + .
步骤D：Step D:
在-78℃下，6,8-二氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)喹唑啉(71.4mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物62(35mg)。At -78°C, 6,8-difluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)quinazoline (71.4 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid Compound 62 (35 mg).
LC/MS(ESI):m/z＝700[M+H]+。LC/MS (ESI): m/z=700 [M+H] + .
实施例63
Embodiment 63
用与实施例62相似的方法得到化合物63(24mg)。LC/MS(ESI):m/z＝707[M+H]+。Compound 63 (24 mg) was obtained in a similar manner to Example 62. LC/MS (ESI): m/z = 707 [M+H] + .
实施例64
Embodiment 64
用与实施例62相似的方法得到化合物64(14mg)。LC/MS(ESI):m/z＝714[M+H]+。Compound 64 (14 mg) was obtained in a similar manner to Example 62. LC/MS (ESI): m/z = 714 [M+H] + .
实施例65
Embodiment 65
用与实施例62相似的方法得到化合物65(12mg)。LC/MS(ESI):m/z＝712[M+H]+。Compound 65 (12 mg) was obtained in a similar manner to Example 62. LC/MS (ESI): m/z = 712 [M+H] + .
实施例66
Embodiment 66
步骤A：Step A:
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(2.52g，10mmol)、(5R)-2-甲基-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-2-酮(2.08g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体2,7-二氯-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-6-氟吡啶并[4,3-d]嘧啶(3.42g)。2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), (5R)-2-methyl-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-2-one (2.08 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 2,7-dichloro-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-6-fluoropyrido[4,3-d]pyrimidine (3.42 g).
LC/MS(ESI):m/z＝406[M+H]+。LC/MS (ESI): m/z=406 [M+H] + .
步骤B：Step B:
将2,7-二氯-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-6-氟吡啶并[4,3-d]嘧啶(406mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到 黄色固体7-氯-6-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)吡啶并[4,3-d]嘧啶(387mg)。2,7-Dichloro-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-6-fluoropyrido[4,3-d]pyrimidine (406 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, stirred and reacted for 4 hours. Cooled to room temperature, evaporated under reduced pressure to obtain 7-Chloro-6-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-7-yl)pyrido[4,3-d]pyrimidine (387 mg) was obtained as a yellow solid.
LC/MS(ESI):m/z＝528[M+H]+。LC/MS (ESI): m/z = 528 [M+H] + .
步骤C：Step C:
将7-氯-6-氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)吡啶[4,3-d]并嘧啶(105.4mg，0.2mmol)、3-甲氧基-7-氟-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到6-氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶(91mg)。7-Chloro-6-fluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]dec-7-yl)pyridin[4,3-d]pyrimidine (105.4 mg, 0.2 mmol), 3-methoxy-7-fluoro-8-ethylisoquinolinylboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, then heated under reflux to 60° C. and stirred for reaction for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL), and the solid was collected by filtration. The crude product was column chromatographed to obtain 6-fluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinoline-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decane-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridine ring-7a(5H)-yl)methoxy)pyridine[4,3-d]pyrimidine (91 mg).
LC/MS(ESI):m/z＝697[M+H]+.LC/MS (ESI): m/z = 697 [M+H] + .
步骤D：Step D:
在-78℃下，6-氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-((5R)-2-甲基-2-氧代-1,3,7-三氮螺-2-磷杂螺[4.5]癸烷-7-基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)吡啶[4,3-d]并嘧啶(69.7mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物66(28mg)。At -78°C, 6-fluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-((5R)-2-methyl-2-oxo-1,3,7-triazaspiro-2-phosphaspiro[4.5]decan-7-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)pyridin[4,3-d]pyrimidine (69.7 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid Compound 66 (28 mg).
LC/MS(ESI):m/z＝683[M+H]+.LC/MS (ESI): m/z = 683 [M + H] + .
实施例67
Embodiment 67
用与实施例66相似的方法得到化合物67(28mg)。LC/MS(ESI):m/z＝690[M+H]+。Compound 67 (28 mg) was obtained in a similar manner to Example 66. LC/MS (ESI): m/z = 690 [M+H] + .
实施例68
Embodiment 68
用与实施例66相似的方法得到化合物68(32mg)。LC/MS(ESI):m/z＝697[M+H]+。Compound 68 (32 mg) was obtained in a similar manner to Example 66. LC/MS (ESI): m/z = 697 [M+H] + .
实施例69
Embodiment 69
用与实施例66相似的方法得到化合物69(14mg)。LC/MS(ESI):m/z＝695[M+H]+。Compound 69 (14 mg) was obtained in a similar manner to Example 66. LC/MS (ESI): m/z = 695 [M+H] + .
实施例70
Embodiment 70
步骤A：Step A:
将2,4,7-三氯-8-氟吡啶并[4,3-d]嘧啶(2.52g，10mmol)、N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(2.29g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体5-(2,7-二氯-6-氟吡啶并[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(3.61g)。2,4,7-Trichloro-8-fluoropyrido[4,3-d]pyrimidine (2.52 g, 10 mmol), N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.29 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain a yellow solid 5-(2,7-dichloro-6-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (3.61 g).
