WO2023098825A1 - Sos1 inhibitor, pharmaceutical composition comprising same, and use thereof - Google Patents

Sos1 inhibitor, pharmaceutical composition comprising same, and use thereof Download PDF

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WO2023098825A1
WO2023098825A1 PCT/CN2022/135958 CN2022135958W WO2023098825A1 WO 2023098825 A1 WO2023098825 A1 WO 2023098825A1 CN 2022135958 W CN2022135958 W CN 2022135958W WO 2023098825 A1 WO2023098825 A1 WO 2023098825A1
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compound
alkyl
alkylene
ring
cycloalkyl
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PCT/CN2022/135958
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French (fr)
Chinese (zh)
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张贵平
李家鹏
王奎锋
王旭
张涛
徐浩杰
童晨骅
刘涛
徐亮亮
董雪
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勤浩医药（苏州）有限公司
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Publication of WO2023098825A1 publication Critical patent/WO2023098825A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

Definitions

  • the present invention relates to SOS1 inhibitors, pharmaceutical compositions containing them, and uses thereof for preventing or treating diseases.
  • RAS-RAF-MEK-ERK is a classic tumor signaling pathway, which is closely related to the occurrence of various cancers.
  • Ras is a group of closely related globular monomeric proteins (molecular weight 21kDa) composed of 189 amino acids. It has GTPase activity, can bind to GDP or GTP, and plays a key role in cell signaling pathways.
  • SOS1 plays an important role in the activation of RAS, and can coordinately regulate cell proliferation, differentiation, apoptosis, inflammation and other related biological functions.
  • SOS Non of Sevenless, SOS
  • GEF guanine nucleotide exchange factor
  • SOS1 is a multi-domain protein containing 1333 amino acids, which consists of histone folds, Dbl (DH) and Pleckstrin (PH) homology domains, a Ras exchange motif (REM), and Cdc25 homologues and polymorphisms. Proline domain composition. SOS1 can bind to adapter proteins such as GRB2, and plays an important role in the RAS-RAF-MEK-ERK signaling pathway and PI3K-AKT-mTOR signaling.
  • GEF guanine nucleotide exchange factor
  • SOS1 can catalyze the conversion of KRAS-OFF to KRAS-ON conformation, and is an important bimolecular switch in cell signal transduction. Under normal circumstances, KRAS protein is mainly combined with GDP. Once KRAS-SOS1 binds, it will lead to a decrease in GTP hydrolysis or an increase in GTP loading rate, changing the steady-state balance of GDP and GTP binding, thereby making KRAS active.
  • KRAS G12C inhibitors Although selective KRAS G12C inhibitors have demonstrated clinical efficacy in KRAS G12C-mutated cancers, G12C mutations account for only about 15% of KRAS-driven malignancies. Therefore, it is particularly important to develop related research on SOS1 inhibitors, which can bind to the catalytic domain of SOS1, block the interaction between SOS1 and KRAS, and shift the balance in the pathway to the KRAS-GDP binding form, forming a KRAS-OFF state. Thereby reducing the signal transduction of MAPK kinase pathway and inhibiting tumor cell proliferation.
  • the present application provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS1.
  • the compounds of the present invention also have good physicochemical properties (such as solubility, physical and/or chemical stability), good pharmacokinetic properties (such as improved bioavailability, good metabolic stability, suitable half-life and duration of action), good safety (lower toxicity (such as reduced cardiotoxicity) and/or fewer side effects), less likely to develop drug resistance and other excellent properties.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein
  • the compound has the structure of formula (I):
  • Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring
  • two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
  • R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
  • R 4 and R 4' together with the carbon atom to which they are attached form The condition is that at this time, Indicates a single key
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3 or 4;
  • compositions comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of the prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for use as an SOS1 inhibitor.
  • Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs or pharmaceutical compositions of the invention for use as SOS1 inhibitors.
  • Another aspect of the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, Tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is referred to as "haloalkyl” ) ( eg CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2-6 carbon atoms (“ C2-6 alkenyl”).
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) same or different substituents.
  • alkynylene is a corresponding divalent group, including, for example, “C 2-8 alkynylene", “C 2-6 alkynylene", “C 2-4 alkynylene” and the like. Examples include but are not limited to etc., the alkynylene group is optionally substituted with one or more (such as 1 to 3) same or different substituents.
  • merged ring or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spiro ring refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including Spiro ring, ax ring (fused ring) or bridged ring system), which includes but not limited to () cyclopropyl (ring), () cyclobutyl (ring), () cyclopentyl (ring), () cyclopentyl (ring), (A) cyclohexyl (ring), (a) cycloheptyl (ring), (a) cyclooctyl (ring), (a) cyclononyl (ring), (a) cyclohexeny
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or Bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl
  • the cycloalkyl has 3 to 15 carbon atoms
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclo hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • a 3-10 membered heterocyclic group is a group with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuryl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyrrolidinyl pyryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heterocyclyl encompasses an amalgamated ring structure, and the connection point of the amalgamated ring structure to other groups may be on any ring in the amalgamated ring structure. Therefore, the heterocyclyl group of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example 3-7 membered (single) heterocyclic group and 3-7 membered (single) heterocyclic group, 3-7 membered (single) heterocyclic group and (single) cycloalkyl group, 3-7 membered (single) heterocyclic group C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridine, pyrrolidinocyclo
  • heterocyclyl encompasses both bridged and spiroheterocyclyls.
  • bridged heterocycle refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (eg, 1, 2, 3, or 4) heteroatoms. (such as oxygen atom, nitrogen atom and/or sulfur atom) ring structure, including but not limited to 7-10 membered bridged heterocycle, 8-10 membered bridged heterocycle, 7-10 membered nitrogen-containing bridged heterocycle, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example wait.
  • the "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle”, and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a heterocyclic ring formed by two or more saturated rings sharing one ring atom and containing one or more (for example, 1, 2, 3 or 4) heteroatoms (such as oxygen atom, nitrogen atom, sulfur atom), including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle, Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
  • the "nitrogen-containing spiroheterocycle", “oxygen-containing spiroheterocycle”, and “sulfur-containing spiroheterocycle” optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur.
  • 6-10 membered nitrogen-containing spiroheterocyclyl refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring).
  • ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • aralkyl preferably denotes an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6-14 carbon atoms
  • the alkyl group may have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroarylene and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen , nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
  • (ylidene)heteroaryl or “heteroaryl ring” is selected from (ylidene)thienyl (ring), (ylidene)furyl (ring), (ylidene)pyrrolyl (ring), (ylidene)oxa Azolyl (ring), (sub)thiazolyl (ring), (sub)imidazolyl (ring), (sub)pyrazolyl (ring), (sub)isoxazolyl (ring), (sub)isothiazole (ring), (sub)oxadiazolyl (ring), (sub)triazolyl (ring), (sub)thiadiazolyl (ring), etc., and their benzo derivatives; or (sub) Pyridyl (ring), (sub)pyridazinyl (ring), (sub)pyrimidinyl (ring), (sub)pyrazinyl (ring), (sub)triazinyl (ring), and their benzene and derivatives.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkylthio as used herein means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the nitrogen-containing heterocyclic ring is preferably a saturated nitrogen-containing monocyclic ring.
  • a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazole group, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl) , Seven-membered nitrogen-containing heterocycle, etc.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g.
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
  • compositions of the invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoro Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably within ⁇ 5%, more preferably within ⁇ 2% of the stated numerical value.
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (I):
  • Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring
  • two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
  • R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
  • R 4 and R 4' together with the carbon atom to which they are attached form The condition is that at this time, Indicates a single key
  • R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • n is an integer of 0, 1, 2 or 3;
  • n is an integer of 0, 1, 2, 3 or 4;
  • the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (II), (III) or (IV):
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein ring A is a benzene ring or a pyridine ring, preferably a benzene ring.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein each occurrence of R 1 is independently selected from halogen, -OH, -NH 2 , -CN, -NO 2.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein:
  • two adjacent R 1 together with the group it is connected to optionally jointly form a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaromatic ring; the hydrocarbon
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein selected from
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein selected from
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein -LR 2 is selected from Methoxy,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein -LR 2 is selected from Methoxy,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 3 , R 4 , R 4' and R 5 are each independently selected from H, F, Cl, Br, formazan base, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 3 is selected from H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a and -C 1-6 alkylene-OR a ; each of the alkyl, alkylene and cyclohydrocarbyl groups is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH and -CN;
  • R is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
  • R is selected from H, methyl, ethyl and Most preferably, R3 is selected from H and methyl.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 4 and R 4' are each independently selected from H, halogen, C 1-6 alkyl, C 3-6 Cycloalkyl, -OR a , -NR a R b and -C 1-6 alkylene-OR a ; the alkyl and cycloalkyl are each optionally substituted by one or more substituents independently selected from the following : halogen, -OH and -CN;
  • R and R are each independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, cyclopropyl,
  • R4 and R4 ' are each independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, isopropyl, tert-butyl,
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Constructs, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a , -SR a , -NR a R b or -C 1-6 alkylene-NR a R b , preferably H, methyl, ethyl, isopropyl, cyclopropyl,
  • the present invention encompasses compounds resulting from any combination of the various embodiments.
  • the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein the compound is selected from:
  • the present invention provides a method for preparing a compound of formula (IV), comprising one or more steps selected from the group consisting of:
  • compound (IV)-1 reacts with hydrazine to obtain compound (IV)-2
  • compound (IV)-2 obtains compound (IV)-3 through appropriate coupling reaction
  • compound (IV)-3 chlorine
  • Substitution to obtain compound (IV)-4 compound (IV)-4 obtains the compound of formula (IV) through nucleophilic substitution reaction or coupling reaction.
  • compound (IV)-3 obtains compound formula (IV)-5 by reacting with a thio reagent, and then undergoes a one-step methylation reaction to obtain compound (IV)-6, and compound (IV)-6 obtains compound (IV) by oxidation )-7, compound (IV)-7 obtains compound (IV)-8 through nucleophilic substitution reaction or coupling reaction, and finally compound (IV)-8 obtains the compound of formula (IV) through coupling reaction.
  • the present invention provides a method of preparing a compound of formula (III), comprising one or more steps selected from the group consisting of:
  • compound (III)-1 obtains compound (III)-2 by bromination reaction, then obtains compound (III)-3 by coupling reaction, and compound (III)-3 reacts with hydrazine to obtain compound ( III)-4, compound (III)-4 obtains compound (III)-5 by appropriate coupling reaction, compound (III)-5 carries out one-step chlorination and obtains compound (III)-6, finally compound (III)-6
  • the compound of formula (III) is obtained by nucleophilic substitution reaction or coupling reaction.
  • compound (III)-5 can obtain compound (III)-7 by reacting with a thio reagent, and then carry out a one-step methylation reaction to obtain compound (III)-8, and compound (III)-8 obtains compound (III) by oxidation )-9, and finally compound (III)-9 can obtain the compound of formula (III) through nucleophilic substitution reaction or coupling reaction.
  • compositions and methods of treatment are provided.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic form thereof Compounds, solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • the pharmaceutical composition may also include one or more additional therapeutic agents.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Use of a compound or a prodrug or a pharmaceutical composition of the invention for the preparation of a medicament for use as a SOS1 inhibitor.
  • the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Compounds or prodrugs or pharmaceutical compositions of the invention for use as SOS1 inhibitors.
  • the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer isomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs or pharmaceutical compositions of the present invention.
  • the SOS1-associated disease includes cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate carcinoma, glioblastoma, renal carcinoma, and sarcoma), RAS disorders (e.g., neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with Vascular malformations-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Legers syndrome, and hereditary gingival fibromatos
  • cancer
  • “Pharmaceutically acceptable carrier” in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
  • A-1a (25 g, 123 mmol) was dissolved in DAST (65 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was slowly poured into a cooled aqueous sodium bicarbonate solution, and ethyl acetate (500 mL*3) was added for extraction. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-1b (10 g, 37%) as a colorless oil.
  • A-1b (9g, 40mmol), tributyl (1-ethoxyethylene) tin (17.34g, 48mmol), Pd (PPh 3 ) 2 Cl 2 (2.81g, 4mmol) and triethylamine (10.11g , 100mmol) was dissolved in anhydrous 1,4-dioxane (150mL). After nitrogen replacement, the mixture was stirred overnight at 100°C.
  • A-1c (6.17g, 33mmol), (S)-tert-butylsulfinamide (6.0g, 49.5mmol) and tetraethyl titanate (22.6g, 99mmol) were sequentially added to tetrahydrofuran (100ml) and refluxed overnight . After the reaction was completed, it was cooled to room temperature, water (500ml) was added, extracted with ethyl acetate (500ml), the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain yellow oily intermediate A-1d (9.2g, 97%).
  • A-1d (9.42g, 32mmol) was dissolved in anhydrous tetrahydrofuran (150mL), and tri-sec-butyl lithium borohydride (64mL, 64mmol) was slowly added at -78°C. The reaction solution was stirred and reacted at -78°C for 1 hour. After the reaction was completed, ammonium chloride aqueous solution was added to quench it, and extracted with dichloromethane (300 mL*3). The dichloromethane phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-1e (7.2 g, 84%) as a colorless oil.
  • A-1e (8.0g, 27.3mmol) was dissolved in hydrogen chloride/dioxane solution (4M, 20ml), stirred at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried, petroleum ether (50ml) was added, stirred, and suction filtered to obtain white solid intermediate A-1 (5.6g, 91%).
  • A-2a (4.5g, 21.6mmol), N, O-dimethylhydroxylamine hydrochloride (2.53g, 26mmol), EDCI (6.2g, 32.4mmol), HOBt (4.38g, 32.4mmol) and triethyl
  • the amine (10.9 g, 108 mmol) was added to DMF (50 ml). Stir overnight at room temperature, after the reaction is complete, add water (200ml) to the reaction solution, extract with ethyl acetate (200ml), wash the ethyl acetate phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain Intermediate A-2b (4.0 g, 74%).
  • A-2b (4g, 15.9mmol) was dissolved in anhydrous tetrahydrofuran (8ml), stirred at 0°C for 5 minutes, and methylmagnesium bromide (11ml) was added dropwise. The reaction was continued to stir for 2 hours at 0°C. After the reaction was completed, saturated aqueous ammonium chloride was added, extracted with ethyl acetate (300ml), the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-2c (2.5 g, 76%).
  • A-2d (2.3g, 7.4mmol) was dissolved in hydrogen chloride/dioxane solution (16ml), and stirred at 50°C for 2 hours. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50ml) was added, stirred, and filtered with suction to obtain white solid intermediate A-2 (1.5g, 80%).
  • A-3a (4.4g, 0.02mol), trimethylsilylacetylene (4.0g, 0.04mol), triethylamine (6.15g, 0.06mol), cuprous iodide (0.38g, 0.002mol) and bis( Triphenylphosphine)palladium dichloride (1.42g, 0.002mol) was successively added into tetrahydrofuran (60mL) under nitrogen protection. The resulting solution was stirred at 80°C for 16 hours. The solvent was spin-dried and purified by column chromatography to obtain the yellow oil product A-3b (4.5 g, yield: 95%).
  • A-3b (4.5g, 19.2mmol) was dissolved in dichloromethane (6ml) and methanol (6ml), and potassium carbonate (26.5g, 0.19mol) was added. Stir at room temperature for 2 hours, spin dry the solvent, and purify by column chromatography to obtain yellow solid product A-3c (2.9 g, yield: 93%).
  • A-3e (1.7g, 5.5mmol) was added into hydrogen chloride dioxane solution (16mL), and the reaction was stirred at 50°C for 2 hours. After the reaction was completed, it was concentrated, and the residue was added to ethyl acetate (50 mL), stirred, and filtered with suction to obtain a white solid A-3 (1.1 g, yield: 83%).
  • A-4a (5 g, 18.6 mmol), tributyl(1-ethoxyethylene) tin (8 g, 22.3 mmol), Pd(PPh 3 ) 2 Cl 2 (1.3 g, 1.85 mmol) and triethylamine ( 5.6g, 55.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL). After nitrogen replacement, the mixture was stirred overnight at 80°C.
  • A-4 (200mg, 0.74mmol) was dissolved in methanol (5mL), 10% wet palladium carbon (20mg, 10%wt) was added to replace the hydrogen, and the reaction was stirred overnight at room temperature. After the reaction was completed, it was filtered, the filtrate was concentrated, and purified by column chromatography to obtain A-5 (70 mg, 46%).
  • A-6a (10g, 46mol) was heated and stirred in DAST (22ml) at 45°C for 48 hours, the reaction solution was poured into a saturated solution of sodium bicarbonate at 0°C, then extracted with ethyl acetate, dried, and spin-dried, Purified by column chromatography to obtain product A-6b (6.6 g, 60%) as a colorless oil.
  • A-6c (2g, 7.1mmol), (R)-tert-butylsulfinamide (1.29g, 10.65mmol) and tetraethyl titanate (4.86g, 21.3mmol) were successively added to tetrahydrofuran (20ml) and refluxed overnight. Then cooled to -15°C, methanol (2ml) and lithium borohydride (200mg, 9.23mmol) were added. After reacting for one hour, water (500ml) and ethyl acetate (500ml) were added, filtered with suction, separated into layers, and the organic phase was dried and concentrated. Purified by column chromatography to obtain the product A-6d (1.3 g, 47%) as a white solid.
  • A-6d (1.2g, 3.1mmol), p-methoxybenzylamine (427mg, 3.1mmol), Pd 2 (dba) 3 (285mg, 0.31mmol), Xantphos (360mg, 0.62mmol) and cesium carbonate (2g , 6.2mmol) was added into dioxane (15ml), and heated to reflux overnight under nitrogen protection. Water (100ml) and ethyl acetate (100ml) were added for extraction, the organic phase was dried and concentrated, and purified by column chromatography to obtain product A-6e (500mg, 36%).
  • A-6f (400mg, 1mmol) was dissolved in trifluoroacetic acid (10mL), and the reaction solution was stirred at 50°C for 16 hours. After the reaction was complete, it was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution and saturated brine. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain product A-6 (156 mg, 67%).
  • A-7d (1.3g, 3.37mmol), zinc cyanide (0.59g, 5.05mmol), dppf (0.38g, 0.27mmol), Pd 2 (dba) 3 (0.31g, 0.34mmol) and DIPEA (1.31g , 10.11 mmol) was dissolved in DMF (20 mL), replaced with nitrogen three times, and heated to 120° C. for 12 hours. It was diluted with ethyl acetate, washed 5 times with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain gray solid A-7e (400mg, 35.7%).
  • a solution of A-7e (1 g, 2.6 mmol) in TFA (10 mL) was stirred at 50 °C for 16 h. Concentrate and spin dry, treat with saturated aqueous sodium bicarbonate, and extract with ethyl acetate. The obtained ethyl acetate solution was washed with saturated brine, concentrated, and separated by column chromatography to obtain yellow oil A-7 (380 mg, 67%).
  • A-7d (1.8g, 4.7mmol), potassium ferrocyanide (1.97g, 4.7mmol), tetrakis(triphenylphosphine)palladium (560mg, 0.47mmol) and DBU (0.86g, 5.6mmol) were added to di Hexane (20ml) and water (20ml), under nitrogen protection, heated and stirred at 100°C for 16 hours.
  • the reaction solution was poured into water (200ml), extracted with ethyl acetate, dried, spin-dried, and purified by column chromatography to obtain product A-8a (700mg, 43%).
  • A-9a (42 g, 0.2 mol) and 1,2-ethanedithiol (18.8 g, 0.2 mol) were dissolved in toluene (450 mL).
  • P-toluenesulfonic acid (7.6 g, 0.04 mol) was added at room temperature, and the reaction solution was heated to reflux and stirred for 12 hours.
  • 10% aqueous sodium hydroxide solution was added and extracted with ethyl acetate (400 mL*3).
  • the ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9b (48 g, 84%) as a white solid.
