WO2023116763A1 - Pyridazine compound, and pharmaceutical composition and use thereof - Google Patents

Pyridazine compound, and pharmaceutical composition and use thereof Download PDF

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WO2023116763A1
WO2023116763A1 PCT/CN2022/140697 CN2022140697W WO2023116763A1 WO 2023116763 A1 WO2023116763 A1 WO 2023116763A1 CN 2022140697 W CN2022140697 W CN 2022140697W WO 2023116763 A1 WO2023116763 A1 WO 2023116763A1
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optionally substituted
alkyl
substituted
compound
group
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PCT/CN2022/140697
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Chinese (zh)
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陈旭星
陈艳红
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上海优理惠生医药有限公司
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Publication of WO2023116763A1 publication Critical patent/WO2023116763A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to a pyridazine compound, its pharmaceutical composition and application.
  • Rat sarcoma protein is an important signal transduction regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration and survival.
  • RAS belongs to guanosine triphosphate hydrolase (GTPase), and regulates the downstream RAF/MEK/ Several important signaling pathways such as ERK and PI3K/AKT.
  • GTPase guanosine triphosphate hydrolase
  • This cycle includes two processes, in which the negative regulation catalyzes the hydrolysis of RAS-GTP to RAS-GDP through GTPase-activating protein (GAP), and the positive regulation guanylate exchange factor (GEF) catalyzes the dissociation of RAS from GDP, followed by RAS Will bind to the high concentration of GTP in the cell.
  • GAP GTPase-activating protein
  • GEF positive regulation guanylate exchange factor
  • the RAS protein family includes KRAS (kirsten rat sarcoma viral oncogene), NRAS (neuroblastoma RAS viral oncogene) and HRAS (Harvey murine sarcoma viral oncogene), among which the tumors caused by KRAS mutations are the most common.
  • KRAS mutation causes the protein to remain in the RAS-GTP state, continuously activating downstream signaling pathways, and SOS1 plays an important role in this cancer-causing physiological process. Knockdown of SOS1 effectively reduced the growth rate of KRAS mutant tumors and did not affect the growth of KRAS wild-type cell lines.
  • Small-molecule inhibitors bind to the catalytic pocket of SOS1, affect the binding of SOS1 and RAS protein, and can effectively inhibit the phosphorylation level of downstream RAS signaling pathways such as ERK (extracellular regulated protein kinases), thereby inhibiting tumor growth.
  • ERK extracellular regulated protein kinases
  • the purpose of the present invention is to provide a new pyridazine compound and a pharmaceutical composition containing it, which can effectively inhibit the interaction between SOS1 and RAS mutein.
  • the first aspect of the present invention provides a compound represented by formula I, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, Solvates, polymorphs, deuterated compounds or combinations thereof,
  • X 1 is selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; Preferably, X 1 is CH;
  • X 2 is selected from: sulfur atom, oxygen atom, nitrogen atom, -NR x - or -CR x ,; wherein, R x is selected from: H, optionally substituted C1-C3 alkyl; preferably, X 2 is sulfur Atom; wherein, the substitution refers to being substituted by one or more R;
  • R is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, cyano, wherein, R 1a and R 1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclic group; wherein, The substitution refers to being substituted by one or more R;
  • R 2 is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being replaced by one or more R replaces;
  • Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16 Member heterocycle and C6-C10 aryl, optionally substituted C3-C16 carbocycle and 5-16 member heteroaryl or optionally substituted 4-16 member heterocycle and 5-16 member heteroaryl; wherein, The above substitution refers to being substituted by one or more R;
  • Each R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo
  • the R 1 is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclyl, preferably, R 1 is selected from: H, halogen or methyl; wherein, the substitution refers to substitution by one or more R, and the definition of R is as above.
  • the A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic and C6-C10 aryl Base, optionally substituted 4-8 membered heterocycle and C6-C10 aryl, optionally substituted C3-C8 carbocycle and 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocycle and 5- 10-membered heteroaryl; preferably ring A is optionally substituted phenyl, 5-6-membered heteroaryl, optionally substituted C3-C8 carbocyclophenyl, optionally substituted 4-8-membered heterocyclic Phenyl, optionally substituted C3-C8 carbocyclic and 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic and 5-6 membered heteroaryl; more preferably, ring A is selected from: any Optionally substituted phenyl, optionally substituted 5-10
  • the A ring is wherein, q is 0, 1, 2, 3 or 4, and each R d is independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl Or an optionally substituted 5-16 membered heteroaryl group, or any adjacent 2 R d and the carbon atom connected to it form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbon ring group;
  • substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo R'substituted or unsubstituted C1-C6 alkyl, R'substituted or unsubstituted C1-C6 alkoxy, R'substituted or unsubstituted C1-C6 alkylsulfone, R'substituted or unsubstituted C3 -C16 carbocyclyl, R'substituted or unsubstituted 4-16 membered heterocyclic group, -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted Substituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), wherein,
  • the A ring is selected from:
  • R d1 , R d2 , R d3 are independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally Substituted C1-C6 alkylsulfone group, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 Member heteroaryl;
  • R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl and q is 0, 1, 2 or 3;
  • R d5 is selected from: hydrogen, optionally substituted C6-C10 membered aromatic group or optionally substituted 5-16 membered heteroaromatic ring group;
  • Z is selected from: O or NR N ;
  • R N is selected from: H or optionally substituted C1-C6 alky
  • substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl sulfone, C3-C16 carbocyclyl, 4-16 membered heterocyclic group, -N(R' substituted or Unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), where R' One or more groups selected from the group consisting of H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;
  • ring A is wherein, R d5a and R d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R d5a , R d5b and connected N atoms form a 4-8 membered heterocyclic group; R d5c is selected from : H, halogen or substituted or unsubstituted C1-C3 alkyl;
  • substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo C1-C6 alkyl and C1-C6 alkoxy;
  • R 2 is Wherein, X 3 is selected from: CR 2' or N;
  • R2 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • R 2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, Difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl;
  • Ring B is selected from: optionally substituted C3-C16 carbocyclic group or optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R; the definition of R is as above;
  • ring B is selected from: optionally substituted C3-C11 carbocyclyl or optionally substituted 4-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5- C11 carbocyclyl or optionally substituted 5-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5-C8 carbocyclic group or optionally substituted 5-8 membered heterocyclic group, more preferably
  • ring B is an optionally substituted 6-membered heterocyclic group, such as, optionally substituted tetrahydropyranyl Optionally substituted piperidinyl
  • the substitution refers to substitution by one or more R; the definition of R is as above.
  • ring B is selected from: optionally substituted 4-6 membered monocyclic heterocyclic group or optionally substituted 7-11 membered spiro heterocyclic group or optionally substituted 7-11 membered bridged heterocyclic group group, wherein the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkane Base, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH 2 ) 1-2 C3-C6 cycloalkyl, (CH 2 ) 1-2 4-6 membered heterocyclyl , C(O)C1-C6 alkyl, C(O)C1-C6 alkoxy, C(O)C3-C6 cycloalkyl, C(O)4-6 membered heterocyclyl, CONH(C
  • R is selected from:
  • X 1 , X 2 , R 1 , R 2 , ring A, ring B and R 2' are groups corresponding to specific compounds in the examples.
  • the compound is selected from the following group:
  • the present invention provides a compound represented by formula II, or a salt, solvate, polymorph or deuterated product thereof,
  • a pharmaceutical composition wherein the pharmaceutical composition comprises:
  • a therapeutically effective amount selected from the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, One or more of solvates, polymorphs and deuterated compounds as active ingredients; and
  • the fourth aspect of the present invention provides the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, Use of the solvate, polymorph or deuterated product or the pharmaceutical composition described in the third aspect in the preparation of a medicament for preventing or treating cancer mediated by RAS mutation.
  • the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovium Sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, especially selected from non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
  • the term “comprises” or “includes (comprising)” can be open, semi-closed and closed. In other words, the term also includes “consisting essentially of”, or “consisting of”.
  • reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein.
  • the techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
  • C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms.
  • the total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.
  • halogen means fluorine, chlorine, bromine or iodine.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below substituted with a hydroxyl group (-OH).
  • Niro means -NO2 .
  • Amino refers to -NH2 .
  • Substituted amino means an amino group substituted by one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, Alkylamido, arylalkylamino, heteroarylalkylamino.
  • Carboxy means -COOH.
  • alkyl refers to a fully saturated straight-chain or branched hydrocarbon chain group, Consists solely of carbon and hydrogen atoms, has for example 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is connected to the rest of the molecule by 1 or more single bonds, Examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2- Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, etc.
  • alkyl refers to a fully saturated straight-chain or branched hydrocarbon chain group, Consists solely of carbon and hydrogen atoms, has for example 1 to 12 (preferably 1 to 8, more preferably 1 to 6)
  • alkenyl as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and is connected to the rest of the molecule by 1 or more single bonds, such as but not limited to vinyl, propenyl, alkenyl Propyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
  • alkynyl herein, as a group or part of another group, means consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by 1 or more single bonds, straight or branched hydrocarbon chain groups, such as but not limited to ethynyl, 1-propyne base, 1-butynyl, heptynyl, octynyl, etc.
  • the term "carbocycle (group)” means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed only of carbon atoms and hydrogen atoms, which may include A fused, bridged or spiro ring system having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and It is a saturated or unsaturated ring (ie cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule by 1 or more single bonds via any suitable carbon atom.
  • a fused, bridged or spiro ring system having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and It is a saturated or unsaturated ring (ie cycloalkyl, cycloalkenyl, etc.) and can be connected to the
  • carbocyclyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-indanyl, octahydro-4, 7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclo Hexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5 ,6,7,8,9
  • cycloalkyl refers to the above-mentioned fully saturated carbocycle (group), preferably C3-C6 cycloalkyl.
  • Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
  • cycloalkenyl refers to a partially unsaturated carbocyclic (group)
  • typical cycloalkenyl groups include but not limited to cyclobutenyl, cyclopentenyl alkenyl, cyclohexenyl, etc.
  • heterocycle (group) means 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Composed of stable 3- to 20-membered non-aromatic cyclic groups.
  • the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon, or sulfur atoms of can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl can be partially or fully saturated.
  • a heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and via 1 or more single bonds.
  • one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl , 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] Heptane-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolyl, tetrahydroisoquinyl Linyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinozinyl, thiazolidinyl, isothiazo
  • aryl as a group or part of another group, means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a carbocyclyl or heterocyclyl as defined above, provided that the aryl is via The atoms in the aromatic ring are connected to the rest of the molecule by 1 or more single bonds.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group, means having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 carbon atoms selected from the group consisting of nitrogen A 5- to 16-membered conjugated ring system group of heteroatoms of oxygen and sulfur.
  • heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may also be fused to a carbocyclyl or heterocyclyl as defined above, provided that the heteroaryl An aryl group is attached to the rest of the molecule by one or more single bonds through atoms on the heteroaromatic ring.
  • a nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridine Base, phena
  • heteroarylalkyl refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.
  • absent means that the two sides of the group defined above are directly connected by a chemical bond.
  • B is absent in A-B-C
  • A-C means "A-C”.
  • substituents When an atom or group is substituted by multiple substituents, the substituents may be the same or different.
  • the terms “moiety”, “structural moiety”, “chemical moiety”, “group”, “chemical group” refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules. In the present invention, “optionally substituted” and “substituted or unsubstituted” have the same meaning and can be used interchangeably.
  • (C1-C4 alkyl) 2 amino represents 2 C1-C4 alkyl substituted amines, such as wait.
  • Multiple in the present invention means 2, 3 or 4.
  • C(O)OC1-C6 alkyl namely Represents a C1-C6 alkyl substituted ester group, such as
  • N(C1-C6 alkyl) 2 or called (C1-C6 alkyl) 2 amino, represents that two hydrogens on NH 2 are replaced by 2 C1-C6 alkyl groups, for example, it can be wait.
  • Intermediates refer to semi-finished products, which are products formed in the process of producing the required products.
  • inventors can proceed with the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby achieving the purpose of increasing yield, saving time and cost.
  • the intermediate refers to the following compounds
  • R 1 , X 1 , and X 2 are as above.
  • the intermediate is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the preparation method of the intermediate comprises steps:
  • compound a-1 is reacted with a cyanide reagent (such as cuprous cyanide) to obtain compound a-2;
  • a cyanide reagent such as cuprous cyanide
  • compound a-2 is reacted with hydrazine or a salt thereof (such as hydrazine hydrochloride) to obtain compound a-3;
  • compound a-3 is reacted in the presence of nitrite (tert-butyl nitrite) and cuprous chloride to obtain compound a.
  • a solvent such as acetonitrile
  • reaction time and reaction temperature can be selected according to the specific reactants.
  • compound of the present invention or “active ingredient” refers to the compound shown in formula I, and also includes its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer isomers, cis-trans isomers, solvates, polymorphs, deuteriums, or combinations thereof.
  • Stepoisomer refers to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures.
  • the present invention will encompass each stereoisomer and mixtures thereof.
  • the compounds of the present invention are intended to include both E- and Z-geometric isomers.
  • Tautomer refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.
  • the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
  • the preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects.
  • Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.
  • organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine,
  • the functional groups of intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • compositions and methods of administration are provided.
  • a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • the compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases.
  • the administration method and dose of the original drug can be kept unchanged, and the compound of formula I can be administered simultaneously or subsequently.
  • the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used.
  • Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time.
  • the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
  • Drugs or active ingredients that can be combined with the compound described in general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors ( Such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.), KRAS inhibitors ( Such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib , erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as soraf
  • 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 nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the "tumor” mentioned in the present invention includes but not limited to lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, Endometrioma, stomach cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer and other diseases.
  • the terms “prophylactic”, “prevention” and “prevention” include reducing the likelihood of a disease or condition occurring or worsening in a patient.
  • treatment and other similar synonyms include the following meanings:
  • a therapeutically effective amount refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system.
  • a therapeutically “effective amount” is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
  • administering refers to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
  • the terms “pharmaceutical combination”, “drug combination”, “combination”, “administration of other treatments”, “administration of other therapeutic agents” and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, It includes both fixed and non-fixed combinations of active ingredients.
  • the term “fixed combination” refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form.
  • variable combination refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
  • the pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier.
  • safe and effective dose refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose.
  • the "one dose” is a capsule or tablet.
  • the functional groups of intermediate compounds may need to be protected by appropriate protecting groups.
  • Such functional groups include hydroxyl, amino, mercapto and carboxylic acid.
  • Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, allyl, etc.
  • Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyloxycarbonyl , p-toluenesulfonyl, pivaloyl, trifluoroacetyl, etc.
  • Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C).
  • the reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
  • the compound of formula I can be prepared by the following method:
  • Compound a and b-1 undergo Friedel-Crafts acylation in the presence of a Lewis acid to generate compound c, and the Lewis acid is selected from: aluminum trichloride, tin dichloride, zinc chloride, boron trifluoride , titanium tetrachloride, titanium tetraisopropyloxide, etc.; or compound a reacts with compound b-2 in the presence of a strong base to generate compound c, and the strong base is from the following group: n-butyllithium, diisopropyl Lithium amide, tert-butyllithium, sec-butyllithium, lithium hexamethyldisilazide, or combinations thereof;
  • the aromatic nucleophilic substitution reaction between compound c and compound d generates compound I
  • the reducing agent is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydrogen Potassium oxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate , sodium phosphate, potassium phosphate, triethylamine, diisopropylethylamine, 1.8-diazabicyclo[5.4.0]undecane-7-ene, or a combination thereof; or compound c and compound d occur Buchwald-Hartwig reaction generates compound I;
  • the compound of the application can effectively inhibit the binding of SOS1 and RAS protein
  • the compound of the present application has better pharmacokinetics and pharmacodynamics.
  • 1 H NMR is recorded by a BRUKER AVANCE NEO 400MHz nuclear magnetic resonance instrument, and the chemical shift is expressed in ⁇ (ppm); -M20A, CBM-20A, LCMS-2020 type mass spectrometer records; preparative HPLC separation using Gilson-281 type liquid chromatograph.
  • Embodiment 1415,17 synthetic compound 14,15 and 17 are identical to Embodiment 14,15,17 synthetic compound 14,15 and 17
  • Embodiment 30 synthetic compound 30
  • KRAS (G12C) mutant protein was purchased from Pujian Biotechnology Co., Ltd.
  • SOS1 protein was purchased from Cytoskeleton Co., Ltd.
  • labeled antibodies Mab Anti 6HIS-XL665 and Mab Anti GST-Eu cryptate were purchased from Cisbio;
  • the stock solution concentration of the compound is 1000 ⁇ mol/L starting, 5-fold dilution, set 8 gradient concentrations, use 1-fold concentration buffer solution to dilute each gradient of the compound to be tested into 2% DMSO working solution, add 5 ⁇ L/well to the corresponding well , each concentration is set to duplicate hole detection.
  • the IC 50 of the compound was calculated with Graphpad software. The results are shown in Table 1.
  • test compound IC 50 (nM) Example 1 389.4 Example 2 62.78 Example 3 340.90 Example 4 125.70 Example 5 123.30 Example 6 340.40 Example 7 25.85 Example 8 50.89 Example 9 18.96
  • Example 10 81.84 Example 11 73.93 Example 12 152.9 Example 13 38.62 Example 14 572.60 Example 15 75.60 Example 16 105.80 Example 18 113.20 Example 19 102.60 Example 20 44.04 Example 21 36.21 Example 22 45.17 Example 23 224.1 Example 24 69.57 Example 25 89.75 Example 26 242.2 Example 27 92.95 Example 28 111.7 Example 29 239.8 Example 30 99.27 Example 31 387.8 Example 32 193.7 Example 33 221.5 Example 35 130.7 Example 36 44.88 Example 37 195.0 Example 38 31.59
  • the present invention illustrates the pyridazine compounds, pharmaceutical compositions containing them and their applications through the above examples, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above implementation example can be implemented.
  • Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

Abstract

Provided are a pyridazine compound, and a pharmaceutical composition and the use thereof. Specifically, the compound has a structure as shown in formula (I), can interfere with the interaction between an SOS1 protein and an RAS protein, and is expected to be used in the preparation of a drug for treating diseases such as tumors with RAS mutations.

Description

一种哒嗪类化合物、其药物组合物及应用A kind of pyridazine compound, its pharmaceutical composition and application 技术领域technical field
本发明属于药物化学领域，具体涉及一种哒嗪类化合物、其药物组合物及应用。The invention belongs to the field of medicinal chemistry, and in particular relates to a pyridazine compound, its pharmaceutical composition and application.
背景技术Background technique
大鼠肉瘤蛋白(RAS蛋白)是人体内重要的信号传导调节因子，调控包括细胞增殖、分化、迁移和生存等重要生理过程。RAS属于三磷酸鸟苷水解酶(GTPase)，通过RAS与三磷酸鸟苷(GTP)结合的活性状态和RAS与二磷酸鸟苷(GDP)结合的失活状体的循环调控下游RAF/MEK/ERK和PI3K/AKT等多条重要的信号通路。这一循环包括两个过程，其中负向调节通过GTPase激活蛋白(GAP)催化RAS-GTP水解为RAS-GDP，正向调节的鸟苷酸交换因子(GEF)催化RAS与GDP解离，随后RAS会与细胞内高浓度的GTP结合。SOS1(Son of Sevenless 1)是人体内表达最广泛，功能最重要的GEF之一。Rat sarcoma protein (RAS protein) is an important signal transduction regulator in the human body, regulating important physiological processes including cell proliferation, differentiation, migration and survival. RAS belongs to guanosine triphosphate hydrolase (GTPase), and regulates the downstream RAF/MEK/ Several important signaling pathways such as ERK and PI3K/AKT. This cycle includes two processes, in which the negative regulation catalyzes the hydrolysis of RAS-GTP to RAS-GDP through GTPase-activating protein (GAP), and the positive regulation guanylate exchange factor (GEF) catalyzes the dissociation of RAS from GDP, followed by RAS Will bind to the high concentration of GTP in the cell. SOS1 (Son of Sevenless 1) is one of the most widely expressed and functionally important GEFs in the human body.
RAS蛋白家族包括KRAS(kirsten rat sarcoma viral oncogene)，NRAS(neuroblastoma RAS viral oncogene)和HRAS(Harvey murine sarcoma viral oncogene)，其中KRAS突变导致的肿瘤最为常见。KRAS突变导致蛋白一直处于RAS-GTP的状态，持续激活下游信号通路，在这一致癌生理过程中SOS1扮演这重要的角色。敲除SOS1能有效降低KRAS突变肿瘤的生长速度，并且不影响KRAS野生型细胞系的生长。The RAS protein family includes KRAS (kirsten rat sarcoma viral oncogene), NRAS (neuroblastoma RAS viral oncogene) and HRAS (Harvey murine sarcoma viral oncogene), among which the tumors caused by KRAS mutations are the most common. The KRAS mutation causes the protein to remain in the RAS-GTP state, continuously activating downstream signaling pathways, and SOS1 plays an important role in this cancer-causing physiological process. Knockdown of SOS1 effectively reduced the growth rate of KRAS mutant tumors and did not affect the growth of KRAS wild-type cell lines.
小分子抑制剂结合在SOS1的催化口袋，影响SOS1与RAS蛋白的结合，可以有效的抑制RAS信号通路下游如ERK(extracellular regulated protein kinases)磷酸化水平，从而抑制肿瘤的生长。目前，勃林格殷格翰公司开发的小分子SOS1抑制剂BI-1701963(WO2018115380，WO2019122129)正处于I期临床研究阶段，并且与Mirati公司的KRAS G12C抑制剂MRTX-849合作开发联合用药的方案。此外，拜耳公司(WO2018172250，WO2019201848)和Revolution公司(WO2020180770，WO2020180768)也在这一领域发表了多篇专利，但是本领域仍然迫切需要研发出能够抑制SOS1与RAS突变蛋白相互作用的有效药物。Small-molecule inhibitors bind to the catalytic pocket of SOS1, affect the binding of SOS1 and RAS protein, and can effectively inhibit the phosphorylation level of downstream RAS signaling pathways such as ERK (extracellular regulated protein kinases), thereby inhibiting tumor growth. Currently, the small-molecule SOS1 inhibitor BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim is in Phase I clinical research, and is working with Mirati’s KRAS G12C inhibitor MRTX-849 to develop a combined drug regimen. In addition, Bayer (WO2018172250, WO2019201848) and Revolution (WO2020180770, WO2020180768) have also published a number of patents in this field, but there is still an urgent need in this field to develop effective drugs that can inhibit the interaction between SOS1 and RAS mutant proteins.
发明内容Contents of the invention
本发明目的是提供一种新的哒嗪类化合物和包含其的药物组合物，其可以有效抑制SOS1与RAS突变蛋白相互作用。The purpose of the present invention is to provide a new pyridazine compound and a pharmaceutical composition containing it, which can effectively inhibit the interaction between SOS1 and RAS mutein.