LC/MS(ESI):m/z＝424[M+H]+。LC/MS (ESI): m/z=424 [M+H] + .
步骤B：Step B:
将5-(2,7-二氯-6-氟吡啶并[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(424mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体5-(2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-7-氯-6-氟吡啶并[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(437mg)。Mix 5-(2,7-dichloro-6-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (424 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL), heat to 120°C, and stir to react for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to give 5-(2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-7-chloro-6-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (437 mg) as a yellow solid.
LC/MS(ESI):m/z＝548[M+H]+。LC/MS (ESI): m/z=548 [M+H] + .
步骤C：Step C:
将5-(2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-7-氯-6-氟吡啶并[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(109.6mg，0.2mmol)、3-甲氧基-7-氟-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固 体。粗产物柱层析得到得到5-(2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-6-氟吡啶并[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(94mg)。5-(2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-7-chloro-6-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (109.6 mg, 0.2 mmol), 3-methoxy-7-fluoro-8-ethylisoquinolinylboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed, then heated under reflux to 60° C. and stirred for reaction for 16 hours. The reaction was cooled to room temperature and stirred overnight to give a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was subjected to column chromatography to obtain 5-(2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-6-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (94 mg).
LC/MS(ESI):m/z＝716[M+H]+.LC/MS (ESI): m/z = 716 [M + H] + .
步骤D：Step D:
在-78℃下，5-(2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-6-氟吡啶并[4,3-d]嘧啶-4-基)-N,N-二甲基-5,6,7,8-四氢-4H-吡唑[1,5-a][1,4]二氮杂卓-2-甲酰胺(71.6mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物66(32mg)。At -78°C, 5-(2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-6-fluoropyrido[4,3-d]pyrimidin-4-yl)-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (71.6 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid Compound 66 (32 mg).
LC/MS(ESI):m/z＝702[M+H]+.LC/MS (ESI): m/z = 702 [M + H] + .
实施例71
Embodiment 71
用与实施例70相似的方法得到化合物71(25mg)。LC/MS(ESI):m/z＝709[M+H]+。Compound 71 (25 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 709 [M+H] + .
实施例72
Embodiment 72
用与实施例70相似的方法得到化合物72(29mg)。LC/MS(ESI):m/z＝684[M+H]+。Compound 72 (29 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 684 [M+H] + .
实施例73
Embodiment 73
用与实施例70相似的方法得到化合物73(34mg)。LC/MS(ESI):m/z＝691[M+H]+。Compound 73 (34 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 691 [M+H] + .
实施例74
Embodiment 74
用与实施例70相似的方法得到化合物74(28mg)。LC/MS(ESI):m/z＝702[M+H]+。Compound 74 (28 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 702 [M+H] + .
实施例75
Embodiment 75
用与实施例70相似的方法得到化合物75(24mg)。LC/MS(ESI):m/z＝709[M+H]+。Compound 75 (24 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 709 [M+H] + .
实施例76
Embodiment 76
用与实施例70相似的方法得到化合物71(15mg)。LC/MS(ESI):m/z＝719[M+H]+。Compound 71 (15 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 719 [M+H] + .
实施例75
Embodiment 75
用与实施例70相似的方法得到化合物75(18mg)。LC/MS(ESI):m/z＝726[M+H]+。Compound 75 (18 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 726 [M+H] + .
实施例76
Embodiment 76
用与实施例70相似的方法得到化合物76(16mg)。LC/MS(ESI):m/z＝731[M+H]+。Compound 76 (16 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 731 [M+H] + .
实施例77
Embodiment 77
用与实施例70相似的方法得到化合物77(13mg)。LC/MS(ESI):m/z＝733[M+H]+。Compound 77 (13 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 733 [M+H] + .
实施例78
Embodiment 78
用与实施例70相似的方法得到化合物78(24mg)。LC/MS(ESI):m/z＝714[M+H]+。Compound 78 (24 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 714 [M+H] + .
实施例79
Embodiment 79
用与实施例70相似的方法得到化合物71(19mg)。LC/MS(ESI):m/z＝716[M+H]+。Compound 71 (19 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 716 [M+H] + .
实施例80
Embodiment 80
用与实施例70相似的方法得到化合物80(15mg)。LC/MS(ESI):m/z＝696[M+H]+。Compound 80 (15 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 696 [M+H] + .
实施例81
Embodiment 81
用与实施例70相似的方法得到化合物81(14mg)。LC/MS(ESI):m/z＝698[M+H]+。Compound 81 (14 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 698 [M+H] + .
实施例82
Embodiment 82
用与实施例70相似的方法得到化合物82(18mg)。LC/MS(ESI):m/z＝714[M+H]+。Compound 82 (18 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 714 [M+H] + .
实施例83
Embodiment 83
用与实施例70相似的方法得到化合物83(19mg)。LC/MS(ESI):m/z＝716[M+H]+。Compound 83 (19 mg) was obtained in a similar manner to Example 70. LC/MS (ESI): m/z = 716 [M+H] + .