  • A-9c (33 g, 0.11 mol) was dissolved in dichloromethane (300 mL), and DBU (24.1 g, 0.16 mol) was added under ice-cooling. The reaction solution was stirred and reacted at room temperature for 12 hours. After the reaction was completed, dichloromethane was added for dilution, and the organic phase was washed with 0.5N hydrochloric acid aqueous solution and saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9d (19.8 g, 79%).
  • A-9i (5.5 g, 27.3 mmol) was dissolved in dioxane (10 mL), and dioxane hydrochloride solution (4M, 50 mL) was added. The reaction solution was stirred and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated, petroleum ether was added to the residue, stirred, and filtered to obtain white solid intermediate A-9 (4.1 g, 99%).
  • Diisopropylamine (2.96g, 29.3mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and n-butyllithium (8.1mL, 20.3mmol) was slowly added dropwise at -78°C. After the reaction solution was stirred at -78°C for 2 hours, a solution of A-10a (5 g, 22.5 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution at -78°C. After the reaction solution was stirred and reacted for 2 hours, TMSCl (2.7 g, 24.8 mmol) was added.
  • reaction solution continued to stir and react for 2 hours, then rose to room temperature, and continued to stir and react for 16 hours. After the reaction was completed, it was quenched by adding aqueous ammonium chloride solution, and extracted with ethyl acetate (50 mL*3). The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10b (6.1 g, 92%).
  • A-10c (5g, 19mmol) was dissolved in DMSO (50mL), and ethyl difluorobromoacetate (11.5g, 56.8mmol) and copper (3.6g, 56.8mmol) were added at room temperature.
  • the reaction solution was heated to 80°C and stirred for 16 hours.
  • water and diethyl ether were added, and a solid precipitated out, which was filtered, and ethyl acetate (300 mL) was added to the aqueous phase for extraction.
  • the ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10d (3.3 g, 66%).
  • A-10d (3.3g, 12.7mmol) was dissolved in tetrahydrofuran (40mL), and (R)-tert-butylsulfinamide and tetraethyl titanate (8.7g, 38mmol) were added at room temperature.
  • the reaction solution was heated to 70°C and stirred for 16 hours.
  • water and diethyl ether were added, and a solid precipitated out, which was filtered, and ethyl acetate (100 mL) was added to the aqueous phase for extraction.
  • the ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10e (2.9 g, 63%).
  • A-10e (5 g, 13.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and DIBAL-H (62.2 mL, 96.3 mmol) was slowly added dropwise at -78°C after nitrogen replacement.
  • the reaction solution was raised to room temperature and stirred for 16 hours.
  • methanol (20 mL) was added, filtered, and the filtrate was diluted with ethyl acetate (300 mL).
  • the ethyl acetate phase was washed with saturated aqueous citric acid (100 mL).
  • the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10f (2.3 g, 51%).
  • A-10f (1.3 g, 4 mmol) was dissolved in tetrahydrofuran (20 mL), cesium carbonate (3.93 g, 12 mmol) and 18-crown-6 (531 mg, 2 mmol) were added. The reaction solution was heated to 80° C. and stirred for 16 hours. After the reaction was completed, ethyl acetate (80 mL*3) and water (80 mL) were added for extraction. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10g (950 mg, 78%).
  • A-10g (1.3g, 4.3mmol) was dissolved in hydrogen chloride dioxane solution (4M, 30mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain white solid A-10 (900 mg, 89%).
  • step 1
  • A-12a (6.6g, 27.6mmol), tributyl (1-ethoxyvinyl) tin (9.97g, 27.6mmol), triethylamine (8.4g, 82.8 mmol) and bis (triphenylphosphine ) palladium dichloride (1.94 g, 2.76 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen replacement, the reaction was stirred at 80° C. for 6 hours. After the reaction was complete, cool to room temperature, filter, add ethyl acetate (100 mL) to the filtrate to dilute, and wash with saturated aqueous sodium bicarbonate and brine.
  • A-12b (4.4g, 21.8mmol) was dissolved in tetrahydrofuran (50mL), and (R)-tert-butylsulfinamide (3.96g, 32.6mmol) and tetraethyl titanate (14.9g, 65.3mmol) were added.
  • the reaction solution was stirred and reacted at 80° C. for 1 hour.
  • the reaction solution was lowered to -15°C, and methanol (5 mL) and lithium borohydride (620 mg, 28.3 mmol) were added.
  • the reaction solution was stirred and reacted for 1 hour at -15°C.
  • A-12c (2.1 g, 6.8 mmol) was dissolved in 4N hydrogen chloride/dioxane solution (20 mL), and stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated, petroleum ether/ethyl acetate was added to obtain a mixed solution, and the mixture was stirred at room temperature for 1 hour. A white solid A-12 (1.28 g, 79%) was obtained by filtration.
  • step 1
  • A-13b (5.95g, 20mmol) was dissolved in tetrahydrofuran (70mL), and methylmagnesium bromide (3M, 20mL, 60mmol) was added under ice-cooling. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, aqueous ammonium chloride solution (50 mL) was added to quench it, and ethyl acetate (100 mL*2) was extracted. The ethyl acetate phase was dried, filtered and concentrated, and the residue was purified by column chromatography to obtain A-13c (5.1 g, 90%).
  • A-13c (5.1g, 18mmol), tributyl (1-ethoxyvinyl) tin (7.8g, 21.6mmol), triethylamine (5.46g, 54mmol) and bis (triphenylphosphine) di Palladium chloride (1.26 g, 1.8 mmol) was dissolved in 1,4-dioxane (50 mL). After nitrogen replacement, the reaction was stirred at 100° C. for 16 hours. After the reaction was complete, cool to room temperature, filter, add ethyl acetate (100 mL) to the filtrate to dilute, and wash with saturated aqueous sodium bicarbonate and brine.
  • A-13d (3.77g, 15.3mmol) was dissolved in tetrahydrofuran (40mL), and (R)-tert-butylsulfinamide (2.78g, 23mmol) and tetraethyl titanate (10.5g, 46mmol) were added.
  • the reaction solution was stirred and reacted at 80° C. for 12 hours.
  • the reaction solution was lowered to -15°C, and methanol (3.5 mL) and lithium borohydride (404 mg, 18.4 mmol) were added.
  • the reaction solution was stirred and reacted for 1 hour at -15°C.
  • A-13e (3.5 g, 10 mmol) was dissolved in 4N hydrogen chloride/dioxane solution (20 mL), and stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated, petroleum ether/ethyl acetate was added to obtain a mixed solution, stirred at room temperature for 1 hour, and a white solid A-13 (2.67 g, 95%) was obtained by filtration.
  • Embodiment I-1 is a diagrammatic representation of Embodiment I-1:
  • step 1
  • I-1a (5 g, 20.49 mmol) was dissolved in 1,4-dioxane (50 mL), and selenium dioxide (6.82 g, 61.47 mmol) was added. The reaction solution was heated to reflux and stirred for 24 hours. After the reaction was completed, it was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-1b (3 g, 57%).
  • I-1d (55 mg, 0.24 mmol) was dissolved in phosphorus oxychloride (1 mL), and the reaction solution was refluxed and stirred for 4 hours. After the reaction was completed, it was concentrated, and the residue was diluted with ethyl acetate (30 mL), washed with aqueous sodium bicarbonate solution, dried with ethyl acetate, filtered, and concentrated. The residue was purified by column chromatography to obtain I-1e (50 mg, 85%).
  • Embodiment I-2 is a diagrammatic representation of Embodiment I-2:
  • step 1
  • I-2a (3.8g, 13mmol) was dissolved in DMF (40mL), and methyl iodide (7.7g, 54mmol) and sodium bicarbonate (9.1g, 108mmol) were slowly added at room temperature. Stir and react at room temperature for 3 hours. After the reaction is complete, pour the reaction solution into ice water (50mL), extract with ethyl acetate (40mL*2), wash the ethyl acetate phase with saturated brine (50mL*3), and filter , dried and concentrated. The residue was purified by preparative chromatography to give I-2b (3.9 g, 98%) as a yellow solid.
  • Embodiment I-3 is a diagrammatic representation of Embodiment I-3.
  • I-1e and A-13 were used as raw materials to obtain I-3 (8 mg, 17%).
  • Embodiment I-4 is a diagrammatic representation of Embodiment I-4:
  • step 1
  • Embodiment I-5 is a diagrammatic representation of Embodiment I-5:
  • Embodiment I-6 is a diagrammatic representation of Embodiment I-6:
  • Embodiment I-7 is a diagrammatic representation of Embodiment I-7.
  • Embodiment I-8
  • I-10 was obtained by using I-2h and 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester as raw materials.
  • Example I-2 the preparation method of step 8, using I-2h and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester as raw materials to obtain I-14.
  • step 1
  • step 8 instead of morpholine, compound 1-16 was prepared.
  • step 8 instead of morpholine, compound 1-17 was prepared.
  • MS(ESI) m/z 529.3[M+H] + .
  • step 8 instead of morpholine, compound 1-18 was prepared.
  • step 8 instead of morpholine, compound 1-32 was prepared.
  • I-153 (50 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL), and aqueous formaldehyde (10 mg, 0.3 mmol) and sodium cyanoborohydride (20 mg, 0.3 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated and the residue was purified by column chromatography to obtain I-34 (28 mg, 53%).
  • step 8 instead of morpholine, compound 1-38 was prepared.
  • MS(ESI)m/z 459.2[M+H] + .
  • step 8 instead of morpholine, compound 1-40 was prepared.
  • step 8 instead of morpholine, compound 1-48 was prepared.
  • MS( ESI) m/z 458.2[M+H] + .
  • step 8 instead of morpholine, compound 1-70 was prepared.
  • step 8 instead of morpholine, compound 1-72 was prepared.
  • step 8 instead of morpholine, compound 1-84 was prepared.
  • step 8 instead of morpholine, compound 1-145 was prepared.
  • step 8 instead of morpholine, compound 1-146 was prepared.
  • step 3 use in step 3 Instead of morpholine, compound 1-147 was prepared.
  • step 1
  • Example I-151 Referring to the preparation method of Example I-151, starting from I-150, compound I-152 (72 mg) was prepared. MS(ESI)m/z444.1[M+H] + .
  • step 1
  • step 1
  • step 8 preparation method using 8-oxa-3-azabicyclo[3,2,1]octane hydrochloride and I-2h as raw materials to obtain I-162 (7mg, 12 %).
  • MS(ESI)m/z 458.1[M+H] + .
  • step 1
  • I-164 60 mg, 67%) was obtained by using I-164a as a raw material.
  • MS(ESI)m/z 447.1[M+H] + .
  • step 8 preparation method, using 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and I-2h as raw materials to obtain I-165 (15 mg, 28%).
  • MS(ESI)m/z 458.1[M+H] + .
  • step 1
  • I-166 (15 mg, 30%) was obtained by using I-166a as a raw material.
  • MS(ESI)m/z 417.2[M+H] + .
  • step 1
  • step 8 preparation method use (3S)-3-methylmorpholine and I-2h as raw materials to obtain I-173.
  • MS(ESI)m/z 446.1[M+H] + .
  • Example I-172 the preparation method in step 3, tetrahydrofuran-3-carboxylic acid and I-172c were used as raw materials to obtain I-174.
  • MS(ESI)m/z 526.1[M+H] + .
  • step 1
  • I-176c was obtained in two steps using I-176a and I-2h as raw materials.
  • MS(ESI)m/z 443.0[M+H] + .
  • step 1
  • step 1
  • step 1
  • Example I-2 the preparation method of step 7, using I-2g and A-1 as raw materials to obtain I-196a.
  • Example I-196 the preparation method of step 2, using 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and I-196a as raw materials to obtain I-198 (7mg, 14%) .
  • MS(ESI)m/z 444.3[M+H] + .
  • step 1
  • step 1
  • I-213b (300 mg, 87%) was obtained by using I-213a and I-196a as raw materials.
  • I-213c (230 mg, 79%) was obtained by using I-213b as a raw material.
  • step 1
  • KRAS-G12C/SOS1 Binding Assay Kit (Cisbio #63ADK000CB16PEG).
  • the initial concentration of the compound to be tested was set at 10 ⁇ M (0.5% DMSO), diluted 1:10, 7 concentration gradients were set, and 2 replicate wells were set for each concentration.
  • Select a white 384-well plate (Corning#3572), add 2 ⁇ L of the compound to be tested, 4 ⁇ L of SOS1, and 4 ⁇ L of KRAS-G12C protein (diluted 100 times with dilution buffer according to the instructions of the assay kit) to each well, and incubate at room temperature for 15 minutes.
  • IC 50 data processing The ratio of RFU665/RFU620 in the compound treatment group was counted, and the GraphPad Prism 7.0 software was used to draw a sigmoid dose-inhibition rate curve using a nonlinear regression model, and the IC 50 value was fitted and calculated.
  • HCC827 cells in the logarithmic growth phase were digested, centrifuged, resuspended, and counted.
  • the initial concentration of the compound to be tested was set at 10 ⁇ M, diluted 1:5, 9 concentration gradients were set, and 3 replicate wells were set for each concentration. 20 ⁇ L of the compound to be tested was added to the 96-well plate; in addition, a DMSO control group and a blank group were set.
  • the culture medium was discarded and rinsed twice with PBST.
  • Cells were fixed with 150 ⁇ L/well of 4% paraformaldehyde and incubated at room temperature for 20 min. Discard the fixative and rinse twice with PBST.
  • GraphPad Prism 7.0 software a sigmoid dose-inhibition rate curve was drawn using a nonlinear regression model, and the EC 50 value was fitted and calculated.
  • CCL detection method was used to evaluate the anti-proliferative activity of the compounds in this application on human non-small cell lung cancer cell line NCI-H358, human pancreatic cancer cell line KP-4, human colorectal adenocarcinoma cell line SW620 and human lung adenocarcinoma cell line HCC827 .
  • the above normal growing cells were taken, digested with trypsin cell digestion solution, centrifuged, counted, and plated in a 96-well plate at a suitable cell density (6000 cells/well), 100 ⁇ L per well.
  • the administration was carried out on the second day after the cells were plated, and compounds with different concentration gradients were added to each well, and three replicate wells were set at each concentration point, and a corresponding DMSO negative treatment control group was also set.
  • After 5 days of drug treatment take out the cell culture plate to be tested in the incubator, and after the CCL solution and the 96-well plate return to room temperature, add 100 ⁇ L of CCL solution to each well, shake for 10 minutes and then let it stand for 10 minutes, then transfer the liquid to be tested to Quanbai 96 Well culture plate, after stable luminescence, detect chemiluminescence with a microplate reader. After subtracting the background value from the value of each well, the inhibition rate was calculated.
  • Inhibition Rate (%) (1-Sample/Vehicle)*100.
  • Sample is the luminescence value of the drug treatment group
  • Vehicle is the luminescence value of the DMSO control group.
  • GraphPad Prism 7.0 software a sigmoid dose-survival curve was drawn using a nonlinear regression model and IC 50 values were calculated.
  • HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a CO concentration of 5%.
  • the cells were digested with TrypLE TM Express and then centrifuged to adjust the cell density to 2 ⁇ 106cells/mL. Then, the cells were gently mixed with a room temperature balance shaker for 15-20min, and the patch clamp detection was carried out on the machine.
  • the culture medium of the prepared cells was replaced with extracellular fluid. The intracellular and extracellular fluids are sucked from the liquid pool and added to the intracellular pool, cell and test substance pool of the QPlate chip respectively.
  • the whole-cell patch clamp records the voltage stimulation of the whole-cell hERG potassium current, and the experimental data is collected and stored by Qpatch.
  • the compound was started at 30 ⁇ M, diluted 3 times, and 6 concentration points were set, and each drug concentration was set to be administered twice, and the time was at least 5 minutes.
  • the current detected by each cell in the external fluid without the compound was used as its own control group, and at least two cells were used for each concentration to repeat the detection twice independently. All electrophysiological experiments were performed at room temperature.
  • 100mM K-Buffer Mix 9.5mL stock solution A into 40.5mL stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer with KOH or H 3 PO 4 to pH 7.4.
  • Raw material A (1M potassium dihydrogen phosphate): 136.5g potassium dihydrogen phosphate in 1L water;
  • the powder of the test substance is prepared into a stock solution of a certain concentration with DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
  • liver microsomes for CYP450 enzyme metabolic phenotype research is carried out by preparing liver microsomes supplemented with redox-type coenzymes, and then adding enzyme-specific selective inhibitors, under the conditions of simulating physiological temperature and physiological environment biochemical reaction.
  • the concentration of the original drug or its metabolites in the incubation solution was determined by LC-MS/MS.
  • mice Take 6-8 weeks old male Balb/c mice. Animals in group IV were given corresponding compounds through tail vein, and animals in group PO were given corresponding compounds by gavage. Animals in group IV were given free access to food and water. Animals in group PO were fasted overnight before administration and fed 4 hours after administration. During the entire experiment, animals were given free access to water. Plasma samples were collected at 0.083 (group IV only), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, respectively. About 100 ⁇ L of blood was taken from the orbit of the animal and placed in a 1.5 mL anticoagulant centrifuge tube, centrifuged at 8000 rpm for 10 minutes at 4 °C, and the upper plasma sample was transferred to an EP tube. Plasma samples were stored in a -80°C freezer until sample analysis.
  • SPF-grade female BALB/C nude mice (source: Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with 5x106 NCI-H358 cells on the right back.
  • the day of grouping was d0 day, d1 day began to gavage administration, twice a day.
  • the control group was given vehicle.
  • the administration was continued for 21 days, the tumor volume was measured 2-3 times a week, and the mice were weighed at the same time, and the data was recorded: observe and record the general performance of the mice every day. After the experiment, the tumors were weighed and photographed.

Abstract

Involved are an SOS1 inhibitor of formula (I), a pharmaceutical composition comprising same, and a use thereof for preventing or treating a disease.

Description

SOS1抑制剂、包含其的药物组合物及其用途SOS1 inhibitors, pharmaceutical compositions comprising them and uses thereof 发明领域field of invention
本发明涉及SOS1抑制剂、包含其的药物组合物、及其用于预防或治疗疾病的用途。The present invention relates to SOS1 inhibitors, pharmaceutical compositions containing them, and uses thereof for preventing or treating diseases.
发明背景Background of the invention
RAS-RAF-MEK-ERK是经典的肿瘤信号通路，其与多种癌症的发生密切相关。Ras是由189个氨基酸组成的一组紧密相关的球状单体蛋白(分子量21kDa)，具有GTP酶活性，可以与GDP或GTP结合，在细胞信号通路中起关键作用。SOS1在RAS的激活中发挥着重要功能，可协同调控细胞的增殖、分化、凋亡及炎症等相关生物学功能。RAS-RAF-MEK-ERK is a classic tumor signaling pathway, which is closely related to the occurrence of various cancers. Ras is a group of closely related globular monomeric proteins (molecular weight 21kDa) composed of 189 amino acids. It has GTPase activity, can bind to GDP or GTP, and plays a key role in cell signaling pathways. SOS1 plays an important role in the activation of RAS, and can coordinately regulate cell proliferation, differentiation, apoptosis, inflammation and other related biological functions.