本发明的第一方面，提供一种式I所示的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，The first aspect of the present invention provides a compound represented by formula I, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, Solvates, polymorphs, deuterated compounds or combinations thereof,
Figure PCTCN2022140697-appb-000001
Figure PCTCN2022140697-appb-000001
其中，in,
X 1选自：CH、氧原子、硫原子、氮原子或-NH；优选地，X 1为CH； X 1 is selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; Preferably, X 1 is CH;
X 2选自：硫原子、氧原子、氮原子、-NR x-或-CR x、；其中，R x选自：H、任选取代的C1-C3烷基；优选地，X 2为硫原子；其中，所述取代是指被一个或多个R取代； X 2 is selected from: sulfur atom, oxygen atom, nitrogen atom, -NR x - or -CR x ,; wherein, R x is selected from: H, optionally substituted C1-C3 alkyl; preferably, X 2 is sulfur Atom; wherein, the substitution refers to being substituted by one or more R;
R 1选自：H、卤素、任选取代的C1-C3烷基、任选取代的C3-C8碳环基、任选取代的4-8元杂环基、氰基、
Figure PCTCN2022140697-appb-000002
其中，R 1a和R 1b各自独立地选自：H、任选取代的C1-C6烷基、任选取代的C3-C8碳环基或任选取代的4-8元杂环基；其中，所述取代是指被一个或多个R取代； R is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, cyano,
Figure PCTCN2022140697-appb-000002
Wherein, R 1a and R 1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclic group; wherein, The substitution refers to being substituted by one or more R;
R 2选自：任选取代的C1-C6烷基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基；其中，所述取代是指被一个或多个R取代； R 2 is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being replaced by one or more R replaces;
A环选自：任选取代的C6-C16芳基、任选取代的5-16元杂芳基、任选取代的C3-C16碳环并C6-C10芳基、任选取代的4-16元杂环并C6-C10芳基、任选取代的C3-C16碳环并5-16元杂芳基或任选取代的4-16元杂环并5-16元杂芳基；其中，所述取代是指被一个或多个R取代；Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16 Member heterocycle and C6-C10 aryl, optionally substituted C3-C16 carbocycle and 5-16 member heteroaryl or optionally substituted 4-16 member heterocycle and 5-16 member heteroaryl; wherein, The above substitution refers to being substituted by one or more R;
R各自独立地选自：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000003
任选取代的C1-C6烷基、任选取代的C2-C6烯基、任选取代的C2-C6炔基、任选取代的C1-C6烷氧基、-N(任选取代的C 1-C 6烷基) 2、NH(任选取代的C 1-C 6烷基)、-N(任选取代的C 1-C 6烷基)(任选取代的C 1-C 6烷基苯基)、-NH(任选取代的C 1-C 6烷基苯基)、任选取代的C1-C6烷基-S-、-S(O) 2-任选取代的C1-C6烷基、-S(O)-任选取代的C1-C6烷基、-S(O) 2-任选取代的苯基、-S(O) 2NH 2、-S(O) 2NH(任选取代的C1-C6烷基)、-S(O) 2NH(任选取代的苯基)、-NHS(O) 2(任选取代的C1-C6烷基)、-NHS(O) 2(任选取代的苯基)、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基；或任意相邻的2个R和与其相连的原子形成任选取代的4-8元杂环基或任选取代的C3-C8元碳环基；其中，R中所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000004
R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基砜基、R’取代或未取代的C3-C16碳环基、R’取代或未取代的4-16元杂环基、R’取代或未取代的C6-C16芳基、R’取代或未取代的5-16元杂芳基、-N(R’ 取代或未取代的C1-C6烷基) 2、-CH 2-N(R’取代或未取代的C1-C6烷基) 2，其中，R’选自下组的一个或多个基团：H、卤素、氘(D)、卤素、-OH、氧代(＝O)、巯基、氰基、-CD 3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基和4-8元杂环基，其中所述的烷基、烯基、炔基、环烷基和杂环基中的每一个任选被一个或多个选自以下的取代基进一步取代：H、C1-C6烷基、C1-C6烷氧基、卤素、-OH、氧代(＝O)、-NH 2、-N(R”取代或未取代的C1-C6烷基) 2、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、C3-C8环烷基、4-8元杂环基、C1-C4卤代烷基-、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基) 2、-CONH(C1-C6烷基)、-CONH 2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO 2(C1-C6烷基)、-SO 2(苯基)、-SO 2(C1-C6卤代烷基)、-SO 2NH 2、-SO 2NH(C1-C6烷基)、-SO 2NH(苯基)、-NHSO 2(C1-C6烷基)、-NHSO 2(苯基)、-NHSO 2(C1-C6卤代烷基)和-C1-C6烷基-NH 2，其中R”选自下组的一个或多个基团：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000005
C1-C6烷基和C1-C6烷氧基； Each R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000003
Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -N (optionally substituted C1 -C 6 alkyl) 2 , NH (optionally substituted C 1 -C 6 alkyl), -N (optionally substituted C 1 -C 6 alkyl) (optionally substituted C 1 -C 6 alkyl phenyl), -NH (optionally substituted C 1 -C 6 alkylphenyl), optionally substituted C1-C6 alkyl-S-, -S(O) 2 -optionally substituted C1-C6 alkane -S(O)-optionally substituted C1-C6 alkyl, -S(O) 2 -optionally substituted phenyl, -S(O) 2 NH 2 , -S(O) 2 NH (any Optionally substituted C1-C6 alkyl), -S(O) 2 NH (optionally substituted phenyl), -NHS(O) 2 (optionally substituted C1-C6 alkyl), -NHS(O) 2 (optionally substituted phenyl), optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered Heteroaryl; or any adjacent 2 R and the atom connected to it form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein, the substitution in R is means substituted by one or more groups selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000004
R'substituted or unsubstituted C1-C6 alkyl, R'substituted or unsubstituted C1-C6 alkoxy, R'substituted or unsubstituted C1-C6 alkylsulfone, R'substituted or unsubstituted C3 -C16 carbocyclyl, R'substituted or unsubstituted 4-16 membered heterocyclic group, R'substituted or unsubstituted C6-C16 aryl group, R'substituted or unsubstituted 5-16 membered heteroaryl group,- N(R' substituted or unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R' substituted or unsubstituted C1-C6 alkyl) 2 , wherein R' is selected from one or more of the following groups Groups: H, halogen, deuterium (D), halogen, -OH, oxo (=O), mercapto, cyano, -CD 3 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 Alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally Further substituted with one or more substituents selected from the group consisting of: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH2 , -N(R" Substituted or unsubstituted C1-C6 alkyl) 2 , -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkyl Phenyl), -N(C1-C6 alkyl) (aryl), -NH (aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclyl, C1-C4 haloalkyl-, -C1- C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 Alkyl, -CON(C1-C6 alkyl) 2 , -CONH(C1-C6 alkyl), -CONH 2 , -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl) C(O)(C1-C6 alkyl), -SO 2 (C1-C6 alkyl), -SO 2 (phenyl), -SO 2 (C1-C6 haloalkyl), -SO 2 NH 2 , -SO 2 NH (C1-C6 alkyl), -SO 2 NH (phenyl), -NHSO 2 (C1-C6 alkyl), -NHSO 2 (phenyl), -NHSO 2 (C1-C6 haloalkyl) and - C1-C6 alkyl-NH 2 , wherein R" is selected from one or more groups of the following group: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000005
C1-C6 alkyl and C1-C6 alkoxy;
Figure PCTCN2022140697-appb-000006
表示基团的连接位置。
Figure PCTCN2022140697-appb-000006
Indicates the attachment position of the group.
在另一优选例中，所述R 1选自：H、卤素、任选取代的C1-C3烷基或任选取代的C3-C8碳环基，优选地，R 1选自：H、卤素或甲基；其中，所述取代是指被一个或多个R取代，R的定义如上所述。 In another preferred example, the R 1 is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclyl, preferably, R 1 is selected from: H, halogen or methyl; wherein, the substitution refers to substitution by one or more R, and the definition of R is as above.
在另一优选例中，所述A环选自：任选取代的C6-C10芳基、任选取代的5-10元杂芳基、任选取代的C3-C8碳环并C6-C10芳基、任选取代的4-8元杂环并C6-C10芳基、任选取代的C3-C8碳环并5-10元杂芳基或任选取代的4-8元杂环并5-10元杂芳基；优选地A环为任选取代的苯基、5-6元杂芳基、任选取代的C3-C8碳环并苯基、任选取代的4-8元杂环并苯基、任选取代的C3-C8碳环并5-6元杂芳基或任选取代的4-8元杂环并5-6元杂芳基；更优选地，A环选自：任选取代的苯基、任选取代的吡啶基、任选取代的吡嗪基、任选取代的噻吩基、任选取代的呋喃基、任选取代的吡咯基、任选取代的噻唑基、任选取代的咪唑基、任选取代的吡唑基；其中，所述取代是指被一个或多个R取代；R的定义如上所述。In another preferred example, the A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic and C6-C10 aryl Base, optionally substituted 4-8 membered heterocycle and C6-C10 aryl, optionally substituted C3-C8 carbocycle and 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocycle and 5- 10-membered heteroaryl; preferably ring A is optionally substituted phenyl, 5-6-membered heteroaryl, optionally substituted C3-C8 carbocyclophenyl, optionally substituted 4-8-membered heterocyclic Phenyl, optionally substituted C3-C8 carbocyclic and 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic and 5-6 membered heteroaryl; more preferably, ring A is selected from: any Optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, any Select substituted imidazolyl, optionally substituted pyrazolyl; wherein, the substitution refers to being substituted by one or more R; the definition of R is as above.
在另一优选例中，所述A环为
Figure PCTCN2022140697-appb-000007
Figure PCTCN2022140697-appb-000008
Figure PCTCN2022140697-appb-000009
其中，q为0、1、2、3或4，每个R d各自独立的选自：H、卤素、氨基、羟基、氰基、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基，或任意相邻的2个R d和与其相连的碳原子形成任选取代的4-8元杂环基或任选取代的C3-C8元碳环基； In another preferred embodiment, the A ring is
Figure PCTCN2022140697-appb-000007
Figure PCTCN2022140697-appb-000008
Figure PCTCN2022140697-appb-000009
Wherein, q is 0, 1, 2, 3 or 4, and each R d is independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1-C6 alkylsulfone, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl Or an optionally substituted 5-16 membered heteroaryl group, or any adjacent 2 R d and the carbon atom connected to it form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbon ring group;
其中，所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000010
R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基砜基、R’取代或未取代的C3-C16碳环基、R’取代或未取代的4-16元杂环基、-N(R’取代或未取代的C1-C6烷基) 2、-CH 2-N(R’取代或未取代的C1-C6烷基) 2、和-CH 2-(4-8元杂环基)，其中，R’选自下组的一个或多个基团：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000011
C1-C6烷基和C1-C6烷氧基； Wherein, the substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000010
R'substituted or unsubstituted C1-C6 alkyl, R'substituted or unsubstituted C1-C6 alkoxy, R'substituted or unsubstituted C1-C6 alkylsulfone, R'substituted or unsubstituted C3 -C16 carbocyclyl, R'substituted or unsubstituted 4-16 membered heterocyclic group, -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted Substituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), wherein, R' is selected from one or more groups of the following group: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000011
C1-C6 alkyl and C1-C6 alkoxy;
Figure PCTCN2022140697-appb-000012
表示基团的连接位置。
Figure PCTCN2022140697-appb-000012
Indicates the attachment position of the group.
在另一优选例中，所述A环选自：In another preferred example, the A ring is selected from:
Figure PCTCN2022140697-appb-000013
Figure PCTCN2022140697-appb-000013
其中，R d1、R d2、R d3分别独立地选自：H、卤素、氨基、羟基、氰基、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基；R d4分别独立地选自：卤素、任选取代的C1-C6烷基和
Figure PCTCN2022140697-appb-000014
q为0、1、2或3；R d5选自：氢、任选取代的C6-C10元芳香基或任选取代的5-16元杂芳香环基；Z选自：O或NR N；R N选自：H或任选取代的C1-C6烷基； Wherein, R d1 , R d2 , R d3 are independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally Substituted C1-C6 alkylsulfone group, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 Member heteroaryl; R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl and
Figure PCTCN2022140697-appb-000014
q is 0, 1, 2 or 3; R d5 is selected from: hydrogen, optionally substituted C6-C10 membered aromatic group or optionally substituted 5-16 membered heteroaromatic ring group; Z is selected from: O or NR N ; R N is selected from: H or optionally substituted C1-C6 alkyl;
其中，所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000015
R’取代或未取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷基砜基、C3-C16碳环基、4-16元杂环基、-N(R’取代或未取代的C1-C6烷基) 2、-CH 2-N(R’取代或未取代的C1-C6烷基) 2、和-CH 2-(4-8元杂环基)，其中R’选自下组的一个或多个基团：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000016
C1-C6烷基和C1-C6烷氧基； Wherein, the substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000015
R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl sulfone, C3-C16 carbocyclyl, 4-16 membered heterocyclic group, -N(R' substituted or Unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), where R' One or more groups selected from the group consisting of H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000016
C1-C6 alkyl and C1-C6 alkoxy;
Figure PCTCN2022140697-appb-000017
表示基团的连接位置。
Figure PCTCN2022140697-appb-000017
Indicates the attachment position of the group.
在另一优选例中，A环为
Figure PCTCN2022140697-appb-000018
Figure PCTCN2022140697-appb-000019
Figure PCTCN2022140697-appb-000020
其中，R d5a和R d5b分别独立地选自：H或取代或未取代的C1-C3烷基，或者R d5a、R d5b和相连的N原子形成4-8元杂环基；R d5c选自：H、卤素或取代或未取代的C1-C3烷基； In another preferred embodiment, ring A is
Figure PCTCN2022140697-appb-000018
Figure PCTCN2022140697-appb-000019
Figure PCTCN2022140697-appb-000020
Wherein, R d5a and R d5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or R d5a , R d5b and connected N atoms form a 4-8 membered heterocyclic group; R d5c is selected from : H, halogen or substituted or unsubstituted C1-C3 alkyl;
其中，所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
Figure PCTCN2022140697-appb-000021
C1-C6烷基和C1-C6烷氧基； Wherein, the substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo
Figure PCTCN2022140697-appb-000021
C1-C6 alkyl and C1-C6 alkoxy;
Figure PCTCN2022140697-appb-000022
表示基团的连接位置。
Figure PCTCN2022140697-appb-000022
Indicates the attachment position of the group.
在另一优选例中，所述R 2为
Figure PCTCN2022140697-appb-000023
其中，X 3选自：CR 2’或N； In another preferred embodiment, the R 2 is
Figure PCTCN2022140697-appb-000023
Wherein, X 3 is selected from: CR 2' or N;
优选地，R 2为
Figure PCTCN2022140697-appb-000024
Preferably, R2 is
Figure PCTCN2022140697-appb-000024
R 2’选自：甲基、乙基、丙基、单氟甲基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、甲硫基、二氟甲硫基、三氟甲硫基、氰基、卤素、羟甲基或甲氧基甲基； R 2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, Difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl;
B环选自：任选取代的C3-C16碳环基或任选取代的4-16元杂环基；其中，所述取代是指被一个或多个R取代；R的定义如上所述；Ring B is selected from: optionally substituted C3-C16 carbocyclic group or optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R; the definition of R is as above;
Figure PCTCN2022140697-appb-000025
表示基团的连接位置。
Figure PCTCN2022140697-appb-000025
Indicates the attachment position of the group.
在另一优选例中，B环选自：任选取代的C3-C11碳环基或任选取代的4-11元杂环基，更优选地，B环选自：任选取代的C5-C11碳环基或任选取代的5-11元杂环基，更优选地，B环选自：任选取代的C5-C8碳环基或任选取代的5-8元杂环基，更优选地，B环为任选取代的6元杂环基，如，任选取代的四氢吡喃基
Figure PCTCN2022140697-appb-000026
任选取代的哌啶基
Figure PCTCN2022140697-appb-000027
其中，所述取代是指被一个或多个R取代；R的定义如上所述。 In another preferred example, ring B is selected from: optionally substituted C3-C11 carbocyclyl or optionally substituted 4-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5- C11 carbocyclyl or optionally substituted 5-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5-C8 carbocyclic group or optionally substituted 5-8 membered heterocyclic group, more preferably Preferably, ring B is an optionally substituted 6-membered heterocyclic group, such as, optionally substituted tetrahydropyranyl
Figure PCTCN2022140697-appb-000026
Optionally substituted piperidinyl
Figure PCTCN2022140697-appb-000027
Wherein, the substitution refers to substitution by one or more R; the definition of R is as above.
在另一优选例中，B环选自：任选取代的4-6元单环杂环基或任选取代的7-11元螺杂环基或任选取代的7-11元桥杂环基，其中，所述取代是指被选自下组的一个或多个基团取代：卤素、羟基、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、(CH 2) 1-2C3-C6环烷基、(CH 2) 1-24-6元杂环基、C(O)C1-C6烷基、C(O)C1-C6烷氧基、C(O)C3-C6环烷基、C(O)4-6元杂环基、CONH(C1-C6烷基)、CON(C1-C6烷基) 2，5-8元杂芳基，其中，所述的C1-C6烷基、C1-C6烷氧基、C3-C6环烷基、4-6元杂环基、C2-C6烯基、C2-C6炔基、5-8元杂芳基可任选地被1-3个选自下组的基团取代：卤素、羟基、氨基、氰基、NH(C1-C6烷基)、N(C1-C6烷基) 2、C1-C6烷基、C1-C6烷氧基。 In another preferred example, ring B is selected from: optionally substituted 4-6 membered monocyclic heterocyclic group or optionally substituted 7-11 membered spiro heterocyclic group or optionally substituted 7-11 membered bridged heterocyclic group group, wherein the substitution refers to being substituted by one or more groups selected from the following group: halogen, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkane Base, 4-6 membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH 2 ) 1-2 C3-C6 cycloalkyl, (CH 2 ) 1-2 4-6 membered heterocyclyl , C(O)C1-C6 alkyl, C(O)C1-C6 alkoxy, C(O)C3-C6 cycloalkyl, C(O)4-6 membered heterocyclyl, CONH(C1-C6 Alkyl), CON(C1-C6 alkyl) 2 , 5-8 membered heteroaryl, wherein, the C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 Membered heterocyclyl, C2-C6 alkenyl, C2-C6 alkynyl, 5-8 membered heteroaryl can be optionally substituted by 1-3 groups selected from the group consisting of halogen, hydroxyl, amino, cyano , NH(C1-C6 alkyl), N(C1-C6 alkyl) 2 , C1-C6 alkyl, C1-C6 alkoxy.
在另一优选例中，R 2选自：
Figure PCTCN2022140697-appb-000028
In another preference, R is selected from:
Figure PCTCN2022140697-appb-000028
Figure PCTCN2022140697-appb-000029
Figure PCTCN2022140697-appb-000029
Figure PCTCN2022140697-appb-000030
Figure PCTCN2022140697-appb-000030
在另一优选例中，X 1、X 2、R 1、R 2、A环、B环和R 2’为实施例中具体化合物所对应基团。 In another preferred example, X 1 , X 2 , R 1 , R 2 , ring A, ring B and R 2' are groups corresponding to specific compounds in the examples.
在另一优选例中，所述化合物选自下组：In another preferred embodiment, the compound is selected from the following group:
Figure PCTCN2022140697-appb-000031
Figure PCTCN2022140697-appb-000031
Figure PCTCN2022140697-appb-000032
Figure PCTCN2022140697-appb-000032
Figure PCTCN2022140697-appb-000033
Figure PCTCN2022140697-appb-000033
Figure PCTCN2022140697-appb-000034
Figure PCTCN2022140697-appb-000034
Figure PCTCN2022140697-appb-000035
Figure PCTCN2022140697-appb-000035
本发明第二方面，提供一种式II所示的化合物、或其盐、溶剂化物、多晶型物或 氘代物，In a second aspect, the present invention provides a compound represented by formula II, or a salt, solvate, polymorph or deuterated product thereof,
Figure PCTCN2022140697-appb-000036
Figure PCTCN2022140697-appb-000036
本发明第三方面，提供一种药物组合物，其中，所述药物组合物包括：In the third aspect of the present invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises:
(1)治疗有效量的选自第一方面所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物和氘代物中的一种或多种作为活性成分；和(1) A therapeutically effective amount selected from the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, One or more of solvates, polymorphs and deuterated compounds as active ingredients; and
(2)任选地，药学上可接受的载体。(2) Optionally, a pharmaceutically acceptable carrier.
本发明第四方面，提供一种第一方面所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物或第三方面所述的药物组合物在制备预防或治疗RAS突变介导的癌症的药物中的用途。The fourth aspect of the present invention provides the compound described in the first aspect, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, Use of the solvate, polymorph or deuterated product or the pharmaceutical composition described in the third aspect in the preparation of a medicament for preventing or treating cancer mediated by RAS mutation.
在另一优选例中，所述癌症选自：肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、***癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、***、头颈癌、食管癌、甲状腺癌和膀胱癌，特别是选自非小细胞肺癌、胰腺癌和结直肠癌。In another preferred example, the cancer is selected from: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovium Sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer, especially selected from non-small cell lung cancer, pancreatic cancer, and colorectal cancer.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
本发明人经过广泛而深入地研究，开发了一种新的哒嗪类化合物，其可以有效抑制SOS1与RAS突变蛋白相互作用。在此基础上完成了本发明。After extensive and in-depth research, the inventors have developed a new pyridazine compound, which can effectively inhibit the interaction between SOS1 and RAS mutein. The present invention has been accomplished on this basis.
术语说明Glossary
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the term "comprises" or "includes (comprising)" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of", or "consisting of".
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
基团定义Group definition
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH  ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。Definitions of standard chemical terms can be found in references including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods within the skill of the art, such as mass spectroscopy, NMR, IR and UV/VIS spectroscopy and pharmacological methods are employed. Unless specific definitions are set forth, terms employed herein in the relevant descriptions of analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are those that are known in the art. Standard techniques can be used in chemical syntheses, chemical analyses, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, reactions and purifications can be carried out using the manufacturer's instructions for the kit, or by methods known in the art or as described herein. The techniques and methods described above can generally be performed according to conventional methods well known in the art as described in various general and more specific documents that are cited and discussed in this specification. In this specification, groups and substituents thereof can be selected by those skilled in the art to provide stable moieties and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing the article only and should not be construed as limitations on the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals, and treatises, are hereby incorporated by reference in their entirety.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, C1-C6 alkyl refers to an alkyl group as defined below having a total of 1 to 6 carbon atoms. The total number of carbon atoms in the abbreviated notation does not include carbons that may be present in substituents of the stated group.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings shown below unless otherwise specified.
在本申请中，术语“卤素”是指氟、氯、溴或碘。In this application, the term "halogen" means fluorine, chlorine, bromine or iodine.
“羟基”是指-OH基团。"Hydroxy" means an -OH group.
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。"Hydroxyalkyl" means an alkyl group as defined below substituted with a hydroxyl group (-OH).
“羰基”是指-C(＝O)-基团。"Carbonyl" means a -C(=O)- group.
“硝基”是指-NO 2。 "Nitro" means -NO2 .
“氰基”是指-CN。"Cyano" means -CN.
“氨基”是指-NH 2。 "Amino" refers to -NH2 .
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳基烷基、杂芳基烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳基烷基氨基、杂芳基烷基氨基。"Substituted amino" means an amino group substituted by one or two alkyl, alkylcarbonyl, arylalkyl, heteroarylalkyl groups as defined below, for example, monoalkylamino, dialkylamino, Alkylamido, arylalkylamino, heteroarylalkylamino.
“羧基”是指-COOH。"Carboxy" means -COOH.
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个)碳原子，且通过1个或多个单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲 基己基、辛基、壬基和癸基等。就本发明而言，术语“烷基”优选指含有1至6个碳原子的烷基。In this application, as a group or a part of other groups (such as used in groups such as halogen-substituted alkyl groups), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group, Consists solely of carbon and hydrogen atoms, has for example 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms, and is connected to the rest of the molecule by 1 or more single bonds, Examples include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2- Dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, etc. For the purposes of the present invention, the term "alkyl" preferably refers to an alkyl group containing 1 to 6 carbon atoms.