实施例84
Embodiment 84
步骤A：Step A:
将7-溴-2,4-二氯-6,8-二氟喹唑啉(3.13g，10mmol)、3-氮杂双环[3.2.1]辛烷-6-醇盐酸盐(1.79g，11mmol)、碳酸钾(2.07g，15mmol)催化量碘化钾和DMF(60mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶，得到黄色固体7-溴-2-氯-4-(6-羟基-3-氮杂双环[3.2.1]辛烷-3基)-6,8-二氟喹唑啉(2.82g)。7-Bromo-2,4-dichloro-6,8-difluoroquinazoline (3.13 g, 10 mmol), 3-azabicyclo[3.2.1]octan-6-ol hydrochloride (1.79 g, 11 mmol), potassium carbonate (2.07 g, 15 mmol), a catalytic amount of potassium iodide and DMF (60 mL) were mixed, heated to 120°C, stirred and reacted for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain 7-bromo-2-chloro-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-6,8-difluoroquinazoline (2.82 g) as a yellow solid.
LC/MS(ESI):m/z＝343[M+H]+。LC/MS (ESI): m/z = 343 [M+H] + .
步骤B：Step B:
将7-溴-2-氯-4-(6-羟基-3-氮杂双环[3.2.1]辛烷-3基)-6,8-二氟喹唑啉(467mg，1mmol)、(2R,8S)-2-氟-1,2,3,5,6,7-六氢吡咯嗪-7-基]甲醇(175mg，1.1mmol)、碳酸钾(0.18mg，2.1mmol)催化量碘化钾和DMF(8mL)混合，加热到120℃，搅拌反应4小时。冷却至室温，减压蒸溶得到黄色固体7-溴-6,8-二氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(6-羟基-3-氮杂双环[3.2.1]辛烷-3基)喹唑啉(342mg)。7-Bromo-2-chloro-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-6,8-difluoroquinazoline (467 mg, 1 mmol), (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-7-yl]methanol (175 mg, 1.1 mmol), potassium carbonate (0.18 mg, 2.1 mmol), a catalytic amount of potassium iodide and DMF (8 mL) were mixed, heated to 120°C, and stirred for 4 hours. The mixture was cooled to room temperature and evaporated under reduced pressure to obtain 7-bromo-6,8-difluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)quinazoline (342 mg) as a yellow solid.
LC/MS(ESI):m/z＝466[M+H]+。LC/MS (ESI): m/z=466 [M+H] + .
步骤C：Step C:
将7-溴-6,8-二氟-2(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)-4-(6-羟基-3-氮杂双环[3.2.1]辛烷-3基)喹唑啉(93mg，0.2mmol)、3-甲氧基-7-氟-8-乙基异喹啉硼酸频哪醇酯(66.4mg，0.2mmol)、甲磺酸[正丁基二(1-金刚烷基)膦](2-氨基-1,1'-联苯-2-基)钯(II)(16mg，0.022mmol)、K3PO4、THF(5mL)和水(1mL)混合后，然后回流加热到60℃，搅拌反应16小时。将反应物冷却至室温并搅拌过夜，得到淡黄色沉淀物。用水(2mL)稀释反应混合物，并通过过滤收集固体。粗产物柱层析得到得到6,8-二氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-(6-羟基-3-氮杂双环[3.2.1]辛烷-3基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)喹唑啉(88mg)。7-Bromo-6,8-difluoro-2(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)quinazoline (93 mg, 0.2 mmol), 3-methoxy-7-fluoro-8-ethylisoquinolineboronic acid pinacol ester (66.4 mg, 0.2 mmol), methanesulfonic acid [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) (16 mg, 0.022 mmol), K 3 PO 4 , THF (5 mL) and water (1 mL) were mixed and then refluxed to 60° C. and stirred for 16 hours. The reactant was cooled to room temperature and stirred overnight to obtain a light yellow precipitate. The reaction mixture was diluted with water (2 mL) and the solid was collected by filtration. The crude product was purified by column chromatography to obtain 6,8-difluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)quinazoline (88 mg).
LC/MS(ESI):m/z＝635[M+H]+.LC/MS (ESI): m/z = 635 [M+H] + .
步骤D：Step D:
在-78℃下，6,8-二氟-7-(3-甲氧基-7-氟-8-乙基异喹啉-1-基)-4-(6-羟基-3-氮杂双环[3.2.1]辛烷-3基)-2-(((2R,7aS)-2-氟四氢-1H-吡呤环-7a(5H)-基)甲氧基)喹唑啉(63.5mg，0.1mmol)溶于DCM(2mL)中，加入BBr3((0.4mL,1M in DCM,0.4mmol)，然后升至室温搅拌5h，然冷却至-78℃，用1N NaOH调至Ph＝7，用EA萃取，然后过滤减压浓缩并用制备HPLC纯化得到淡黄色固体化合物84(24mg)。 At -78°C, 6,8-difluoro-7-(3-methoxy-7-fluoro-8-ethylisoquinolin-1-yl)-4-(6-hydroxy-3-azabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyridin-7a(5H)-yl)methoxy)quinazoline (63.5 mg, 0.1 mmol) was dissolved in DCM (2 mL), BBr 3 ((0.4 mL, 1 M in DCM, 0.4 mmol) was added, and the mixture was warmed to room temperature and stirred for 5 h. The mixture was then cooled to -78°C, adjusted to pH = 7 with 1N NaOH, extracted with EA, filtered, concentrated under reduced pressure and purified by preparative HPLC to give a pale yellow solid Compound 84 (24 mg).