SOS(Son of Sevenless,SOS)是一种鸟嘌呤核苷酸交换因子(GEF)，其以SOS1和SOS2两个同源物的形式存在。其中SOS1是一个含有1333个氨基酸的多结构域蛋白，其由组蛋白折叠、Dbl(DH)以及Pleckstrin(PH)同源结构域、一个Ras交换基序(REM)，以及Cdc25同源物与聚脯氨酸结构域组成。SOS1可与GRB2等接头蛋白结合，在RAS-RAF-MEK-ERK信号通路以及PI3K-AKT-mTOR信号中发挥着重要作用。SOS1可以催化KRAS-OFF到KRAS-ON构象的转换，是细胞信号转导中一个重要的双分子开关。在正常情况下KRAS蛋白主要与GDP结合，一旦KRAS-SOS1结合便会导致GTP水解减少或GTP负载率增加，改变GDP和GTP结合的稳态平衡，从而使KRAS处于激活状态。SOS (Son of Sevenless, SOS) is a guanine nucleotide exchange factor (GEF), which exists in the form of two homologs of SOS1 and SOS2. Among them, SOS1 is a multi-domain protein containing 1333 amino acids, which consists of histone folds, Dbl (DH) and Pleckstrin (PH) homology domains, a Ras exchange motif (REM), and Cdc25 homologues and polymorphisms. Proline domain composition. SOS1 can bind to adapter proteins such as GRB2, and plays an important role in the RAS-RAF-MEK-ERK signaling pathway and PI3K-AKT-mTOR signaling. SOS1 can catalyze the conversion of KRAS-OFF to KRAS-ON conformation, and is an important bimolecular switch in cell signal transduction. Under normal circumstances, KRAS protein is mainly combined with GDP. Once KRAS-SOS1 binds, it will lead to a decrease in GTP hydrolysis or an increase in GTP loading rate, changing the steady-state balance of GDP and GTP binding, thereby making KRAS active.
尽管选择性KRAS G12C抑制剂已证明在KRAS G12C突变癌症中具有临床治疗效果，但G12C突变仅占KRAS驱动的恶性肿瘤的15％左右。因此开发SOS1抑制剂的相关研究显得尤为重要，它能与SOS1催化域结合，阻断SOS1与KRAS的相互作用，并将通路中的平衡转向KRAS-GDP结合形式，形成KRAS-OFF状态。从而减少了MAPK激酶途径的信号传导，抑制肿瘤细胞增殖。Although selective KRAS G12C inhibitors have demonstrated clinical efficacy in KRAS G12C-mutated cancers, G12C mutations account for only about 15% of KRAS-driven malignancies. Therefore, it is particularly important to develop related research on SOS1 inhibitors, which can bind to the catalytic domain of SOS1, block the interaction between SOS1 and KRAS, and shift the balance in the pathway to the KRAS-GDP binding form, forming a KRAS-OFF state. Thereby reducing the signal transduction of MAPK kinase pathway and inhibiting tumor cell proliferation.
发明概述Summary of the invention
本申请提供用作SOS1抑制剂的化合物，其对于SOS1具有优异的抑制活性。此外，本发明的化合物还具有良好的物理化学性质(例如溶解度、物理和/或化学稳定性)、良好的药物代谢动力学性质(例如改善的生物利用度、良好的代谢稳定性、合适的半衰期和作用持续时间)、良好的安全性(较低的毒性(例如降低的心脏毒性)和/或较少的副作用)、较不易产生耐药性等优异的性质。The present application provides compounds useful as SOS1 inhibitors, which have excellent inhibitory activity against SOS1. In addition, the compounds of the present invention also have good physicochemical properties (such as solubility, physical and/or chemical stability), good pharmacokinetic properties (such as improved bioavailability, good metabolic stability, suitable half-life and duration of action), good safety (lower toxicity (such as reduced cardiotoxicity) and/or fewer side effects), less likely to develop drug resistance and other excellent properties.
本发明的一个方面提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein The compound has the structure of formula (I):
Figure PCTCN2022135958-appb-000001
Figure PCTCN2022135958-appb-000001
其中：in:
Figure PCTCN2022135958-appb-000002
表示单键或双键，条件是，当其表示双键时，R 3和R 4’不存在；
Figure PCTCN2022135958-appb-000002
represents a single bond or a double bond, with the proviso that, when it represents a double bond, R 3 and R 4' are absent;
环A为C 6-10芳环或5-14元杂芳环； Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
L为直接键、-C 1-6亚烷基-、-C(＝O)-、-NR a-、-O-(CH 2) m-、-S-(CH 2) m-、-S(＝O)-(CH 2) m-、-S(＝O) 2-(CH 2) m-或-C(＝O)NR a-； L is a direct bond, -C 1-6 alkylene-, -C(=O)-, -NR a -, -O-(CH 2 ) m -, -S-(CH 2 ) m -, -S (=O)-(CH 2 ) m -, -S(=O) 2 -(CH 2 ) m - or -C(=O)NR a -;
R 1在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、- OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； Each occurrence of R 1 is independently selected from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R a , -OC(= O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S( =O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and - OC 1-6 alkylene-NR a R b ;
当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环； When n>1, two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
R 2选自C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
R 3、R 4、R 4’和R 5各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 3 , R 4 , R 4' and R 5 are each independently selected from H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O) R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S (=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene -NR a R b and -OC 1-6 alkylene-NR a R b ;
或者R 4和R 4’连同其所连接的碳原子共同构成
Figure PCTCN2022135958-appb-000003
条件是此时，
Figure PCTCN2022135958-appb-000004
表示单键； Or R 4 and R 4' together with the carbon atom to which they are attached form
Figure PCTCN2022135958-appb-000003
The condition is that at this time,
Figure PCTCN2022135958-appb-000004
Indicates a single key;
R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
m为0、1、2或3的整数；m is an integer of 0, 1, 2 or 3;
n为0、1、2、3或4的整数；n is an integer of 0, 1, 2, 3 or 4;
上述烷基、亚烷基、烯基、炔基、环烃基、烃环、杂环基、杂环、芳基、芳环、杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R c、-OC(＝O)R c、-C(＝O)OR c、-OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR cR d、-NR cR d、-C(＝O)NR cR d、-NR c-C(＝O)R d、-NR c-C(＝O)OR d、-NR c-S(＝O) 2-R d、-NR c-C(＝O)-NR cR d、-C 1-6亚烷基-OR c、-C 1-6亚烷基-NR cR d和-O-C 1-6亚烷基-NR cR d，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-O-C 1-6烷基和-C 1-6亚烷基-O-C 1-6烷基；并且 The above-mentioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaryl ring and aralkyl are each Optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 - R d , -NR c -C(=O)-NR c R d , -C 1-6 alkylene-OR c , -C 1-6 alkylene-NR c R d and -OC 1-6 alkylene Alkyl-NR c R d , said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from the following: halogen , -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -OC 1-6 alkyl and -C 1-6 alkylene-OC 1-6 alkyl; and
R c和R d在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基和-C 1-6亚烷基-O-C 1-6烷基。 R c and R d are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more independently selected from the following Substitution: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3 -6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl and -C 1-6 alkylene-OC 1-6 alkane base.
本发明的另一方面提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用作SOS1抑制剂的药物中的用途。Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Use of the prodrug or the pharmaceutical composition of the present invention in the preparation of a medicament for use as an SOS1 inhibitor.
本发明的另一方面提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用作SOS1抑制剂。Another aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or Prodrugs or pharmaceutical compositions of the invention for use as SOS1 inhibitors.
本发明的另一方面提供预防或治疗SOS1相关疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。Another aspect of the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, Tautomers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs or pharmaceutical compositions of the invention.
发明详述Detailed description of the invention
定义definition
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人 员很好理解，但仍然阐述以下定义以更好地解释本发明。Unless defined otherwise hereinafter, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including those variations of the techniques or substitutions of equivalent techniques that are obvious to those skilled in the art. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。The terms "comprising", "comprising", "having", "containing" or "involving" and other variations thereof herein are inclusive or open-ended and do not exclude other unlisted elements or method steps.
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。As used herein, the term "alkylene" means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
如本文中所使用，术语“烷基”定义为直链或支链饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C 1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF 3、C 2F 5、CHF 2、CH 2F、CH 2CF 3、CH 2Cl或-CH 2CH 2CF 3等)。术语“C 1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。 As used herein, the term "alkyl" is defined as a straight or branched chain saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 alkyl" refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl group, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is referred to as "haloalkyl" ) ( eg CF3 , C2F5 , CHF2 , CH2F , CH2CF3 , CH2Cl or -CH2CH2CF3 , etc.). The term "C 1-4 alkyl" refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个或多个双键，且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如-CH＝CH 2、-CH 2CH＝CH 2、-C(CH 3)＝CH 2、-CH 2-CH＝CH-CH 3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。术语“亚烯基”为相应的二价基团，包括例如“C 2-6亚烯基”、“C 2-4亚烯基”等，其具体实例包括但不限于：-CH＝CH-、-CH 2CH＝CH-、-C(CH 3)＝CH-、亚丁烯基、亚戊烯基、亚己烯基、亚环戊烯基、亚环己烯基等。 As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2-6 carbon atoms (" C2-6 alkenyl"). The alkenyl group is, for example, -CH=CH 2 , -CH 2 CH=CH 2 , -C(CH 3 )=CH 2 , -CH 2 -CH=CH-CH 3 , 2-pentenyl, 3-pentenyl Alkenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3- pentenyl. When a compound of the present invention contains an alkenyl group, the compound may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof. The term "alkenylene" is a corresponding divalent group, including, for example, "C 2-6 alkenylene", "C 2-4 alkenylene", etc., and its specific examples include but are not limited to: -CH=CH- , -CH 2 CH=CH-, -C(CH 3 )=CH-, butenylene, pentenylene, hexenylene, cyclopentenylene, cyclohexenylene and the like.
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。术语“亚炔基”为相应的二价基团，包括例如“C 2-8亚炔基”、“C 2-6亚炔基”、“C 2-4亚炔基”等。其实例包括但不限于
Figure PCTCN2022135958-appb-000005
Figure PCTCN2022135958-appb-000006
等，所述亚炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。 As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynyl, 2-propynyl, 2 -butynyl, 1,3-butadiynyl, etc. The alkynyl group is optionally substituted with one or more (such as 1 to 3) same or different substituents. The term "alkynylene" is a corresponding divalent group, including, for example, "C 2-8 alkynylene", "C 2-6 alkynylene", "C 2-4 alkynylene" and the like. Examples include but are not limited to
Figure PCTCN2022135958-appb-000005
Figure PCTCN2022135958-appb-000006
etc., the alkynylene group is optionally substituted with one or more (such as 1 to 3) same or different substituents.
如本文中所使用，术语“并环”或“稠环”指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的环系。As used herein, the term "merged ring" or "fused ring" refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
如本文中所使用，术语“螺环”指由两个或两个以上环状结构彼此共用一个环原子所形成的环系。As used herein, the term "spiro ring" refers to a ring system formed by two or more ring structures sharing one ring atom with each other.
如本文中所使用，术语“桥环”指由两个或两个以上环状结构彼此共用两个不直接相连的原子所形成的环系。As used herein, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环(包括螺环、并环(稠环)或桥环***)，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。As used herein, the terms "cycloalkylene", "cycloalkyl" and "hydrocarbon ring" mean ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., "cycloalkylene" and "cycloalkyl") or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings (including Spiro ring, ax ring (fused ring) or bridged ring system), which includes but not limited to () cyclopropyl (ring), () cyclobutyl (ring), () cyclopentyl (ring), () cyclopentyl (ring), (A) cyclohexyl (ring), (a) cycloheptyl (ring), (a) cyclooctyl (ring), (a) cyclononyl (ring), (a) cyclohexenyl (ring), etc. .
如本文中所使用，术语“环烷基”指饱和单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连***(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C 3-6环烷基”指3至6个成环碳原子的饱和单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。 As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or Bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl has 3 to 15 carbon atoms For example, the term "C 3-6 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclo hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
如本文中所使用，术语“杂环基”指饱和或不饱和的一价单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自O、S、N、S(＝O)、S(＝O) 2、S(＝O)(＝NR Z)、NR Z或P(＝O)(R Z)的含杂原子的基团，其中R Z在每次出现时各自独立地表示氢原子或C 1-6烷基或卤代-C 1-6烷基；所述杂环烷基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基 (oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。 As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms in the ring and one or more (eg one, two, three or four) selected from O, S, N, S(=O), S(=O) 2 , S(=O)(=NR Z ), A heteroatom-containing group of NR Z or P(=O)(R Z ), wherein each occurrence of R Z independently represents a hydrogen atom or a C 1-6 alkyl or halo-C 1-6 alkane group; said heterocycloalkyl group may be attached to the rest of the molecule through any of said carbon atoms or a nitrogen atom, if present. In particular, a 3-10 membered heterocyclic group is a group with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl (oxetanyl), tetrahydrofuryl, dioxolinyl (dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyrrolidinyl pyryl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
如本文中所使用，术语“杂环基”涵盖并环结构，所述并环结构与其他基团的连接点可以在并环结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C 4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌嗪基、哌啶基并吗啉基、
Figure PCTCN2022135958-appb-000007
As used herein, the term "heterocyclyl" encompasses an amalgamated ring structure, and the connection point of the amalgamated ring structure to other groups may be on any ring in the amalgamated ring structure. Therefore, the heterocyclyl group of the present invention also includes, but is not limited to, heterocyclyl and heterocyclyl, heterocyclyl and cycloalkyl, monoheterocyclyl and monoheterocyclyl, monoheterocyclyl and monocycloalkyl, for example 3-7 membered (single) heterocyclic group and 3-7 membered (single) heterocyclic group, 3-7 membered (single) heterocyclic group and (single) cycloalkyl group, 3-7 membered (single) heterocyclic group C 4-6 (mono)cycloalkyl, examples of which include, but are not limited to, pyrrolidinocyclopropyl, cyclopentylaziridine, pyrrolidinocyclobutyl, pyrrolidinopyrrolidine Base, pyrrolidinyl piperidinyl, pyrrolidinyl piperazinyl, piperidinyl morpholinyl,
Figure PCTCN2022135958-appb-000007
如本文中所使用，术语“杂环基”涵盖桥杂环基和螺杂环基。As used herein, the term "heterocyclyl" encompasses both bridged and spiroheterocyclyls.
如本文中所使用，术语“桥杂环”是指两个饱和环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子和/或硫原子)的环状结构，包括但不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等，例如
Figure PCTCN2022135958-appb-000008
Figure PCTCN2022135958-appb-000009
Figure PCTCN2022135958-appb-000010
等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个选自氧、氮和硫的其他杂原子。 As used herein, the term "bridged heterocycle" refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (eg, 1, 2, 3, or 4) heteroatoms. (such as oxygen atom, nitrogen atom and/or sulfur atom) ring structure, including but not limited to 7-10 membered bridged heterocycle, 8-10 membered bridged heterocycle, 7-10 membered nitrogen-containing bridged heterocycle, 7- 10-membered oxygen-containing bridged heterocycle, 7-10-membered sulfur-containing bridged heterocycle, etc., for example
Figure PCTCN2022135958-appb-000008
Figure PCTCN2022135958-appb-000009
Figure PCTCN2022135958-appb-000010
wait. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", and "sulfur-containing bridged heterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
如本文中所使用，术语“螺杂环”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子、硫原子)的环状结构，包括但不限于5-10元螺杂环、6-10元螺杂环、6-10元含氮螺杂环、6-10元含氧螺杂环、6-10元含硫螺杂环等，例如
Figure PCTCN2022135958-appb-000011
Figure PCTCN2022135958-appb-000012
Figure PCTCN2022135958-appb-000013
所述“含氮螺杂环”、“含氧螺杂环”、“含硫螺杂环”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。 As used herein, the term "spiroheterocycle" refers to a heterocyclic ring formed by two or more saturated rings sharing one ring atom and containing one or more (for example, 1, 2, 3 or 4) heteroatoms (such as oxygen atom, nitrogen atom, sulfur atom), including but not limited to 5-10 membered spiroheterocycle, 6-10 membered spiroheterocycle, 6-10 membered nitrogen-containing spiroheterocycle, 6-10 membered spiroheterocycle, Oxygen-containing spiroheterocycle, 6-10 membered sulfur-containing spiroheterocycle, etc., for example
Figure PCTCN2022135958-appb-000011
Figure PCTCN2022135958-appb-000012
Figure PCTCN2022135958-appb-000013
The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms selected from oxygen, nitrogen, and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子***的全碳单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C 6-10(亚)芳基”和“C 6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO 2、C 1-6烷基等)取代。 As used herein, the terms "()arylene" and "aromatic ring" refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the terms "C 6-10 ()arylene" and "C 6-10 aromatic ring" mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring). ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
术语“芳烷基”优选表示芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。The term "aralkyl" preferably denotes an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein. Typically, the aryl group may have 6-14 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原 子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基(环)、(亚)呋喃基(环)、(亚)吡咯基(环)、(亚)噁唑基(环)、(亚)噻唑基(环)、(亚)咪唑基(环)、(亚)吡唑基(环)、(亚)异噁唑基(环)、(亚)异噻唑基(环)、(亚)噁二唑基(环)、(亚)***基(环)、(亚)噻二唑基(环)等，以及它们的苯并衍生物；或(亚)吡啶基(环)、(亚)哒嗪基(环)、(亚)嘧啶基(环)、(亚)吡嗪基(环)、(亚)三嗪基(环)等，以及它们的苯并衍生物。As used herein, the terms "(heteroarylene)" and "heteroaromatic ring" refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms and which contain at least one heteroatom which may be the same or different (the heteroatom is for example oxygen , nitrogen or sulfur), and, additionally, in each case may be benzo-fused. In particular, "(ylidene)heteroaryl" or "heteroaryl ring" is selected from (ylidene)thienyl (ring), (ylidene)furyl (ring), (ylidene)pyrrolyl (ring), (ylidene)oxa Azolyl (ring), (sub)thiazolyl (ring), (sub)imidazolyl (ring), (sub)pyrazolyl (ring), (sub)isoxazolyl (ring), (sub)isothiazole (ring), (sub)oxadiazolyl (ring), (sub)triazolyl (ring), (sub)thiadiazolyl (ring), etc., and their benzo derivatives; or (sub) Pyridyl (ring), (sub)pyridazinyl (ring), (sub)pyrimidinyl (ring), (sub)pyrazinyl (ring), (sub)triazinyl (ring), and their benzene and derivatives.
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br or I.
如本文中所使用，术语“烷基硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C 1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。 The term "alkylthio" as used herein means an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O) 2的环成员；所述含氮杂环通过氮原子与分子的其余部分连接。所述含氮杂环优选为饱和含氮单环。特别地，3至14元含氮杂环为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的基团，其包括但不限于三元含氮杂环(如氮丙啶基)、四元含氮杂环(如氮杂环丁烷基)、五元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、六元含氮杂环(如哌啶基(哌啶环)、吗啉基、硫吗啉基、哌嗪基)、七元含氮杂环等。 As used herein, the term "nitrogen-containing heterocycle" refers to a saturated or unsaturated monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12 or 13 carbon atoms and at least one nitrogen atom, which may also optionally contain one or more (for example one, two, three or four) selected from N, O, C=O, S, S Ring members of =O and S(=O) 2 ; the nitrogen-containing heterocycle is attached to the rest of the molecule through a nitrogen atom. The nitrogen-containing heterocyclic ring is preferably a saturated nitrogen-containing monocyclic ring. In particular, a 3- to 14-membered nitrogen-containing heterocycle is a group having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to a three-membered nitrogen-containing heterocycle (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidinyl ring), pyrrolinyl, pyrrolidonyl, imidazole group, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidinyl ring), morpholinyl, thiomorpholinyl, piperazinyl) , Seven-membered nitrogen-containing heterocycle, etc.
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。The term "substituted" means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present The normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。If a substituent is described as "optionally substituted," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。If substituents are described as being "independently selected from" a group, each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。As used herein, unless otherwise indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。When a bond for a substituent is shown as being through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring-forming atom in such a substitutable ring.
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(D， 2H)、氚(T， 3H))；碳的同位素(例如 11C、 13C及 14C)；氯的同位素(例如 36Cl)；氟的同位素(例如 18F)；碘的同位素(例如 123I及 125I)；氮的同位素(例如 13N及 15N)；氧的同位素(例如 15O、 17O及 18O)；磷的同位素(例如 32P)；及硫的同位素(例如 35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即 3H)及碳-14(即 14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如 11C、 18F、 15O及 13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D 2O、丙酮-d 6或DMSO-d 6。 The present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions. Examples of isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g. deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g. 11 C, 13 C and 14 C); isotopes of chlorine (such as 36 Cl); isotopes of fluorine (such as 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (such as 13 N and 15 N); (eg 15 O, 17 O and 18 O); phosphorus isotopes (eg 32 P); and sulfur isotopes (eg 35 S). Certain isotopically-labeled compounds of the invention (eg, those incorporating radioactive isotopes) are useful in drug and/or substrate tissue distribution studies (eg, assays). The radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection. Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。It will also be understood that certain compounds of the invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which can directly Or indirectly provide a compound of the invention or a metabolite or residue thereof. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。The pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢 盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoro Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methylsulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, diethylamine salts, lysine salts, magnesium salts, meglumine salts, potassium salts, and other similar salts.