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In this application, the term "alkenyl", as a group or part of another group, means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and is connected to the rest of the molecule by 1 or more single bonds, such as but not limited to vinyl, propenyl, alkenyl Propyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-1,4-dienyl and the like.
本文中作为基团或是其它基团的一部分，术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个碳-碳三键、具有例如2至14个(优选为2至10个，更优选为2至6个)碳原子且通过1个或多个单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙炔基、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。The term "alkynyl" herein, as a group or part of another group, means consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having, for example, 2 to 14 (preferably 2 to 10 2, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by 1 or more single bonds, straight or branched hydrocarbon chain groups, such as but not limited to ethynyl, 1-propyne base, 1-butynyl, heptynyl, octynyl, etc.
在本申请中，作为基团或是其它基团的一部分，术语“碳环(基)”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至16个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，更优选3至6个碳原子，且其为饱和或不饱和环(即环烷基、环烯基等)并可经由任何适宜的碳原子通过1个或多个单键与分子的其余部分连接。除非本说明书中另外特别指明，碳环基中的碳原子可以任选地被氧化。碳环基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、2,3-二氢化茚基、八氢-4,7-亚甲基-1H-茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、环戊烯基、环己烯基、环己二烯基、1H-茚基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[1.1.1]戊烷、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基和八氢-2,5-亚甲基-并环戊二烯基等。In this application, as a group or a part of other groups, the term "carbocycle (group)" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group composed only of carbon atoms and hydrogen atoms, which may include A fused, bridged or spiro ring system having 3 to 16 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and It is a saturated or unsaturated ring (ie cycloalkyl, cycloalkenyl, etc.) and can be connected to the rest of the molecule by 1 or more single bonds via any suitable carbon atom. Unless specifically stated otherwise in this specification, the carbon atoms in the carbocyclyl group can be optionally oxidized. Examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, 2,3-indanyl, octahydro-4, 7-methylene-1H-indenyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, cyclopentenyl, cyclohexenyl, cyclo Hexadienyl, 1H-indenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5 ,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[1.1.1]pentane, bicyclo[2.2.1]heptyl, 7,7-dimethyl Base-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1] Octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, octahydro-2,5-methylene-pentalenyl, etc.
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”是指上述完全饱和的碳环(基)，优选C3-C6环烷基。典型的环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基等。In this application, as a group or a part of other groups, the term "cycloalkyl" refers to the above-mentioned fully saturated carbocycle (group), preferably C3-C6 cycloalkyl. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
在本申请中，作为基团或是其它基团的一部分，术语“环烯基”是指部分不饱和的碳环(基)，典型的环烯基包括但不限于环丁烯基、环戊烯基、环己烯基等。In this application, as a group or part of other groups, the term "cycloalkenyl" refers to a partially unsaturated carbocyclic (group), typical cycloalkenyl groups include but not limited to cyclobutenyl, cyclopentenyl alkenyl, cyclohexenyl, etc.
在本申请中，作为基团或是其它基团的一部分，术语“杂环(基)”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过1个或多个单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子 的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2-氮杂双环[2.2.2]辛烷基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。In this application, the term "heterocycle (group)", as a group or part of another group, means 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur Composed of stable 3- to 20-membered non-aromatic cyclic groups. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon, or sulfur atoms of can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. A heterocyclyl group can be attached to the rest of the molecule via a carbon atom or a heteroatom and via 1 or more single bonds. In heterocyclyl groups comprising fused rings, one or more rings may be aryl or heteroaryl as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, heterocyclyl is preferably a stable 4- to 11-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group comprising 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur group, more preferably a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spirocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2-azabicyclo[2.2.2]octanyl , 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo [2.2.1] Heptane-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolyl, tetrahydroisoquinyl Linyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinozinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydro Hydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, and the like.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的碳环基或杂环基稠合，条件是芳基经由芳香环上的原子通过1个或多个单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。In the present application, the term "aryl", as a group or part of another group, means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, aryl can be a monocyclic, bicyclic, tricyclic or multicyclic ring system and can also be fused to a carbocyclyl or heterocyclyl as defined above, provided that the aryl is via The atoms in the aromatic ring are connected to the rest of the molecule by 1 or more single bonds. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-Benzoxazin-3(4H)-on-7-yl and the like.
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的碳环基或杂环基稠合，条件是杂芳基经由杂芳香环上的原子通过1个或多个单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。In this application, the term "heteroaryl", as a group or part of another group, means having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 carbon atoms selected from the group consisting of nitrogen A 5- to 16-membered conjugated ring system group of heteroatoms of oxygen and sulfur. Unless specifically stated otherwise in this specification, heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may also be fused to a carbocyclyl or heterocyclyl as defined above, provided that the heteroaryl An aryl group is attached to the rest of the molecule by one or more single bonds through atoms on the heteroaromatic ring. A nitrogen, carbon or sulfur atom in a heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized. For the purposes of the present invention, heteroaryl is preferably a stable 5- to 12-membered aromatic group containing 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably 1 to 4 heteroatoms selected from A stable 5- to 10-membered aromatic group of heteroatoms selected from nitrogen, oxygen and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoindolyl, indazolyl, isoindazolyl , Purinyl, quinolinyl, isoquinolinyl, diazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizyl, o-phenanthrenyl, Isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 ,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine wait.
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above substituted by a heteroaryl group as defined above.
在本申请中，术语“不存在”是指被上文所定义的基团的两侧直接通过化学键相连。例 如，“A-B-C中B是不存在”表示“A-C”。In the present application, the term "absent" means that the two sides of the group defined above are directly connected by a chemical bond. For example, "B is absent in A-B-C" means "A-C".
在本申请中，“
Figure PCTCN2022140697-appb-000037
”中的“
Figure PCTCN2022140697-appb-000038
”表示基团R的连接位置。 In this application, "
Figure PCTCN2022140697-appb-000037
"middle"
Figure PCTCN2022140697-appb-000038
" indicates the attachment position of the group R.
在本申请中，除权利要求中特殊说明外，“任选地”、“任选”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选取代的芳基”表示芳基上的氢被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。例如，在没有明确列出取代基的情况下，本文所用的术语“任选取代的”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代，所述取代基独立地选自：氘(D)、卤素、-OH、氧代(＝O)、巯基、氰基、-CD 3、-C1-C6烷基(优选-C1-3烷基)、C2-C6烯基、C2-C6炔基、碳环基(优选C3-C8碳环基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基-C1-C6烷基-、杂芳基-C1-C6烷基-、C1-C6卤代烷基-、-OC1-C6烷基(优选-OC1-C3烷基)、-OC2-C6烯基、-O环烷基、-O杂环基、-O芳基、-O杂芳基、-OC1-C6烷基苯基、-C1-C6烷基-OH(优选-C1-C4烷基-OH)、-C1-C6烷基-SH、-C1-C6烷基-O-C1-C6烷基、-OC1-C6卤代烷基、-NH 2、-C1-C6烷基-NH 2(优选-C1-C3烷基-NH 2)、-N(C1-C6烷基) 2(优选-N(C1-C3烷基) 2)、-NH(C1-C6烷基)(优选-NH(C1-C3烷基))、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、硝基、-C(O)-OH、-C(O)OC1-C6烷基(优选-C(O)OC1-C3烷基)、-CONR iR ii(其中R i和R ii是H、D和C1-6烷基，优选C1-3烷基)、-NHC(O)(C1-C6烷基)、-NHC(O)(苯基)、-N(C1-C6烷基)C(O)(C1-C6烷基)、-N(C1-C6烷基)C(O)(苯基)、-C(O)C1-C6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C1-C6烷基苯基、-C(O)C1-C6卤代烷基、-OC(O)C1-C6烷基(优选-OC(O)C1-C3烷基)、-S(O) 2-C1-C6烷基、-S(O)-C1-C6烷基、-S(O) 2-苯基、-S(O) 2-C1-C6卤代烷基、-S(O) 2NH 2、-S(O) 2NH(C1-C6烷基)、-S(O) 2NH(苯基)、-NHS(O) 2(C1-C6烷基)、-NHS(O) 2(苯基)和-NHS(O) 2(C1-C6卤代烷基)，其中所述的烷基、烯基、炔基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代：卤素、-OH、氧代(＝O)、-NH 2、碳环基、3-8元杂环基、C1-C4烷基、C1-C4卤代烷基-、-OC1-C4烷基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基) 2、-CONH(C1-C6烷基)、-CONH 2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO 2(C1-C6烷基)、-SO 2(苯基)、-SO 2(C1-C6卤代烷基)、-SO 2NH 2、-SO 2NH(C1-C6烷基)、-SO 2NH(苯基)、-NHSO 2(C1-C6烷基)、-NHSO 2(苯基)和-NHSO 2(C1-C6卤代烷基)。当一个原子或基团被多个取代基取代时，所述取代基可以相同或不同。本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。本发明中，“任选取代的”和“取代或未取代”具有相同含义，可互换使用。 In this application, except for the special instructions in the claims, "optionally" and "optionally" mean that the subsequently described event or situation may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation Case. For example, "optionally substituted aryl" means that the hydrogens on the aryl are substituted or unsubstituted, and the description includes both substituted and unsubstituted aryls. For example, the term "optionally substituted", "substituted" or "substituted by" as used herein, where no substituent is explicitly listed, means that one or more of the given atom or group hydrogen atoms are independently substituted by one or more, such as 1, 2, 3 or 4, substituents independently selected from: deuterium (D), halogen, -OH, oxo (=O), Mercapto, cyano, -CD 3 , -C1-C6 alkyl (preferably -C1-3 alkyl), C2-C6 alkenyl, C2-C6 alkynyl, carbocyclyl (preferably C3-C8 carbocyclyl), Aryl, heterocyclic group (preferably 3-8 membered heterocyclic group), heteroaryl, aryl-C1-C6 alkyl-, heteroaryl-C1-C6 alkyl-, C1-C6 haloalkyl-,- OC1-C6 alkyl (preferably -OC1-C3 alkyl), -OC2-C6 alkenyl, -O cycloalkyl, -O heterocyclyl, -O aryl, -O heteroaryl, -OC1-C6 alkane phenyl, -C1-C6 alkyl-OH (preferably -C1-C4 alkyl-OH), -C1-C6 alkyl-SH, -C1-C6 alkyl-O-C1-C6 alkyl, -OC1 -C6 haloalkyl, -NH 2 , -C1-C6 alkyl-NH 2 (preferably -C1-C3 alkyl-NH 2 ), -N(C1-C6 alkyl) 2 (preferably -N(C1-C3 alkane base) 2 ), -NH(C1-C6 alkyl) (preferably -NH(C1-C3 alkyl)), -N(C1-C6 alkyl) (C1-C6 alkylphenyl), -NH(C1 -C6alkylphenyl), -N(C1-C6alkyl)(aryl), -NH(aryl), nitro, -C(O)-OH, -C(O)OC1-C6alkyl (preferably -C(O)OC1-C3 alkyl), -CONR i R ii (wherein R i and R ii are H, D and C1-6 alkyl, preferably C1-3 alkyl), -NHC (O) (C1-C6 alkyl), -NHC (O) (phenyl), -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -N (C1-C6 alkyl) C ( O)(phenyl), -C(O)C1-C6 alkyl, -C(O)heteroaryl (preferably -C(O)-5-7 membered heteroaryl), -C(O)C1- C6 alkylphenyl, -C(O)C1-C6 haloalkyl, -OC(O)C1-C6 alkyl (preferably -OC(O)C1-C3 alkyl), -S(O) 2 -C1- C6 alkyl, -S(O)-C1-C6 alkyl, -S(O) 2 -phenyl, -S(O) 2 -C1-C6 haloalkyl, -S(O) 2 NH 2 , -S (O) 2 NH(C1-C6 alkyl), -S(O) 2 NH (phenyl), -NHS(O) 2 (C1-C6 alkyl), -NHS(O) 2 (phenyl) and -NHS(O) 2 (C1-C6 haloalkyl), wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, aryl, heterocyclyl and heteroaryl is optionally Further substituted by one or more substituents selected from the group consisting of halogen, -OH, oxo (=O), -NH 2 , carbocyclyl, 3-8 membered heterocyclyl, C1-C4 alkyl, C1- C4 haloalkyl-, -OC1-C4 alkyl, -C1-C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, - C(O)-OH, -C(O)OC1-C6 alkyl, -CON(C1-C6 alkyl) 2 , -CONH(C1-C6 alkyl), -CONH 2 , -NHC(O)(C1 -C6 alkyl), -NH(C1-C6 alkyl)C(O)(C1-C6 alkyl), -SO 2 (C1-C6 alkyl), -SO 2 (phenyl), -SO 2 ( C1-C6 haloalkyl), -SO 2 NH 2 , -SO 2 NH (C1-C6 alkyl), -SO 2 NH (phenyl), -NHSO 2 (C1-C6 alkyl), -NHSO 2 (benzene radical) and -NHSO 2 (C1-C6 haloalkyl). When an atom or group is substituted by multiple substituents, the substituents may be the same or different. As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", "chemical group" refer to a specific segment or functional group in a molecule. Chemical moieties are generally considered to be chemical entities embedded or attached to molecules. In the present invention, "optionally substituted" and "substituted or unsubstituted" have the same meaning and can be used interchangeably.
在本发明中，(C1-C4烷基) 2氨基，代表2个C1-C4烷基取代的胺，例如可以是
Figure PCTCN2022140697-appb-000039
Figure PCTCN2022140697-appb-000040
等。 In the present invention, (C1-C4 alkyl) 2 amino represents 2 C1-C4 alkyl substituted amines, such as
Figure PCTCN2022140697-appb-000039
Figure PCTCN2022140697-appb-000040
wait.
本发明中“多个”是指2、3或4个。"Multiple" in the present invention means 2, 3 or 4.
在本发明中，C(O)OC1-C6烷基，即
Figure PCTCN2022140697-appb-000041
代表C1-C6烷基取代的酯基，例如可以是
Figure PCTCN2022140697-appb-000042
Figure PCTCN2022140697-appb-000043
In the present invention, C(O)OC1-C6 alkyl, namely
Figure PCTCN2022140697-appb-000041
Represents a C1-C6 alkyl substituted ester group, such as
Figure PCTCN2022140697-appb-000042
Figure PCTCN2022140697-appb-000043
在本发明中，N(C1-C6烷基) 2，或者称为(C1-C6烷基) 2氨基，代表NH 2上的两个氢被2个C1-C6烷基取代，例如可以是
Figure PCTCN2022140697-appb-000044
Figure PCTCN2022140697-appb-000045
等。 In the present invention, N(C1-C6 alkyl) 2 , or called (C1-C6 alkyl) 2 amino, represents that two hydrogens on NH 2 are replaced by 2 C1-C6 alkyl groups, for example, it can be
Figure PCTCN2022140697-appb-000044
Figure PCTCN2022140697-appb-000045
wait.
中间体intermediate
中间体是指半成品，是生产所需要的产品过程中形成的产物。通常，发明人可以从中间体作为起始原料进行产品的生产。因此，筛选合适的中间体可以优化工艺路线，进而达到提高收率，节约时间、成本的目的。Intermediates refer to semi-finished products, which are products formed in the process of producing the required products. Generally, inventors can proceed with the production of products from intermediates as starting materials. Therefore, screening suitable intermediates can optimize the process route, thereby achieving the purpose of increasing yield, saving time and cost.
本发明中，所述中间体是指以下化合物In the present invention, the intermediate refers to the following compounds
Figure PCTCN2022140697-appb-000046
Figure PCTCN2022140697-appb-000046
其中，R 1、X 1、X 2的定义如上所述。 Wherein, the definitions of R 1 , X 1 , and X 2 are as above.
优选地，所述中间体为Preferably, the intermediate is
Figure PCTCN2022140697-appb-000047
Figure PCTCN2022140697-appb-000047
中间体的制备方法The preparation method of the intermediate
本发明中，所述中间体的制备方法包括步骤：In the present invention, the preparation method of the intermediate comprises steps:
Figure PCTCN2022140697-appb-000048
Figure PCTCN2022140697-appb-000048
(i)在溶剂(如DMF)中，化合物a-1与氰化试剂(如氰化亚铜)反应，得到化合物a-2；(i) In a solvent (such as DMF), compound a-1 is reacted with a cyanide reagent (such as cuprous cyanide) to obtain compound a-2;
(ii)在溶剂(如乙醇)中，化合物a-2与肼或其盐(如盐酸肼)反应，得到化合物a-3；(ii) in a solvent (such as ethanol), compound a-2 is reacted with hydrazine or a salt thereof (such as hydrazine hydrochloride) to obtain compound a-3;
(iii)在溶剂(如乙腈)中，化合物a-3在亚硝酸酯(亚硝酸叔丁酯)和氯化亚铜存在下反应，得到化合物a。(iii) In a solvent (such as acetonitrile), compound a-3 is reacted in the presence of nitrite (tert-butyl nitrite) and cuprous chloride to obtain compound a.
上述各步骤中，反应时间和反应温度等可以根据具体的反应物进行选择。In the above steps, the reaction time and reaction temperature can be selected according to the specific reactants.
活性成分active ingredient
如本文所用，“本发明化合物”或“活性成分”指式I所示的化合物，并且还包含其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合。As used herein, "compound of the present invention" or "active ingredient" refers to the compound shown in formula I, and also includes its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer isomers, cis-trans isomers, solvates, polymorphs, deuteriums, or combinations thereof.
“立体异构体”是指由相同原子组成，通过相同的键键合，但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。"Stereoisomer" refers to compounds composed of the same atoms, bonded by the same bonds, but having different three-dimensional structures. The present invention will encompass each stereoisomer and mixtures thereof.
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。When olefinic double bonds are contained in the compounds of the present invention, unless otherwise stated, the compounds of the present invention are intended to include both E- and Z-geometric isomers.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。"Tautomer" refers to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention are also intended to be within the scope of the invention.
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。The compounds of the present invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereoisomers and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIAOF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from suitable optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography. ), see, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol.243, 2004; A.M.Stalcup, Chiral Separations, Annu.Rev.Anal.Chem.3 :341-63, 2010; Fumiss et al.(eds.), VOGEL'S ENCYCLOPEDIAOF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc.Chem. Res. 1990, 23, 128.
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable acid addition salt" refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. Inorganic acid salts include but not limited to hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include but not limited to formate, acetate, 2,2-dichloroacetate , Trifluoroacetate, Propionate, Caproate, Caprylate, Caprate, Undecylenate, Glycolate, Gluconate, Lactate, Sebacate, Hexanoate glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, mesylate, benzenesulfonate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-amino salicylate, naphthalene disulfonate, etc. These salts can be prepared by methods known in the art.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，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、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic base or an organic base that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, those of primary, secondary, and tertiary amines, substituted amines, including natural substituted amines, cyclic amines, and basic ion exchange resins , such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclic Hexylamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Choline, Betaine, Ethylenediamine, Glucosamine, Methylglucamine, Theobromine, Purine, Piperazine, Piperazine Pyridine, N-ethylpiperidine, polyamine resin, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
药物组合物和施用方法Pharmaceutical compositions and methods of administration
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In this application, a "pharmaceutical composition" refers to a formulation of a compound of the present invention with a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human). The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时，原来药物的给药方式和剂量可以保持不变，而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时，可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时，式I化合物或已知药物的剂量可能比它们单独用药的剂量低。The compound of general formula (I) can be used in combination with other known drugs for treating or improving similar diseases. In the case of combined administration, the administration method and dose of the original drug can be kept unchanged, and the compound of formula I can be administered simultaneously or subsequently. When the compound of formula I is taken together with one or several other drugs, the pharmaceutical composition containing one or several known drugs and the compound of formula I can be preferably used. Drug combinations also include administration of a compound of formula I and one or more other known drugs for overlapping periods of time. When the compound of formula I is used in combination with one or several other drugs, the dosage of the compound of formula I or known drugs may be lower than that of their single administration.
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为：PD-1抑制剂(如纳武单抗、派姆单抗等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗atezolizumab等)、CD47抗体(如Hu5F9-G4，CC-90002等)、CD20抗体(如利妥昔单抗、伊布单抗等)、KRAS抑制剂(如AMG510等)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、艾克替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、卡博替尼、舒尼替尼等)、PI3K抑制剂(如Dactolisib、Taselisib等)、BTK抑制剂(如依鲁替尼、替拉布替尼、阿卡布替尼、泽布替尼、维卡布替尼等)、HDAC抑制剂(如Vorinostat、Fimepinostat、Givinostat、Tucidinostat等)、CDK抑制剂(如帕博西尼、Ribociclib、Abemaciclib等)、MEK抑制剂(如司美替尼(AZD6244)、Trametinib等)、ERK抑制剂(如BVD523、HH2710等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068)或其组合。Drugs or active ingredients that can be combined with the compound described in general formula (I) include but are not limited to: PD-1 inhibitors (such as nivolumab, pembrolizumab, etc.), PD-L1 inhibitors ( Such as durvalumab, atezolizumab, etc.), CD47 antibodies (such as Hu5F9-G4, CC-90002, etc.), CD20 antibodies (such as rituximab, ibrutinib, etc.), KRAS inhibitors ( Such as AMG510, etc.), ALK inhibitors (such as ceritinib, alectinib, brigatinib, lorlatinib, ocatinib), EGFR inhibitors (such as afatinib, gefitinib , erlotinib, lapatinib, dacomitinib, icotinib, osimertinib, etc.), VEGFR inhibitors (such as sorafenib, pazopanib, regorafenib, carbo Tini, sunitinib, etc.), PI3K inhibitors (such as Dactolisib, Taselisib, etc.), BTK inhibitors (such as ibrutinib, tirabrutinib, acabrutinib, zanubrutinib, Vicat Butinib, etc.), HDAC inhibitors (such as Vorinostat, Fimepinostat, Givinostat, Tucidinostat, etc.), CDK inhibitors (such as Palbociclib, Ribociclib, Abemaciclib, etc.), MEK inhibitors (such as Selumetinib (AZD6244), Trametinib, etc.), ERK inhibitors (such as BVD523, HH2710, etc.), mTOR inhibitors (such as Vistusertib, etc.), SHP2 inhibitors (such as RMC-4630, JAB-3068) or combinations thereof.
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 nontoxic, i.e., the substance can be administered to an individual without causing adverse biological effects. React or interact in an undesirable manner with any component contained in the composition.
在本申请中，“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In this application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener approved by the relevant government regulatory agency as acceptable for human or livestock use , diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizing agent, isotonic agent, solvent or emulsifying agent.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration .
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚 乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
本发明所述“肿瘤”包括但不限于肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、***癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、***、头颈癌、食管癌、甲状腺癌和膀胱癌等疾病。本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。The "tumor" mentioned in the present invention includes but not limited to lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, malignant rhabdomyoma, synovial sarcoma, Endometrioma, stomach cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, cholangiocarcinoma, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and bladder cancer and other diseases. As used herein, the terms "prophylactic", "prevention" and "prevention" include reducing the likelihood of a disease or condition occurring or worsening in a patient.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：As used herein, the term "treatment" and other similar synonyms include the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing the occurrence of a disease or condition in a mammal, especially when such mammal is susceptible to the disease or condition but has not been diagnosed as having the disease or condition;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, i.e. arresting its development;
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) ameliorating a disease or condition, i.e., causing regression of the state of the disease or condition; or
(iv)减轻该疾病或病症所造成的症状。(iv) Alleviating the symptoms caused by the disease or condition.