LC/MS(ESI):m/z＝621[M+H]+。LC/MS (ESI): m/z = 621 [M+H] + .
实施例85Embodiment 85
用与实施例84相似的方法得到化合物85(24mg)。LC/MS(ESI):m/z＝621[M+H]+。 Compound 85 (24 mg) was obtained in a similar manner to Example 84. LC/MS (ESI): m/z = 621 [M+H] + .
实施例86
Embodiment 86
用与实施例84相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝628[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 84. LC/MS (ESI): m/z = 628 [M+H] + .
实施例87
Embodiment 87
用与实施例84相似的方法得到化合物87(19mg)。LC/MS(ESI):m/z＝628[M+H]+。Compound 87 (19 mg) was obtained in a similar manner to Example 84. LC/MS (ESI): m/z = 628 [M+H] + .
实施例88
Embodiment 88
用与实施例17相似的方法得到化合物88(22mg)。LC/MS(ESI):m/z＝584[M+H]+。Compound 88 (22 mg) was obtained in a similar manner to Example 17. LC/MS (ESI): m/z = 584 [M+H] + .
实施例89
Embodiment 89
用与实施例25相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝583[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 25. LC/MS (ESI): m/z = 583 [M+H] + .
实施例90
Embodiment 90
用与实施例17相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝602[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 17. LC/MS (ESI): m/z = 602 [M+H] + .
实施例91
Embodiment 91
用与实施例25相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝601[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 25. LC/MS (ESI): m/z = 601 [M+H] + .
实施例92
Embodiment 92
用与实施例13相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝602[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 13. LC/MS (ESI): m/z = 602 [M+H] + .
实施例93
Embodiment 93
用与实施例1相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝584[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 1. LC/MS (ESI): m/z = 584 [M+H] + .
实施例94
Embodiment 94
用与实施例13相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝601[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 13. LC/MS (ESI): m/z = 601 [M+H] + .
实施例95
Embodiment 95
用与实施例13相似的方法得到化合物86(22mg)。LC/MS(ESI):m/z＝683[M+H]+。Compound 86 (22 mg) was obtained in a similar manner to Example 13. LC/MS (ESI): m/z = 683 [M+H] + .
采用类似实施例88-95的合成，可以得到如下化合物：
Using a synthesis similar to Examples 88-95, the following compounds can be obtained:
实施例96生物活性测试Example 96 Biological Activity Test
实验例1.KRAS抑制活性测试Experimental Example 1. KRAS Inhibitory Activity Test
1.实验目的：1. Experimental purpose:
通过TR-FRET的方法，筛选出能有效抑制KRas<WT>，KRas<G12A>，KRas<G12C>，KRas<G12D>，KRas<G12R>，KRas<G12S>，KRas<G12V>，KRas<G13D>，KRas<Q61H>与GTP结合的化合物。Using the TR-FRET method, we screened out compounds that can effectively inhibit the binding of KRas<WT>, KRas<G12A>, KRas<G12C>, KRas<G12D>, KRas<G12R>, KRas<G12S>, KRas<G12V>, KRas<G13D>, and KRas<Q61H> to GTP.
2.试剂准备：2. Reagent preparation:
a.储存试剂：a. Storage of reagents:
1)KRAS核苷酸交换缓冲液1) KRAS Nucleotide Exchange Buffer
取20mL 1000mM HEPES，20mL 500mM EDTA，10mL 5M氯化钠，100％0.1mL吐温20，949.9mL水，配制成1L溶液，用过滤法消毒，4℃条件下储存。Take 20mL 1000mM HEPES, 20mL 500mM EDTA, 10mL 5M sodium chloride, 0.1mL 100% Tween 20, and 949.9mL water to prepare 1L solution, sterilize by filtration, and store at 4°C.
2)KRAS实验缓冲液2) KRAS assay buffer
取20mL 1000mM HEPES，10mL 1000mM氯化镁，30mL5M氯化钠，100％0.05mL吐温20，939.95mL水，配制成1L溶液，用过滤法消毒，4℃条件下储存。Take 20mL 1000mM HEPES, 10mL 1000mM magnesium chloride, 30mL 5M sodium chloride, 0.05mL 100% Tween 20, and 939.95mL water to prepare 1L solution, sterilize by filtration, and store at 4°C.