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。For a review of suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound). The compounds of the invention may also themselves be esters.
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。The compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound. The amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。Also included within the scope of the present invention are metabolites of the compounds of the present invention, ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。The present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association). The prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。The invention also encompasses compounds of the invention which contain protecting groups. During any of the preparations of the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting groups, these references are incorporated herein by reference. Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。As used herein, the term "about" means within ±10%, preferably within ±5%, more preferably within ±2% of the stated numerical value.
化合物compound
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (I):
Figure PCTCN2022135958-appb-000014
Figure PCTCN2022135958-appb-000014
其中：in:
Figure PCTCN2022135958-appb-000015
表示单键或双键，条件是，当其表示双键时，R 3和R 4’不存在；
Figure PCTCN2022135958-appb-000015
represents a single bond or a double bond, with the proviso that, when it represents a double bond, R 3 and R 4' are absent;
环A为C 6-10芳环或5-14元杂芳环； Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
L为直接键、-C 1-6亚烷基-、-C(＝O)-、-NR a-、-O-(CH 2) m-、-S-(CH 2) m-、-S(＝O)-(CH 2) m-、-S(＝O) 2-(CH 2) m-或-C(＝O)NR a-； L is a direct bond, -C 1-6 alkylene-, -C(=O)-, -NR a -, -O-(CH 2 ) m -, -S-(CH 2 ) m -, -S (=O)-(CH 2 ) m -, -S(=O) 2 -(CH 2 ) m - or -C(=O)NR a -;
R 1在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； Each occurrence of R 1 is independently selected from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-14 membered heteroaryl group, C 6-12 aralkyl group, -C(=O)R a , -OC(= O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S( =O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and - OC 1-6 alkylene-NR a R b ;
当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环； When n>1, two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
R 2选自C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
R 3、R 4、R 4’和R 5各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 3 , R 4 , R 4' and R 5 are each independently selected from H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O) R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S (=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene -NR a R b and -OC 1-6 alkylene-NR a R b ;
或者R 4和R 4’连同其所连接的碳原子共同构成
Figure PCTCN2022135958-appb-000016
条件是此时，
Figure PCTCN2022135958-appb-000017
表示单键； Or R 4 and R 4' together with the carbon atom to which they are attached form
Figure PCTCN2022135958-appb-000016
The condition is that at this time,
Figure PCTCN2022135958-appb-000017
Indicates a single key;
R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
m为0、1、2或3的整数；m is an integer of 0, 1, 2 or 3;
n为0、1、2、3或4的整数；n is an integer of 0, 1, 2, 3 or 4;
上述烷基、亚烷基、烯基、炔基、环烃基、烃环、杂环基、杂环、芳基、芳环、杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R c、-OC(＝O)R c、-C(＝O)OR c、-OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR cR d、-NR cR d、-C(＝O)NR cR d、-NR c-C(＝O)R d、-NR c-C(＝O)OR d、-NR c-S(＝O) 2-R d、-NR c-C(＝O)-NR cR d、-C 1-6亚烷基-OR c、-C 1-6亚烷基-NR cR d和-O-C 1-6亚烷基-NR cR d，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-O-C 1-6烷基和-C 1-6亚烷基-O-C 1-6烷基，优选地，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基和-C 1-6亚烷基-O-C 1-6烷基；并且 The above-mentioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaryl ring and aralkyl are each Optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 - R d , -NR c -C(=O)-NR c R d , -C 1-6 alkylene-OR c , -C 1-6 alkylene-NR c R d and -OC 1-6 alkylene Alkyl-NR c R d , said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from the following: halogen , -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -OC 1-6 alkyl and -C 1-6 alkylene-OC 1-6 alkyl, preferably, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from the following: Halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 ring Hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl and -C 1-6 alkylene-OC 1-6 alkyl; and
R c和R d在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基和-C 1-6亚烷基-O-C 1-6烷基。 R c and R d are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more independently selected from the following Substitution: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3 -6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl and -C 1-6 alkylene-OC 1-6 alkane base.
在一些实施方案中，本发明提供化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(II)、(III)或(IV)的结构：In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or precursor thereof Drug, wherein said compound has the structure of formula (II), (III) or (IV):
Figure PCTCN2022135958-appb-000018
Figure PCTCN2022135958-appb-000018
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中环A为苯环或吡啶环，优选为苯环。In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein ring A is a benzene ring or a pyridine ring, preferably a benzene ring.
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中L为直接键、-CH 2-、-C(＝O)-、-NH-、-O-、-S-、-S(＝O) 2-、-C(＝O)N(CH 3)-或-O-CH 2-。 In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein L is a direct bond, -CH 2 -, -C(=O)-, -NH-, -O-, -S-, -S(=O) 2 -, -C(=O)N(CH 3 )- or -O-CH 2 -.
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、-C(＝O)R a、-C(＝O)OR a、-OR a、-S(＝O) 2R a、-NR aR b、-C(＝O)NR aR b、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR aR b；上述烷基、亚烷基、环烃基和杂环基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、C 1-6烷基、C 3-6环烃基和3-10元杂环基； In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein each occurrence of R 1 is independently selected from halogen, -OH, -NH 2 , -CN, -NO 2. C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, -C(=O)R a , -C(=O)OR a , -OR a , -S(= O) 2 R a , -NR a R b , -C(=O)NR a R b , -C 1-6 alkylene-OR a and -C 1-6 alkylene-NR a R b ; above Each occurrence of alkyl, alkylene, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH2 , - CN, C 1-6 alkyl, C 3-6 cycloalkyl and 3-10 membered heterocyclyl;
优选地，R 1选自-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-NO 2、-CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 3、-CH 2CF 3、-CF 2CH 3、-CF 2CN、-CH 2NHCH 3、-CF 2CH 2NH 2、-CH(CH 3)OH、-C(CH 3) 2OH、-CF 2CH 2OH、-CF 2C(CH 3) 2OH、-CF 2OCH 3、-CF 2CH 2OCH 3、-CF 2O-(环丙基)、环丙基、
Figure PCTCN2022135958-appb-000019
-C(＝O)CH 3、-C(＝O)OCH 3、-OCH 3、-S(＝O) 2CH 3和-C(＝O)NH 2。 Preferably, R 1 is selected from -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, -NO 2 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CF 2 CH 3 , -CF 2 CN, -CH 2 NHCH 3 , -CF 2 CH 2 NH 2 , -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CF 2 CH 2 OH, -CF 2 C(CH 3 ) 2 OH, -CF 2 OCH 3 , -CF 2 CH 2 OCH 3 , -CF 2 O-(cyclopropyl), cyclopropyl ,
Figure PCTCN2022135958-appb-000019
-C(=O) CH3 , -C(=O) OCH3 , -OCH3 , -S(= O ) 2CH3 , and -C(=O) NH2 .
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中：In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein:
当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成C 3-6烃环、3-10元杂环或5-14元杂芳环；所述烃环、杂环和杂芳环各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、C 1-6烷基和-C 1-6亚烷基-OR c； When n>1, two adjacent R 1 together with the group it is connected to optionally jointly form a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaromatic ring; the hydrocarbon Each ring, heterocycle and heteroaromatic ring is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, =O, C 1-6 alkyl and -C 1-6 alkylene -OR c ;
优选地，当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成
Figure PCTCN2022135958-appb-000020
Figure PCTCN2022135958-appb-000021
Figure PCTCN2022135958-appb-000022
Preferably, when n>1, two adjacent R 1 together with the groups to which they are connected optionally jointly form
Figure PCTCN2022135958-appb-000020
Figure PCTCN2022135958-appb-000021
Figure PCTCN2022135958-appb-000022
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
Figure PCTCN2022135958-appb-000023
选自
Figure PCTCN2022135958-appb-000024
Figure PCTCN2022135958-appb-000025
Figure PCTCN2022135958-appb-000026
Figure PCTCN2022135958-appb-000027
In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein
Figure PCTCN2022135958-appb-000023
selected from
Figure PCTCN2022135958-appb-000024
Figure PCTCN2022135958-appb-000025
Figure PCTCN2022135958-appb-000026
Figure PCTCN2022135958-appb-000027
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
Figure PCTCN2022135958-appb-000028
选自
Figure PCTCN2022135958-appb-000029
Figure PCTCN2022135958-appb-000030
Figure PCTCN2022135958-appb-000031
Figure PCTCN2022135958-appb-000032
In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein
Figure PCTCN2022135958-appb-000028
selected from
Figure PCTCN2022135958-appb-000029
Figure PCTCN2022135958-appb-000030
Figure PCTCN2022135958-appb-000031
Figure PCTCN2022135958-appb-000032
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中-L-R 2选自
Figure PCTCN2022135958-appb-000033
Figure PCTCN2022135958-appb-000034
Figure PCTCN2022135958-appb-000035
Figure PCTCN2022135958-appb-000036
Figure PCTCN2022135958-appb-000037
Figure PCTCN2022135958-appb-000038
Figure PCTCN2022135958-appb-000039
Figure PCTCN2022135958-appb-000040
Figure PCTCN2022135958-appb-000041
甲氧基、
Figure PCTCN2022135958-appb-000042
Figure PCTCN2022135958-appb-000043
Figure PCTCN2022135958-appb-000044
In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein -LR 2 is selected from
Figure PCTCN2022135958-appb-000033
Figure PCTCN2022135958-appb-000034
Figure PCTCN2022135958-appb-000035
Figure PCTCN2022135958-appb-000036
Figure PCTCN2022135958-appb-000037
Figure PCTCN2022135958-appb-000038
Figure PCTCN2022135958-appb-000039
Figure PCTCN2022135958-appb-000040
Figure PCTCN2022135958-appb-000041
Methoxy,
Figure PCTCN2022135958-appb-000042
Figure PCTCN2022135958-appb-000043
Figure PCTCN2022135958-appb-000044
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中-L-R 2选自
Figure PCTCN2022135958-appb-000045
Figure PCTCN2022135958-appb-000046
Figure PCTCN2022135958-appb-000047
Figure PCTCN2022135958-appb-000048
Figure PCTCN2022135958-appb-000049
Figure PCTCN2022135958-appb-000050
Figure PCTCN2022135958-appb-000051
Figure PCTCN2022135958-appb-000052
甲氧基、
Figure PCTCN2022135958-appb-000053
Figure PCTCN2022135958-appb-000054
Figure PCTCN2022135958-appb-000055
In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein -LR 2 is selected from
Figure PCTCN2022135958-appb-000045
Figure PCTCN2022135958-appb-000046
Figure PCTCN2022135958-appb-000047
Figure PCTCN2022135958-appb-000048
Figure PCTCN2022135958-appb-000049
Figure PCTCN2022135958-appb-000050
Figure PCTCN2022135958-appb-000051
Figure PCTCN2022135958-appb-000052
Methoxy,
Figure PCTCN2022135958-appb-000053
Figure PCTCN2022135958-appb-000054
Figure PCTCN2022135958-appb-000055
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3、R 4、R 4’和R 5各自独立地选自H、F、Cl、Br、甲基、二氟甲基、三氟甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、
Figure PCTCN2022135958-appb-000056
Figure PCTCN2022135958-appb-000057
In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 3 , R 4 , R 4' and R 5 are each independently selected from H, F, Cl, Br, formazan base, difluoromethyl, trifluoromethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
Figure PCTCN2022135958-appb-000056
Figure PCTCN2022135958-appb-000057
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3选自H、卤素、C 1-6烷基、C 3-6环烃基、-OR a和-C 1-6亚烷基-OR a；所述烷基、亚烷基和环烃基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH和-CN； In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 3 is selected from H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a and -C 1-6 alkylene-OR a ; each of the alkyl, alkylene and cyclohydrocarbyl groups is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH and -CN;
优选地，R 3选自H、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、
Figure PCTCN2022135958-appb-000058
Preferably, R is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
Figure PCTCN2022135958-appb-000058
更优选地，R 3选自H、甲基、乙基和
Figure PCTCN2022135958-appb-000059
最优选地，R 3选自H和甲基。 More preferably, R is selected from H, methyl, ethyl and
Figure PCTCN2022135958-appb-000059
Most preferably, R3 is selected from H and methyl.
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 4和R 4’各自独立地选自H、卤素、C 1-6烷基、C 3-6环烃基、-OR a、-NR aR b和-C 1-6亚烷基-OR a；所述烷基和环烃基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH和-CN； In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 4 and R 4' are each independently selected from H, halogen, C 1-6 alkyl, C 3-6 Cycloalkyl, -OR a , -NR a R b and -C 1-6 alkylene-OR a ; the alkyl and cycloalkyl are each optionally substituted by one or more substituents independently selected from the following : halogen, -OH and -CN;
R 4和R 4’各自独立地选自H、F、Cl、Br、甲基、二氟甲基、三氟甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、
Figure PCTCN2022135958-appb-000060
Figure PCTCN2022135958-appb-000061
R and R are each independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, cyclopropyl,
Figure PCTCN2022135958-appb-000060
Figure PCTCN2022135958-appb-000061
优选地，R 4和R 4’各自独立地选自H、F、甲基、二氟甲基、三氟甲基、异丙基、叔丁基、
Figure PCTCN2022135958-appb-000062
Preferably, R4 and R4 ' are each independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, isopropyl, tert-butyl,
Figure PCTCN2022135958-appb-000062
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上 可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 5为H、C 1-6烷基、C 3-6环烃基、-OR a、-SR a、-NR aR b或-C 1-6亚烷基-NR aR b，优选为H、甲基、乙基、异丙基、环丙基、
Figure PCTCN2022135958-appb-000063
Figure PCTCN2022135958-appb-000064
In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Constructs, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs, wherein R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a , -SR a , -NR a R b or -C 1-6 alkylene-NR a R b , preferably H, methyl, ethyl, isopropyl, cyclopropyl,
Figure PCTCN2022135958-appb-000063
Figure PCTCN2022135958-appb-000064
本发明涵盖对各个实施方案进行任意组合所得的化合物。The present invention encompasses compounds resulting from any combination of the various embodiments.
在一些实施方案中，本发明提供具有式(I)、式(II)、(III)或(IV)的结构的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自：In some embodiments, the present invention provides a compound having a structure of formula (I), formula (II), (III) or (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer thereof Conformers, polymorphs, solvates, metabolites, isotopically labeled compounds or prodrugs, wherein the compound is selected from:
Figure PCTCN2022135958-appb-000065
Figure PCTCN2022135958-appb-000065
Figure PCTCN2022135958-appb-000066
Figure PCTCN2022135958-appb-000066
Figure PCTCN2022135958-appb-000067
Figure PCTCN2022135958-appb-000067
Figure PCTCN2022135958-appb-000068
Figure PCTCN2022135958-appb-000068
Figure PCTCN2022135958-appb-000069
Figure PCTCN2022135958-appb-000069
Figure PCTCN2022135958-appb-000070
Figure PCTCN2022135958-appb-000070
Figure PCTCN2022135958-appb-000071
Figure PCTCN2022135958-appb-000071
Figure PCTCN2022135958-appb-000072
Figure PCTCN2022135958-appb-000072
Figure PCTCN2022135958-appb-000073
Figure PCTCN2022135958-appb-000073
Figure PCTCN2022135958-appb-000074
Figure PCTCN2022135958-appb-000074
Figure PCTCN2022135958-appb-000075
Figure PCTCN2022135958-appb-000075
Figure PCTCN2022135958-appb-000076
Figure PCTCN2022135958-appb-000076
Figure PCTCN2022135958-appb-000077
Figure PCTCN2022135958-appb-000077
Figure PCTCN2022135958-appb-000078
Figure PCTCN2022135958-appb-000078
Figure PCTCN2022135958-appb-000079
Figure PCTCN2022135958-appb-000079
Figure PCTCN2022135958-appb-000080
Figure PCTCN2022135958-appb-000080
Figure PCTCN2022135958-appb-000081
Figure PCTCN2022135958-appb-000081
Figure PCTCN2022135958-appb-000082
Figure PCTCN2022135958-appb-000082
Figure PCTCN2022135958-appb-000083
Figure PCTCN2022135958-appb-000083
Figure PCTCN2022135958-appb-000084
Figure PCTCN2022135958-appb-000084
Figure PCTCN2022135958-appb-000085
Figure PCTCN2022135958-appb-000085
Figure PCTCN2022135958-appb-000086
Figure PCTCN2022135958-appb-000086
化合物的合成方法Compound Synthesis Method
在一些实施方案中，本发明提供制备式(IV)的化合物的方法，其包括选自以下的一个或多个步骤：In some embodiments, the present invention provides a method for preparing a compound of formula (IV), comprising one or more steps selected from the group consisting of:
路线1Route 1
Figure PCTCN2022135958-appb-000087
Figure PCTCN2022135958-appb-000087
在所述方法中，化合物(IV)-1与肼反应得到化合物(IV)-2，化合物(IV)-2通过适当的偶联反应得到化合物(IV)-3，化合物(IV)-3氯代得到化合物(IV)-4，化合物(IV)-4通过亲核取代反应或者偶联反应得到式(IV)的化合物。In said method, compound (IV)-1 reacts with hydrazine to obtain compound (IV)-2, compound (IV)-2 obtains compound (IV)-3 through appropriate coupling reaction, compound (IV)-3 chlorine Substitution to obtain compound (IV)-4, compound (IV)-4 obtains the compound of formula (IV) through nucleophilic substitution reaction or coupling reaction.
或者，化合物(IV)-3通过与硫代试剂反应得到化合物式(IV)-5，然后进行一步甲基化反应得到化合物(IV)-6，化合物(IV)-6通过氧化得到化合物(IV)-7，化合物(IV)-7通过亲核取代反应或者偶联反应得到化合物(IV)-8，最后化合物(IV)-8通过偶联反应得到式(IV)的化合物。Alternatively, compound (IV)-3 obtains compound formula (IV)-5 by reacting with a thio reagent, and then undergoes a one-step methylation reaction to obtain compound (IV)-6, and compound (IV)-6 obtains compound (IV) by oxidation )-7, compound (IV)-7 obtains compound (IV)-8 through nucleophilic substitution reaction or coupling reaction, and finally compound (IV)-8 obtains the compound of formula (IV) through coupling reaction.
在一些实施方案中，本发明提供制备式(III)的化合物的方法，其包括选自以下的一个或多个步骤：In some embodiments, the present invention provides a method of preparing a compound of formula (III), comprising one or more steps selected from the group consisting of:
路线2route 2
Figure PCTCN2022135958-appb-000088
Figure PCTCN2022135958-appb-000088
在所述方法中，化合物(III)-1通过溴代反应得到化合物(III)-2，接着通过偶联反应得到化合物(III)-3，化合物(III)-3与肼进行反应得到化合物(III)-4，化合物(III)-4通过适当的偶联反应得到化合物(III)-5，化合物(III)-5进行一步氯代得到化合物(III)-6，最后化合物(III)-6通过亲核取代反应或者偶联反应得到式(III)的化合物。In said method, compound (III)-1 obtains compound (III)-2 by bromination reaction, then obtains compound (III)-3 by coupling reaction, and compound (III)-3 reacts with hydrazine to obtain compound ( III)-4, compound (III)-4 obtains compound (III)-5 by appropriate coupling reaction, compound (III)-5 carries out one-step chlorination and obtains compound (III)-6, finally compound (III)-6 The compound of formula (III) is obtained by nucleophilic substitution reaction or coupling reaction.