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***的任何其它所需变化。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。The term "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" as used herein refers to at least one agent or compound which, when administered, is sufficient to relieve to some extent one or more symptoms of the disease or condition being treated amount. The result may be a reduction and/or alleviation of a sign, symptom or cause, or any other desired change in a biological system. For example, a therapeutically "effective amount" is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant disease-modifying effect. Effective amounts suitable for any individual case can be determined using techniques such as dose escalation assays.
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。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。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。As used herein, the terms "administering", "administering", "administering" and the like refer to methods capable of delivering a compound or composition to the desired site of biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Administration techniques useful for the compounds and methods described herein are well known to those skilled in the art, as described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa. In preferred embodiments, the compounds and compositions discussed herein are administered orally.
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。As used herein, the terms "pharmaceutical combination", "drug combination", "combination", "administration of other treatments", "administration of other therapeutic agents" and the like refer to drug treatments obtained by mixing or combining more than one active ingredient, It includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one co-agent in the form of a single entity or single dosage form. The term "variable combination" refers to simultaneous, concomitant or sequential administration at variable intervals of at least one compound described herein and at least one synergistic agent as separate entities to a patient. These also apply to cocktail therapy, eg the administration of three or more active ingredients.
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof within a safe and effective amount range and a pharmaceutically acceptable excipient or carrier. Wherein, "safe and effective dose" refers to: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.
化合物的制备方法Compound preparation method
以下方案中描述了制备式I所示化合物的方法。在某些情况下，可以改变执行反应方案的步骤的顺序，以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。Methods for preparing compounds of formula I are described in the following schemes. In some cases, the order in which the steps of a reaction scheme are performed can be altered to facilitate a reaction or to avoid undesired side reaction products. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations can be easily performed by those skilled in the art to which the present invention belongs.
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基、烯丙基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基、9-芴基甲氧基羰基、苄基、对甲氧基苄基、烯丙基、烯丙基氧羰基、对甲苯磺酰基、特戊酰基、三氟乙酰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。Those skilled in the art will also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (eg tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, allyl, etc. Suitable protecting groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, benzyl, p-methoxybenzyl, allyl, allyloxycarbonyl , p-toluenesulfonyl, pivaloyl, trifluoroacetyl, etc. Suitable protecting groups for mercapto include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
通常，在制备流程中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃-150℃，优选10℃-100℃)下进行。反应时间通常为0.1小时-60小时，较佳地为0.5-48小时。Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0°C-150°C, preferably 10°C-100°C). The reaction time is usually 0.1-60 hours, preferably 0.5-48 hours.
优选地，所述式I化合物其可通过如下方法制备：Preferably, the compound of formula I can be prepared by the following method:
Figure PCTCN2022140697-appb-000049
Figure PCTCN2022140697-appb-000049
(1)化合物a与b-1在路易斯酸的存在下发生傅克酰基化生成化合物c，所述的路易斯酸选自：三氯化铝、二氯化锡、氯化锌、三氟化硼、四氯化钛、四异丙基氧钛等；或者化合物a在强碱的存在下与化合物b-2发生反应生成化合物c，所述强碱自下组：正丁基锂、二异丙基氨基锂、叔丁基锂、仲丁基锂、六甲基二硅基氨基锂、或其组合；(1) Compound a and b-1 undergo Friedel-Crafts acylation in the presence of a Lewis acid to generate compound c, and the Lewis acid is selected from: aluminum trichloride, tin dichloride, zinc chloride, boron trifluoride , titanium tetrachloride, titanium tetraisopropyloxide, etc.; or compound a reacts with compound b-2 in the presence of a strong base to generate compound c, and the strong base is from the following group: n-butyllithium, diisopropyl Lithium amide, tert-butyllithium, sec-butyllithium, lithium hexamethyldisilazide, or combinations thereof;
(2)在碱的存在下，化合物c与化合物d芳香亲核取代反应生成化合物I，所述还原剂选自下组：氢化钠、叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化钾、正丁基锂、二异丙基氨基锂、六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、碳酸钾、碳酸铯、碳酸钠、磷酸钠、磷酸钾、三乙胺、二异丙基乙基胺、1.8-二氮杂二环[5.4.0]十一烷-7-烯、或其组合；或者化合物c与化合物d发生Buchwald-Hartwig反应生成化合物I；(2) In the presence of a base, the aromatic nucleophilic substitution reaction between compound c and compound d generates compound I, and the reducing agent is selected from the group consisting of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, hydrogen Potassium oxide, n-butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, potassium carbonate, cesium carbonate, sodium carbonate , sodium phosphate, potassium phosphate, triethylamine, diisopropylethylamine, 1.8-diazabicyclo[5.4.0]undecane-7-ene, or a combination thereof; or compound c and compound d occur Buchwald-Hartwig reaction generates compound I;
其中，X 1、X 2、R 1、R 2、A环的定义如上所述。 Wherein, the definitions of X 1 , X 2 , R 1 , R 2 , and ring A are as above.
本发明主要优点：Main advantage of the present invention:
1.本申请化合物结构新颖；1. The compound of this application has a novel structure;
2.本申请化合物能够有效抑制SOS1与RAS蛋白结合；2. The compound of the application can effectively inhibit the binding of SOS1 and RAS protein;
3.本申请化合物具有较好的药代动力学和药效。3. The compound of the present application has better pharmacokinetics and pharmacodynamics.
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。The technical solutions of the present invention will be further described below through specific embodiments. It should be clear to those skilled in the art that the examples are only for helping to understand the present invention, and should not be regarded as specific limitations on the present invention.
下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Percentages and parts are by weight unless otherwise indicated.
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。The experimental materials and reagents used in the following examples can be obtained from commercially available channels unless otherwise specified.
各实施例中, 1H NMR由BRUKER AVANCE NEO 400MHz型核磁共振仪记录,化学位移以δ(ppm)表示；液质联用(LCMS)由Shimadzu LC-20AD,SIL-20A,CTO-20AC,SPD-M20A,CBM-20A,LCMS-2020型质谱仪记录；制备HPLC分离使用 Gilson-281型号液相色谱仪。 In each embodiment, 1 H NMR is recorded by a BRUKER AVANCE NEO 400MHz nuclear magnetic resonance instrument, and the chemical shift is expressed in δ (ppm); -M20A, CBM-20A, LCMS-2020 type mass spectrometer records; preparative HPLC separation using Gilson-281 type liquid chromatograph.
实施例Example
中间体的制备Preparation of intermediates
1、中间体A的制备1. Preparation of Intermediate A
Figure PCTCN2022140697-appb-000050
Figure PCTCN2022140697-appb-000050
(1)向化合物A-1(10.0g,48.8mmol)的N,N-二甲基甲酰胺(100mL)溶液中，加入氰化亚铜(8.73g,97.5mmol)。反应液在氮气保护下100℃搅拌16小时。反应液加入水(100mL)，用乙酸乙酯(200mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤并减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到5:1)分离得到化合物A-2。(1) To a solution of compound A-1 (10.0 g, 48.8 mmol) in N,N-dimethylformamide (100 mL), cuprous cyanide (8.73 g, 97.5 mmol) was added. The reaction solution was stirred at 100° C. for 16 hours under the protection of nitrogen. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 5:1) to obtain compound A-2.
1H NMR(400MHz,DMSO-d6)δ8.15(d,J＝5.2Hz,1H),7.69(d,J＝5.2Hz,1H),2.65(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.15 (d, J=5.2Hz, 1H), 7.69 (d, J=5.2Hz, 1H), 2.65 (s, 3H).
(2)向化合物A-2(3.50g,23.2mmol)的乙醇(20.0mL)溶液中，加入盐酸肼(2.92g,27.78mmol)。反应液在氮气保护下80℃搅拌12小时。反应液减压浓缩，加入水(50.0mL)，用乙酸乙酯(50.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤并减压浓缩得到粗品化合物A-3。(2) To a solution of compound A-2 (3.50 g, 23.2 mmol) in ethanol (20.0 mL), hydrazine hydrochloride (2.92 g, 27.78 mmol) was added. The reaction solution was stirred at 80° C. for 12 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, water (50.0 mL) was added, extracted with ethyl acetate (50.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude compound A-3.
MS-ESI[M+H] +，计算值166，实测值166。 MS-ESI [M+H] + , calcd. 166, found 166.
(3)向化合物A-3(2.00g,12.1mmol)的乙腈(30.0mL)溶液中，加入亚硝酸叔丁酯(2.50g,24.2mmol)和氯化亚铜(2.40g,24.2mmol)。反应液在氮气保护下60℃搅拌12小时。反应液减压浓缩，加入水(30.0mL)，用乙酸乙酯(50.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝10:1到1:1)分离得到化合物A-4。(3) To a solution of compound A-3 (2.00 g, 12.1 mmol) in acetonitrile (30.0 mL), tert-butyl nitrite (2.50 g, 24.2 mmol) and cuprous chloride (2.40 g, 24.2 mmol) were added. The reaction solution was stirred at 60° C. for 12 hours under the protection of nitrogen. The reaction solution was concentrated under reduced pressure, water (30.0 mL) was added, extracted with ethyl acetate (50.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was subjected to silica gel column chromatography (petroleum Ether/ethyl acetate=10:1 to 1:1) Compound A-4 was isolated.
MS-ESI[M+H] +,计算值185,实测值185。 MS-ESI [M+H] + , calculated 185, found 185.
(4)向化合物A-4(1.00g,5.42mmol)的甲苯(10.0mL)溶液中，加入化合物A-5(1.52g,6.50mmol)，醋酸钯(122mg,542μmol)，碳酸铯(3.53g,10.8mmol)和1,1'-联萘-2,2'-双二苯膦(675mg,1.08mmol)。反应液在氮气保护下105℃搅拌2小时。反应液加入水(100mL)，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到10:1)分离得到化合物A。(4) To compound A-4 (1.00g, 5.42mmol) in toluene (10.0mL) solution, add compound A-5 (1.52g, 6.50mmol), palladium acetate (122mg, 542μmol), cesium carbonate (3.53g , 10.8mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (675mg, 1.08mmol). The reaction solution was stirred at 105° C. for 2 hours under the protection of nitrogen. Add water (100mL) to the reaction solution, extract with ethyl acetate (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 10:1) Compound A was isolated.
MS-ESI[M+H] +，计算值383，实测值383。 MS-ESI [M+H] + , calcd. 383, found 383.
2、中间体B的制备2. Preparation of Intermediate B
Figure PCTCN2022140697-appb-000051
Figure PCTCN2022140697-appb-000051
(1)0℃下向化合物B-1(2.00g,20.0mmol)的三溴甲烷(10.0mL)溶液中，滴加氢氧化钾(3.36g,59.9mmol)的甲醇(2.43mL)溶液。反应液在氮气保护下25℃搅拌12小时。反应液加入二氯甲烷(30.0mL)，用水(15.0mL×3)萃取，无水硫酸钠干燥，过滤并减压浓缩。粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到3:1)分离得到化合物B-2。(1) To a solution of compound B-1 (2.00 g, 20.0 mmol) in bromoform (10.0 mL) was added dropwise a solution of potassium hydroxide (3.36 g, 59.9 mmol) in methanol (2.43 mL) at 0°C. The reaction solution was stirred at 25° C. for 12 hours under nitrogen protection. The reaction solution was added with dichloromethane (30.0 mL), extracted with water (15.0 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 3:1) to obtain compound B-2.
1H NMR(400MHz,DMSO-d6)δ3.69(s,3H),3.57(dd,J＝7.2,3.2Hz,4H),3.16(s,3H),1.84-1.92(m,2H),1.71-1.76(m,2H)。 1 H NMR (400MHz, DMSO-d6) δ3.69 (s, 3H), 3.57 (dd, J = 7.2, 3.2Hz, 4H), 3.16 (s, 3H), 1.84-1.92 (m, 2H), 1.71 -1.76(m,2H).
(2)向化合物B-2(5.00g,28.7mmol)的四氢呋喃(30.mL)溶液中加入一水合氢氧化锂(3.61g,86.1mmol)和水(10.0mL)。反应液在25℃下搅拌12小时。反应液减压浓缩，加入水(10.0mL)，用稀盐酸调节pH到5，用乙酸乙酯(15.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤并减压浓缩得到化合物B-3。(2) To a solution of compound B-2 (5.00 g, 28.7 mmol) in tetrahydrofuran (30. mL) were added lithium hydroxide monohydrate (3.61 g, 86.1 mmol) and water (10.0 mL). The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, water (10.0 mL) was added, the pH was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate (15.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the compound B-3.
1H NMR(400MHz,CDCl 3)δ3.74-3.78(m,4H),3.33(s,3H),2.11-2.14(m,1H),2.05-2.11(m,1H),1.86-1.89(m,1H),1.82-1.86(m,1H)。 1 H NMR (400MHz, CDCl 3 ) δ3.74-3.78(m,4H),3.33(s,3H),2.11-2.14(m,1H),2.05-2.11(m,1H),1.86-1.89(m ,1H), 1.82-1.86(m,1H).
(3)向化合物B-3(3.30g,20.6mmol)的二氯甲烷(30.0mL)溶液中，加入二异丙基乙基胺(7.99g,61.8mmol)，化合物B-4的盐酸盐(2.01g,20.6mmol)和丙基磷酸酐(26.2g,41.2mmol,50％)。反应液在氮气保护下25℃搅拌1小时。反应液加入二氯甲烷(20.0mL)，用水(10.0mL×3)洗涤，有机相用无水硫酸钠干燥，过滤并减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到2:1)分离得到化合物B。(3) To compound B-3 (3.30g, 20.6mmol) in dichloromethane (30.0mL) solution, add diisopropylethylamine (7.99g, 61.8mmol), the hydrochloride of compound B-4 (2.01 g, 20.6 mmol) and propylphosphoric anhydride (26.2 g, 41.2 mmol, 50%). The reaction solution was stirred at 25° C. for 1 hour under the protection of nitrogen. Dichloromethane (20.0 mL) was added to the reaction solution, washed with water (10.0 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 1:0 to 2:1) to isolate compound B.
MS-ESI[M+H] +，计算值204，实测值204。 MS-ESI [M+H] + , calcd. 204, found 204.
1H NMR(400MHz,CDCl 3)δ3.73-3.79(m,4H),3.72(s,3H),3.32(s,3H),3.23(s,3H),2.05-2.15(m,2H),1.92-2.00(m,2H)。 1 H NMR (400MHz, CDCl 3 )δ3.73-3.79(m,4H),3.72(s,3H),3.32(s,3H),3.23(s,3H),2.05-2.15(m,2H), 1.92-2.00(m,2H).
实施例1合成化合物1Embodiment 1 synthetic compound 1
Figure PCTCN2022140697-appb-000052
Figure PCTCN2022140697-appb-000052
(1)向中间体A(100mg,262μmol)的四氢呋喃(6.0mL)溶液中加入二异丙基氨基锂(2.0mol/L,523μL)。反应液在氮气保护下-78℃下搅拌1小时，加入碳酸二甲酯(70.7mg,785μmol)的四氢呋喃(6.0mL)溶液，反应液在氮气保护下-0℃下搅拌2小时，然后加入饱和氯化铵水溶液(100mL)，加入水(100mL)，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物1-1。(1) To a solution of intermediate A (100 mg, 262 μmol) in tetrahydrofuran (6.0 mL) was added lithium diisopropylamide (2.0 mol/L, 523 μL). The reaction solution was stirred at -78°C under the protection of nitrogen for 1 hour, a solution of dimethyl carbonate (70.7 mg, 785 μmol) in tetrahydrofuran (6.0 mL) was added, the reaction solution was stirred at -0°C under the protection of nitrogen for 2 hours, and then saturated Aqueous ammonium chloride solution (100mL), added water (100mL), extracted with ethyl acetate (100mL×2), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was subjected to silica gel column chromatography (2 Chloromethane/methanol=1:0 to 10:1) isolated to obtain compound 1-1.
(2)向化合物1-1(40.0mg,90.8μmol)的四氢呋喃(30.mL)溶液中加入一水合氢氧化锂(6.53mg,2 73μmol)和水(1.0mL)。反应液在25℃下搅拌1小时。反应液减压浓缩，加入水(50.0mL)，用乙酸乙酯(50.0mL×2)洗涤，水相用稀盐酸调节pH到5，用乙酸乙酯(50.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤并减压浓缩得到化合物1-2。(2) To a solution of compound 1-1 (40.0 mg, 90.8 μmol) in tetrahydrofuran (30.mL) were added lithium hydroxide monohydrate (6.53 mg, 2 73 μmol) and water (1.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, water (50.0 mL) was added, washed with ethyl acetate (50.0 mL×2), the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid, extracted with ethyl acetate (50.0 mL×2), and the organic phases were combined , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 1-2.
MS-ESI[M+H] +，计算值427，实测值427。 MS-ESI [M+H] + , calcd. 427, found 427.
(3)向化合物1-2(20.0mg,46.9μmol)的二氯甲烷(4.0mL)溶液中加入化合物1-3(9.68mg,56.3μmol)，丙基磷酸酐(74.6mg,117μmol,50％)和二异丙基乙基胺(30.3mg,235μmol)。反应液在25℃下搅拌2小时，然后加入饱和碳酸氢钠水溶液(30.0mL)，用乙酸乙酯(50.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到化合物1-4。(3) Compound 1-3 (9.68 mg, 56.3 μmol), propyl phosphoric anhydride (74.6 mg, 117 μmol, 50% ) and diisopropylethylamine (30.3 mg, 235 μmol). The reaction solution was stirred at 25°C for 2 hours, then saturated aqueous sodium bicarbonate solution (30.0 mL) was added, extracted with ethyl acetate (50.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compounds 1-4 were obtained.
MS-ESI[M+H] +，计算值508，实测值508。 MS-ESI [M+H] + , calculated 508, found 508.
(4)向化合物1-4(20.0mg,39.4μmol)的四氢呋喃(3.0mL)溶液中加入钯碳(0.05g,10％)。反应液在氢气氛(15psi)下25℃下搅拌10小时，反应液过滤，减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm，A:水(碳酸氢铵)；B:乙腈，25％-60％:12分钟)分离得到化合物1。(4) To a solution of compound 1-4 (20.0 mg, 39.4 μmol) in tetrahydrofuran (3.0 mL) was added palladium on carbon (0.05 g, 10%). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15psi), the reaction solution was filtered, and concentrated under reduced pressure. ; B: acetonitrile, 25%-60%: 12 minutes) isolated to obtain compound 1.
MS-ESI[M+H] +，计算值478，实测值478。 MS-ESI [M+H] + , calcd. 478, found 478.
1H NMR(400MHz,MeOD)δ8.38(s,1H),6.97(s,2H),6.77(s,1H),5.31-5.45(m,2H),4.08-4.34(m,4H),3.81(d,J＝13.6Hz,1H),2.65(s,3H),2.19(t,J＝7.6Hz,1H),1.96(d,J＝9.2Hz,1H),1.62(d,J＝7.2Hz,3H)。 1 H NMR (400MHz,MeOD)δ8.38(s,1H),6.97(s,2H),6.77(s,1H),5.31-5.45(m,2H),4.08-4.34(m,4H),3.81 (d, J=13.6Hz, 1H), 2.65(s, 3H), 2.19(t, J=7.6Hz, 1H), 1.96(d, J=9.2Hz, 1H), 1.62(d, J=7.2Hz ,3H).
实施例2合成化合物2Embodiment 2 synthetic compound 2
Figure PCTCN2022140697-appb-000053
Figure PCTCN2022140697-appb-000053
(1)向中间体A(250mg,654μmol)的四氢呋喃(3.0mL)溶液中加入二异丙基氨基锂(2.0mol/L,1.31mL)。反应液在氮气保护下-78℃下搅拌1小时，加入化合物B(399mg,1.96mmol)的四氢呋喃(3.0mL)溶液，反应液在氮气保护下-0℃下搅拌2小时，然后加入饱和氯化铵水溶液(100mL)，加入水(100mL)，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm，A:水(碳酸氢铵)；B:乙腈，40％-80％:12分钟)分离得到化合物2-1。(1) To a solution of intermediate A (250 mg, 654 μmol) in tetrahydrofuran (3.0 mL) was added lithium diisopropylamide (2.0 mol/L, 1.31 mL). The reaction solution was stirred at -78°C under the protection of nitrogen for 1 hour, and a solution of compound B (399mg, 1.96mmol) in tetrahydrofuran (3.0mL) was added, and the reaction solution was stirred at -0°C under the protection of nitrogen for 2 hours, and then saturated chloride was added Aqueous ammonium solution (100mL), added water (100mL), extracted with ethyl acetate (100mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the crude product was subjected to preparative high performance liquid chromatography (Welch Xtimate C18, 150mm×30mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 40%-80%: 12 minutes) were isolated to obtain compound 2-1.
MS-ESI[M+H] +，计算值525，实测值525。 MS-ESI [M+H] + , calcd. 525, found 525.
(2)向化合物2-1(100mg,191μmol)的四氢呋喃(3.0mL)溶液中加入钯碳(0.10g,10％)。反应液在氢气氛(15psi)下25℃下搅拌10小时，反应液过滤，减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm，A:水(碳酸氢铵)；B:乙腈, 37％-74％:12分钟)分离得到化合物2。(2) To a solution of compound 2-1 (100 mg, 191 μmol) in tetrahydrofuran (3.0 mL) was added palladium on carbon (0.10 g, 10%). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15psi), the reaction solution was filtered, and concentrated under reduced pressure. ; B: acetonitrile, 37%-74%: 12 minutes) isolated to obtain compound 2.
MS-ESI[M+H] +，计算值495，实测值495。 MS-ESI [M+H] + , calcd. 495, found 495.
1H NMR(400MHz,MeOD)δ8.96(s,1H),6.98(d,J＝5.6Hz,2H),6.78(s,1H),5.41(q,J＝6.8Hz,1H),3.76-3.92(m,4H),3.32-3.34(m,3H),,2.66(s,3H),2.04-2.14(m,4H),1.63(d,J＝7.2Hz,3H)。 1 H NMR (400MHz, MeOD) δ8.96(s, 1H), 6.98(d, J=5.6Hz, 2H), 6.78(s, 1H), 5.41(q, J=6.8Hz, 1H), 3.76- 3.92 (m, 4H), 3.32-3.34 (m, 3H), 2.66 (s, 3H), 2.04-2.14 (m, 4H), 1.63 (d, J=7.2Hz, 3H).
实施例3合成化合物3Embodiment 3 synthetic compound 3
Figure PCTCN2022140697-appb-000054
Figure PCTCN2022140697-appb-000054
(1)向化合物3-1(1.00g,6.21mmol)的甲苯(10.0mL)溶液中，加入化合物3-2(2.31g,12.4mmol)，三[二亚苄基丙酮]二钯(569mg,621μmol)，叔丁醇钠(1.19g,12.4mmol)和2-二环己膦基-2'-(N,N-二甲胺)-联苯(244mg,621μmol)。反应液在氮气保护下100℃搅拌10小时。反应液加入水(100mL)，用乙酸乙酯(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到10:1)分离得到化合物3-3。MS-ESI[M+H] +，计算值267，实测值267。 (1) To a solution of compound 3-1 (1.00g, 6.21mmol) in toluene (10.0mL), add compound 3-2 (2.31g, 12.4mmol), tris[dibenzylideneacetone]dipalladium (569mg, 621 μmol), sodium tert-butoxide (1.19 g, 12.4 mmol) and 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (244 mg, 621 μmol). The reaction solution was stirred at 100° C. for 10 hours under nitrogen protection. Add water (100mL) to the reaction solution, extract with ethyl acetate (100mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the crude product is subjected to silica gel column chromatography (dichloromethane/methanol=1 :0 to 10:1) to isolate compound 3-3. MS-ESI [M+H] + , calcd. 267, found 267.