3)KRAS/Bodipy GDP/Tb-SA混合液3) KRAS/Bodipy GDP/Tb-SA mixture
取9.5μL 95μM KRAS<G12D>蛋白，440.5μL KRAS核苷酸交换缓冲液混合，室温下孵育1小时后，与8.4μL 17.9μM Tb-SA，1.8μL 5mM Bodipy GDP，9539.8μL KRAS实验缓冲液，配制成1L溶液，混合后室温下静置6小时，储存至-80℃条件下。 Take 9.5 μL of 95 μM KRAS<G12D> protein and mix it with 440.5 μL KRAS nucleotide exchange buffer. After incubation at room temperature for 1 hour, add 8.4 μL 17.9 μM Tb-SA, 1.8 μL 5mM Bodipy GDP, and 9539.8 μL KRAS experimental buffer to prepare 1 L solution. After mixing, let it stand at room temperature for 6 hours and store it at -80°C.
b.实验试剂：b. Experimental reagents:
1)KRAS酶溶液1) KRAS enzyme solution
取73.3μL KRAS/Bodipy GDP/Tb-SA混合液，2126.7μL KRAS实验缓冲液，配制成2200μL溶液。Take 73.3μL of KRAS/Bodipy GDP/Tb-SA mixture and 2126.7μL of KRAS experimental buffer to prepare 2200μL solution.
2)SOS/GTP混合液2) SOS/GTP mixture
c.实验过程:c. Experimental process:
取1.59μL 166μM SOS蛋白，198μL 100mM GTP，2000.41μL KRAS实验缓冲液，配制成2200μL溶液。对照化合物母液浓度为1mM，待测化合物母液浓度为10mM。转移9μL对照化合物和待测化合物至384-LDV板内；使用Bravo将LDV板上的化合物进行10点3倍稀释；使用ECHO将LDV板上的化合物转移9nL至实验板；使用Dragonfly自动加样仪依次向实验板每孔中加入3μL3nM Kras/0.5nM TB-SA/30nM BodipyGDP混合液和3μL Ras buffer，以1000rpm/min，将实验板离心1分钟；实验板在室温中孵育1小时；使用Dragonfly自动加样仪在实验板每孔加入3μL 120nM SOS/9mM GTP混合液，以1000rpm/min，将实验板离心1分钟；实验板在室温中孵育1小时；使用Envision读板并记录数据；使用Excel和Xlfit进行数据分析，计算待测化合物IC50。其中“++++”表示IC50≤5nM；“+++”表示5nM<IC50≤50nM；“++”表示50nM<IC50≤2000nM；“+”表示2000nM<IC50。Take 1.59 μL 166 μM SOS protein, 198 μL 100 mM GTP, and 2000.41 μL KRAS assay buffer to prepare a 2200 μL solution. The concentration of the control compound stock solution is 1 mM, and the concentration of the test compound stock solution is 10 mM. Transfer 9 μL of control compound and test compound to 384-LDV plate; use Bravo to dilute the compound on LDV plate 3-fold in 10 points; use ECHO to transfer 9 nL of compound on LDV plate to experimental plate; use Dragonfly automatic sampler to add 3 μL of 3nM Kras/0.5nM TB-SA/30nM BodipyGDP mixture and 3 μL of Ras buffer to each well of the experimental plate in sequence, and centrifuge the experimental plate at 1000 rpm/min for 1 minute; incubate the experimental plate at room temperature for 1 hour; use Dragonfly automatic sampler to add 3 μL of 120nM SOS/9mM GTP mixture to each well of the experimental plate, and centrifuge the experimental plate at 1000 rpm/min for 1 minute; incubate the experimental plate at room temperature for 1 hour; use Envision to read the plate and record the data; use Excel and Xlfit to analyze the data and calculate the IC50 of the test compound. Wherein, “++++” indicates IC 50 ≤5 nM; “+++” indicates 5 nM<IC 50 ≤50 nM; “++” indicates 50 nM<IC 50 ≤2000 nM; and “+” indicates 2000 nM<IC 50 .
表1化合物对KRAS酶抑制的IC50值。


Table 1 IC50 values of compounds for KRAS enzyme inhibition.


实验例2.细胞p-ERK抑制测试Experimental Example 2. Cell p-ERK inhibition test
通过HTRF的方法，筛选出能有效抑制AsPC-1(G12D)，A549(G12S)，HCT116(G13D)，NCI-H358(G12C)，NCI-H460(Q61H)，NCI-H727(G12V)，MKN1(WTdep)，PSN-1(G12R)细胞p-ERK的化合物。Using the HTRF method, we screened out compounds that can effectively inhibit p-ERK in AsPC-1 (G12D), A549 (G12S), HCT116 (G13D), NCI-H358 (G12C), NCI-H460 (Q61H), NCI-H727 (G12V), MKN1 (WTdep), and PSN-1 (G12R) cells.