或者，化合物(III)-5通过与硫代试剂反应可以得到化合物(III)-7，然后进行一步甲基化反应得到化合物(III)-8，化合物(III)-8通过氧化得到化合物(III)-9，最后化合物(III)-9通过亲核取代反应或者偶联反应得到式(III)的化合物。Alternatively, compound (III)-5 can obtain compound (III)-7 by reacting with a thio reagent, and then carry out a one-step methylation reaction to obtain compound (III)-8, and compound (III)-8 obtains compound (III) by oxidation )-9, and finally compound (III)-9 can obtain the compound of formula (III) through nucleophilic substitution reaction or coupling reaction.
药物组合物和治疗方法Pharmaceutical compositions and methods of treatment
在一些实施方案中，本发明提供药物组合物，其包含预防或治疗有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药以及一种或多种药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。在一些实施方案中，所述药物组合物还可包含一种或多种其它治疗剂。In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorphic form thereof Compounds, solvates, metabolites, isotope-labeled compounds or prodrugs and one or more pharmaceutically acceptable carriers, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation. In some embodiments, the pharmaceutical composition may also include one or more additional therapeutic agents.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物在制备用作SOS1抑制剂的药物中的用途。In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Use of a compound or a prodrug or a pharmaceutical composition of the invention for the preparation of a medicament for use as a SOS1 inhibitor.
在一些实施方案中，本发明提供本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物，其用作SOS1抑制剂。In some embodiments, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled Compounds or prodrugs or pharmaceutical compositions of the invention for use as SOS1 inhibitors.
在一些实施方案中，本发明提供预防或治疗SOS1相关疾病的方法，所述方法包括向需要其的个体给药有效量的本发明的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者本发明的药物组合物。In some embodiments, the present invention provides a method for preventing or treating SOS1-related diseases, the method comprising administering to an individual in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, stereoisomer isomers, tautomers, polymorphs, solvates, metabolites, isotope-labeled compounds or prodrugs or pharmaceutical compositions of the present invention.
在一些实施方案中，所述SOS1相关疾病包括癌症(例如胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、***、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、***癌、胶质母细胞瘤、肾癌和肉瘤)、RAS病(例如1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病)。In some embodiments, the SOS1-associated disease includes cancer (e.g., pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid Leukemia, bladder cancer, urothelial carcinoma, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate carcinoma, glioblastoma, renal carcinoma, and sarcoma), RAS disorders (e.g., neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with Vascular malformations-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facial-cutaneous syndrome (CFC), Legers syndrome, and hereditary gingival fibromatosis).
本发明中“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并 且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。"Pharmaceutically acceptable carrier" in the present invention refers to a diluent, adjuvant, excipient or vehicle administered together with a therapeutic agent, and it is suitable for contacting human beings and/or Tissues from other animals without undue toxicity, irritation, allergic response or other problems or complications commensurate with a reasonable benefit/risk ratio.
除非另外说明，否则如本文中所使用，术语“治疗”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。As used herein, unless otherwise stated, the term "treating" means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or preventing such A disorder or condition or one or more symptoms of such a disorder or condition.
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。"Individual" as used herein includes a human or non-human animal. Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects. "Non-human animals" in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
在另一种实施方案中，本发明的药物组合物还可以包含一种或多种另外的治疗剂或预防剂。In another embodiment, the pharmaceutical compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents.
实施例Example
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。The present invention is further described below in conjunction with the examples, but the provision of these examples is not intended to limit the scope of the present invention.
本发明中的缩写具有以下含义：Abbreviations in the present invention have the following meanings:
缩写abbreviation 含义meaning
AcClAcCl 乙酰氯Acetyl chloride
ACNACN 乙腈Acetonitrile
AIBNAIBN 偶氮二异丁腈Azobisisobutyronitrile
n-BuLin-BuLi 正丁基锂n-BuLi
n-BuOHn-BuOH 正丁醇Butanol
s-Bus-Bu 仲丁基sec-butyl
t-BuOKt-BuOK 叔丁醇钾Potassium tert-butoxide
t-BuONat-BuONa 叔丁醇钠Sodium tert-butoxide
CuICuI 碘化亚铜Cuprous iodide
DASTDAST 二乙氨基三氟化硫Diethylaminosulfur trifluoride
DBUDBU 1,8-二氮杂双环[5.4.0]十一碳-7-烯1,8-Diazabicyclo[5.4.0]undec-7-ene
DCMDCM 二氯甲烷Dichloromethane
DIBAL-HDIBAL-H 二异丁基氢化铝Diisobutylaluminum hydride
DIEA/DIPEADIEA/DIPEA N,N-二异丙基乙胺N,N-Diisopropylethylamine
DMFDMF N,N-二甲基甲酰胺N,N-Dimethylformamide
DMSODMSO 二甲基亚砜Dimethyl sulfoxide
dppfdppf 1,1'-双(二苯基膦)二茂铁1,1'-bis(diphenylphosphino)ferrocene
dioxanedioxane 1,4-二氧六环1,4-dioxane
EDCIEDCI 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺1-Ethyl-(3-dimethylaminopropyl)carbodiimide
EtEt 乙基Ethyl
FeFe 铁iron
hh 小时Hour
HATUHATU O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
HClHCl 盐酸hydrochloric acid
HOBtHOB 1-羟基苯并***1-Hydroxybenzotriazole
K 2CO 3 K 2 CO 3 碳酸钾potassium carbonate
LDALDA 二异丙基氨基锂lithium diisopropylamide
LiBH 4 LiBH 4 硼氢化锂lithium borohydride
LiHMDSLiHMDS 双(三甲基硅基)氨基锂Lithium bis(trimethylsilyl)amide
mCPBAmCPBA 间氯过氧苯甲酸m-chloroperoxybenzoic acid
MeCNMeCN 乙腈Acetonitrile
MeOHMeOH 甲醇Methanol
Mn(TMHD) 3 Mn(TMHD) 3 三(2,2,6,6-四甲基-3,5-庚烯酸)锰Tris(2,2,6,6-tetramethyl-3,5-heptenoate) manganese
NBSNBS N-溴代琥珀酰亚胺N-Bromosuccinimide
Pd/CPd/C 钯/碳palladium/carbon
Pd(dba) 2 Pd(dba) 2 双(二亚芐基丙酮)钯Bis(dibenzylideneacetone)palladium
Pd 2(dba) 3 Pd 2 (dba) 3 三(二亚苄基丙酮)二钯Tris(dibenzylideneacetone)dipalladium
Pd(PPh 3) 4 Pd(PPh 3 ) 4 四(三苯基膦)钯Tetrakis(triphenylphosphine)palladium
Pd(PPh 3) 2Cl 2 Pd(PPh 3 ) 2 Cl 2 双(三苯基膦)二氯化钯Bis(triphenylphosphine)palladium dichloride
PMBPMB 对甲氧基苄基p-Methoxybenzyl
POCl 3 POCl3 三氯氧磷Phosphorus oxychloride
Py.HFPy.HF 氟化氢吡啶Pyridine Hydrogen Fluoride
rfxrfx 回流reflow
Rh 2(OAc) 4 Rh 2 (OAc) 4 醋酸铑Rhodium acetate
RuPHOSRuPHOS 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯2-Dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl
RT/rtRT/rt 室温room temperature
SeO 2 SeO 2 二氧化硒selenium dioxide
TBABTBAB 四丁基溴化铵Tetrabutylammonium bromide
TEATEA 三乙胺Triethylamine
TFATFA 三氟乙酸Trifluoroacetate
THFTHF 四氢呋喃Tetrahydrofuran
Ti(OEt) 4 Ti(OEt) 4 钛酸四乙酯Tetraethyl titanate
TMSClTMSCl 三甲基氯硅烷Trimethylchlorosilane
TsOHTOH 对甲苯磺酸p-Toluenesulfonic acid
XantphosXantphos 4,5-双二苯基膦-9,9-二甲基氧杂蒽4,5-bisdiphenylphosphine-9,9-dimethylxanthene
ZnCN 2 ZnCN 2 氰化锌Zinc cyanide
中间体实施例A-1：Intermediate Example A-1:
Figure PCTCN2022135958-appb-000089
Figure PCTCN2022135958-appb-000089
步骤1step 1
将A-1a(25g,123mmol)溶于DAST(65mL)，室温下搅拌反应12小时。反应完成后，反应液缓慢倒入冷却的碳酸氢钠水溶液中，加入乙酸乙酯(500mL*3)萃取。乙酸乙酯相干燥，浓缩，经柱层析纯化得无色油状中间体A-1b(10g,37％)。A-1a (25 g, 123 mmol) was dissolved in DAST (65 mL), and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was slowly poured into a cooled aqueous sodium bicarbonate solution, and ethyl acetate (500 mL*3) was added for extraction. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-1b (10 g, 37%) as a colorless oil.
1H NMR(400MHz,DMSO-d 6)δ7.93(dd,J＝7.9,7.0Hz,1H),7.68(t,J＝7.1Hz,1H),7.44–7.06(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.93 (dd, J=7.9, 7.0Hz, 1H), 7.68(t, J=7.1Hz, 1H), 7.44–7.06 (m, 2H).
步骤2step 2
将A-1b(9g,40mmol)、三丁基(1-乙氧基乙烯)锡(17.34g,48mmol)、Pd(PPh 3) 2Cl 2(2.81g,4mmol)和三乙胺(10.11g,100mmol)溶于无水1,4-二氧六环(150mL)。置换氮气后100℃搅拌过夜。反应完成后过滤，滤液浓缩加入乙酸乙酯(200mL)和饱和食盐水(200mL)萃取，乙酸乙酯相干燥，浓缩，然后残余物溶于四氢呋喃(50mL)中，加入3M盐酸水溶液(20mL)，常温搅拌过夜。反应完成后，加入乙酸乙酯(300mL*3)萃取，乙酸乙酯相干燥，浓缩，经柱层析纯化得A-1c(5.6g,74％)。 A-1b (9g, 40mmol), tributyl (1-ethoxyethylene) tin (17.34g, 48mmol), Pd (PPh 3 ) 2 Cl 2 (2.81g, 4mmol) and triethylamine (10.11g , 100mmol) was dissolved in anhydrous 1,4-dioxane (150mL). After nitrogen replacement, the mixture was stirred overnight at 100°C. After completion of the reaction, filter, concentrate the filtrate, add ethyl acetate (200 mL) and saturated brine (200 mL) for extraction, dry the ethyl acetate phase, concentrate, then dissolve the residue in tetrahydrofuran (50 mL), add 3M aqueous hydrochloric acid (20 mL), Stir overnight at room temperature. After the reaction was completed, ethyl acetate (300 mL*3) was added for extraction, the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain A-1c (5.6 g, 74%).
1H NMR(400MHz,DMSO-d 6)δ8.06–7.94(m,1H),7.89(t,J＝6.9Hz,1H),7.53–7.44(m,1H),7.29(m,J＝54.1Hz,1H),2.62(d,J＝4.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.06–7.94(m,1H),7.89(t,J=6.9Hz,1H),7.53–7.44(m,1H),7.29(m,J=54.1 Hz,1H),2.62(d,J=4.1Hz,3H).
步骤3step 3
将A-1c(6.17g,33mmol)、(S)-叔丁基亚磺酰胺(6.0g,49.5mmol)和钛酸四乙酯(22.6g,99mmol)依次加入到四氢呋喃(100ml)中回流过夜。反应完成后冷却至室温，加入水(500ml)，乙酸乙酯(500ml)萃取，乙酸乙酯相干燥，浓缩，经柱层析纯化得黄色油状中间体A-1d(9.2g,97％)。A-1c (6.17g, 33mmol), (S)-tert-butylsulfinamide (6.0g, 49.5mmol) and tetraethyl titanate (22.6g, 99mmol) were sequentially added to tetrahydrofuran (100ml) and refluxed overnight . After the reaction was completed, it was cooled to room temperature, water (500ml) was added, extracted with ethyl acetate (500ml), the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain yellow oily intermediate A-1d (9.2g, 97%).
1H NMR(400MHz,DMSO-d 6)δ7.91–7.81(m,1H),7.78(t,J＝6.7Hz,1H),7.45(t,J＝7.7Hz,1H),7.27(t,J＝54.2Hz,1H),2.71(s,3H),1.21(d,J＝11.9Hz,9H).MS(ESI)m/z 292.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ7.91–7.81(m, 1H), 7.78(t, J=6.7Hz, 1H), 7.45(t, J=7.7Hz, 1H), 7.27(t, J＝54.2Hz, 1H), 2.71(s, 3H), 1.21(d, J＝11.9Hz, 9H). MS(ESI) m/z 292.1[M+H] + .
步骤4step 4
将A-1d(9.42g,32mmol)溶于无水四氢呋喃(150mL)，-78℃下缓慢加入三仲丁基硼氢化锂(64mL,64mmol)。将反应液在-78℃下继续搅拌反应1小时，反应完成后加入氯化铵水溶液淬灭，二氯甲烷萃取(300mL*3)。二氯甲烷相干燥，浓缩，经柱层析纯化得无色油状中间体A-1e(7.2g,84％)。A-1d (9.42g, 32mmol) was dissolved in anhydrous tetrahydrofuran (150mL), and tri-sec-butyl lithium borohydride (64mL, 64mmol) was slowly added at -78°C. The reaction solution was stirred and reacted at -78°C for 1 hour. After the reaction was completed, ammonium chloride aqueous solution was added to quench it, and extracted with dichloromethane (300 mL*3). The dichloromethane phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-1e (7.2 g, 84%) as a colorless oil.
1H NMR(400MHz,DMSO-d 6)δ7.68(t,J＝7.3Hz,1H),7.53(t,J＝7.0Hz,1H),7.34(t,J＝7.7Hz,1H),7.32–6.98(m,1H),5.54(d,J＝5.7Hz,1H),4.73(p,J＝6.6Hz,1H),1.50(d,J＝6.8Hz,3H),1.09(s,9H).MS(ESI)m/z 294.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 ) δ7.68(t, J=7.3Hz, 1H), 7.53(t, J=7.0Hz, 1H), 7.34(t, J=7.7Hz, 1H), 7.32 –6.98(m, 1H), 5.54(d, J=5.7Hz, 1H), 4.73(p, J=6.6Hz, 1H), 1.50(d, J=6.8Hz, 3H), 1.09(s, 9H) .MS(ESI)m/z 294.1[M+H] + .
步骤5step 5
将A-1e(8.0g,27.3mmol)溶于氯化氢/二氧六环溶液(4M,20ml)中，常温搅拌反应1小时。反应完成后，溶剂旋干，加入石油醚(50ml)，搅拌，抽滤，得白色固体中间体A-1(5.6g,91％)。A-1e (8.0g, 27.3mmol) was dissolved in hydrogen chloride/dioxane solution (4M, 20ml), stirred at room temperature for 1 hour. After the reaction was completed, the solvent was spin-dried, petroleum ether (50ml) was added, stirred, and suction filtered to obtain white solid intermediate A-1 (5.6g, 91%).
1H NMR(400MHz,DMSO-d 6)δ8.78(s,3H),7.93(d,J＝5.1Hz,1H),7.67(t,J＝7.1Hz,1H),7.45(t,J＝7.8Hz,1H),7.26(t,J＝54.1Hz,1H),4.71–4.58(m,1H),1.55(d,J＝6.8Hz,3H).MS(ESI)m/z190.2[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ8.78(s, 3H), 7.93(d, J=5.1Hz, 1H), 7.67(t, J=7.1Hz, 1H), 7.45(t, J= 7.8Hz, 1H), 7.26(t, J＝54.1Hz, 1H), 4.71–4.58(m, 1H), 1.55(d, J＝6.8Hz, 3H).MS(ESI) m/z190.2[M +H] + .
中间体实施例A-2：Intermediate Example A-2:
Figure PCTCN2022135958-appb-000090
Figure PCTCN2022135958-appb-000090
步骤1step 1
将A-2a(4.5g,21.6mmol)、N,O-二甲基羟胺盐酸盐(2.53g,26mmol)、EDCI(6.2g,32.4mmol)、HOBt(4.38g,32.4mmol)和三乙胺(10.9g,108mmol)加入到DMF(50ml)中。常温搅拌过夜，反应完成后，向反应液中加入水(200ml)，乙酸乙酯(200ml)萃取，乙酸乙酯相用饱和食盐水洗涤，无水硫酸钠干燥，浓缩，经柱层析纯化得中间体A-2b(4.0g,74％)。A-2a (4.5g, 21.6mmol), N, O-dimethylhydroxylamine hydrochloride (2.53g, 26mmol), EDCI (6.2g, 32.4mmol), HOBt (4.38g, 32.4mmol) and triethyl The amine (10.9 g, 108 mmol) was added to DMF (50 ml). Stir overnight at room temperature, after the reaction is complete, add water (200ml) to the reaction solution, extract with ethyl acetate (200ml), wash the ethyl acetate phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography to obtain Intermediate A-2b (4.0 g, 74%).
1H NMR(400MHz,DMSO-d 6)δ7.93–7.83(m,2H),7.51(t,J＝7.8Hz,1H),3.48(s,3H),3.30(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.93–7.83 (m, 2H), 7.51 (t, J=7.8Hz, 1H), 3.48 (s, 3H), 3.30 (s, 3H).
MS(ESI)m/z[M+H] +:252.2. MS(ESI)m/z[M+H] + :252.2.
步骤2step 2
将A-2b(4g,15.9mmol)溶于无水四氢呋喃(8ml)中，在0℃下搅拌5分钟后滴加甲基溴化镁(11ml)。反应在0℃下继续搅拌2小时，反应完成后，加入饱和氯化铵水溶液，乙酸乙酯(300ml)萃取，乙酸乙酯相干燥，浓缩，经柱层析纯化得中间体A-2c(2.5g,76％)。A-2b (4g, 15.9mmol) was dissolved in anhydrous tetrahydrofuran (8ml), stirred at 0°C for 5 minutes, and methylmagnesium bromide (11ml) was added dropwise. The reaction was continued to stir for 2 hours at 0°C. After the reaction was completed, saturated aqueous ammonium chloride was added, extracted with ethyl acetate (300ml), the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain intermediate A-2c (2.5 g, 76%).
1H NMR(400MHz,DMSO-d 6)δ8.08(dd,J＝10.6,4.0Hz,1H),7.80(t,J＝7.2Hz,1H),7.34(t,J＝7.8Hz,1H),2.69(d,J＝5.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.08(dd, J=10.6,4.0Hz,1H),7.80(t,J=7.2Hz,1H),7.34(t,J=7.8Hz,1H) ,2.69(d,J=5.2Hz,3H).
步骤3step 3
将A-2c(2.5g,12.1mmol)、(R)-(+)-叔丁基亚磺酰胺(2.2g,18.1mmol)和钛酸四乙酯(8.3g,36.3mmol)溶于四氢呋喃(25ml)。回流搅拌反应过夜。将反应液冷却至-15℃，加入甲醇(2ml)和硼氢化锂(400mg,18.1mmol)。继续搅拌反应1小时，反应完成后加入水(100ml)，乙酸乙酯(100ml)，抽滤，分液，乙酸乙酯相干燥浓缩。剩余物经柱层析纯化得白色固体中间体A-2d(2.4g,64％)。A-2c (2.5g, 12.1mmol), (R)-(+)-tert-butylsulfinamide (2.2g, 18.1mmol) and tetraethyl titanate (8.3g, 36.3mmol) were dissolved in tetrahydrofuran ( 25ml). The reaction was stirred at reflux overnight. The reaction solution was cooled to -15°C, and methanol (2ml) and lithium borohydride (400mg, 18.1mmol) were added. Continue to stir and react for 1 hour. After the reaction is completed, water (100ml) and ethyl acetate (100ml) are added, filtered with suction, separated, and the ethyl acetate phase is dried and concentrated. The residue was purified by column chromatography to obtain white solid intermediate A-2d (2.4 g, 64%).