1H NMR(400MHz,CDCl 3)δ7.20(s,1H),6.97(s,1H),3.83(s,3H),3.51-3.60(m,4H),2.83-2.92(m,4H),1.474(s,9H)。 1 H NMR (400MHz, CDCl 3 )δ7.20(s,1H),6.97(s,1H),3.83(s,3H),3.51-3.60(m,4H),2.83-2.92(m,4H), 1.474(s,9H).
(2)向化合物3-3(100mg,375μmol)的二氯甲烷(2.0mL)溶液中加入三氟乙酸(214mg,1.88mmol)。反应液在25℃下搅拌1小时。反应液减压浓缩，得到化合物3-4的三氟乙酸盐。MS-ESI[M+H] +，计算值167，实测值167。 (2) To a solution of compound 3-3 (100 mg, 375 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (214 mg, 1.88 mmol). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 3-4. MS-ESI [M+H] + , calcd. 167, found 167.
(3)向化合物1-2(100mg,234μmol)的二氯甲烷(4.0mL)溶液中加入化合物3-4(46.8mg,281μmol)，丙基磷酸酐(373mg,586μmol,50％)和二异丙基乙基胺(151mg,1.17μmol)。反应液在25℃下搅拌2小时，然后加入饱和碳酸氢钠水溶液(30.0mL)，用乙酸乙酯(50.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，得到化合物3-5。MS-ESI[M+H] +，计算值575，实测值575。 (3) Add compound 3-4 (46.8mg, 281μmol), propylphosphoric anhydride (373mg, 586μmol, 50%) and diiso Propylethylamine (151 mg, 1.17 μmol). The reaction solution was stirred at 25°C for 2 hours, then saturated aqueous sodium bicarbonate solution (30.0 mL) was added, extracted with ethyl acetate (50.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 3-5 was obtained. MS-ESI [M+H] + , calcd. 575, found 575.
(4)向化合物3-5(80.0mg,139μmol)的四氢呋喃(2.0mL)溶液中加入钯碳(0.1g,10％)。反应液在氢气氛(15psi)下25℃下搅拌10小时，反应液过滤，减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm，A:水(0.225％甲酸)；B:乙腈，15％-45％:10分钟)分离得到化合物3的甲酸盐。MS-ESI[M+H] +，计算值545，实测值545。 (4) To a solution of compound 3-5 (80.0 mg, 139 μmol) in tetrahydrofuran (2.0 mL) was added palladium on carbon (0.1 g, 10%). The reaction solution was stirred at 25°C for 10 hours under a hydrogen atmosphere (15psi), the reaction solution was filtered, and concentrated under reduced pressure. ; B: acetonitrile, 15%-45%: 10 minutes) isolated to obtain the formate of compound 3. MS-ESI [M+H] + , calcd. 545, found 545.
1H NMR(400MHz,MeOD)δ8.17(s,1H),7.29(d,J＝14.0Hz,3H),6.75-7.00(m,2H),3.87-3.97(m,5H),3.81(s,3H),3.03-3.08(m,4H),2.65(s,3H),1.54-1.72(m,3H)。 1 H NMR (400MHz, MeOD) δ8.17(s, 1H), 7.29(d, J=14.0Hz, 3H), 6.75-7.00(m, 2H), 3.87-3.97(m, 5H), 3.81(s ,3H), 3.03-3.08(m,4H), 2.65(s,3H), 1.54-1.72(m,3H).
实施例4合成化合物4Embodiment 4 synthetic compound 4
Figure PCTCN2022140697-appb-000055
Figure PCTCN2022140697-appb-000055
(1)向化合物A-4(150mg,812mmol)的四氢呋喃(6.0mL)溶液中加入二异丙基氨基锂(2.00mol/L,1.22mL)。反应液在氮气保护下-78℃下搅拌1小时,加入化合物4-1(330mg,1.62mmol),反应液在氮气保护下-78℃下搅拌1小时,缓慢升温至室温，继续搅拌2小时。加入饱和氯化铵水溶液(5.0mL),加入水(5.0mL),用二氯甲烷(5.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×2)洗涤，无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到1:1)分离得到化合物4-1。(1) To a solution of compound A-4 (150 mg, 812 mmol) in tetrahydrofuran (6.0 mL) was added lithium diisopropylamide (2.00 mol/L, 1.22 mL). The reaction solution was stirred at -78°C under the protection of nitrogen for 1 hour, compound 4-1 (330 mg, 1.62 mmol) was added, the reaction solution was stirred at -78°C under the protection of nitrogen for 1 hour, slowly warmed to room temperature, and continued to stir for 2 hours. Add saturated ammonium chloride aqueous solution (5.0mL), add water (5.0mL), extract with dichloromethane (5.0mL×2), combine organic phases, wash with saturated brine (5.0mL×2), anhydrous sodium sulfate After drying, filtering, and concentrating under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 1:1) to obtain compound 4-1.
MS-ESI[M+H] +,计算值327,实测值327。 MS-ESI [M+H] + , calcd. 327, found 327.
(2)化合物4-2的合成参考专利WO2021127429。向化合物4-2(160mg,35.0μmol)的甲苯(1.0mL)溶液中,加入化合物4-2(100mg,306μmol),醋酸钯(7.91mg,35.2μmol),二异丙基乙基胺(45.2mg,350)，碳酸铯(228mg,699μmol)和1,1'-联萘-2,2'-双二苯膦(43.9mg,70.4μmol)。反应液在氮气保护下100℃搅拌4小时。反应液加入水(30.0mL),用乙酸乙酯(10.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×2)洗涤，无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到20:1)分离得到化合物4-3。(2) For the synthesis of compound 4-2, refer to patent WO2021127429. To a solution of compound 4-2 (160 mg, 35.0 μmol) in toluene (1.0 mL), add compound 4-2 (100 mg, 306 μmol), palladium acetate (7.91 mg, 35.2 μmol), diisopropylethylamine (45.2 mg, 350), cesium carbonate (228mg, 699μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.9mg, 70.4μmol). The reaction solution was stirred at 100° C. for 4 hours under the protection of nitrogen. Add water (30.0mL) to the reaction solution, extract with ethyl acetate (10.0mL×2), combine the organic phases, wash with saturated brine (5.0mL×2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the crude product Compound 4-3 was isolated by silica gel column chromatography (dichloromethane/methanol=1:0 to 20:1).
MS-ESI[M+H] +,计算值748,实测值748。 MS-ESI [M+H] + , calculated 748, found 748.
(3)0℃下向化合物4-3(44.0mg,58.8μmol)的四氢呋喃(1.0mL)溶液中加入四丁基氟化铵(1.00mol/L,88.2μL)。反应液在25℃下搅拌1小时。。反应液加入水(5.0mL),用乙酸乙酯(5.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×2)洗涤，无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Phenomenex C18,75mm×30mm 3μm，A:水(碳酸氢铵)；B:乙腈，31％-61％:10分钟)分离得到化合物4。MS-ESI[M+H] +，计算值510，实测值510。 (3) To a solution of compound 4-3 (44.0 mg, 58.8 μmol) in tetrahydrofuran (1.0 mL) was added tetrabutylammonium fluoride (1.00 mol/L, 88.2 μL) at 0°C. The reaction solution was stirred at 25°C for 1 hour. . Add water (5.0mL) to the reaction solution, extract with ethyl acetate (5.0mL×2), combine the organic phases, wash with saturated brine (5.0mL×2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the crude product Compound 4 was isolated by preparative high performance liquid chromatography (Phenomenex C18, 75mm×30mm 3μm, A: water (ammonium bicarbonate); B: acetonitrile, 31%-61%: 10 minutes). MS-ESI [M+H] + , calculated 510, found 510.
1H NMR(400MHz,MeOD)δ9.00(s,1H),7.54(t,J＝7.2Hz,1H),7.42(t,J＝7.2Hz,1H),7.15(t,J＝7.6Hz,1H),5.72(q,J＝6.8Hz,1H),4.03(t,J＝14.0Hz,2H),3.77-3.93(m,4H),3.32(br s,3H),2.64(s,3H),2.03-2.14(m,4H),1.67(d,J＝6.8Hz,3H)。 1 H NMR (400MHz, MeOD) δ9.00(s, 1H), 7.54(t, J=7.2Hz, 1H), 7.42(t, J=7.2Hz, 1H), 7.15(t, J=7.6Hz, 1H), 5.72(q, J=6.8Hz, 1H), 4.03(t, J=14.0Hz, 2H), 3.77-3.93(m, 4H), 3.32(br s, 3H), 2.64(s, 3H) , 2.03-2.14 (m, 4H), 1.67 (d, J=6.8Hz, 3H).
实施例5合成化合物5Embodiment 5 synthetic compound 5
Figure PCTCN2022140697-appb-000056
Figure PCTCN2022140697-appb-000056
(1)向化合物5-1(1.70g,6.56mmol)的二氯甲烷(5.0mL)溶液中,加入二异丙基乙基胺(4.24g,32.8mmol),化合物B-4的盐酸盐(959mg,9.83mmol)和丙基磷酸酐(10.4g,16.4mmol,50％)。反应液在氮气保护下25℃搅拌1小时。反应液加入二氯甲烷(30.0mL)稀释,用饱和碳酸氢钠(100.0mL)洗涤。有机相用无水硫酸钠干燥,过滤并减压浓缩得到化合物5-2。MS-ESI[M-Boc+H] +,计算值203,实测值203。 (1) To compound 5-1 (1.70g, 6.56mmol) in dichloromethane (5.0mL) solution, add diisopropylethylamine (4.24g, 32.8mmol), the hydrochloride of compound B-4 (959mg, 9.83mmol) and propylphosphoric anhydride (10.4g, 16.4mmol, 50%). The reaction solution was stirred at 25° C. for 1 hour under the protection of nitrogen. The reaction solution was diluted with dichloromethane (30.0 mL), washed with saturated sodium bicarbonate (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 5-2. MS-ESI [M-Boc+H] + , calculated 203, found 203.
(2)向化合物5-2(500mg,2.71mmol)的四氢呋喃(6.0mL)溶液中加入二异丙基氨基锂(2.00mol/L,5.42mL)。反应液在氮气保护下-78℃下搅拌1小时,加入中间体A-4(983mg,3.25mmol),反应液在氮气保护下0℃下搅拌2小时,加入饱和氯化铵水溶液(100.0mL),加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到10:1)分离得到化合物5-3。MS-ESI[M+H] +,计算值426,实测值426。 (2) To a solution of compound 5-2 (500 mg, 2.71 mmol) in tetrahydrofuran (6.0 mL) was added lithium diisopropylamide (2.00 mol/L, 5.42 mL). The reaction solution was stirred at -78°C under nitrogen protection for 1 hour, intermediate A-4 (983mg, 3.25mmol) was added, the reaction solution was stirred at 0°C under nitrogen protection for 2 hours, and saturated ammonium chloride aqueous solution (100.0mL) was added , added water (100.0mL), extracted with ethyl acetate (100.0mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:0 to 10:1) Compound 5-3 was isolated. MS-ESI [M+H] + , calculated 426, found 426.
(3)向化合物5-3(150mg,352μmol)的二氧六环(2.0mL)溶液中,加入化合物A-5(90.7mg,388μmol),醋酸钯(7.91mg,35.2μmol),碳酸铯(229mg,704μmol)和1,1'-联萘-2,2'-双二苯膦(43.9mg,70.4μmol)。反应液在氮气保护下80℃搅拌2小时。反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到10:1)分离得到化合物5-4。MS-ESI[M+H] +,计算值624,实测值624。 (3) To compound 5-3 (150 mg, 352 μmol) in dioxane (2.0 mL), add compound A-5 (90.7 mg, 388 μmol), palladium acetate (7.91 mg, 35.2 μmol), cesium carbonate ( 229mg, 704μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (43.9mg, 70.4μmol). The reaction solution was stirred at 80° C. for 2 hours under the protection of nitrogen. Add water (100.0 mL) to the reaction solution, extract with ethyl acetate (100.0 mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the crude product is subjected to silica gel column chromatography (petroleum ether/ethyl acetate Esters = 1:0 to 10:1) Compound 5-4 was isolated. MS-ESI [M+H] + , calculated 624, found 624.
(4)向化合物5-4(70.0mg,112μmol)的二氯甲烷(5.0mL)溶液中加入三氟乙酸(128mg,1.12mmol)。反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物5-5。MS-ESI[M+H] +,计算值524,实测值524。 (4) To a solution of compound 5-4 (70.0 mg, 112 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (128 mg, 1.12 mmol). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 5-5. MS-ESI [M+H] + , calculated 524, found 524.
(5)向化合物5-5(50.0mg,78.4μmol)的乙醇(5.0mL)溶液中加入多聚甲醛(11.8mg,392μmol),三乙胺(7.94mg,78.4μmol),醋酸(471μg,7.84μmol)和氰基硼氢化钠(7.39mg,118μmol)。反应液在25℃下搅拌10小时,反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物5-6。MS-ESI[M+H] +,计算值538,实测值538。 (5) Add paraformaldehyde (11.8 mg, 392 μmol), triethylamine (7.94 mg, 78.4 μmol), acetic acid (471 μg, 7.84 μmol) to compound 5-5 (50.0 mg, 78.4 μmol) in ethanol (5.0 mL) μmol) and sodium cyanoborohydride (7.39mg, 118μmol). The reaction solution was stirred at 25°C for 10 hours, water (100.0 mL) was added to the reaction solution, extracted with ethyl acetate (100.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 5 -6. MS-ESI [M+H] + , calculated 538, found 538.
(6)向化合物5-6(20.0mg,37.2μmol)的乙醇(2.0mL)溶液中加入铁(20.8mg,372 μmol),氯化铵(1.99mg,37.2μmol)。反应液在60℃下搅拌1小时,反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(C18-1,150mm×30mm 5μm,A:水(碳酸氢铵)；B:乙腈,25％-65％:25分钟)分离得到化合物5。MS-ESI[M+H] +,计算值508,实测值508。 (6) Iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) were added to a solution of compound 5-6 (20.0 mg, 37.2 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 60°C for 1 hour, water (100.0 mL) was added to the reaction solution, extracted with ethyl acetate (100.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was prepared by Compound 5 was isolated by high performance liquid chromatography (C18-1, 150mm×30mm 5μm, A: water (ammonium bicarbonate); B: acetonitrile, 25%-65%: 25 minutes). MS-ESI [M+H] + , calculated 508, found 508.
1H NMR(400MHz,MeOD)δ8.94(s,1H),6.97(br d,J＝6.4Hz,2H),6.77(s,1H),5.40(q,J＝7.2Hz,1H),3.28(s,3H),2.76(br d,J＝10.8Hz,2H),2.65(s,3H),2.46-2.56(m,2H),2.34(s,3H),2.15-2.24(m,2H),2.01-2.12(m,2H),1.62(d,J＝7.2Hz,3H)。 1 H NMR (400MHz,MeOD)δ8.94(s,1H),6.97(br d,J=6.4Hz,2H),6.77(s,1H),5.40(q,J=7.2Hz,1H),3.28 (s,3H),2.76(br d,J=10.8Hz,2H),2.65(s,3H),2.46-2.56(m,2H),2.34(s,3H),2.15-2.24(m,2H) , 2.01-2.12 (m, 2H), 1.62 (d, J=7.2Hz, 3H).
实施例6合成化合物6Embodiment 6 synthetic compound 6
Figure PCTCN2022140697-appb-000057
Figure PCTCN2022140697-appb-000057
(1)化合物6-1的合成参考专利WO2021127429。向化合物6-1(100mg,227μmol)的二氧六环(2.0mL)溶液中,加入化合物5-3(107mg,250μmol),醋酸钯(5.11mg,22.6μmol)，碳酸铯(148mg,455μmol)和1,1'-联萘-2,2'-双二苯膦(28.3mg,45.5μmol)。反应液在氮气保护下80℃搅拌1小时。反应液加入水(10.0mL),用乙酸乙酯(5.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×2)洗涤，无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到10:1)分离得到化合物6-2。(1) For the synthesis of compound 6-1, refer to patent WO2021127429. To compound 6-1 (100mg, 227μmol) in dioxane (2.0mL) solution, add compound 5-3 (107mg, 250μmol), palladium acetate (5.11mg, 22.6μmol), cesium carbonate (148mg, 455μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (28.3 mg, 45.5 μmol). The reaction solution was stirred at 80° C. for 1 hour under the protection of nitrogen. Add water (10.0mL) to the reaction solution, extract with ethyl acetate (5.0mL×2), combine the organic phases, wash with saturated brine (5.0mL×2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the crude product Compound 6-2 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 10:1).
MS-ESI[M+H] +,计算值829,实测值829。 MS-ESI [M+H] + , calculated 829, found 829.
(2)向化合物6-2(100mg,121μmol)的二氯甲烷(3.0mL)溶液中加入三氟乙酸(138mg,1.21mmol)。反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物6-3的三氟乙酸盐。(2) To a solution of compound 6-2 (100 mg, 121 μmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (138 mg, 1.21 mmol). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 6-3.
MS-ESI[M+H] +,计算值729,实测值729。 MS-ESI [M+H] + , calculated 729, found 729.
(3)向化合物6-3的三氟乙酸盐(60.0mg,82.3μmol)的乙醇(2.0mL)溶液中加入多聚甲醛(2.4mg,412μmol),三乙胺(8.33mg,82.3μmol),醋酸(4.94mg,82.3μmol)和氰基硼氢化钠(5.17mg,82.3μmol)。反应液在25℃下搅拌1小时,反应液加入水(100.0mL),用乙酸乙酯(50.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物6-4。(3) Add paraformaldehyde (2.4 mg, 412 μmol) and triethylamine (8.33 mg, 82.3 μmol) to a solution of trifluoroacetate (60.0 mg, 82.3 μmol) in ethanol (2.0 mL) of compound 6-3 , acetic acid (4.94 mg, 82.3 μmol) and sodium cyanoborohydride (5.17 mg, 82.3 μmol). The reaction solution was stirred at 25°C for 1 hour, water (100.0 mL) was added to the reaction solution, extracted with ethyl acetate (50.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 6 -4.
MS-ESI[M+H] +,计算值743实测值743。 MS-ESI [M+H] + , calculated 743 found 743.
(4)0℃下向化合物6-4(50.0mg,67.3μmol)的四氢呋喃(1.0mL)溶液中加入四丁基氟化铵(1.00mol/L,101μL)。反应液在25℃下搅拌1小时。。反应液加入水(5.0mL),用乙酸乙酯(5.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×2)洗涤，无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×25mm 5μm，A:水(0.225％甲酸)；B:乙腈，5％-35％:25分钟)分离得到化合物6。(4) To a solution of compound 6-4 (50.0 mg, 67.3 μmol) in tetrahydrofuran (1.0 mL) was added tetrabutylammonium fluoride (1.00 mol/L, 101 μL) at 0°C. The reaction solution was stirred at 25°C for 1 hour. . Add water (5.0mL) to the reaction solution, extract with ethyl acetate (5.0mL×2), combine the organic phases, wash with saturated brine (5.0mL×2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the crude product Compound 6 was isolated by preparative high performance liquid chromatography (Welch Xtimate C18, 150mm×25mm 5μm, A: water (0.225% formic acid); B: acetonitrile, 5%-35%: 25 minutes).
MS-ESI[M+H] +，计算值505，实测值505。 MS-ESI [M+H] + , calcd. 505, found 505.
1H NMR(400MHz,MeOD)δ8.98(s,1H),7.64(s,1H),7.57(br d,J＝6.8Hz,1H),7.33-7.44(m,2H),5.53(q,J＝7.2Hz,1H),3.86(t,J＝13.6Hz,2H),3.17-3.23(m,2H),2.99-3.09(m,2H),2.72(s,3H),2.66(s,3H),2.37(br d,J＝14.0Hz,2H),2.15-2.25(m,2H),1.67(d,J＝7.2Hz,3H)。 1 H NMR (400MHz, MeOD) δ8.98(s, 1H), 7.64(s, 1H), 7.57(br d, J=6.8Hz, 1H), 7.33-7.44(m, 2H), 5.53(q, J＝7.2Hz, 1H), 3.86(t, J＝13.6Hz, 2H), 3.17-3.23(m, 2H), 2.99-3.09(m, 2H), 2.72(s, 3H), 2.66(s, 3H ), 2.37 (br d, J = 14.0Hz, 2H), 2.15-2.25 (m, 2H), 1.67 (d, J = 7.2Hz, 3H).
实施例7合成化合物7Embodiment 7 synthetic compound 7
Figure PCTCN2022140697-appb-000058
Figure PCTCN2022140697-appb-000058
(1)化合物7-1的合成参考专利WO2021127429。向化合物7-1(35.0mg,141μmol)的二氧六环(2.0mL)溶液中,加入化合物5-3(50.2mg,118μmol),醋酸钯(2.65mg,11.8μmol)，碳酸铯(76.9mg,236μmol)和1,1'-联萘-2,2'-双二苯膦(14.7mg,23.6μmol)。反应液在氮气保护下100℃搅拌12小时。反应液加入水(10.0mL),用乙酸乙酯(5.0mL×2)萃取,合并有机相,用饱和食盐水(5.0mL×2)洗涤，无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到20:1)分离得到化合物7-2。(1) For the synthesis of compound 7-1, refer to patent WO2021127429. To compound 7-1 (35.0mg, 141μmol) in dioxane (2.0mL) solution, add compound 5-3 (50.2mg, 118μmol), palladium acetate (2.65mg, 11.8μmol), cesium carbonate (76.9mg , 236 μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (14.7 mg, 23.6 μmol). The reaction solution was stirred at 100° C. for 12 hours under the protection of nitrogen. Add water (10.0mL) to the reaction solution, extract with ethyl acetate (5.0mL×2), combine the organic phases, wash with saturated brine (5.0mL×2), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, the crude product Compound 7-2 was isolated by silica gel column chromatography (dichloromethane/methanol=1:0 to 20:1).
MS-ESI[M+H] +,计算值637,实测值637。 MS-ESI [M+H] + , calculated 637, found 637.
(2)向化合物7-2(20.0mg,31.4μmol)的二氯甲烷(1.0mL)溶液中加入三氟乙酸(154mg,1.35mmol)。反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物7-3的三氟乙酸盐。(2) To a solution of compound 7-2 (20.0 mg, 31.4 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (154 mg, 1.35 mmol). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 7-3.
MS-ESI[M+H] +,计算值537,实测值537。 MS-ESI [M+H] + , calculated 537, found 537.
(3)向化合物7-3的三氟乙酸盐(30.0mg,55.9μmol)的乙醇(0.5mL)溶液中加入多聚甲醛(5.04mg,168μmol),三乙胺(8.33mg,82.3μmol),醋酸(4.94mg,82.3μmol)和氰基硼氢化钠(3.51mg,55.9μmol)。反应液减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,100mm×30mm 10μm，A:水(0.225％甲酸)；B:乙腈，15％-35％:10分钟)分离得到化合物7。MS-ESI[M+H] +，计算值551，实测值551。 (3) Add paraformaldehyde (5.04 mg, 168 μmol) and triethylamine (8.33 mg, 82.3 μmol) to a solution of trifluoroacetate (30.0 mg, 55.9 μmol) in ethanol (0.5 mL) of compound 7-3 , acetic acid (4.94 mg, 82.3 μmol) and sodium cyanoborohydride (3.51 mg, 55.9 μmol). The reaction solution was concentrated under reduced pressure, and the crude product was separated by preparative high-performance liquid chromatography (Welch Xtimate C18, 100mm×30mm 10 μm, A: water (0.225% formic acid); B: acetonitrile, 15%-35%: 10 minutes) to obtain compound 7 . MS-ESI [M+H] + , calcd. 551, found 551.