细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个细胞，细胞板放入二氧化碳培养箱，37度过夜孵育；取2μL化合物加入78μL细胞培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时；结束孵育后，弃掉细胞上清加入50μL 1X细胞裂解液每孔，室温摇晃孵育30分钟；使用detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育至少4小时孵育结束后使用多标记分析仪读取HTRF excitation：320nm，emission：615nm，665nm；Cells were seeded in a transparent 96-well cell culture plate, with 80 μL of cell suspension per well, and each well contained 8,000 cells. The cell plate was placed in a carbon dioxide incubator and incubated overnight at 37 degrees. 2 μL of compound was added to 78 μL of cell culture medium, mixed, and 20 μL of compound solution was added to the corresponding well of the cell plate. The cell plate was returned to the carbon dioxide incubator and incubated for 1 hour. After the incubation, the cell supernatant was discarded and 50 μL of 1X cell lysis buffer was added to each well, and incubated at room temperature for 30 minutes. Phospho-ERK1/2 Eu Cryptate an Dilute tibody and Phospho-ERK1/2 d2 antibody 20 times and take 16 μL cell lysate supernatant into each well of a new 384 white microplate, then add 2 μL Phospho-ERK1/2 Eu Cryptate antibody dilution and 2 μL Phospho-ERK1/2 d2 antibody dilution, incubate at room temperature for at least 4 hours. After the incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm;
计算待测化合物IC50。其中“++++”表示IC50≤10nM；“+++”表示10nM<IC50≤100nM；“++”表示100nM<IC50≤2000nM；“+”表示2000nM<IC50。Calculate the IC 50 of the test compound. Wherein "++++" indicates IC 50 ≤10 nM; "+++" indicates 10 nM<IC 50 ≤100 nM; "++" indicates 100 nM<IC 50 ≤2000 nM; "+" indicates 2000 nM<IC 50 .
表2、化合物对肿瘤细胞p-ERK抑制的IC50(nM)。

Table 2. IC 50 (nM) of compounds on inhibition of p-ERK in tumor cells.

尽管以上已经对本发明作了详细描述，但是本领域技术人员理解，在不偏离本发明的精神和范围的前提下可以对本发明进行各种修改和改变。本发明的权利范围并不限于上文所作的详细描述，而应归属于权利要求书。 Although the present invention has been described in detail above, it is understood by those skilled in the art that various modifications and changes can be made to the present invention without departing from the spirit and scope of the present invention. The scope of the present invention is not limited to the detailed description above, but should be attributed to the claims.

Claims (7)

  1. 一种具有通式(I)所示化合物、立体异构体或可药用的盐，
    A compound represented by general formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof,
    每个L2在每次出现时独立地选自键、OC0-6烷基、NHC0-6烷基、C1-6烷基、COC0-6烷基或SC0-6烷基；each L 2 at each occurrence is independently selected from a bond, OC 0-6 alkyl, NHC 0-6 alkyl, C 1-6 alkyl, COC 0-6 alkyl or SC 0-6 alkyl;
    每个R1在每次出现时独立地选自H、D、卤素、C1-6烷基、-C2-6烯基、-C2-6炔基、CN、OC1-6烷基；每个R1独立地可选地被1、2、3、4、5或6个选自氘、卤素、-C1-6烷基的取代基取代或不取代；Each R 1 is independently selected at each occurrence from H, D, halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, CN, OC 1-6 alkyl; each R 1 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C 1-6 alkyl;
    n为1-3n is 1-3
    每个X1，X2，X3在每次出现时独立地选自N，CR3；Each X 1 , X 2 , X 3 at each occurrence is independently selected from N, CR 3 ;
    每个R3独立地选自H、D、氰基、卤素、C1-6烷基、CN；Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
    每个R4独立地选自H、D、C1-6烷基、C2-6烯基、C2-6炔基、CN、C3-6碳环基、3-10元杂环、4-10元杂稠环；3-8元杂环在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子；每个R4独立地可选地被1、2、3、4、5或6个选自氘、卤素、C1-6烷基、-C1-6烷氧基、氧代、OC1-6烷基、C3-6碳环基、3-10元杂环的取代基取代或不取代；Each R 4 is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 3-6 carbocyclyl, 3-10 membered heterocycle, 4-10 membered heterocondensed ring; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 4 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C 1-6 alkyl, -C 1-6 alkoxy, oxo, OC 1-6 alkyl, C 3-6 carbocyclyl, 3-10 membered heterocycle;
    U选3-8元环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，每个杂环烷基、稠杂环基、螺杂环基、杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G1所取代；G is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aromatic or heteroaromatic, each heterocycloalkyl, fused heterocyclyl, spiroheterocyclyl, heteroaromatic independently containing 1, 2, 3 or 4 heteroatoms selected from N, O or S at each occurrence, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiroheterocyclyl, aromatic or heteroaromatic is optionally substituted with one or more G;
    G1各自独立选自氘、氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR5、-OC(O)NR5R6、-C(O)OR5、-C(O)NR5R6、-C(O)R5、-NR5R6、-NR5C(O)R6、-NR5C(O)NR6R7、-S(O)iR5或-NR5S(O)iR6，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氘、氰基，卤素、C1-7烷基、C2-7烯基、C2-7炔基、C3-9环烷基或3-9元杂环基、C7-10芳基、6-10元杂芳香基、-OR8、-OC(O)NR8R9、-C(O)OR8、-C(O)NR8R9、-C(O)R8、-NR8R9、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)iR8或-NR8S(O)iR9的取代基所取代； G1 is each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaromatic, -OR5 , -OC(O) NR5R6 , -C(O) OR5 , -C(O ) NR5R6, -C(O) R5 , -NR5R6 , -NR5C (O) R6 , -NR5C (O) NR6R7 , -S(O) iR5 or -NR5S (O) iR6 , wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaromatic is optionally substituted by one or more deuterium, cyano, halogen, C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C The group is substituted by a 3-9- membered cycloalkyl group or a 3-9-membered heterocyclyl group, a C 7-10 aryl group, a 6-10-membered heteroaryl group, -OR 8 , -OC(O)NR 8 R 9 , -C(O)OR 8 , -C(O)NR 8 R 9 , -C(O)R 8 , -NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 , -S(O) i R 8 or -NR 8 S(O) i R 9 ;
    R5、R6、R7、R8、R9和R10各自独立选自氢、氘、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
    且i为1或2。And i is 1 or 2.