1H NMR(400MHz,DMSO-d 6)δ7.89(t,J＝7.0Hz,1H),7.67(t,J＝7.0Hz,1H),7.42(t,J＝7.8Hz,1H),5.91(d,J＝7.8Hz,1H),4.72(p,J＝7.0Hz,1H),1.43(d,J＝6.8Hz,3H),1.10(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.89(t, J=7.0Hz, 1H), 7.67(t, J=7.0Hz, 1H), 7.42(t, J=7.8Hz, 1H), 5.91 (d, J=7.8Hz, 1H), 4.72(p, J=7.0Hz, 1H), 1.43(d, J=6.8Hz, 3H), 1.10(s, 9H).
MS(ESI)m/z[M+H] +:312.3. MS(ESI)m/z[M+H] + :312.3.
步骤4step 4
将A-2d(2.3g,7.4mmol)溶于氯化氢/二氧六环溶液(16ml)中，50℃搅拌2小时。反应完成后，溶剂旋干，加入乙酸乙酯(50ml)，搅拌，抽滤，得白色固体中间体A-2(1.5g,80％)。A-2d (2.3g, 7.4mmol) was dissolved in hydrogen chloride/dioxane solution (16ml), and stirred at 50°C for 2 hours. After the reaction was completed, the solvent was spin-dried, ethyl acetate (50ml) was added, stirred, and filtered with suction to obtain white solid intermediate A-2 (1.5g, 80%).
1H NMR(400MHz,DMSO-d 6)δ8.80(s,3H),8.08(t,J＝7.2Hz,1H),7.82(t,J＝7.2Hz,1H),7.52(t,J＝7.8Hz,1H),4.70(q,J＝6.8Hz,1H),1.56(d,J＝6.8Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.80(s, 3H), 8.08(t, J=7.2Hz, 1H), 7.82(t, J=7.2Hz, 1H), 7.52(t, J= 7.8Hz, 1H), 4.70(q, J=6.8Hz, 1H), 1.56(d, J=6.8Hz, 3H).
MS(ESI)m/z[M+H] +:208.4. MS(ESI)m/z[M+H] + :208.4.
中间体实施例A-3：Intermediate Example A-3:
Figure PCTCN2022135958-appb-000091
Figure PCTCN2022135958-appb-000091
步骤1step 1
将A-3a(4.4g,0.02mol)、三甲基硅乙炔(4.0g,0.04mol)、三乙胺(6.15g,0.06mol)、碘化亚铜(0.38g,0.002mol)和双(三苯基膦)二氯化钯(1.42g,0.002mol)依次在氮气保护下加入四氢呋喃(60mL)中。得到的溶液在80℃下搅拌16小时。溶剂旋干，柱色谱法纯化，得到黄色油状物产品A-3b(4.5g,产率：95％)。A-3a (4.4g, 0.02mol), trimethylsilylacetylene (4.0g, 0.04mol), triethylamine (6.15g, 0.06mol), cuprous iodide (0.38g, 0.002mol) and bis( Triphenylphosphine)palladium dichloride (1.42g, 0.002mol) was successively added into tetrahydrofuran (60mL) under nitrogen protection. The resulting solution was stirred at 80°C for 16 hours. The solvent was spin-dried and purified by column chromatography to obtain the yellow oil product A-3b (4.5 g, yield: 95%).
1H NMR(400MHz,CDCl 3)δ7.84–7.78(m,1H),7.64–7.60(m,1H),7.16(t,J＝7.8Hz,1H),2.65(d,J＝5.2Hz,3H),0.28(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ7.84–7.78(m,1H),7.64–7.60(m,1H),7.16(t,J=7.8Hz,1H),2.65(d,J=5.2Hz, 3H), 0.28(s, 9H).
MS(ESI)m/z[M+H] +:235.2. MS(ESI)m/z[M+H] + :235.2.
步骤2step 2
将A-3b(4.5g,19.2mmol)溶于二氯甲烷(6ml)和甲醇(6ml)，加入碳酸钾(26.5g,0.19mol)。室温搅拌2小时，溶剂旋干，柱色谱法纯化，纯化得到黄色固体产品A-3c(2.9g,产率：93％)。A-3b (4.5g, 19.2mmol) was dissolved in dichloromethane (6ml) and methanol (6ml), and potassium carbonate (26.5g, 0.19mol) was added. Stir at room temperature for 2 hours, spin dry the solvent, and purify by column chromatography to obtain yellow solid product A-3c (2.9 g, yield: 93%).
1H NMR(400MHz,CDCl 3)δ7.88–7.83(m,1H),7.68–7.63(m,1H),7.20(t,J＝7.8Hz,1H),3.36(s,1H),2.66(d,J＝5.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.88–7.83(m,1H),7.68–7.63(m,1H),7.20(t,J=7.8Hz,1H),3.36(s,1H),2.66( d,J=5.2Hz,3H).
步骤3step 3
向A-3c(2.4g,14.8mmol)的六氟异丙醇(20ml)溶液中加入氟化氢吡啶(70％,6.3ml)。室温搅拌三天。反应液用二氯甲烷稀释后倒入冰的碳酸氢钠溶液中，二氯甲烷萃取，干燥，浓缩，柱色谱法 纯化，得到产品A-3d(1.68g，产率：56％)。To a solution of A-3c (2.4 g, 14.8 mmol) in hexafluoroisopropanol (20 ml) was added pyridine hydrogen fluoride (70%, 6.3 ml). Stir at room temperature for three days. The reaction solution was diluted with dichloromethane and poured into iced sodium bicarbonate solution, extracted with dichloromethane, dried, concentrated, and purified by column chromatography to obtain product A-3d (1.68g, yield: 56%).
1H NMR(400MHz,DMSO-d 6)δ7.96–7.90(m,1H),7.75–7.70(m,1H),7.29(t,J＝7.8Hz,1H),2.67(d,J＝5.2Hz,3H),2.03(t,J＝18.6Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ7.96–7.90(m,1H),7.75–7.70(m,1H),7.29(t,J=7.8Hz,1H),2.67(d,J=5.2 Hz,3H),2.03(t,J=18.6Hz,3H).
步骤4step 4
将A-3d(1.88g,9.3mmol)、(R)-叔丁基亚磺酰胺(1.69g,13.95mmol)和钛酸四乙脂(6.36g,27.9mmol)依次加入到四氢呋喃(25ml)中，回流过夜。冷却至-15℃后加入甲醇(2ml)和硼氢化锂(307mg,13.95mmol)。反应一小时，加入水(500ml)，乙酸乙酯(500ml)，抽滤，分层，取有机相干燥浓缩。柱色谱法纯化，得到产品白色固体A-3e(1.8g,产率：63％)。Add A-3d (1.88g, 9.3mmol), (R)-tert-butylsulfinamide (1.69g, 13.95mmol) and tetraethyl titanate (6.36g, 27.9mmol) to tetrahydrofuran (25ml) in sequence , reflux overnight. After cooling to -15°C, methanol (2ml) and lithium borohydride (307mg, 13.95mmol) were added. After reacting for one hour, water (500ml) and ethyl acetate (500ml) were added, filtered with suction, separated into layers, and the organic phase was dried and concentrated. Purified by column chromatography to obtain the product A-3e (1.8 g, yield: 63%) as a white solid.
1H NMR(400MHz,DMSO-d 6)δ7.70(t,J＝7.0Hz,1H),7.46(dd,J＝10.6,4.4Hz,1H),7.30(t,J＝7.8Hz,1H),5.87(d,J＝7.8Hz,1H),4.73–4.66(m,1H),2.00(t,J＝19.2Hz,3H),1.41(d,J＝6.8Hz,3H),1.10(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.70(t, J=7.0Hz, 1H), 7.46(dd, J=10.6, 4.4Hz, 1H), 7.30(t, J=7.8Hz, 1H) ,5.87(d,J=7.8Hz,1H),4.73–4.66(m,1H),2.00(t,J=19.2Hz,3H),1.41(d,J=6.8Hz,3H),1.10(s, 9H).
MS(ESI)m/z[M+H] +:308.2. MS(ESI)m/z[M+H] + :308.2.
步骤5step 5
将A-3e(1.7g,5.5mmol)加入到氯化氢二氧六环溶液(16mL)中，50℃搅拌反应2小时。反应完成后，浓缩，剩余物加入乙酸乙酯(50mL)，搅拌，抽滤，得到白色固体A-3(1.1g,产率：83％)。A-3e (1.7g, 5.5mmol) was added into hydrogen chloride dioxane solution (16mL), and the reaction was stirred at 50°C for 2 hours. After the reaction was completed, it was concentrated, and the residue was added to ethyl acetate (50 mL), stirred, and filtered with suction to obtain a white solid A-3 (1.1 g, yield: 83%).
1H NMR(400MHz,DMSO-d 6)δ8.72(s,3H),7.86(t,J＝7.2Hz,1H),7.60(t,J＝7.4Hz,1H),7.41(t,J＝7.8Hz,1H),4.66(d,J＝6.4Hz,1H),2.02(t,J＝19.2Hz,3H),1.54(d,J＝6.8Hz,3H).MS(ESI)m/z[M+H] +:204.3. 1 H NMR (400MHz, DMSO-d 6 ) δ8.72(s, 3H), 7.86(t, J=7.2Hz, 1H), 7.60(t, J=7.4Hz, 1H), 7.41(t, J= 7.8Hz, 1H), 4.66(d, J=6.4Hz, 1H), 2.02(t, J=19.2Hz, 3H), 1.54(d, J=6.8Hz, 3H).MS(ESI) m/z[ M+H] + :204.3.
中间体实施例A-4&A-5：Intermediate Examples A-4&A-5:
Figure PCTCN2022135958-appb-000092
Figure PCTCN2022135958-appb-000092
步骤1step 1
将A-4a(5g,18.6mmol)、三丁基(1-乙氧基乙烯)锡(8g,22.3mmol)、Pd(PPh 3) 2Cl 2(1.3g,1.85mmol)和三乙胺(5.6g,55.7mmol)溶于无水四氢呋喃(30mL)。置换氮气后80℃搅拌过夜。反应完成后过滤，滤液浓缩加入乙酸乙酯(200mL)和饱和食盐水(200mL)萃取，乙酸乙酯相干燥，浓缩，然后残余物溶于四氢呋喃(50mL)，加入3M盐酸水溶液(10mL)，常温搅拌过夜。反应完成后，加入乙酸乙酯(200mL)和饱和食盐水(200mL)萃取，乙酸乙酯相干燥，浓缩，经柱层析纯化得A-4b(3.8g,88％)。 A-4a (5 g, 18.6 mmol), tributyl(1-ethoxyethylene) tin (8 g, 22.3 mmol), Pd(PPh 3 ) 2 Cl 2 (1.3 g, 1.85 mmol) and triethylamine ( 5.6g, 55.7mmol) was dissolved in anhydrous tetrahydrofuran (30mL). After nitrogen replacement, the mixture was stirred overnight at 80°C. After the reaction was completed, filter, concentrate the filtrate, add ethyl acetate (200mL) and saturated brine (200mL) for extraction, dry the ethyl acetate phase, concentrate, then dissolve the residue in tetrahydrofuran (50mL), add 3M aqueous hydrochloric acid (10mL), and Stir overnight. After the reaction was complete, ethyl acetate (200 mL) and saturated brine (200 mL) were added for extraction, the ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain A-4b (3.8 g, 88%).
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.69(s,1H),8.53(s,1H),2.75(s,3H). 1 H NMR (400MHz, CDCl 3 )δ8.95(s,1H),8.69(s,1H),8.53(s,1H),2.75(s,3H).
步骤2step 2
将A-4b(2g,8.6mmol)溶于四氢呋喃(20mL)，加入(R)-(+)-叔丁基亚磺酰胺(1.56g,12.9mmol)和钛酸四乙酯(5.9g,25.7mmol)，70℃搅拌反应1小时，反应完成后，冷却至室温，加入甲醇(2mL)，然后-15℃下缓慢加入硼氢化锂(245mg,11.2mmol)，继续搅拌反应1小时，反应完成后加水(100mL)淬灭，加入乙酸乙酯(200mL)萃取，乙酸乙酯相干燥，浓缩，经柱层析纯化得A-4c(1.7g,58％)。Dissolve A-4b (2g, 8.6mmol) in tetrahydrofuran (20mL), add (R)-(+)-tert-butylsulfinamide (1.56g, 12.9mmol) and tetraethyl titanate (5.9g, 25.7 mmol), stirred at 70°C for 1 hour, after the reaction was completed, cooled to room temperature, added methanol (2mL), then slowly added lithium borohydride (245mg, 11.2mmol) at -15°C, continued stirring for 1 hour, after the reaction was completed Add water (100 mL) to quench, add ethyl acetate (200 mL) to extract, ethyl acetate phase is dried, concentrated, and purified by column chromatography to obtain A-4c (1.7 g, 58%).
1H NMR(400MHz,CDCl 3)δ8.44(s,2H),7.96(s,1H),4.77–4.68(m,1H),3.54(d,J＝4.1Hz,1H), 1.62(d,J＝6.7Hz,3H),1.26(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ8.44(s, 2H), 7.96(s, 1H), 4.77–4.68(m, 1H), 3.54(d, J=4.1Hz, 1H), 1.62(d, J＝6.7Hz,3H),1.26(s,9H).
步骤3step 3
将A-4c(1.7g,5mmol)溶于甲醇(20mL)，常温下加入4M氯化氢二氧六环溶液(5mL)，继续常温搅拌反应过夜，反应完成后，浓缩得A-4(1.4g,100％)。Dissolve A-4c (1.7g, 5mmol) in methanol (20mL), add 4M hydrogen chloride dioxane solution (5mL) at room temperature, continue to stir and react overnight at room temperature, after the reaction is completed, concentrate to obtain A-4 (1.4g, 100%).
1H NMR(400MHz,DMSO-d 6)δ8.89(s,2H),8.82(s,1H),8.54(s,1H),8.52(s,1H),4.82–4.74(m,1H),1.61(d,J＝6.8Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.89(s,2H),8.82(s,1H),8.54(s,1H),8.52(s,1H),4.82–4.74(m,1H), 1.61(d,J=6.8Hz,3H).
步骤4step 4
将A-4(200mg,0.74mmol)溶于甲醇(5mL)，加入10％湿钯碳(20mg,10％wt)，置换氢气后，常温搅拌反应过夜。反应完成后，过滤，滤液浓缩，经柱层析纯化得A-5(70mg,46％)。A-4 (200mg, 0.74mmol) was dissolved in methanol (5mL), 10% wet palladium carbon (20mg, 10%wt) was added to replace the hydrogen, and the reaction was stirred overnight at room temperature. After the reaction was completed, it was filtered, the filtrate was concentrated, and purified by column chromatography to obtain A-5 (70 mg, 46%).
1H NMR(400MHz,DMSO-d 6)δ6.82(d,J＝8.0Hz,2H),6.69(s,1H),5.49(s,2H),3.91(q,J＝6.6Hz,1H),1.22(d,J＝6.6Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δ6.82(d,J=8.0Hz,2H),6.69(s,1H),5.49(s,2H),3.91(q,J=6.6Hz,1H) ,1.22(d,J=6.6Hz,3H).
中间体实施例A-6：Intermediate Example A-6:
Figure PCTCN2022135958-appb-000093
Figure PCTCN2022135958-appb-000093
步骤1step 1
将A-6a(10g,46mol)在DAST(22ml)中于45℃加热搅拌48小时，将反应液倒入0℃的碳酸氢钠饱和溶液中，然后用乙酸乙酯萃取，干燥，旋干，柱色谱法纯化，得到无色油状物产品A-6b(6.6g,60％)。A-6a (10g, 46mol) was heated and stirred in DAST (22ml) at 45°C for 48 hours, the reaction solution was poured into a saturated solution of sodium bicarbonate at 0°C, then extracted with ethyl acetate, dried, and spin-dried, Purified by column chromatography to obtain product A-6b (6.6 g, 60%) as a colorless oil.
1H NMR(400MHz,CDCl 3)δ7.67(dd,J＝6.6,2.4Hz,1H),7.54–7.50(m,1H),7.06–6.99(m,1H),1.98(t,J＝18.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.67(dd, J=6.6, 2.4Hz, 1H), 7.54–7.50(m, 1H), 7.06–6.99(m, 1H), 1.98(t, J=18.6 Hz,3H).
步骤2step 2
向A-6b(4.4g,18.4mmol)的四氢呋喃(50ml)溶液在-78℃下滴加LDA(14mL,THF中2M)，搅拌1小时。将N-甲氧基-N-甲基乙酰胺(2.5g,24.2mmol)的四氢呋喃(4ml)溶液通过注射器慢慢滴加到溶液中，恢复至室温搅拌过夜。加入饱和氯化铵溶液，用乙酸乙酯萃取，干燥，旋干，柱色谱法纯化，得到产品A-6c(2.3g,45％)。To a solution of A-6b (4.4g, 18.4mmol) in tetrahydrofuran (50ml) was added dropwise LDA (14mL, 2M in THF) at -78°C and stirred for 1 hour. A solution of N-methoxy-N-methylacetamide (2.5 g, 24.2 mmol) in tetrahydrofuran (4 ml) was slowly added dropwise to the solution via a syringe, returned to room temperature and stirred overnight. Add saturated ammonium chloride solution, extract with ethyl acetate, dry, spin dry, and purify by column chromatography to obtain product A-6c (2.3g, 45%).
1H NMR(400MHz,CDCl 3)δ8.04(dd,J＝6.0,2.6Hz,1H),7.82(dd,J＝6.2,2.6Hz,1H),2.65(d,J＝5.2Hz,3H),2.02(td,J＝18.6,1.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ8.04(dd, J=6.0,2.6Hz,1H),7.82(dd,J=6.2,2.6Hz,1H),2.65(d,J=5.2Hz,3H) ,2.02(td,J=18.6,1.0Hz,3H).
步骤3step 3
将A-6c(2g,7.1mmol)、(R)-叔丁基亚磺酰胺(1.29g,10.65mmol)和钛酸四乙脂(4.86g,21.3mmol)依次加入到四氢呋喃(20ml)中回流过夜。然后冷却至-15℃，加入甲醇(2ml)和硼氢化锂(200mg,9.23mmol)。反应一小时，加入水(500ml)，乙酸乙酯(500ml)，抽滤，分层，取有机相干燥浓缩。柱色谱法纯化，得到产品白色固体A-6d(1.3g,47％)。A-6c (2g, 7.1mmol), (R)-tert-butylsulfinamide (1.29g, 10.65mmol) and tetraethyl titanate (4.86g, 21.3mmol) were successively added to tetrahydrofuran (20ml) and refluxed overnight. Then cooled to -15°C, methanol (2ml) and lithium borohydride (200mg, 9.23mmol) were added. After reacting for one hour, water (500ml) and ethyl acetate (500ml) were added, filtered with suction, separated into layers, and the organic phase was dried and concentrated. Purified by column chromatography to obtain the product A-6d (1.3 g, 47%) as a white solid.
1H NMR(400MHz,DMSO-d 6)δ7.91(dd,J＝6.0,2.4Hz,1H),7.59(dd,J＝6.2,2.4Hz,1H),5.94(d,J＝8.6Hz,1H),4.69–4.62(m,1H),2.01(t,J＝19.2Hz,3H),1.40(d,J＝6.8Hz,3H),1.11(s,9H). 1 H NMR (400MHz, DMSO-d 6 )δ7.91(dd, J=6.0,2.4Hz,1H),7.59(dd,J=6.2,2.4Hz,1H),5.94(d,J=8.6Hz, 1H), 4.69–4.62(m, 1H), 2.01(t, J=19.2Hz, 3H), 1.40(d, J=6.8Hz, 3H), 1.11(s, 9H).
MS(ESI)m/z[M+H] +:388.1. MS(ESI)m/z[M+H] + :388.1.