1H NMR(400MHz,MeOD)δ9.02(d,J＝8.4Hz,1H),7.53(t,J＝6.8Hz,1H),7.35(t,J＝6.8Hz,1H),7.12(t,J＝8.0Hz,1H),5.73(q,J＝6.8Hz,1H),3.35(d,J＝11.2Hz,6H),3.00-3.19(m,2H),2.69-2.83(m,2H),2.59-2.67(m,3H),2.32-2.50(m,2H),2.13-2.28(m,2H),1.62-1.71(m,3H),1.29(br s,6H)。 1 H NMR (400MHz, MeOD) δ9.02(d, J=8.4Hz, 1H), 7.53(t, J=6.8Hz, 1H), 7.35(t, J=6.8Hz, 1H), 7.12(t, J＝8.0Hz, 1H), 5.73(q, J＝6.8Hz, 1H), 3.35(d, J＝11.2Hz, 6H), 3.00-3.19(m, 2H), 2.69-2.83(m, 2H), 2.59-2.67 (m, 3H), 2.32-2.50 (m, 2H), 2.13-2.28 (m, 2H), 1.62-1.71 (m, 3H), 1.29 (br s, 6H).
实施例8合成化合物8Embodiment 8 synthetic compound 8
Figure PCTCN2022140697-appb-000059
Figure PCTCN2022140697-appb-000059
(1)向化合物8-1(1g,6.94mmol)的二氯甲烷(30.0mL)溶液中，加入二异丙基乙基 胺(4.48g,34.7mmol)，化合物8-2的盐酸盐(1.01g,10.4mmol)和丙基磷酸酐(6.62g,10.4mmol,50％)。反应液在氮气保护下25℃搅拌2小时。反应液加入二氯甲烷(20.0mL)，用水(10.0mL×3)洗涤，有机相用无水硫酸钠干燥，过滤并减压浓缩，粗品经硅胶柱层析法(二氯甲烷/甲醇＝1:0到50:1)分离得到化合物8-3。MS-ESI[M+H] +，计算值188，实测值188。 (1) To compound 8-1 (1g, 6.94mmol) in dichloromethane (30.0mL) solution, add diisopropylethylamine (4.48g, 34.7mmol), the hydrochloride of compound 8-2 ( 1.01 g, 10.4 mmol) and propylphosphoric anhydride (6.62 g, 10.4 mmol, 50%). The reaction solution was stirred at 25° C. for 2 hours under the protection of nitrogen. Dichloromethane (20.0 mL) was added to the reaction solution, washed with water (10.0 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol=1 :0 to 50:1) to isolate compound 8-3. MS-ESI [M+H] + , calcd. 188, found 188.
1H NMR(400MHz,CDCl 3)δ3.73-3.81(m,2H),3.66(s,3H),3.58-3.66(m,2H),3.21(s,3H),2.14-2.23(m,2H),1.52-1.61(m,2H),1.29(s,3H)。 1 H NMR (400MHz, CDCl 3 ) δ3.73-3.81(m,2H),3.66(s,3H),3.58-3.66(m,2H),3.21(s,3H),2.14-2.23(m,2H ), 1.52-1.61 (m, 2H), 1.29 (s, 3H).
(2)向中间体A(50mg,130μmol)的四氢呋喃(1.0mL)溶液中加入二异丙基氨基锂(2.0mol/L,0.26mL)。反应液在氮气保护下-78℃下搅拌1小时，加入化合物8-3(73.4mg,392mmol)的四氢呋喃(1.0mL)溶液，反应液在氮气保护下-78到-0℃下搅拌2小时，然后加入饱和氯化铵水溶液(10.0mL)，加入水(10.0mL)，用乙酸乙酯(10.0mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,100mm×30mm 10μm，A:水(0.225％甲酸)；B:乙腈，30％-60％:30分钟)分离得到化合物8-4的甲酸盐。MS-ESI[M+H] +，计算值509，实测值509。 (2) To a solution of intermediate A (50 mg, 130 μmol) in tetrahydrofuran (1.0 mL) was added lithium diisopropylamide (2.0 mol/L, 0.26 mL). The reaction solution was stirred at -78°C under the protection of nitrogen for 1 hour, and a solution of compound 8-3 (73.4 mg, 392 mmol) in tetrahydrofuran (1.0 mL) was added, and the reaction solution was stirred at -78 to -0°C under the protection of nitrogen for 2 hours. Then add saturated ammonium chloride aqueous solution (10.0mL), add water (10.0mL), extract with ethyl acetate (10.0mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the crude product is prepared by High performance liquid chromatography (Welch Xtimate C18, 100mm×30mm 10μm, A: water (0.225% formic acid); B: acetonitrile, 30%-60%: 30 minutes) separated the formate of compound 8-4. MS-ESI [M+H] + , calcd. 509, found 509.
(2)向化合物8-4的甲酸盐(5mg,9.83μmol)的乙醇(2.0mL)溶液中加入铁粉(5.49mg,98.3μmol)和盐酸(1mol/L,100μL)。反应液在65℃下搅拌1小时，反应液过滤，减压浓缩，粗品经制备高效液相色谱法(Welch Xtimate C18,100mm×30mm 10μm，A:水(0.225％甲酸)；B:乙腈,20％-50％:25分钟)分离得到化合物8的甲酸盐。MS-ESI[M+H] +，计算值479，实测值479。 (2) Iron powder (5.49 mg, 98.3 μmol) and hydrochloric acid (1 mol/L, 100 μL) were added to a solution of the formate salt of compound 8-4 (5 mg, 9.83 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 65°C for 1 hour, the reaction solution was filtered, concentrated under reduced pressure, and the crude product was subjected to preparative high performance liquid chromatography (Welch Xtimate C18, 100mm×30mm 10μm, A: water (0.225% formic acid); B: acetonitrile, 20 %-50%: 25 minutes) to isolate the formate salt of compound 8. MS-ESI [M+H] + , calcd. 479, found 479.
1H NMR(400MHz,MeOD)δ8.76(s,1H),6.97(s,2H),6.78(s,1H),5.39(q,J＝6.8Hz,1H),3.77-3.87(m,2H),3.61(ddd,J＝11.6,8.8,3.2Hz,2H),2.65(s,3H),2.31-2.41(m,2H),1.78-1.88(m,2H),1.63(d,J＝7.2Hz,3H),1.61(s,3H)。 1 H NMR (400MHz,MeOD)δ8.76(s,1H),6.97(s,2H),6.78(s,1H),5.39(q,J=6.8Hz,1H),3.77-3.87(m,2H ),3.61(ddd,J=11.6,8.8,3.2Hz,2H),2.65(s,3H),2.31-2.41(m,2H),1.78-1.88(m,2H),1.63(d,J=7.2 Hz,3H), 1.61(s,3H).
实施例9合成化合物9Embodiment 9 synthetic compound 9
Figure PCTCN2022140697-appb-000060
Figure PCTCN2022140697-appb-000060
(1)向化合物A-4(150mg,812μmol)的四氢呋喃(6.0mL)溶液中加入二异丙基氨基锂(2.00mol/L,0.61mL)。反应液在氮气保护下-78℃下搅拌1小时,加入化合物8-1 (203mg,894μmol),反应液在氮气保护下0℃下搅拌2小时,加入饱和氯化铵水溶液(100mL),加入水(100mL),用乙酸乙酯(100mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到3:1)分离得到化合物9-2。MS-ESI[M+H] +,计算值412,实测值412。 (1) To a solution of compound A-4 (150 mg, 812 μmol) in tetrahydrofuran (6.0 mL) was added lithium diisopropylamide (2.00 mol/L, 0.61 mL). The reaction solution was stirred at -78°C under the protection of nitrogen for 1 hour, compound 8-1 (203 mg, 894 μmol) was added, the reaction solution was stirred at 0°C under the protection of nitrogen for 2 hours, saturated aqueous ammonium chloride (100 mL) was added, and water (100mL), extracted with ethyl acetate (100mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 3:1) Compound 9-2 was isolated. MS-ESI [M+H] + , calculated 412, found 412.
(2)向化合物9-2(300mg,728μmol)的二氯乙烷(3.0mL)溶液中加入二氧化锰(633mg,7.28mmol)。反应液在25℃下搅拌10小时。反应液过滤,减压浓缩,到化合物9-3。MS-ESI[M+H] +,计算值410,实测值410。 (2) To a solution of compound 9-2 (300 mg, 728 μmol) in dichloroethane (3.0 mL) was added manganese dioxide (633 mg, 7.28 mmol). The reaction solution was stirred at 25°C for 10 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 9-3. MS-ESI [M+H] + , calculated 410, found 410.
(3)向化合物9-3(50.0mg,122μmol)的二氧六环(2.00mL)溶液中,加入化合物A-5(31.4mg,134μmol),醋酸钯(2.74mg,12.2μmol)，碳酸铯(79.5mg,244μmol)和1,1'-联萘-2,2'-双二苯膦(15.19mg,24.4μmol)。反应液在氮气保护下100℃搅拌12小时。反应液加入水(10.0mL),用乙酸乙酯(10.0mL×2)萃取,合并有机相，用无水硫酸钠干燥，过滤并减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到10:1)分离得到化合物9-4。MS-ESI[M+H] +,计算值608,实测值608。 (3) To compound 9-3 (50.0mg, 122μmol) in dioxane (2.00mL) solution, add compound A-5 (31.4mg, 134μmol), palladium acetate (2.74mg, 12.2μmol), cesium carbonate (79.5mg, 244μmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (15.19mg, 24.4μmol). The reaction solution was stirred at 100° C. for 12 hours under the protection of nitrogen. Add water (10.0mL) to the reaction solution, extract with ethyl acetate (10.0mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, the crude product is subjected to silica gel column chromatography (petroleum ether/acetic acid Ethyl ester = 1:0 to 10:1) Compound 9-4 was isolated. MS-ESI [M+H] + , calculated 608, found 608.
(4)向化合物9-4(50.0mg,82.3μmol)的二氯甲烷(5.0mL)溶液中加入三氟乙酸(93.8mg,823mmol)。反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物9-5的三氟乙酸盐。MS-ESI[M+H] +,计算值508,实测值508。 (4) To a solution of compound 9-4 (50.0 mg, 82.3 μmol) in dichloromethane (5.0 mL) was added trifluoroacetic acid (93.8 mg, 823 mmol). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 9-5. MS-ESI [M+H] + , calculated 508, found 508.
(5)向化合物9-5(40.0mg,64.4μmol)的乙醇(5.0mL)溶液中加入多聚甲醛(9.66mg,322μmol),三乙胺(6.51mg,64.4μmol),醋酸(387μg,6.44μmol)和氰基硼氢化钠(6.07mg,96.5μmol)。反应液在25℃下搅拌10小时,反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到化合物9-6。MS-ESI[M+H] +,计算值524,实测值524。 (5) Add paraformaldehyde (9.66 mg, 322 μmol), triethylamine (6.51 mg, 64.4 μmol), acetic acid (387 μg, 6.44 μmol) and sodium cyanoborohydride (6.07mg, 96.5μmol). The reaction solution was stirred at 25°C for 10 hours, water (100.0 mL) was added to the reaction solution, extracted with ethyl acetate (100.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9 -6. MS-ESI [M+H] + , calculated 524, found 524.
(6)向化合物9-6(19.4mg,37.2μmol)的乙醇(2.0mL)溶液中加入铁(20.8mg,372μmol),氯化铵(1.99mg,37.2μmol)。反应液在60℃下搅拌1小时,反应液加入水(100.0mL),用乙酸乙酯(100.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(C18-6,100mm×30mm 5μm,A:水(0.225％甲酸)；B:乙腈,8％-38％:15分钟)分离得到化合物9的甲酸盐。MS-ESI[M+H] +,计算值492,实测值492。 (6) Iron (20.8 mg, 372 μmol) and ammonium chloride (1.99 mg, 37.2 μmol) were added to a solution of compound 9-6 (19.4 mg, 37.2 μmol) in ethanol (2.0 mL). The reaction solution was stirred at 60°C for 1 hour, water (100.0 mL) was added to the reaction solution, extracted with ethyl acetate (100.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was prepared by High performance liquid chromatography (C18-6, 100mm×30mm 5μm, A: water (0.225% formic acid); B: acetonitrile, 8%-38%: 15 minutes) separated the formate of compound 9. MS-ESI [M+H] + , calculated 492, found 492.
1H NMR(400MHz,MeOD)δ8.80(s,1H),6.98(s,2H),6.79(s,1H),5.41(q,J＝7.2Hz,1H),3.20-3.28(m,2H),2.90-3.04(m,2H),2.72(s,3H),2.54-2.69(m,5H),1.96-2.09(m,2H),1.62-1.69(m,6H)。 1 H NMR (400MHz,MeOD)δ8.80(s,1H),6.98(s,2H),6.79(s,1H),5.41(q,J=7.2Hz,1H),3.20-3.28(m,2H ), 2.90-3.04(m,2H), 2.72(s,3H), 2.54-2.69(m,5H), 1.96-2.09(m,2H), 1.62-1.69(m,6H).
实施例10合成化合物10Embodiment 10 synthetic compound 10
Figure PCTCN2022140697-appb-000061
Figure PCTCN2022140697-appb-000061
(1)向化合物9-3(51.8mg,126μmol)的二氧六环(2.00mL)溶液中,加入化合物10-1(28.7mg,155μmol),甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基 -1,1'-联苯-2-基)钯(II)(21.1mg,25.3μmol)和碳酸铯(103mg,316μmol)。反应液在氮气保护下100℃搅拌12小时。反应液加入水(10.0mL),用乙酸乙酯(10.0mL×2)萃取,合并有机相，用饱和食盐水(10.0mL×2)洗涤，无水硫酸钠干燥，过滤并减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到2:3)分离得到化合物10-2。MS-ESI[M+H] +,计算值563,实测值563。 (1) To compound 9-3 (51.8 mg, 126 μmol) in dioxane (2.00 mL), add compound 10-1 (28.7 mg, 155 μmol), methanesulfonic acid (2-dicyclohexylphosphino- 2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (21.1 mg, 25.3 μmol) and Cesium carbonate (103 mg, 316 μmol). The reaction solution was stirred at 100° C. for 12 hours under the protection of nitrogen. Add water (10.0 mL) to the reaction solution, extract with ethyl acetate (10.0 mL×2), combine the organic phases, wash with saturated brine (10.0 mL×2), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, the crude product Compound 10-2 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 2:3). MS-ESI [M+H] + , calculated 563, found 563.
(2)向化合物10-2(22.0mg,39.1μmol)的二氯甲烷(1.0mL)溶液中加入三氟乙酸(0.1mL)。反应液在25℃下搅拌1小时。反应液减压浓缩得到化合物10-3的三氟乙酸盐。MS-ESI[M+H] +,计算值463,实测值463。 (2) To a solution of compound 10-2 (22.0 mg, 39.1 μmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (0.1 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetate salt of compound 10-3. MS-ESI [M+H] + , calculated 463, found 463.
(3)向化合物10-3的三氟乙酸盐(30.0mg,52.0μmol)的乙醇(1.0mL)溶液中加入多聚甲醛(15.6mg,520μmol),三乙胺(6.51mg,64.4μmol),醋酸(387μg,6.44μmol)和氰基硼氢化钠(8.17mg,130μmol)。反应液在25℃下搅拌10小时,反应液加入水(30.0mL),用乙酸乙酯(30.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Welch Xtimate C18,150mm×30mm 5μm,A:水(碳酸氢铵)；B:乙腈,50％-85％:14分钟)分离得到化合物10。MS-ESI[M+H] +,计算值477,实测值477。 1H NMR(400MHz,MeOD)δ8.79(s,1H),7.59(t,J＝8.0Hz,1H),7.42-7.51(m,1H),7.19(t,J＝7.6Hz,1H),6.83-7.15(m,1H),5.71(q,J＝7.2Hz,1H),2.67(d,J＝6.4Hz,2H),2.61-2.64(m,3H),2.42-2.51(m,2H),2.31-2.41(m,2H),2.28(s,3H),1.82-1.91(m,2H),1.69(d,J＝7.2Hz,3H),1.57(s,3H)。 (3) Add paraformaldehyde (15.6 mg, 520 μmol) and triethylamine (6.51 mg, 64.4 μmol) to a solution of trifluoroacetate (30.0 mg, 52.0 μmol) in ethanol (1.0 mL) of compound 10-3 , acetic acid (387 μg, 6.44 μmol) and sodium cyanoborohydride (8.17 mg, 130 μmol). The reaction solution was stirred at 25°C for 10 hours, water (30.0 mL) was added to the reaction solution, extracted with ethyl acetate (30.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was prepared by Compound 10 was isolated by high performance liquid chromatography (Welch Xtimate C18, 150 mm×30 mm 5 μm, A: water (ammonium bicarbonate); B: acetonitrile, 50%-85%: 14 minutes). MS-ESI [M+H] + , calcd. 477, found 477. 1 H NMR (400MHz, MeOD) δ8.79(s, 1H), 7.59(t, J=8.0Hz, 1H), 7.42-7.51(m, 1H), 7.19(t, J=7.6Hz, 1H), 6.83-7.15(m,1H),5.71(q,J=7.2Hz,1H),2.67(d,J=6.4Hz,2H),2.61-2.64(m,3H),2.42-2.51(m,2H) , 2.31-2.41 (m, 2H), 2.28 (s, 3H), 1.82-1.91 (m, 2H), 1.69 (d, J=7.2Hz, 3H), 1.57 (s, 3H).
实施例11，13，18合成化合物11，13和18Embodiment 11,13,18 synthetic compound 11,13 and 18
采用实施例10中的合成方法，使用相对应的原料合成化合物11，13和18。Using the synthesis method in Example 10, compounds 11, 13 and 18 were synthesized using corresponding starting materials.
Figure PCTCN2022140697-appb-000062
Figure PCTCN2022140697-appb-000062
实施例12合成化合物12Embodiment 12 synthetic compound 12
Figure PCTCN2022140697-appb-000063
Figure PCTCN2022140697-appb-000063
(1)向化合物A-4(400mg,2.17mmol)的四氢呋喃(8.0mL)溶液中加入二异丙基氨基锂(2.00mol/L,1.84mL)。反应液在氮气保护下-78℃下搅拌1小时,加入化合物12-1(305mg,2.38mmol),反应液在氮气保护下-65℃下搅拌2小时,加入饱和氯化铵水溶液(30.0mL),加入水(30.0mL),用乙酸乙酯(30.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到1:1)分离得到化合物12-2。MS-ESI[M+H] +,计算值313,实测值313。 (1) To a solution of compound A-4 (400 mg, 2.17 mmol) in tetrahydrofuran (8.0 mL) was added lithium diisopropylamide (2.00 mol/L, 1.84 mL). The reaction solution was stirred at -78°C under nitrogen protection for 1 hour, compound 12-1 (305mg, 2.38mmol) was added, the reaction solution was stirred at -65°C under nitrogen protection for 2 hours, and saturated aqueous ammonium chloride solution (30.0mL) was added , added water (30.0mL), extracted with ethyl acetate (30.0mL×2), combined the organic phases, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate =1:0 to 1:1) Compound 12-2 was isolated. MS-ESI [M+H] + , calcd. 313, found 313.
(2)向化合物12-2(170mg,543μmol)的二氯乙烷(2.0mL)溶液中加入二氧化锰(1.89g,21.7mmol)。反应液在70℃下搅拌48小时。反应液过滤,减压浓缩,粗品经制备薄层层析法(石油醚/乙酸乙酯＝2:1)分离得到化合物12-3。MS-ESI[M+H] +,计算值311,实测值311。 (2) To a solution of compound 12-2 (170 mg, 543 μmol) in dichloroethane (2.0 mL) was added manganese dioxide (1.89 g, 21.7 mmol). The reaction solution was stirred at 70°C for 48 hours. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was separated by preparative thin-layer chromatography (petroleum ether/ethyl acetate=2:1) to obtain compound 12-3. MS-ESI [M+H] + , calculated 311 , found 311 .
(3)向化合物12-3(13.5mg,16.1μmol)的二氧六环(2.00mL)溶液中,加入化合物12-4((18.3mg,96.5μmol),甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II)(13.5mg,16.1μmol),碳酸铯(52.4mg,161μmol)。反应液在氮气保护下100℃搅拌12小时。反应液加入水(10.0mL),用乙酸乙酯(10.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Xtimate C18,100mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,38％-58％:10分钟)分离得到化合物12。MS-ESI[M+H] +,计算值464,实测值464。 1H NMR(400MHz,MeOD)δ8.80(s,1H),7.59(t,J＝7.2Hz,1H),7.45(t,J＝6.8Hz,1H),7.19(t,J＝7.6Hz,1H),6.83-7.14(m,1H),5.68(q,J＝6.8Hz,1H),3.82(ddd,J＝11.6,6.0,3.6Hz,2H),3.61(ddd,J＝11.2,8.4,2.8Hz,2H),2.63(s,3H),2.37(dd,J＝13.9,1.3Hz,2H),1.79-1.88(m,2H),1.69(d,J＝6.8Hz,3H),1.62(s,3H)。 (3) To a solution of compound 12-3 (13.5 mg, 16.1 μmol) in dioxane (2.00 mL), add compound 12-4 ((18.3 mg, 96.5 μmol), methanesulfonic acid (2-dicyclohexyl Phosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (13.5mg, 16.1 μmol), cesium carbonate (52.4mg, 161μmol). The reaction solution was stirred at 100°C for 12 hours under the protection of nitrogen. The reaction solution was added with water (10.0mL), extracted with ethyl acetate (10.0mL×2), and the organic phase was combined. Dry over sodium sulfate, filter, concentrate under reduced pressure, and the crude product is subjected to preparative high performance liquid chromatography (Xtimate C18, 100mm×30mm 10μm, A: water (0.225% formic acid); B: acetonitrile, 38%-58%: 10 minutes) Compound 12 was isolated. MS-ESI [M+H] + , calculated value 464, found value 464. 1 H NMR (400MHz, MeOD) δ8.80(s, 1H), 7.59(t, J=7.2Hz, 1H ), 7.45(t, J=6.8Hz, 1H), 7.19(t, J=7.6Hz, 1H), 6.83-7.14(m, 1H), 5.68(q, J=6.8Hz, 1H), 3.82(ddd ,J=11.6,6.0,3.6Hz,2H),3.61(ddd,J=11.2,8.4,2.8Hz,2H),2.63(s,3H),2.37(dd,J=13.9,1.3Hz,2H), 1.79-1.88 (m, 2H), 1.69 (d, J=6.8Hz, 3H), 1.62 (s, 3H).
实施例14，15，17合成化合物14，15和17Embodiment 14,15,17 synthetic compound 14,15 and 17
采用实施例12中的合成方法，使用相对应的原料合成化合物14，15和17。Using the synthesis method in Example 12, compounds 14, 15 and 17 were synthesized using corresponding starting materials.