  2. 一种具有通式(II)所示化合物、立体异构体或可药用的盐：
    A compound represented by general formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof:
    每个L2在每次出现时独立地选自键、OC0-6烷基、NHC0-6烷基、C1-6烷基、COC0-6烷基或SC0-6烷基；each L 2 at each occurrence is independently selected from a bond, OC 0-6 alkyl, NHC 0-6 alkyl, C 1-6 alkyl, COC 0-6 alkyl or SC 0-6 alkyl;
    每个R1在每次出现时独立地选自H、D、卤素、C1-6烷基、-C2-6烯基、-C2-6炔基、CN、OC1-6烷基；每个R1独立地可选地被1、2、3、4、5或6个选自氘、卤素、-C1-6烷基的取代基取代或不取代；Each R 1 is independently selected at each occurrence from H, D, halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, CN, OC 1-6 alkyl; each R 1 is independently optionally substituted or unsubstituted with 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, -C 1-6 alkyl;
    n为1-3n is 1-3
    每个X1在每次出现时独立地选自N，CR3；Each X 1 at each occurrence is independently selected from N, CR 3 ;
    每个R3独立地选自H、D、氰基、卤素、C1-6烷基、CN；Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
    Y1、Y2、Y3、Y4最多一个选自杂原子N、O、S，其他选自CR3；At most one of Y 1 , Y 2 , Y 3 and Y 4 is selected from heteroatoms N, O and S, and the others are selected from CR 3 ;
    每个R3独立地选自H、D、氰基、卤素、C1-6烷基、CN；Each R 3 is independently selected from H, D, cyano, halogen, C 1-6 alkyl, CN;
    每个R4独立地选自H、D、C1-6烷基、C2-6烯基、C2-6炔基、CN、C3-6碳环基、3-10元杂环、4-10元杂稠环；3-8元杂环在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子；每个R4独立地可选地被1、2、3、4、5或6个选自氘、卤素、C1-6烷基、-C1-6烷氧基、氧代、OC1-6烷基、C3-6碳环基、3-10元杂环的取代基取代或不取代；Each R 4 is independently selected from H, D, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 3-6 carbocyclyl, 3-10 membered heterocycle, 4-10 membered heterocondensed ring; 3-8 membered heterocycle independently contains 1, 2, 3 or 4 heteroatoms selected from N, O, or S at each occurrence; each R 4 is independently optionally substituted or unsubstituted by 1, 2, 3, 4, 5 or 6 substituents selected from deuterium, halogen, C 1-6 alkyl, -C 1-6 alkoxy, oxo, OC 1-6 alkyl, C 3-6 carbocyclyl, 3-10 membered heterocycle;
    U选3-8元环烷基、3-8元杂环烷基、5-12元稠烷基、5-12元稠杂环基、5-12元螺环基、5-12元螺杂环基、芳香基或者杂芳香基，每个杂环烷基、稠杂环基、螺杂环基、杂芳香基在每次出现时独立地包含1、2、3或4个选自N、O、或S的杂原子，其中所述环烷基、杂环烷基、螺环基、稠环基、稠杂环基、螺杂环基、芳香基或者杂芳香基任选被一个或多个G1所取代；G is selected from 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 5-12 membered fused alkyl, 5-12 membered fused heterocyclyl, 5-12 membered spirocyclyl, 5-12 membered spiroheterocyclyl, aromatic or heteroaromatic, each heterocycloalkyl, fused heterocyclyl, spiroheterocyclyl, heteroaromatic independently containing 1, 2, 3 or 4 heteroatoms selected from N, O or S at each occurrence, wherein the cycloalkyl, heterocycloalkyl, spirocyclyl, fused cyclyl, fused heterocyclyl, spiroheterocyclyl, aromatic or heteroaromatic is optionally substituted with one or more G;
    G1各自独立选自氘、氰基，卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或3-8元杂环基、C6-10芳基、5-10元杂芳香基、-OR5、-OC(O)NR5R6、-C(O)OR5、-C(O)NR5R6、-C(O)R5、-NR5R6、-NR5C(O)R6、-NR5C(O)NR6R7、-S(O)iR5或-NR5S(O)iR6，其中所述烷基、烯基、炔基、环烷基、杂环烷基、芳香基、杂芳香基任选被1个或多个氘、氰基，卤素、C1-7烷基、C2-7烯基、C2-7炔基、C3-9环烷基或3-9元杂环基、C7-10芳基、6-10元杂芳香基、-OR8、-OC(O)NR8R9、-C(O)OR8、-C(O)NR8R9、-C(O)R8、-NR8R9、-NR8C(O)R9、-NR8C(O)NR9R10、-S(O)iR8或-NR8S(O)iR9的取代基所取代； G1 is each independently selected from deuterium, cyano, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaromatic, -OR5 , -OC(O) NR5R6 , -C(O) OR5 , -C(O ) NR5R6 , -C(O) R5 , -NR5R6 , -NR5C(O) R6 , -NR5C (O) NR6R7 , -S(O) iR5 or -NR5S (O) iR6 , wherein the alkyl, alkenyl , alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaromatic is optionally substituted by one or more deuterium, cyano, halogen, C1-7 alkyl, C2-7 alkenyl , C2-7 alkynyl, C The group is substituted by a 3-9- membered cycloalkyl group or a 3-9-membered heterocyclyl group, a C 7-10 aryl group, a 6-10-membered heteroaryl group, -OR 8 , -OC(O)NR 8 R 9 , -C(O)OR 8 , -C(O)NR 8 R 9 , -C(O)R 8 , -NR 8 R 9 , -NR 8 C(O)R 9 , -NR 8 C(O)NR 9 R 10 , -S(O) i R 8 or -NR 8 S(O) i R 9 ;
    R5、R6、R7、R8、R9和R10各自独立选自氢、氘、氰基、卤素、C1-6烷基、C3-8环烷基或3-8元单环杂环基、单环杂芳香基或者苯基；R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from hydrogen, deuterium, cyano, halogen, C 1-6 alkyl, C 3-8 cycloalkyl or 3-8 membered monocyclic heterocyclic group, monocyclic heteroaromatic group or phenyl;
    且i为1或2。And i is 1 or 2.
  3. 根据权利要求1-2所述的通式(I)和(II)的化合物、其药学上可接受的盐或其立体异构体，其选自：


    The compound of the general formula (I) and (II) according to claim 1-2, its pharmaceutically acceptable salt or its stereoisomer, which is selected from:


  4. 权利要求1-3任一所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，其特征在于，所述的药学上可接受的盐选自下组：钾盐、钠盐、镁盐、钙盐、硫酸盐、盐酸盐、磷酸盐、磺酸盐，或碳酸盐。The compound according to any one of claims 1 to 3, or its optical isomers, pharmaceutically acceptable salts, prodrugs, deuterated derivatives, hydrates, solvates, characterized in that the pharmaceutically acceptable salt is selected from the group consisting of potassium salts, sodium salts, magnesium salts, calcium salts, sulfates, hydrochlorides, phosphates, sulfonates, or carbonates.
  5. 一种药物组合物，其特征在于，包含权利要求1至4中任一项所述的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物，以及药学上可接受的载体。A pharmaceutical composition, characterized in that it comprises the compound according to any one of claims 1 to 4, or its optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, solvate, and a pharmaceutically acceptable carrier.
  6. 一种权利要求1至4中任一项的化合物，或其光学异构体，药学上可接受的盐，前药，氘代衍生物，水合物，溶剂合物的用途，其特征在于，用于制备治疗与KRas,KRas G12A,KRas G12C,KRas G12D,KRas G12R,KRas G12S,KRas G12V,KRas G13D or KRas Q61H活性或表达量相关的疾病，病症或病状的药物组合物。A use of a compound according to any one of claims 1 to 4, or an optical isomer, pharmaceutically acceptable salt, prodrug, deuterated derivative, hydrate, or solvate thereof, characterized in that it is used to prepare a pharmaceutical composition for treating a disease, disorder, or condition associated with the activity or expression of KRas, KRas G12A, KRas G12C, KRas G12D, KRas G12R, KRas G12S, KRas G12V, KRas G13D or KRas Q61H.
  7. 如权利要求6所述的用途，其特征在于，所述疾病，病症或病状选自下组：胰腺癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、结肠癌、结直肠癌、甲状腺癌、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、黑色素瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征多发性、骨髓癌等各种实体瘤和血液瘤。 The use according to claim 6, characterized in that the disease, disorder or condition is selected from the group consisting of pancreatic cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, colon cancer, colorectal cancer, thyroid cancer, embryonal rhabdomyosarcoma, cutaneous granular cell tumor, melanoma, liver cancer, rectal cancer, bladder cancer, pharyngeal cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly, polycythemia vera, multiple myeloma, myeloma and other solid tumors and hematological tumors.
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