步骤4step 4
将A-6d(1.2g,3.1mmol)、对甲氧基苄胺(427mg,3.1mmol)、Pd 2(dba) 3(285mg,0.31mmol)、Xantphos(360mg,0.62mmol)和碳酸铯(2g,6.2mmol)加入到二氧六环(15ml)中，氮气保护下加热回流过夜。加入水(100ml)和乙酸乙酯(100ml)萃取，取有机相干燥浓缩，柱色谱法纯化，得到产品A-6e(500mg,36％)。 A-6d (1.2g, 3.1mmol), p-methoxybenzylamine (427mg, 3.1mmol), Pd 2 (dba) 3 (285mg, 0.31mmol), Xantphos (360mg, 0.62mmol) and cesium carbonate (2g , 6.2mmol) was added into dioxane (15ml), and heated to reflux overnight under nitrogen protection. Water (100ml) and ethyl acetate (100ml) were added for extraction, the organic phase was dried and concentrated, and purified by column chromatography to obtain product A-6e (500mg, 36%).
1H NMR(400MHz,DMSO-d 6)δ7.27(d,J＝8.6Hz,2H),6.88(d,J＝8.6Hz,2H),6.81(dd,J＝5.4,2.8Hz,1H),6.60(dd,J＝5.8,2.8Hz,1H),6.30(t,J＝5.8Hz,1H),5.64(d,J＝6.8Hz,1H),4.57(t,J＝6.8Hz,1H),4.16(d,J＝5.8Hz,2H),3.72(s,3H),1.91(t,J＝18.8Hz,3H),1.34(d,J＝6.8Hz,3H),1.07(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.27(d, J=8.6Hz, 2H), 6.88(d, J=8.6Hz, 2H), 6.81(dd, J=5.4, 2.8Hz, 1H) ,6.60(dd,J=5.8,2.8Hz,1H),6.30(t,J=5.8Hz,1H),5.64(d,J=6.8Hz,1H),4.57(t,J=6.8Hz,1H) ,4.16(d,J=5.8Hz,2H),3.72(s,3H),1.91(t,J=18.8Hz,3H),1.34(d,J=6.8Hz,3H),1.07(s,9H) .
MS(ESI)m/z[M+H] +:443.3. MS(ESI)m/z[M+H] + :443.3.
步骤5step 5
将A-6e(500mg,1.1mmol)溶于甲醇(10mL)，常温下加入4M氯化氢二氧六环溶液(5mL)，继续常温搅拌反应过夜，反应完成后，浓缩得A-6f(420mg,100％)。Dissolve A-6e (500mg, 1.1mmol) in methanol (10mL), add 4M hydrogen chloride dioxane solution (5mL) at room temperature, continue to stir and react overnight at room temperature, after the reaction is completed, concentrate to obtain A-6f (420mg, 100 %).
步骤6step 6
将A-6f(400mg,1mmol)溶于三氟乙酸(10mL)中，将反应液在50℃下搅拌反应16小时。反应完成后，浓缩，剩余物加入乙酸乙酯(50mL)稀释，饱和碳酸氢钠水溶液洗涤，饱和食盐水洗涤。乙酸乙酯相干燥，浓缩，柱色谱法纯化，得到产品A-6(156mg,67％)。A-6f (400mg, 1mmol) was dissolved in trifluoroacetic acid (10mL), and the reaction solution was stirred at 50°C for 16 hours. After the reaction was complete, it was concentrated, and the residue was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution and saturated brine. The ethyl acetate phase was dried, concentrated, and purified by column chromatography to obtain product A-6 (156 mg, 67%).
1H NMR(400MHz,DMSO-d 6)δ6.87–6.78(m,1H),6.55(dd,J＝6.0,2.9Hz,1H),5.10(s,2H),4.17(q,J＝6.6Hz,1H),1.92(dd,J＝19.3,18.7Hz,3H),1.21(t,J＝8.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ6.87–6.78(m,1H),6.55(dd,J=6.0,2.9Hz,1H),5.10(s,2H),4.17(q,J=6.6 Hz,1H),1.92(dd,J=19.3,18.7Hz,3H),1.21(t,J=8.1Hz,3H).
中间体实施例A-7：Intermediate Example A-7:
Figure PCTCN2022135958-appb-000094
Figure PCTCN2022135958-appb-000094
步骤1step 1
A-7a(25g,115.19mmol)与DAST(10mL)的混合物在45℃下搅拌48h。加乙酸乙酯稀释，缓慢滴加饱和碳酸氢钠水溶液至无气泡产生，分液。有机相用饱和食盐水洗，无水硫酸钠干燥，旋干得无色油A-7b(25g,90％)。A mixture of A-7a (25 g, 115.19 mmol) and DAST (10 mL) was stirred at 45 °C for 48 h. Add ethyl acetate to dilute, slowly add saturated aqueous sodium bicarbonate solution dropwise until no bubbles are generated, and separate the liquids. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to obtain a colorless oil A-7b (25 g, 90%).
1H NMR(400MHz,CDCl 3)δ7.77–7.69(m,1H),7.62–7.54(m,1H),7.07(t,J＝9.5Hz,1H),2.03(t,J＝18.5Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.77–7.69(m,1H),7.62–7.54(m,1H),7.07(t,J=9.5Hz,1H),2.03(t,J=18.5Hz, 3H).
步骤2step 2
在-78℃氮气保护下，向A-7b(20g,83.67mmol)的THF(200mL)溶液中滴加入LDA(THF中2M,54mL)，-78℃下反应1小时后缓慢滴加N-甲基-N-甲氧基乙酰胺(8.63g,83.67mmol)。继续在-78℃下反应1小时。反应完成后，加饱和氯化铵水溶液淬灭，乙酸乙酯萃取，饱和食盐水洗，无水硫酸钠干燥，旋干，柱层析分离得黄色油状物A-7c(7.5g,31.9％)。Under nitrogen protection at -78°C, LDA (2M in THF, 54mL) was added dropwise to a solution of A-7b (20g, 83.67mmol) in THF (200mL), reacted at -78°C for 1 hour, and N-formazol was slowly added dropwise Ethyl-N-methoxyacetamide (8.63 g, 83.67 mmol). The reaction was continued at -78°C for 1 hour. After the reaction was completed, it was quenched by adding saturated aqueous ammonium chloride solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and separated by column chromatography to obtain yellow oil A-7c (7.5g, 31.9%).
1H NMR(400MHz,DMSO-d 6)δ8.07(dd,J＝5.9,2.7Hz,1H),7.86(dd,J＝6.1,2.7Hz,1H),2.69(d,J＝5.2Hz,3H),2.05(t,J＝18.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.07(dd, J=5.9, 2.7Hz, 1H), 7.86(dd, J=6.1, 2.7Hz, 1H), 2.69(d, J=5.2Hz, 3H), 2.05(t, J=18.2Hz, 3H).
步骤3step 3
使A-7c(7.5g,28.68mmol)、(R)-叔丁基亚磺酰胺(4.85g,40.05mmol)、THF(80mL)和钛酸四乙酯(18.26g,80.1mmol)在70℃下反应1小时。降温至-15℃，加入甲醇(5mL)和硼氢化锂(760mg,34.68mmol)，室温反应过夜。加乙酸乙酯稀释，少量水淬灭，搅拌1h,加硅藻土过滤，滤液旋干，柱层析分离得淡黄色固体A-7d(7.8g,76％)。Make A-7c (7.5g, 28.68mmol), (R)-tert-butylsulfinamide (4.85g, 40.05mmol), THF (80mL) and tetraethyl titanate (18.26g, 80.1mmol) at 70°C The reaction was carried out for 1 hour. Cool down to -15°C, add methanol (5 mL) and lithium borohydride (760 mg, 34.68 mmol), and react overnight at room temperature. Diluted with ethyl acetate, quenched with a small amount of water, stirred for 1 h, filtered with diatomaceous earth, the filtrate was spin-dried, and separated by column chromatography to obtain a pale yellow solid A-7d (7.8 g, 76%).
1H NMR(400MHz,DMSO-d 6)δ7.86(dd,J＝6.0,2.5Hz,1H),7.63(dd,J＝6.2,2.5Hz,1H),5.79(s,1H),5.67(d,J＝6.2Hz,1H),2.03(t,J＝19.2Hz,3H),1.52(d,J＝6.8Hz,3H),1.13(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.86 (dd, J=6.0, 2.5Hz, 1H), 7.63 (dd, J=6.2, 2.5Hz, 1H), 5.79(s, 1H), 5.67( d, J=6.2Hz, 1H), 2.03(t, J=19.2Hz, 3H), 1.52(d, J=6.8Hz, 3H), 1.13(s, 9H).
MS(ESI)m/z[M+H] +:388.1 MS(ESI)m/z[M+H] + :388.1
步骤4step 4
将A-7d(1.3g,3.37mmol)、氰化锌(0.59g,5.05mmol)、dppf(0.38g,0.27mmol)、Pd 2(dba) 3(0.31g,0.34mmol)和DIPEA(1.31g,10.11mmol)在DMF(20mL)中溶解，氮气置换3次，升温至120℃反应12小时。加乙酸乙酯稀释，饱和食盐水洗5次，无水硫酸钠干燥，柱层析分离得灰色固体A-7e(400mg,35.7％)。 A-7d (1.3g, 3.37mmol), zinc cyanide (0.59g, 5.05mmol), dppf (0.38g, 0.27mmol), Pd 2 (dba) 3 (0.31g, 0.34mmol) and DIPEA (1.31g , 10.11 mmol) was dissolved in DMF (20 mL), replaced with nitrogen three times, and heated to 120° C. for 12 hours. It was diluted with ethyl acetate, washed 5 times with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain gray solid A-7e (400mg, 35.7%).
步骤5step 5
将A-7e(1g,2.6mmol)的TFA(10mL)溶液在50℃下搅拌16小时。浓缩旋干，用饱和碳酸氢钠水溶液处理，乙酸乙酯萃取。将得到的乙酸乙酯溶液经饱和食盐水洗后，浓缩、柱层析分离得到黄色油状物A-7(380mg,67％)。A solution of A-7e (1 g, 2.6 mmol) in TFA (10 mL) was stirred at 50 °C for 16 h. Concentrate and spin dry, treat with saturated aqueous sodium bicarbonate, and extract with ethyl acetate. The obtained ethyl acetate solution was washed with saturated brine, concentrated, and separated by column chromatography to obtain yellow oil A-7 (380 mg, 67%).
1H NMR(400MHz,DMSO-d 6)δ6.87–6.78(m,1H),6.55(dd,J＝6.0,2.9Hz,1H),5.10(s,2H),4.17(q,J＝6.6Hz,1H),1.92(dd,J＝19.3,18.7Hz,3H),1.21(t,J＝8.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ6.87–6.78(m,1H),6.55(dd,J=6.0,2.9Hz,1H),5.10(s,2H),4.17(q,J=6.6 Hz,1H),1.92(dd,J=19.3,18.7Hz,3H),1.21(t,J=8.1Hz,3H).
中间体实施例A-8：Intermediate Example A-8:
Figure PCTCN2022135958-appb-000095
Figure PCTCN2022135958-appb-000095
步骤1step 1
将A-7d(1.8g,4.7mmol)、亚铁***(1.97g,4.7mmol)、四(三苯基膦)钯(560mg,0.47mmol)和DBU(0.86g,5.6mmol)加入二氧六环(20ml)和水(20ml)中，氮气保护，100℃加热搅拌16小时。反应液倒入水(200ml)中，乙酸乙酯萃取，干燥，旋干，柱色谱法纯化，纯化得到产品A-8a(700mg,43％)。A-7d (1.8g, 4.7mmol), potassium ferrocyanide (1.97g, 4.7mmol), tetrakis(triphenylphosphine)palladium (560mg, 0.47mmol) and DBU (0.86g, 5.6mmol) were added to di Hexane (20ml) and water (20ml), under nitrogen protection, heated and stirred at 100°C for 16 hours. The reaction solution was poured into water (200ml), extracted with ethyl acetate, dried, spin-dried, and purified by column chromatography to obtain product A-8a (700mg, 43%).
1H NMR(400MHz,DMSO-d 6)δ8.24(d,J＝6.4Hz,1H),8.13(s,1H),7.97(d,J＝6.6Hz,1H),7.52(s,1H),5.89(d,J＝7.4Hz,1H),4.74–4.67(m,1H),2.03(t,J＝18.0Hz,3H),1.44(d,J＝6.7Hz,3H),1.09(s,9H). 1 H NMR (400MHz, DMSO-d 6 )δ8.24(d, J=6.4Hz, 1H), 8.13(s, 1H), 7.97(d, J=6.6Hz, 1H), 7.52(s, 1H) ,5.89(d,J=7.4Hz,1H),4.74–4.67(m,1H),2.03(t,J=18.0Hz,3H),1.44(d,J=6.7Hz,3H),1.09(s, 9H).
MS(ESI)m/z[M+H] +:351.2. MS(ESI)m/z[M+H] + :351.2.
步骤2step 2
将A-8a(700mg,2.0mmol)加入到氯化氢二氧六环溶液(5ml)中，50℃搅拌16小时。溶剂旋干，加入乙酸乙酯(20ml)，搅拌，抽滤，得到产品白色固体A-8(500mg,产率：89％)。Add A-8a (700mg, 2.0mmol) into hydrogen chloride dioxane solution (5ml), and stir at 50°C for 16 hours. The solvent was spin-dried, ethyl acetate (20ml) was added, stirred, and filtered with suction to obtain the product A-8 (500mg, yield: 89%) as a white solid.
1H NMR(400MHz,DMSO-d 6)δ8.68(s,3H),8.47(d,J＝5.8Hz,1H),8.24(s,1H),8.10(d,J＝5.6Hz,1H),7.64(s,1H),4.75–4.63(m,1H),2.05(t,J＝19.2Hz,3H),1.56(d,J＝6.8Hz,3H). 1 H NMR (400MHz,DMSO-d 6 )δ8.68(s,3H),8.47(d,J＝5.8Hz,1H),8.24(s,1H),8.10(d,J＝5.6Hz,1H) ,7.64(s,1H),4.75–4.63(m,1H),2.05(t,J=19.2Hz,3H),1.56(d,J=6.8Hz,3H).
MS(ESI)m/z[M+H] +:246.9. MS(ESI)m/z[M+H] + :246.9.
中间体实施例A-9：Intermediate Example A-9:
Figure PCTCN2022135958-appb-000096
Figure PCTCN2022135958-appb-000096
步骤1step 1
将A-9a(42g,0.2mol)和1,2-乙二硫醇(18.8g,0.2mol)溶于甲苯(450mL)。常温下加入对甲苯磺酸(7.6g,0.04mol)，反应液加热至回流搅拌反应12小时。反应完成后，加入10％氢氧化钠水溶液，乙酸乙酯(400mL*3)萃取。乙酸乙酯相干燥，浓缩，剩余物经柱层析纯化得白色固体中间体A-9b(48g,84％)。A-9a (42 g, 0.2 mol) and 1,2-ethanedithiol (18.8 g, 0.2 mol) were dissolved in toluene (450 mL). P-toluenesulfonic acid (7.6 g, 0.04 mol) was added at room temperature, and the reaction solution was heated to reflux and stirred for 12 hours. After the reaction was completed, 10% aqueous sodium hydroxide solution was added and extracted with ethyl acetate (400 mL*3). The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9b (48 g, 84%) as a white solid.
1H NMR(400MHz,CDCl 3)δ7.48(d,J＝7.6Hz,1H),7.37(d,J＝7.9Hz,1H),7.12(t,J＝7.8Hz,1H),3.61–3.48(m,2H),3.49–3.38(m,2H),2.98(t,J＝6.7Hz,2H),2.70(dd,J＝8.5,5.0Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.48(d, J=7.6Hz, 1H), 7.37(d, J=7.9Hz, 1H), 7.12(t, J=7.8Hz, 1H), 3.61–3.48 (m,2H),3.49–3.38(m,2H),2.98(t,J=6.7Hz,2H),2.70(dd,J=8.5,5.0Hz,2H).
步骤2step 2
将二溴海因(190.4g,0.67mol)溶于二氯甲烷(400mL)，-60℃下缓慢加入吡啶氢氟酸盐(600mL,6.7mol)。将A-9b(48g,0.17mol)溶于二氯甲烷(100mL)中的溶液缓慢加入到反应液中。反应液-60℃反应4小时后升至室温继续搅拌反应16小时。反应完成后加入2N的氢氧化钠水溶液和30％的亚硫酸氢钠水溶液。分液，二氯甲烷相干燥，浓缩，剩余物经柱层析纯化得中间体A-9c(33g,63％)。Dibromohydantoin (190.4g, 0.67mol) was dissolved in dichloromethane (400mL), and pyridine hydrofluoride (600mL, 6.7mol) was slowly added at -60°C. A solution of A-9b (48 g, 0.17 mol) dissolved in dichloromethane (100 mL) was slowly added to the reaction solution. The reaction solution was reacted at -60°C for 4 hours, then raised to room temperature and continued to stir for 16 hours. After the reaction was completed, 2N aqueous sodium hydroxide solution and 30% aqueous sodium bisulfite solution were added. The liquid was separated, the dichloromethane phase was dried, concentrated, and the residue was purified by column chromatography to obtain intermediate A-9c (33 g, 63%).
1H NMR(400MHz,DMSO-d 6)δ7.95–7.78(m,1H),7.72(dd,J＝17.1,5.5Hz,1H),7.50–7.34(m,1H),5.11(ddt,J＝13.3,10.9,7.4Hz,1H),3.62(ddd,J＝16.5,7.7,2.7Hz,1H),3.25–3.03(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.95–7.78(m,1H),7.72(dd,J=17.1,5.5Hz,1H),7.50–7.34(m,1H),5.11(ddt,J =13.3,10.9,7.4Hz,1H),3.62(ddd,J=16.5,7.7,2.7Hz,1H),3.25–3.03(m,1H).
步骤3step 3
将A-9c(33g,0.11mol)溶于二氯甲烷(300mL)，冰浴下加入DBU(24.1g,0.16mol)。反应液常温搅拌反应12小时。反应完成后，加入二氯甲烷稀释，将有机相用0.5N盐酸水溶液洗涤，饱和食盐水洗涤。有机相干燥，浓缩，剩余物经柱层析纯化得中间体A-9d(19.8g,79％)。A-9c (33 g, 0.11 mol) was dissolved in dichloromethane (300 mL), and DBU (24.1 g, 0.16 mol) was added under ice-cooling. The reaction solution was stirred and reacted at room temperature for 12 hours. After the reaction was completed, dichloromethane was added for dilution, and the organic phase was washed with 0.5N hydrochloric acid aqueous solution and saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9d (19.8 g, 79%).
1H NMR(400MHz,DMSO-d 6)δ7.71–7.61(m,1H),7.61–7.49(m,1H),7.34–7.21(m,1H),7.06(t,J＝10.2Hz,1H),6.61(d,J＝6.1Hz,1H). 1 H NMR (400MHz,DMSO-d 6 )δ7.71–7.61(m,1H),7.61–7.49(m,1H),7.34–7.21(m,1H),7.06(t,J=10.2Hz,1H ),6.61(d,J=6.1Hz,1H).
步骤4step 4
将A-9d(19g,82.3mmol)和A-9e(23.7g,106.9mmol)溶于乙腈(500mL)，冰浴下缓慢加入磷酸钾(3.5g,16.5mmol)和水合肼(16.6g,33mol)。反应液常温搅拌反应40小时。反应完成后，加入水(300mL)，二氯甲烷(500mL*3)萃取，有机相干燥，浓缩，剩余物经柱层析纯化得中间体A-9f(17.2g,90％)。Dissolve A-9d (19g, 82.3mmol) and A-9e (23.7g, 106.9mmol) in acetonitrile (500mL), slowly add potassium phosphate (3.5g, 16.5mmol) and hydrazine hydrate (16.6g, 33mol ). The reaction solution was stirred and reacted at room temperature for 40 hours. After the reaction was completed, water (300 mL) was added, extracted with dichloromethane (500 mL*3), the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9f (17.2 g, 90%).