Figure PCTCN2022140697-appb-000064
Figure PCTCN2022140697-appb-000064
Figure PCTCN2022140697-appb-000065
Figure PCTCN2022140697-appb-000065
实施例16合成化合物16Embodiment 16 synthetic compound 16
采用实施例8中的合成方法，使用相对应的原料合成化合物16。Using the synthesis method in Example 8, compound 16 was synthesized using the corresponding starting materials.
Figure PCTCN2022140697-appb-000066
Figure PCTCN2022140697-appb-000066
实施例19合成化合物19Example 19 Synthesis of Compound 19
Figure PCTCN2022140697-appb-000067
Figure PCTCN2022140697-appb-000067
(1)向化合物9-3(600mg,1.46mmol)的二甲基亚砜(10.0mL)溶液中,加入化合物13-1(356mg,1.76mmol),二异丙基乙基胺(945mg,7.32mmol)和氟化钾(850mg,14.64mmol)。反应液在氮气保护下100℃搅拌12小时。反应液加入水(30.0mL),用乙酸乙酯(30.0mL×2)萃取,合并有机相，用饱和食盐水(30.0mL×2)洗涤，无水硫酸钠干燥，过滤并减压浓缩，粗品经硅胶柱层析法(石油醚/乙酸乙酯＝1:0到1:1)分离得到化合物19-1。MS-ESI[M+H] +,计算值577,实测值577。 (1) To compound 9-3 (600 mg, 1.46 mmol) in dimethyl sulfoxide (10.0 mL), add compound 13-1 (356 mg, 1.76 mmol), diisopropylethylamine (945 mg, 7.32 mmol) and potassium fluoride (850mg, 14.64mmol). The reaction solution was stirred at 100° C. for 12 hours under the protection of nitrogen. Add water (30.0 mL) to the reaction solution, extract with ethyl acetate (30.0 mL×2), combine the organic phases, wash with saturated brine (30.0 mL×2), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, the crude product Compound 19-1 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate=1:0 to 1:1). MS-ESI [M+H] + , calculated 577, found 577.
(2)向化合物19-1(700mg,1.21mmol)的二氯甲烷(10.0mL)溶液中加入三氟乙酸(2.0mL)。反应液在25℃下搅拌1小时。反应液减压浓缩,加入碳酸氢钠水溶液调节pH值到8-9,加入水(30.0mL),用二氯甲烷(30.0mL×2)萃取,合并有机相，无水硫酸钠干燥，过滤并减压浓缩，得到化合物19-2。MS-ESI[M+H] +,计算值477,实测值477。 (2) To a solution of compound 19-1 (700 mg, 1.21 mmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (2.0 mL). The reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, adding aqueous sodium bicarbonate solution to adjust the pH to 8-9, adding water (30.0 mL), extracting with dichloromethane (30.0 mL×2), combining the organic phases, drying over anhydrous sodium sulfate, filtering and Concentration under reduced pressure gave compound 19-2. MS-ESI [M+H] + , calculated 477, found 477.
(3)向化合物19-2(18.2mg,202μmol)的二氯甲烷(3.0mL)溶液中,加入二异丙基乙基胺(65.1mg,503μmol),化合物19-3(18.2mg,202μmol)和N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(95.7mg,252μmol)。反应液在氮气保护下25℃搅拌1小时。反应液加入二氯甲烷(30.0mL)稀释,用水(30.0mL)洗涤。有机相用无水硫 酸钠干燥,过滤并减压浓缩,粗品经制备高效液相色谱法(Xtimate C18,150mm×30mm10μm,A:水(0.225％甲酸)；B:乙腈,14％-54％:25分钟)分离得到化合物19的甲酸盐。MS-ESI[M+H] +,计算值549,实测值549。 1H NMR(400MHz,MeOD)δ8.80(s,1H),7.71(d,J＝8.0Hz,1H),7.51(d,J＝4.8Hz,1H),7.27(t,J＝7.6Hz,1H),5.73(q,J＝3.2Hz,J＝10.0Hz,1H),4.10-4.22(m,2H),3.92-4.02(m,1H),3.62-3.72(m,1H),3.39(s,3H),3.32-3.38(m,1H),3.21-3.28(m,1H),2.59-2.65(m,6H),2.37-2.47(m,2H),1.74-1.85(m,2H),1.58-1.68(m,6H)。 (3) To compound 19-2 (18.2mg, 202μmol) in dichloromethane (3.0mL) solution, add diisopropylethylamine (65.1mg, 503μmol), compound 19-3 (18.2mg, 202μmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (95.7 mg, 252 μmol). The reaction solution was stirred at 25° C. for 1 hour under the protection of nitrogen. The reaction solution was diluted with dichloromethane (30.0 mL), washed with water (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was subjected to preparative high performance liquid chromatography (Xtimate C18, 150mm×30mm10μm, A: water (0.225% formic acid); B: acetonitrile, 14%-54%: 25 min) to isolate the formate salt of compound 19. MS-ESI [M+H] + , calculated 549, found 549. 1 H NMR (400MHz, MeOD) δ8.80(s, 1H), 7.71(d, J=8.0Hz, 1H), 7.51(d, J=4.8Hz, 1H), 7.27(t, J=7.6Hz, 1H), 5.73(q, J=3.2Hz, J=10.0Hz, 1H), 4.10-4.22(m, 2H), 3.92-4.02(m, 1H), 3.62-3.72(m, 1H), 3.39(s ,3H),3.32-3.38(m,1H),3.21-3.28(m,1H),2.59-2.65(m,6H),2.37-2.47(m,2H),1.74-1.85(m,2H),1.58 -1.68(m,6H).
实施例20-29合成化合物20-29Embodiment 20-29 synthetic compound 20-29
采用实施例19中的合成方法，使用相对应的原料合成化合物20-29。Using the synthesis method in Example 19, compounds 20-29 were synthesized using corresponding starting materials.
Figure PCTCN2022140697-appb-000068
Figure PCTCN2022140697-appb-000068
Figure PCTCN2022140697-appb-000069
Figure PCTCN2022140697-appb-000069
实施例30合成化合物30Embodiment 30 synthetic compound 30
Figure PCTCN2022140697-appb-000070
Figure PCTCN2022140697-appb-000070
化合物19-2经制备高效液相色谱法(Xtimate C18,150mm×30mm 10μm,A:水(0.225％甲酸)；B:乙腈,16％-54％:25分钟)分离得到化合物30的甲酸盐。MS-ESI[M+H] +,计算值477,实测值477。 1H NMR(400MHz,MeOD)δ9.01(s,1H),7.75(d,J＝7.6Hz,1H),7.59(d,J＝7.6Hz,1H),7.34(t,J＝8.0Hz,1H),5.54(q,J＝7.2Hz,1H),3.35-3.40(m,2H),3.09-3.15(m,2H),2.76(s,3H),2.60(s,3H),1.72(s,6H),1.22-1.33(m,4H)。 Compound 19-2 was separated by preparative high performance liquid chromatography (Xtimate C18, 150mm×30mm 10μm, A: water (0.225% formic acid); B: acetonitrile, 16%-54%: 25 minutes) to obtain the formate salt of compound 30 . MS-ESI [M+H] + , calculated 477, found 477. 1 H NMR (400MHz, MeOD) δ9.01(s, 1H), 7.75(d, J=7.6Hz, 1H), 7.59(d, J=7.6Hz, 1H), 7.34(t, J=8.0Hz, 1H), 5.54(q, J=7.2Hz, 1H), 3.35-3.40(m, 2H), 3.09-3.15(m, 2H), 2.76(s, 3H), 2.60(s, 3H), 1.72(s ,6H), 1.22-1.33(m,4H).
实施例31合成化合物31Example 31 Synthesis of Compound 31
Figure PCTCN2022140697-appb-000071
Figure PCTCN2022140697-appb-000071
0℃下，向化合物19-2(70.0mg,146μmol)的二氯甲烷(5.0mL)溶液中,加入三乙胺(14.8mg,146μmol),化合物31-1(23.6mg,220μmol)。反应液在氮气保护下0℃搅拌1小时。反应液加入水(30.0mL)稀释,用二氯甲烷(30.0mL)萃取。有机相用无水硫酸钠干燥,过滤并减压浓缩,粗品经制备高效液相色谱法(Xtimate C18,150mm×30mm 5μm,A:水(0.225％甲酸)；B:乙腈,18％-58％:25分钟)分离得到化合物31的甲酸盐。MS-ESI[M+H] +,计算值548,实测值548。 1H NMR(400MHz,MeOD)δ8.79(s,1H),7.71(d,J＝8.0Hz,1H),7.51(d,J＝7.6Hz,1H),7.26(t,J＝8.0Hz,1H),5.71(q,J＝4.8Hz,J＝6.8Hz,1H),3.41-3.47(m,2H),3.12(t,J＝10.8Hz,2H),2.84(s,6H),2.57-2.64(m,6H),2.34-2.41(m,2H),1.81(t,J＝10.4Hz,2H),1.56-1.66(m,6H)。 To a solution of compound 19-2 (70.0 mg, 146 μmol) in dichloromethane (5.0 mL) at 0° C. was added triethylamine (14.8 mg, 146 μmol), compound 31-1 (23.6 mg, 220 μmol). The reaction solution was stirred at 0° C. for 1 hour under the protection of nitrogen. The reaction solution was diluted with water (30.0 mL), and extracted with dichloromethane (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to preparative high performance liquid chromatography (Xtimate C18, 150mm×30mm 5μm, A: water (0.225% formic acid); B: acetonitrile, 18%-58% : 25 minutes) to isolate the formate salt of compound 31. MS-ESI [M+H] + , calculated 548, found 548. 1 H NMR (400MHz, MeOD) δ8.79(s, 1H), 7.71(d, J=8.0Hz, 1H), 7.51(d, J=7.6Hz, 1H), 7.26(t, J=8.0Hz, 1H), 5.71(q, J=4.8Hz, J=6.8Hz, 1H), 3.41-3.47(m, 2H), 3.12(t, J=10.8Hz, 2H), 2.84(s, 6H), 2.57- 2.64 (m, 6H), 2.34-2.41 (m, 2H), 1.81 (t, J=10.4Hz, 2H), 1.56-1.66 (m, 6H).
实施例32合成化合物32Embodiment 32 synthetic compound 32
采用实施例31中的合成方法，使用相对应的原料合成化合物32。Using the synthesis method in Example 31, compound 32 was synthesized using the corresponding starting materials.
Figure PCTCN2022140697-appb-000072
Figure PCTCN2022140697-appb-000072
实施例33合成化合物33Embodiment 33 synthetic compound 33
Figure PCTCN2022140697-appb-000073
Figure PCTCN2022140697-appb-000073
0℃下向化合物19-2(80.0mg,168μmol)的N,N-二甲基甲酰胺(1.0mL)溶液中,加入三乙胺(21.7mg,168μmol),化合物33-1(77.9mg,336μmol)。反应液在氮气保护下25℃搅拌2小时。反应液加入水(30.0mL)稀释,用乙酸乙酯(30.0mL)萃取。有机相用无水硫酸钠干燥,过滤并减压浓缩,粗品经制备高效液相色谱法(Xtimate C18,150mm×30mm 5μm,A:水(0.225％甲酸)；B:乙腈,34％-74％:25分钟)分离得到化合物33的甲酸盐。MS-ESI[M+H] +,计算值559,实测值559。 1H NMR(400MHz,MeOD)δ8.82(s,1H),7.71(d,J＝7.6Hz,1H),7.53(d,J＝7.6Hz,1H),7.28(d,J＝8.0Hz,1H),5.61-5.74(m,1H),3.05(q,J＝5.2Hz,J＝15.2Hz,2H),2.81-2.88(m,2H),2.66(s,3H),2.61(s,3H),2.54-2.60(m,2H),2.36-2.47(m,2H),1.83-1.93(m,2H),1.65(d,J＝6.8Hz,3H),1.57(s, 3H)。 To a solution of compound 19-2 (80.0mg, 168μmol) in N,N-dimethylformamide (1.0mL) at 0°C, triethylamine (21.7mg, 168μmol) was added, and compound 33-1 (77.9mg, 336 μmol). The reaction solution was stirred at 25° C. for 2 hours under the protection of nitrogen. The reaction solution was diluted with water (30.0 mL), and extracted with ethyl acetate (30.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was subjected to preparative high performance liquid chromatography (Xtimate C18, 150mm×30mm 5μm, A: water (0.225% formic acid); B: acetonitrile, 34%-74% : 25 minutes) to isolate the formate salt of compound 33. MS-ESI [M+H] + , calculated 559, found 559. 1 H NMR (400MHz, MeOD) δ8.82(s, 1H), 7.71(d, J=7.6Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.28(d, J=8.0Hz, 1H), 5.61-5.74(m, 1H), 3.05(q, J=5.2Hz, J=15.2Hz, 2H), 2.81-2.88(m, 2H), 2.66(s, 3H), 2.61(s, 3H ), 2.54-2.60 (m, 2H), 2.36-2.47 (m, 2H), 1.83-1.93 (m, 2H), 1.65 (d, J=6.8Hz, 3H), 1.57 (s, 3H).
实施例34合成化合物34Example 34 Synthesis of Compound 34
Figure PCTCN2022140697-appb-000074
Figure PCTCN2022140697-appb-000074
向化合物19-2(70.0mg,146μmol)的甲醇(5.0mL)溶液中加入化合物34-1(15.8mg,220μmol),醋酸(1.76mg,29.3μmol)和氰基硼氢化钠(13.8mg,220μmol)。反应液在25℃下搅拌1小时,反应液加入水(15.0mL),用乙酸乙酯(15.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(Phenomenex C18,75mm×30mm 3μm,A:水(碳酸氢铵)；B:乙腈,34％-74％:25分钟)分离得到化合物34。MS-ESI[M+H] +,计算值533,实测值533。 1H NMR(400MHz,MeOD)δ8.77(s,1H),7.70(d,J＝8.0Hz,1H),7.51(d,J＝7.6Hz,1H),7.26(t,J＝7.6Hz,1H),5.72(q,J＝4.8Hz,J＝6.8Hz,1H),4.68(t,J＝6.4Hz,2H),4.56-4.60(m,2H),3.42-3.46(m,1H),3.42-3.52(m,1H),2.62(s,6H),2.52-2.56(m,2H),2.43-2.48(m,2H),2.16-2.24(m,2H),1.87(t,J＝10.0Hz,2H),1.62(d,J＝6.8Hz,3H),1.57(s,3H)。 To compound 19-2 (70.0 mg, 146 μmol) in methanol (5.0 mL) was added compound 34-1 (15.8 mg, 220 μmol), acetic acid (1.76 mg, 29.3 μmol) and sodium cyanoborohydride (13.8 mg, 220 μmol ). The reaction solution was stirred at 25°C for 1 hour, water (15.0 mL) was added to the reaction solution, extracted with ethyl acetate (15.0 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was prepared by Compound 34 was isolated by high performance liquid chromatography (Phenomenex C18, 75mm×30mm 3μm, A: water (ammonium bicarbonate); B: acetonitrile, 34%-74%: 25 minutes). MS-ESI [M+H] + , calculated 533, found 533. 1 H NMR (400MHz, MeOD) δ8.77(s, 1H), 7.70(d, J=8.0Hz, 1H), 7.51(d, J=7.6Hz, 1H), 7.26(t, J=7.6Hz, 1H), 5.72(q, J=4.8Hz, J=6.8Hz, 1H), 4.68(t, J=6.4Hz, 2H), 4.56-4.60(m, 2H), 3.42-3.46(m, 1H), 3.42-3.52(m,1H),2.62(s,6H),2.52-2.56(m,2H),2.43-2.48(m,2H),2.16-2.24(m,2H),1.87(t,J=10.0 Hz, 2H), 1.62 (d, J=6.8Hz, 3H), 1.57 (s, 3H).
实施例35合成化合物35Example 35 Synthesis of compound 35
采用实施例33中的合成方法，使用相对应的原料合成化合物35。Using the synthesis method in Example 33, compound 35 was synthesized using the corresponding starting materials.
Figure PCTCN2022140697-appb-000075
Figure PCTCN2022140697-appb-000075
实施例36-38合成化合物36-38Embodiment 36-38 synthetic compound 36-38
采用实施例34中的合成方法，使用相对应的原料合成化合物36-38。Using the synthesis method in Example 34, compounds 36-38 were synthesized using the corresponding starting materials.
Figure PCTCN2022140697-appb-000076
Figure PCTCN2022140697-appb-000076
Figure PCTCN2022140697-appb-000077
Figure PCTCN2022140697-appb-000077
试验例Test case
化合物对SOS1与KRAS(G12C)突变蛋白结合抑制作用的测定(HTRF方法)：Determination of the inhibitory effect of the compound on the binding of SOS1 and KRAS (G12C) mutant protein (HTRF method):
1、实验原理：利用HTRF方法检测化合物对SOS1与KRAS(G12C)突变蛋白结合的抑制作用。1. Experimental principle: The HTRF method was used to detect the inhibitory effect of the compound on the binding of SOS1 to the KRAS(G12C) mutant protein.
2、实验材料：KRAS(G12C)突变蛋白购自普建生物科技有限公司；SOS1蛋白购自Cytoskeleton有限公司；标记抗体Mab Anti 6HIS-XL665和Mab Anti GST-Eu cryptate购自Cisbio公司；2. Experimental materials: KRAS (G12C) mutant protein was purchased from Pujian Biotechnology Co., Ltd.; SOS1 protein was purchased from Cytoskeleton Co., Ltd.; labeled antibodies Mab Anti 6HIS-XL665 and Mab Anti GST-Eu cryptate were purchased from Cisbio;
3、实验方法：1倍浓度缓冲液配制(现配现用):4-羟乙基哌嗪乙磺酸(Hepes):5mmol/L；氯化钠:150mmol/L；乙二胺四乙酸:10mmol/L；乙基苯基聚乙二醇(Igepal):0.0025％；氟化钾:100mmol/L；二硫苏糖醇(DTT):1mmol/L；牛血清白蛋白(BSA):0.05％；3. Experimental method: preparation of 1-fold concentration buffer solution (prepared and used now): 4-hydroxyethylpiperazineethanesulfonic acid (Hepes): 5mmol/L; sodium chloride: 150mmol/L; ethylenediaminetetraacetic acid: 10mmol/L; Ethylphenyl polyethylene glycol (Igepal): 0.0025%; Potassium fluoride: 100mmol/L; Dithiothreitol (DTT): 1mmol/L; Bovine serum albumin (BSA): 0.05% ;
化合物储备液浓度为1000μmol/L起始，5倍稀释，设置8个梯度浓度，用1倍浓度缓冲液将待测化合物各梯度稀释成2％的DMSO工作液，5μL/孔加到对应孔中，每个浓度设置复孔检测。用1倍浓度缓冲液配制KRAS(G12C)突变蛋白(200nM)和Mab Anti GST-Eu cryptate(1μg/uL)的混和工作液。将该混合工作液放置25℃中孵育5分钟，2.5μL/孔加入到对应孔。用1倍浓度缓冲液配制SOS1蛋白(80nM)和Mab Anti 6HIS-XL665(8μg/uL)的混和工作液，2.5μL/孔加入到对应孔。空白孔中加入2.5μL Mab Anti 6HIS-XL665(8μg/μL)稀释液。反应体系置于25℃反应60分钟。反应结束后采用多标记分析仪读取HTRF。The stock solution concentration of the compound is 1000 μmol/L starting, 5-fold dilution, set 8 gradient concentrations, use 1-fold concentration buffer solution to dilute each gradient of the compound to be tested into 2% DMSO working solution, add 5 μL/well to the corresponding well , each concentration is set to duplicate hole detection. Prepare a mixed working solution of KRAS (G12C) mutant protein (200nM) and Mab Anti GST-Eu cryptate (1μg/uL) with 1-fold concentration buffer. The mixed working solution was incubated at 25°C for 5 minutes, and 2.5 μL/well was added to the corresponding well. Prepare a mixed working solution of SOS1 protein (80nM) and Mab Anti 6HIS-XL665 (8μg/uL) with 1-fold concentration buffer, and add 2.5μL/well to the corresponding well. Add 2.5 μL Mab Anti 6HIS-XL665 (8 μg/μL) dilution solution to the blank well. The reaction system was placed at 25°C for 60 minutes. After the reaction, the HTRF was read using a multi-label analyzer.
4、数据处理：4. Data processing:
用Graphpad软件计算化合物的IC 50。结果如表1所示。 The IC 50 of the compound was calculated with Graphpad software. The results are shown in Table 1.
表1Table 1
测试化合物test compound IC 50(nM) IC 50 (nM)
实施例1Example 1 389.4389.4
实施例2Example 2 62.7862.78
实施例3Example 3 340.90340.90
实施例4Example 4 125.70125.70
实施例5Example 5 123.30123.30
实施例6Example 6 340.40340.40
实施例7Example 7 25.8525.85
实施例8Example 8 50.8950.89
实施例9Example 9 18.9618.96
实施例10Example 10 81.8481.84
实施例11Example 11 73.9373.93
实施例12Example 12 152.9152.9
实施例13Example 13 38.6238.62
实施例14Example 14 572.60572.60
实施例15Example 15 75.6075.60
实施例16Example 16 105.80105.80
实施例18Example 18 113.20113.20
实施例19Example 19 102.60102.60
实施例20Example 20 44.0444.04
实施例21Example 21 36.2136.21
实施例22Example 22 45.1745.17
实施例23Example 23 224.1224.1
实施例24Example 24 69.5769.57
实施例25Example 25 89.7589.75
实施例26Example 26 242.2242.2
实施例27Example 27 92.9592.95
实施例28Example 28 111.7111.7
实施例29Example 29 239.8239.8
实施例30Example 30 99.2799.27
实施例31Example 31 387.8387.8
实施例32Example 32 193.7193.7
实施例33Example 33 221.5221.5
实施例35Example 35 130.7130.7
实施例36Example 36 44.8844.88
实施例37Example 37 195.0195.0
实施例38Example 38 31.5931.59
由表1测试数据可知，本发明所述式I所示化合物对SOS1与KRAS(G12C)突变蛋白结合具有较佳的抑制作用，具有用于制备治疗RAS突变的肿瘤药物的潜力。From the test data in Table 1, it can be seen that the compound represented by formula I of the present invention has a better inhibitory effect on the binding of SOS1 and KRAS (G12C) mutant protein, and has the potential to be used in the preparation of tumor drugs for treating RAS mutations.
申请人声明，本发明通过上述实施例来说明所述哒嗪类化合物、包含其的药物组合物及其应用，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。The applicant declares that the present invention illustrates the pyridazine compounds, pharmaceutical compositions containing them and their applications through the above examples, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above implementation example can be implemented. Those skilled in the art should understand that any improvement of the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, the selection of specific methods, etc., all fall within the scope of protection and disclosure of the present invention.

Claims (13)

  1. 一种式I所示的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，A compound represented by formula I, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, solvate, polymorph, Deuterated substances or combinations thereof,
    Figure PCTCN2022140697-appb-100001
    Figure PCTCN2022140697-appb-100001
    其中，in,
    X 1选自：CH、氧原子、硫原子、氮原子或-NH；优选地，X 1为CH； X 1 is selected from: CH, oxygen atom, sulfur atom, nitrogen atom or -NH; Preferably, X 1 is CH;
    X 2选自：硫原子、氧原子、氮原子、-NR x-或-CR x；其中，R x选自：H、任选取代的C1-C3烷基；优选地，X 2为硫原子；其中，所述取代是指被一个或多个R取代； X 2 is selected from: sulfur atom, oxygen atom, nitrogen atom, -NR x - or -CR x ; wherein, R x is selected from: H, optionally substituted C1-C3 alkyl; preferably, X 2 is a sulfur atom ; Wherein, the substitution refers to being substituted by one or more R;
    R 1选自：H、卤素、任选取代的C1-C3烷基、任选取代的C3-C8碳环基、任选取代的4-8元杂环基、氰基、
    Figure PCTCN2022140697-appb-100002
    其中，R 1a和R 1b各自独立地选自：H、任选取代的C1-C6烷基、任选取代的C3-C8碳环基或任选取代的4-8元杂环基；其中，所述取代是指被一个或多个R取代；     R is selected from: H, halogen, optionally substituted C1-C3 alkyl, optionally substituted C3-C8 carbocyclyl, optionally substituted 4-8 membered heterocyclyl, cyano,
    Figure PCTCN2022140697-appb-100002
    Wherein, R 1a and R 1b are each independently selected from: H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 carbocyclyl or optionally substituted 4-8 membered heterocyclic group; wherein, The substitution refers to being substituted by one or more R;
    R 2选自：任选取代的C1-C6烷基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基；其中，所述取代是指被一个或多个R取代； R 2 is selected from: optionally substituted C1-C6 alkyl, optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being replaced by one or more R replaces;
    A环选自：任选取代的C6-C16芳基、任选取代的5-16元杂芳基、任选取代的C3-C16碳环并C6-C10芳基、任选取代的4-16元杂环并C6-C10芳基、任选取代的C3-C16碳环并5-16元杂芳基或任选取代的4-16元杂环并5-16元杂芳基；其中，所述取代是指被一个或多个R取代；Ring A is selected from: optionally substituted C6-C16 aryl, optionally substituted 5-16 membered heteroaryl, optionally substituted C3-C16 carbocyclic and C6-C10 aryl, optionally substituted 4-16 Member heterocycle and C6-C10 aryl, optionally substituted C3-C16 carbocycle and 5-16 member heteroaryl or optionally substituted 4-16 member heterocycle and 5-16 member heteroaryl; wherein, The above substitution refers to being substituted by one or more R;
    R各自独立地选自：H、卤素、氰基、氨基、羟基、氧代基
    Figure PCTCN2022140697-appb-100003
    任选取代的C1-C6烷基、任选取代的C2-C6烯基、任选取代的C2-C6炔基、任选取代的C1-C6烷氧基、-N(任选取代的C 1-C 6烷基) 2、NH(任选取代的C 1-C 6烷基)、-N(任选取代的C 1-C 6烷基)(任选取代的C 1-C 6烷基苯基)、-NH(任选取代的C 1-C 6烷基苯基)、任选取代的C1-C6烷基-S-、-S(O) 2-任选取代的C1-C6烷基、-S(O)-任选取代的C1-C6烷基、-S(O) 2-任选取代的苯基、-S(O) 2NH 2、-S(O) 2NH(任选取代的C1-C6烷基)、-S(O) 2NH(任选取代的苯基)、-NHS(O) 2(任选取代的C1-C6烷基)、-NHS(O) 2(任选取代的苯基)、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基；或任意相邻的2个R和与其相连的原子形成任选取代的4-8元杂环基或任选取代的C3-C8元碳环基； 其中，R中所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
    Figure PCTCN2022140697-appb-100004
    R’取代或未取代的C1-C6烷基、R’取代或未取代的C1-C6烷氧基、R’取代或未取代的C1-C6烷基砜基、R’取代或未取代的C3-C16碳环基、R’取代或未取代的4-16元杂环基、R’取代或未取代的C6-C16芳基、R’取代或未取代的5-16元杂芳基、-N(R’取代或未取代的C1-C6烷基) 2、-CH 2-N(R’取代或未取代的C1-C6烷基) 2，其中，R’选自下组的一个或多个基团：H、卤素、氘(D)、卤素、-OH、氧代(＝O)、巯基、氰基、-CD 3、C1-C6烷基、C1-C6烷氧基、C2-C6烯基、C2-C6炔基、C3-C8环烷基和4-8元杂环基，其中所述的烷基、烯基、炔基、环烷基和杂环基中的每一个任选被一个或多个选自以下的取代基进一步取代：H、C1-C6烷基、C1-C6烷氧基、卤素、-OH、氧代(＝O)、-NH 2、-N(R”取代或未取代的C1-C6烷基) 2、-NH(C1-C6烷基)、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、C3-C8环烷基、4-8元杂环基、C1-C4卤代烷基-、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基) 2、-CONH(C1-C6烷基)、-CONH 2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO 2(C1-C6烷基)、-SO 2(苯基)、-SO 2(C1-C6卤代烷基)、-SO 2NH 2、-SO 2NH(C1-C6烷基)、-SO 2NH(苯基)、-NHSO 2(C1-C6烷基)、-NHSO 2(苯基)、-NHSO 2(C1-C6卤代烷基)和-C1-C6烷基-NH 2，其中，R”选自下组的一个或多个基团：H、卤素、氰基、氨基、羟基、氧代基
    Figure PCTCN2022140697-appb-100005
    C1-C6烷基和C1-C6烷氧基；     Each R is independently selected from: H, halogen, cyano, amino, hydroxyl, oxo
    Figure PCTCN2022140697-appb-100003
    Optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, -N (optionally substituted C1 -C 6 alkyl) 2 , NH (optionally substituted C 1 -C 6 alkyl), -N (optionally substituted C 1 -C 6 alkyl) (optionally substituted C 1 -C 6 alkyl phenyl), -NH (optionally substituted C 1 -C 6 alkylphenyl), optionally substituted C1-C6 alkyl-S-, -S(O) 2 -optionally substituted C1-C6 alkane -S(O)-optionally substituted C1-C6 alkyl, -S(O) 2 -optionally substituted phenyl, -S(O) 2 NH 2 , -S(O) 2 NH (any Optionally substituted C1-C6 alkyl), -S(O) 2 NH (optionally substituted phenyl), -NHS(O) 2 (optionally substituted C1-C6 alkyl), -NHS(O) 2 (optionally substituted phenyl), optionally substituted C3-C16 carbocyclyl, optionally substituted 4-16 membered heterocyclyl, optionally substituted C6-C16 aryl or optionally substituted 5-16 membered Heteroaryl; or any adjacent 2 R and the atom connected to it form an optionally substituted 4-8 membered heterocyclic group or an optionally substituted C3-C8 membered carbocyclic group; wherein, the substitution in R is means substituted by one or more groups selected from the group consisting of: H, halogen, cyano, amino, hydroxyl, oxo
    Figure PCTCN2022140697-appb-100004
    R'substituted or unsubstituted C1-C6 alkyl, R'substituted or unsubstituted C1-C6 alkoxy, R'substituted or unsubstituted C1-C6 alkylsulfone, R'substituted or unsubstituted C3 -C16 carbocyclyl, R'substituted or unsubstituted 4-16 membered heterocyclic group, R'substituted or unsubstituted C6-C16 aryl group, R'substituted or unsubstituted 5-16 membered heteroaryl group,- N(R'substituted or unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , wherein R'is selected from one or more of the following groups Groups: H, halogen, deuterium (D), halogen, -OH, oxo (=O), mercapto, cyano, -CD 3 , C1-C6 alkyl, C1-C6 alkoxy, C2-C6 Alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl and 4-8 membered heterocyclyl, wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl and heterocyclyl is optionally Further substituted with one or more substituents selected from the group consisting of: H, C1-C6 alkyl, C1-C6 alkoxy, halogen, -OH, oxo (=O), -NH2 , -N(R" Substituted or unsubstituted C1-C6 alkyl) 2 , -NH(C1-C6 alkyl), -N(C1-C6 alkyl)(C1-C6 alkylphenyl), -NH(C1-C6 alkyl Phenyl), -N(C1-C6 alkyl) (aryl), -NH (aryl), C3-C8 cycloalkyl, 4-8 membered heterocyclyl, C1-C4 haloalkyl-, -C1- C4 alkyl-OH, -C1-C4 alkyl-O-C1-C4 alkyl, -OC1-C4 haloalkyl, cyano, nitro, -C(O)-OH, -C(O)OC1-C6 Alkyl, -CON(C1-C6 alkyl) 2 , -CONH(C1-C6 alkyl), -CONH 2 , -NHC(O)(C1-C6 alkyl), -NH(C1-C6 alkyl) C(O)(C1-C6 alkyl), -SO 2 (C1-C6 alkyl), -SO 2 (phenyl), -SO 2 (C1-C6 haloalkyl), -SO 2 NH 2 , -SO 2 NH (C1-C6 alkyl), -SO 2 NH (phenyl), -NHSO 2 (C1-C6 alkyl), -NHSO 2 (phenyl), -NHSO 2 (C1-C6 haloalkyl) and - C1-C6 alkyl-NH 2 , wherein, R" is selected from one or more groups of the following group: H, halogen, cyano, amino, hydroxyl, oxo
    Figure PCTCN2022140697-appb-100005
    C1-C6 alkyl and C1-C6 alkoxy;
    Figure PCTCN2022140697-appb-100006
    表示基团的连接位置。
    Figure PCTCN2022140697-appb-100006
    Indicates the attachment position of the group.
  2. 如权利要求1中所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，The compound as claimed in claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph , deuterated substances or combinations thereof, characterized in that,
    所述R 1选自：H、卤素、任选取代的C1-C3烷基或任选取代的C3-C8碳环基，优选地，R 1选自：H、卤素或甲基；其中，所述取代是指被一个或多个R取代，R的定义如权利要求1所述。 The R 1 is selected from: H, halogen, optionally substituted C1-C3 alkyl or optionally substituted C3-C8 carbocyclyl, preferably, R 1 is selected from: H, halogen or methyl; wherein, Said substitution refers to being substituted by one or more R, and the definition of R is as described in claim 1.
  3. 如权利要求1和2所述的化合物，其药学上可接受的盐、对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，The compound as claimed in claims 1 and 2, its pharmaceutically acceptable salt, enantiomer, tautomer, cis-trans isomer, solvate, polymorph, deuterium or its combination , characterized in that,
    所述A环选自：任选取代的C6-C10芳基、任选取代的5-10元杂芳基、任选取代的C3-C8碳环并C6-C10芳基、任选取代的4-8元杂环并C6-C10芳基、任选取代的C3-C8碳环并5-10元杂芳基或任选取代的4-8元杂环并5-10元杂芳基；优选地A环为任选取代的苯基、5-6元杂芳基、任选取代的C3-C8碳环并苯基、任选取代的4-8元杂环并苯基、任选取代的C3-C8碳环并5-6元杂芳基或任选取代的4-8元杂环并5-6元杂芳基；更优选地，A环选自：任选取代的苯基、任选取代的吡啶基、任选取代的吡嗪基、任选取代的噻吩基、任选取代的呋喃基、任选取代的吡咯基、任选取代的噻唑基、任选取代的咪唑基、任选取代的吡唑基；其中，所述取代是指被一个或多个R取代；R的定义如权利要求1所述。The A ring is selected from: optionally substituted C6-C10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-C8 carbocyclic and C6-C10 aryl, optionally substituted 4 -8-membered heterocycle and C6-C10 aryl, optionally substituted C3-C8 carbocycle and 5-10 membered heteroaryl or optionally substituted 4-8 membered heterocycle and 5-10 membered heteroaryl; preferably Ring A is optionally substituted phenyl, 5-6 membered heteroaryl, optionally substituted C3-C8 carbocyclophenyl, optionally substituted 4-8 membered heterocyclic phenyl, optionally substituted C3-C8 carbocyclic and 5-6 membered heteroaryl or optionally substituted 4-8 membered heterocyclic and 5-6 membered heteroaryl; more preferably, ring A is selected from: optionally substituted phenyl, any Optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted thienyl, optionally substituted furyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted imidazolyl, any Optionally substituted pyrazolyl; wherein, the substitution refers to being substituted by one or more R; the definition of R is as described in claim 1.
  4. 如权利要求1-3中任一项所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，所述A环选自：The compound according to any one of claims 1-3, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate , polymorph, deuterium or combination thereof, it is characterized in that, described A ring is selected from:
    Figure PCTCN2022140697-appb-100007
    Figure PCTCN2022140697-appb-100007
    其中，R d1、R d2、R d3分别独立地选自：H、卤素、氨基、羟基、氰基、任选取代的C1-C6烷基、任选取代的C1-C6烷氧基、任选取代的C1-C6烷基砜基、任选取代的C3-C16碳环基、任选取代的4-16元杂环基、任选取代的C6-C16芳基或任选取代的5-16元杂芳基；R d4分别独立地选自：卤素、任选取代的C1-C6烷基和
    Figure PCTCN2022140697-appb-100008
    q为0、1、2或3；R d5选自：氢、任选取代的C6-C10元芳香基或任选取代的5-16元杂芳香环基；Z选自：O或NR N；R N选自：H或任选取代的C1-C6烷基；     Wherein, R d1 , R d2 , R d3 are independently selected from: H, halogen, amino, hydroxyl, cyano, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally Substituted C1-C6 alkylsulfone group, optionally substituted C3-C16 carbocyclic group, optionally substituted 4-16 membered heterocyclic group, optionally substituted C6-C16 aryl group or optionally substituted 5-16 Member heteroaryl; R d4 are independently selected from: halogen, optionally substituted C1-C6 alkyl and
    Figure PCTCN2022140697-appb-100008
    q is 0, 1, 2 or 3; R d5 is selected from: hydrogen, optionally substituted C6-C10 membered aromatic group or optionally substituted 5-16 membered heteroaromatic ring group; Z is selected from: O or NR N ; R N is selected from: H or optionally substituted C1-C6 alkyl;
    其中，所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
    Figure PCTCN2022140697-appb-100009
    R’取代或未取代的C1-C6烷基、C1-C6烷氧基、C1-C6烷基砜基、C3-C16碳环基、4-16元杂环基、-N(R’取代或未取代的C1-C6烷基) 2、-CH 2-N(R’取代或未取代的C1-C6烷基) 2、和-CH 2-(4-8元杂环基)，其中R’选自下组的一个或多个基团：H、卤素、氰基、氨基、羟基、氧代基
    Figure PCTCN2022140697-appb-100010
    C1-C6烷基和C1-C6烷氧基；     Wherein, the substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo
    Figure PCTCN2022140697-appb-100009
    R' substituted or unsubstituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl sulfone, C3-C16 carbocyclyl, 4-16 membered heterocyclic group, -N(R' substituted or Unsubstituted C1-C6 alkyl) 2 , -CH 2 -N(R'substituted or unsubstituted C1-C6 alkyl) 2 , and -CH 2 -(4-8 membered heterocyclic group), where R' One or more groups selected from the group consisting of H, halogen, cyano, amino, hydroxyl, oxo
    Figure PCTCN2022140697-appb-100010
    C1-C6 alkyl and C1-C6 alkoxy;
    Figure PCTCN2022140697-appb-100011
    表示基团的连接位置。
    Figure PCTCN2022140697-appb-100011
    Indicates the attachment position of the group.
  5. 如权利要求1-4中任一项所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，The compound according to any one of claims 1-4, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate , polymorphs, deuteriums or combinations thereof, characterized in that,
    A环为
    Figure PCTCN2022140697-appb-100012
    Figure PCTCN2022140697-appb-100013
    Figure PCTCN2022140697-appb-100014
    Figure PCTCN2022140697-appb-100015
    其中R d5a和R d5b分别独立地选自：H或取代或未取代的C1-C3烷基，或者R d5a、R d5b和相连的N原子形成4-8元杂环基；R d5c选自：H、卤素或取代或未取代的C1-C3烷基；     A ring is
    Figure PCTCN2022140697-appb-100012
    Figure PCTCN2022140697-appb-100013
    Figure PCTCN2022140697-appb-100014
    Figure PCTCN2022140697-appb-100015
    Wherein Rd5a and Rd5b are independently selected from: H or substituted or unsubstituted C1-C3 alkyl, or Rd5a , Rd5b and connected N atoms form a 4-8 membered heterocyclic group; Rd5c is selected from: H, halogen or substituted or unsubstituted C1-C3 alkyl;
    其中，所述取代是指被选自下组的一个或多个基团取代：H、卤素、氰基、氨基、羟基、氧代基
    Figure PCTCN2022140697-appb-100016
    C1-C6烷基和C1-C6烷氧基；     Wherein, the substitution refers to being substituted by one or more groups selected from the following group: H, halogen, cyano, amino, hydroxyl, oxo
    Figure PCTCN2022140697-appb-100016
    C1-C6 alkyl and C1-C6 alkoxy;
    Figure PCTCN2022140697-appb-100017
    表示基团的连接位置。
    Figure PCTCN2022140697-appb-100017
    Indicates the attachment position of the group.
  6. 如权利要求1-5中任一项所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，The compound according to any one of claims 1-5, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate , polymorphs, deuteriums or combinations thereof, characterized in that,
    所述R 2为
    Figure PCTCN2022140697-appb-100018
    其中，X 3选自：CR 2’或N；     The R2 is
    Figure PCTCN2022140697-appb-100018
    Wherein, X 3 is selected from: CR 2' or N;
    优选地，R 2为
    Figure PCTCN2022140697-appb-100019
    Preferably, R2 is
    Figure PCTCN2022140697-appb-100019
    R 2’选自：甲基、乙基、丙基、单氟甲基、二氟甲基、三氟甲基、甲氧基、二氟甲氧基、三氟甲氧基、甲硫基、二氟甲硫基、三氟甲硫基、氰基、卤素、羟甲基或甲氧基甲基； R 2' is selected from: methyl, ethyl, propyl, monofluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, Difluoromethylthio, trifluoromethylthio, cyano, halogen, hydroxymethyl or methoxymethyl;
    B环选自：任选取代的C3-C16碳环基或任选取代的4-16元杂环基；其中，所述取代是指被一个或多个R取代；R的定义如权利要求1所述；Ring B is selected from: optionally substituted C3-C16 carbocyclic group or optionally substituted 4-16 membered heterocyclic group; wherein, the substitution refers to being substituted by one or more R; the definition of R is as claimed in claim 1 said;
    Figure PCTCN2022140697-appb-100020
    表示基团的连接位置。
    Figure PCTCN2022140697-appb-100020
    Indicates the attachment position of the group.
  7. 如权利要求6所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，The compound as claimed in claim 6, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, A deuterium or a combination thereof, characterized in that,
    B环选自：任选取代的C3-C11碳环基或任选取代的4-11元杂环基，更优选地，B环选自：任选取代的C5-C11碳环基或任选取代的5-11元杂环基，更优选地，B环选自：任选取代的C5-C8碳环基或任选取代的5-8元杂环基，更优选地，B环为任选取代的6元杂环基，如，任选取代的四氢吡喃基
    Figure PCTCN2022140697-appb-100021
    任选取代的哌啶基
    Figure PCTCN2022140697-appb-100022
    其中，所述取代是指被一个或多个R取代；R的定义如权利要求1所述。     B ring is selected from: optionally substituted C3-C11 carbocyclyl or optionally substituted 4-11 membered heterocyclyl, more preferably, B ring is selected from: optionally substituted C5-C11 carbocyclyl or optionally Substituted 5-11 membered heterocyclic group, more preferably, ring B is selected from: optionally substituted C5-C8 carbocyclic group or optionally substituted 5-8 membered heterocyclic group, more preferably, ring B is any Optionally substituted 6-membered heterocyclyl, such as optionally substituted tetrahydropyranyl
    Figure PCTCN2022140697-appb-100021
    Optionally substituted piperidinyl
    Figure PCTCN2022140697-appb-100022
    Wherein, the substitution refers to substitution by one or more R; the definition of R is as described in claim 1.
  8. 如权利要求1所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、 互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，R 2选自：
    Figure PCTCN2022140697-appb-100023
    Figure PCTCN2022140697-appb-100024
    The compound as claimed in claim 1, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate, polymorph, Deuterium or its combination, it is characterized in that, R 2 is selected from:
    Figure PCTCN2022140697-appb-100023
    Figure PCTCN2022140697-appb-100024
    Figure PCTCN2022140697-appb-100025
    Figure PCTCN2022140697-appb-100025
  9. 如权利要求1-8中任一项所述的化合物，其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合，其特征在于，所述化合物选自下组：The compound according to any one of claims 1-8, its pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, cis-trans isomer, solvate , polymorphs, deuteriums or combinations thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2022140697-appb-100026
    Figure PCTCN2022140697-appb-100026
    Figure PCTCN2022140697-appb-100027
    Figure PCTCN2022140697-appb-100027
    Figure PCTCN2022140697-appb-100028
    Figure PCTCN2022140697-appb-100028
    Figure PCTCN2022140697-appb-100029
    Figure PCTCN2022140697-appb-100029
    Figure PCTCN2022140697-appb-100030
    Figure PCTCN2022140697-appb-100030
    Figure PCTCN2022140697-appb-100031
    Figure PCTCN2022140697-appb-100031
  10. 一种式II所示的化合物、或其盐、溶剂化物、多晶型物或氘代物，A compound represented by formula II, or a salt, solvate, polymorph or deuterated product thereof,
    Figure PCTCN2022140697-appb-100032
    Figure PCTCN2022140697-appb-100032
  11. 一种药物组合物，其特征在于，所述药物组合物包括：A kind of pharmaceutical composition, is characterized in that, described pharmaceutical composition comprises:
    (1)治疗有效量的选自权利要求1～9中任一项所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物和氘代物中的一种或多种作为活性成分；和(1) A therapeutically effective amount of the compound selected from any one of claims 1 to 9, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, One or more of cis-trans isomers, solvates, polymorphs and deuterated compounds as active ingredients; and
    (2)任选地，药学上可接受的载体。(2) Optionally, a pharmaceutically acceptable carrier.
  12. 如权利要求1～9中任一项所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物或如权利要求11所述的药物组合物在制备预防或治疗RAS突变介导的癌症的药物中的用途。The compound according to any one of claims 1 to 9, its pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, cis-trans isomer, solvate , polymorph or deuterium, or the pharmaceutical composition as claimed in claim 11 in the preparation of medicines for preventing or treating RAS mutation-mediated cancer.
  13. 如权利要求12所述的用途，其特征在于，所述癌症选自：肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、***癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、***、头颈癌、食管癌、甲状腺癌和膀胱癌，特别是选自非小细胞肺癌、胰腺癌和结直肠癌。The use according to claim 12, wherein the cancer is selected from the group consisting of: lung cancer, pancreatic cancer, colorectal cancer, leukemia, Ewing's sarcoma, breast cancer, prostate cancer, T-cell lymphoma, B-cell lymphoma, Malignant rhabdomyoma, synovial sarcoma, endometrioma, gastric cancer, liver cancer, kidney cancer, melanoma, ovarian cancer, glioma, bile duct cancer, nasopharyngeal cancer, cervical cancer, head and neck cancer, esophageal cancer, thyroid cancer and Bladder cancer, especially selected from non-small cell lung cancer, pancreatic cancer and colorectal cancer.
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CN102711475A (en) * 2009-09-18 2012-10-03 吴章桂 Novel compounds and therapeutic use thereof for protein kinase inhibition
CN110366550A (en) * 2016-12-22 2019-10-22 美国安进公司 As the benzisothiazole of the KRAS G12C inhibitor for treating lung cancer, cancer of pancreas or colorectal cancer, isothiazole simultaneously [3,4-b] pyridine, quinazoline, phthalazines, pyrido [2,3-d] pyridazine and pyrido [2,3-d] pyrimidine derivatives
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