1H NMR(400MHz,DMSO-d 6)δ7.77(dd,J＝7.9,0.8Hz,1H),7.61(dd,J＝13.5,6.6Hz,1H),7.44 –7.24(m,1H),3.00(tt,J＝6.9,3.3Hz,2H),2.71–2.57(m,2H). 1 H NMR (400MHz, DMSO-d 6 )δ7.77(dd, J=7.9,0.8Hz,1H),7.61(dd,J=13.5,6.6Hz,1H),7.44-7.24(m,1H), 3.00(tt,J＝6.9,3.3Hz,2H),2.71–2.57(m,2H).
步骤5step 5
将A-9f(15.2g,65.2mmol)溶于无水二氧六环(320mL)，加入三乙胺(16.5g,163mmol)、三丁基(1-乙氧基乙烯)锡(28.3g,78.3mmol)和双(三苯基膦)二氯化钯(4.6g,6.5mmol)。置换氮气后，反应液加热至100℃搅拌反应2小时。反应完成后，冷却至室温，加入1N盐酸水溶液(260mL)，常温继续搅拌反应16小时。加入二氯甲烷(200mL*3)萃取，二氯甲烷相干燥，浓缩，剩余物经柱层析纯化得中间体A-9g(8.8g,68％)。Dissolve A-9f (15.2g, 65.2mmol) in anhydrous dioxane (320mL), add triethylamine (16.5g, 163mmol), tributyl (1-ethoxyethylene) tin (28.3g, 78.3 mmol) and bis(triphenylphosphine)palladium dichloride (4.6 g, 6.5 mmol). After nitrogen replacement, the reaction solution was heated to 100° C. and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, 1N hydrochloric acid aqueous solution (260 mL) was added, and stirring reaction was continued at room temperature for 16 hours. Dichloromethane (200mL*3) was added for extraction, the dichloromethane phase was dried and concentrated, and the residue was purified by column chromatography to obtain Intermediate A-9g (8.8g, 68%).
1H NMR(400MHz,DMSO-d 6)δ8.17(d,J＝7.7Hz,1H),7.81(d,J＝7.6Hz,1H),7.58(dd,J＝20.4,12.8Hz,1H),3.31(ddd,J＝10.5,6.9,3.5Hz,2H),2.70–2.53(m,5H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.17(d, J=7.7Hz, 1H), 7.81(d, J=7.6Hz, 1H), 7.58(dd, J=20.4, 12.8Hz, 1H) ,3.31(ddd,J＝10.5,6.9,3.5Hz,2H),2.70–2.53(m,5H).
步骤6step 6
将A-9g(5g,25.4mmol)和(S)-叔丁基亚磺酰胺(4.6g,38.2mmol)溶于无水四氢呋喃(135mL)，置换氮气后加入钛酸四乙酯(17.4g,76.2mmol)。反应液加热到70℃搅拌反应16小时。反应完成后，冷却至室温，加入水(200mL)和乙酸乙酯(200mL)萃取，有机相干燥，浓缩，剩余物经柱层析纯化得中间体A-9h(5.7g,75％)。Dissolve A-9g (5g, 25.4mmol) and (S)-tert-butylsulfinamide (4.6g, 38.2mmol) in anhydrous tetrahydrofuran (135mL), replace nitrogen and add tetraethyl titanate (17.4g, 76.2 mmol). The reaction solution was heated to 70°C and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, added water (200 mL) and ethyl acetate (200 mL) for extraction, the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9h (5.7 g, 75%).
1H NMR(400MHz,DMSO-d 6)δ7.95(d,J＝7.7Hz,1H),7.72(d,J＝7.5Hz,1H),7.59–7.44(m,1H),3.24(t,J＝14.0Hz,2H),2.73(d,J＝7.1Hz,3H),2.67–2.54(m,2H),1.21(d,J＝10.8Hz,9H).MS(ESI)m/z＝300.1[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ7.95(d, J=7.7Hz, 1H), 7.72(d, J=7.5Hz, 1H), 7.59–7.44(m, 1H), 3.24(t, J＝14.0Hz, 2H), 2.73(d, J＝7.1Hz, 3H), 2.67–2.54(m, 2H), 1.21(d, J＝10.8Hz, 9H).MS(ESI)m/z＝300.1 [M+H] + .
步骤7step 7
将A-9h(5.7g,19mmol)溶于无水四氢呋喃(95mL)，-78℃下缓慢滴加三仲丁基硼氢化锂(38mL,38mmol)。反应液-78℃下继续搅拌反应2小时。反应完成后，加入氯化铵水溶液淬灭，二氯甲烷(200mL*3)萃取。有机相干燥，浓缩，剩余物经柱层析纯化得中间体A-9i(5g,88％)。A-9h (5.7g, 19mmol) was dissolved in anhydrous tetrahydrofuran (95mL), and tri-sec-butyl lithium borohydride (38mL, 38mmol) was slowly added dropwise at -78°C. The reaction solution was stirred and reacted at -78°C for 2 hours. After the reaction was completed, ammonium chloride aqueous solution was added to quench, and dichloromethane (200 mL*3) was extracted. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain intermediate A-9i (5 g, 88%).
1H NMR(400MHz,DMSO-d 6)δ7.56(d,J＝6.8Hz,1H),7.47–7.31(m,2H),5.39(d,J＝5.0Hz,1H),4.57–4.46(m,1H),3.06(d,J＝3.1Hz,2H),2.65–2.54(m,2H),1.47(d,J＝6.7Hz,3H),1.09(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.56 (d, J=6.8Hz, 1H), 7.47–7.31 (m, 2H), 5.39 (d, J=5.0Hz, 1H), 4.57–4.46 ( m, 1H), 3.06(d, J=3.1Hz, 2H), 2.65–2.54(m, 2H), 1.47(d, J=6.7Hz, 3H), 1.09(s, 9H).
步骤8Step 8
将A-9i(5.5g,27.3mmol)溶于二氧六环(10mL)，加入盐酸二氧六环溶液(4M,50mL)。反应液常温搅拌反应1小时。反应完成后，浓缩，向剩余物中加入石油醚，搅拌，过滤，得到白色固体中间体A-9(4.1g,99％)。A-9i (5.5 g, 27.3 mmol) was dissolved in dioxane (10 mL), and dioxane hydrochloride solution (4M, 50 mL) was added. The reaction solution was stirred and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated, petroleum ether was added to the residue, stirred, and filtered to obtain white solid intermediate A-9 (4.1 g, 99%).
1H NMR(400MHz,DMSO-d 6)δ8.70(s,2H),7.83(d,J＝7.4Hz,1H),7.64–7.41(m,2H),4.45(s,1H),3.14(dd,J＝38.4,16.6Hz,2H),2.69–2.52(m,2H),1.56(t,J＝13.3Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.70(s, 2H), 7.83(d, J=7.4Hz, 1H), 7.64–7.41(m, 2H), 4.45(s, 1H), 3.14( dd,J=38.4,16.6Hz,2H),2.69–2.52(m,2H),1.56(t,J=13.3Hz,3H).
中间体实施例A-10：Intermediate Example A-10:
Figure PCTCN2022135958-appb-000097
Figure PCTCN2022135958-appb-000097
步骤1step 1
将二异丙胺(2.96g,29.3mmol)溶于无水四氢呋喃(50mL)，-78℃下缓慢滴加正丁基锂(8.1mL,20.3mmol)。反应液-78℃下搅拌2小时后，将A-10a(5g,22.5mmol)溶于无水四氢呋喃(10mL)中的溶液在-78℃下缓慢滴加入反应液中。反应液继续搅拌反应2小时后，加入TMSCl(2.7g,24.8mmol)。反应液继续搅拌反应2小时后升至室温，继续搅拌反应16小时。反应完成后，加入氯化铵水溶液淬灭，乙酸乙酯(50mL*3)萃取。乙酸乙酯相干燥，浓缩，剩余物经柱层析纯化得A-10b(6.1g,92％)。Diisopropylamine (2.96g, 29.3mmol) was dissolved in anhydrous tetrahydrofuran (50mL), and n-butyllithium (8.1mL, 20.3mmol) was slowly added dropwise at -78°C. After the reaction solution was stirred at -78°C for 2 hours, a solution of A-10a (5 g, 22.5 mmol) dissolved in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise to the reaction solution at -78°C. After the reaction solution was stirred and reacted for 2 hours, TMSCl (2.7 g, 24.8 mmol) was added. The reaction solution continued to stir and react for 2 hours, then rose to room temperature, and continued to stir and react for 16 hours. After the reaction was completed, it was quenched by adding aqueous ammonium chloride solution, and extracted with ethyl acetate (50 mL*3). The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10b (6.1 g, 92%).
1H NMR(400MHz,DMSO-d 6)δ7.90–7.84(m,1H),7.41(ddd,J＝7.0,5.2,1.6Hz,1H),7.05–6.93(m,1H),0.35–0.25(m,9H). 1 H NMR (400MHz, DMSO-d 6 )δ7.90–7.84(m,1H),7.41(ddd,J=7.0,5.2,1.6Hz,1H),7.05–6.93(m,1H),0.35–0.25 (m,9H).
步骤2step 2
将三氯化铝(544mg,4.1mmol)溶于二氯甲烷(10mL)，冰浴下加入乙酰氯(320mg,4.1mmol)。反应液搅拌30分钟后，将A-10b(1g,3.4mmol)溶于二氯甲烷(5mL)中的溶液缓慢滴加入反应液中。反应液升至室温继续搅拌反应2小时。反应完成后缓慢加入碳酸氢钠水溶液(10％,25mL)。将水相用乙酸乙酯(30mL*3)萃取。乙酸乙酯相干燥，浓缩，剩余物经柱层析纯化得A-10c(370mg,41％)。Aluminum trichloride (544 mg, 4.1 mmol) was dissolved in dichloromethane (10 mL), and acetyl chloride (320 mg, 4.1 mmol) was added under ice-cooling. After the reaction solution was stirred for 30 minutes, a solution of A-10b (1 g, 3.4 mmol) dissolved in dichloromethane (5 mL) was slowly added dropwise to the reaction solution. The reaction solution was raised to room temperature and continued to stir for 2 hours. After the reaction was complete, aqueous sodium bicarbonate solution (10%, 25 mL) was added slowly. The aqueous phase was extracted with ethyl acetate (30 mL*3). The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10c (370 mg, 41%).
1H NMR(400MHz,DMSO-d 6)δ8.08(ddd,J＝7.6,5.9,1.7Hz,1H),7.81–7.73(m,1H),7.13(t,J＝7.8Hz,1H),2.58(d,J＝4.2Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.08(ddd, J=7.6,5.9,1.7Hz,1H),7.81–7.73(m,1H),7.13(t,J=7.8Hz,1H), 2.58(d,J=4.2Hz,3H).
步骤3step 3
将A-10c(5g,19mmol)溶于DMSO(50mL)，常温下加入二氟溴乙酸乙酯(11.5g,56.8mmol)和铜(3.6g,56.8mmol)。反应液加热到80℃搅拌反应16小时。反应完成后，加入水和***，有固体析出，过滤，水相加入乙酸乙酯(300mL)萃取。乙酸乙酯相干燥，浓缩，剩余物经柱层析纯化得A-10d(3.3g,66％)。A-10c (5g, 19mmol) was dissolved in DMSO (50mL), and ethyl difluorobromoacetate (11.5g, 56.8mmol) and copper (3.6g, 56.8mmol) were added at room temperature. The reaction solution was heated to 80°C and stirred for 16 hours. After the reaction was completed, water and diethyl ether were added, and a solid precipitated out, which was filtered, and ethyl acetate (300 mL) was added to the aqueous phase for extraction. The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10d (3.3 g, 66%).
1H NMR(400MHz,DMSO-d 6)δ8.06(t,J＝7.3Hz,1H),7.96(t,J＝7.3Hz,1H),7.53(t,J＝7.8Hz,1H),4.45–4.30(dd,2H),2.60(d,J＝4.0Hz,3H),1.24(t,J＝2.9Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.06(t, J=7.3Hz, 1H), 7.96(t, J=7.3Hz, 1H), 7.53(t, J=7.8Hz, 1H), 4.45 –4.30(dd, 2H), 2.60(d, J=4.0Hz, 3H), 1.24(t, J=2.9Hz, 3H).
步骤4step 4
将A-10d(3.3g,12.7mmol)溶于四氢呋喃(40mL)，常温下加入(R)-叔丁基亚磺酰胺和钛酸四乙酯(8.7g,38mmol)。反应液加热至70℃搅拌反应16小时。反应完成后加入水和***，有固体析出，过滤，水相加入乙酸乙酯(100mL)萃取。乙酸乙酯相干燥，浓缩，剩余物经柱层析纯化得A-10e(2.9g,63％)。A-10d (3.3g, 12.7mmol) was dissolved in tetrahydrofuran (40mL), and (R)-tert-butylsulfinamide and tetraethyl titanate (8.7g, 38mmol) were added at room temperature. The reaction solution was heated to 70°C and stirred for 16 hours. After the reaction was completed, water and diethyl ether were added, and a solid precipitated out, which was filtered, and ethyl acetate (100 mL) was added to the aqueous phase for extraction. The ethyl acetate phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10e (2.9 g, 63%).
1H NMR(400MHz,DMSO-d 6)δ7.92(t,J＝7.0Hz,1H),7.85(t,J＝6.9Hz,1H),7.50(t,J＝7.7Hz,1H),4.39–4.28(m,2H),2.69(s,3H),1.23(t,J＝1.9Hz,3H),1.22–1.15(m,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.92(t, J=7.0Hz, 1H), 7.85(t, J=6.9Hz, 1H), 7.50(t, J=7.7Hz, 1H), 4.39 –4.28(m,2H),2.69(s,3H),1.23(t,J＝1.9Hz,3H),1.22–1.15(m,9H).
步骤5step 5
将A-10e(5g,13.8mmol)溶于无水四氢呋喃(50mL)，置换氮气后-78℃下缓慢滴加DIBAL-H(62.2mL,96.3mmol)。反应液升至室温继续搅拌反应16小时。反应完成后加入甲醇(20mL)，过滤，滤液加入乙酸乙酯(300mL)稀释。乙酸乙酯相用饱和柠檬酸水溶液(100mL)洗涤。有机相干燥，浓缩，剩余物经柱层析纯化得A-10f(2.3g,51％)。A-10e (5 g, 13.8 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL), and DIBAL-H (62.2 mL, 96.3 mmol) was slowly added dropwise at -78°C after nitrogen replacement. The reaction solution was raised to room temperature and stirred for 16 hours. After the reaction was completed, methanol (20 mL) was added, filtered, and the filtrate was diluted with ethyl acetate (300 mL). The ethyl acetate phase was washed with saturated aqueous citric acid (100 mL). The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10f (2.3 g, 51%).
1H NMR(400MHz,DMSO-d 6)δ7.70(t,J＝7.5Hz,1H),7.44(dd,J＝10.4,4.4Hz,1H),7.30(t,J＝7.7Hz,1H),5.85(d,J＝7.7Hz,1H),5.69(t,J＝5.8Hz,1H),4.68(dd,J＝14.2,7.1Hz,1H),3.94–3.87(m,2H),1.41(d,J＝6.8Hz,3H),1.10(s,9H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.70(t, J=7.5Hz, 1H), 7.44(dd, J=10.4, 4.4Hz, 1H), 7.30(t, J=7.7Hz, 1H) ,5.85(d,J=7.7Hz,1H),5.69(t,J=5.8Hz,1H),4.68(dd,J=14.2,7.1Hz,1H),3.94–3.87(m,2H),1.41( d,J=6.8Hz,3H),1.10(s,9H).
步骤6step 6
将A-10f(1.3g,4mmol)溶于四氢呋喃(20mL)，加入碳酸铯(3.93g,12mmol)和18-冠醚-6(531mg,2mmol)。反应液加热至80℃搅拌反应16小时。反应完成后，加入乙酸乙酯(80mL*3)和水(80mL)萃取。有机相干燥，浓缩，剩余物经柱层析纯化得A-10g(950mg,78％)。A-10f (1.3 g, 4 mmol) was dissolved in tetrahydrofuran (20 mL), cesium carbonate (3.93 g, 12 mmol) and 18-crown-6 (531 mg, 2 mmol) were added. The reaction solution was heated to 80° C. and stirred for 16 hours. After the reaction was completed, ethyl acetate (80 mL*3) and water (80 mL) were added for extraction. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-10g (950 mg, 78%).
1H NMR(400MHz,DMSO-d 6)δ7.64(d,J＝7.6Hz,1H),7.53–7.49(m,1H),7.12(t,J＝7.6Hz,1H),5.72(d,J＝7.5Hz,1H),4.82(td,J＝16.6,1.7Hz,2H),4.57(dd,J＝14.0,6.9Hz,1H),1.40(d,J＝6.8Hz,3H),1.10(d,J＝2.7Hz,9H).MS(ESI)m/z 304.2[M+H] +. 1 H NMR (400MHz, DMSO-d 6 )δ7.64(d, J=7.6Hz, 1H), 7.53–7.49(m, 1H), 7.12(t, J=7.6Hz, 1H), 5.72(d, J＝7.5Hz, 1H), 4.82(td, J＝16.6, 1.7Hz, 2H), 4.57(dd, J＝14.0, 6.9Hz, 1H), 1.40(d, J＝6.8Hz, 3H), 1.10( d,J＝2.7Hz,9H).MS(ESI)m/z 304.2[M+H] + .
步骤7step 7
将A-10g(1.3g,4.3mmol)溶于氯化氢二氧六环溶液(4M,30mL)。常温搅拌反应1小时。反应完成后，浓缩得白色固体A-10(900mg,89％)。A-10g (1.3g, 4.3mmol) was dissolved in hydrogen chloride dioxane solution (4M, 30mL). The reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain white solid A-10 (900 mg, 89%).
1H NMR(400MHz,DMSO-d 6)δ7.63(d,J＝7.5Hz,1H),7.45(dd,J＝7.6,1.4Hz,1H),7.09(t,J＝7.6Hz,1H),4.79(td,J＝16.7,3.1Hz,2H),4.17(q,J＝6.6Hz,1H),2.06–1.88(m,2H),1.26(d,J＝6.6Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ7.63(d, J=7.5Hz, 1H), 7.45(dd, J=7.6, 1.4Hz, 1H), 7.09(t, J=7.6Hz, 1H) ,4.79(td,J=16.7,3.1Hz,2H),4.17(q,J=6.6Hz,1H),2.06–1.88(m,2H),1.26(d,J=6.6Hz,3H).
中间体实施例A-12：Intermediate Example A-12:
Figure PCTCN2022135958-appb-000098
Figure PCTCN2022135958-appb-000098
步骤1：step 1:
将A-12a(6.6g,27.6mmol)、三丁基(1-乙氧基乙烯基)锡(9.97g,27.6mmol)、三乙胺(8.4g,82.8 mmol)和双(三苯基膦)二氯化钯(1.94g,2.76mmol)溶于四氢呋喃(50mL)。置换氮气后，80℃搅拌反应6小时。反应完成后，冷却至室温，过滤，滤液加入乙酸乙酯(100mL)稀释，饱和碳酸氢钠水溶液和食盐水洗涤。乙酸乙酯相干燥，浓缩，剩余物溶于乙醇(50mL)，加入3N盐酸溶液(20mL)，室温搅拌反应4小时。反应完成后，浓缩，剩余物加入乙酸乙酯(200mL)稀释，饱和碳酸氢钠水溶液洗涤，饱和食盐水洗涤，乙酸乙酯相干燥，过滤，浓缩。剩余物经柱层析(石油醚:乙酸乙酯＝20:1)纯化得A-12b(4.4g,79％)。A-12a (6.6g, 27.6mmol), tributyl (1-ethoxyvinyl) tin (9.97g, 27.6mmol), triethylamine (8.4g, 82.8 mmol) and bis (triphenylphosphine ) palladium dichloride (1.94 g, 2.76 mmol) was dissolved in tetrahydrofuran (50 mL). After nitrogen replacement, the reaction was stirred at 80° C. for 6 hours. After the reaction was complete, cool to room temperature, filter, add ethyl acetate (100 mL) to the filtrate to dilute, and wash with saturated aqueous sodium bicarbonate and brine. The ethyl acetate phase was dried and concentrated, and the residue was dissolved in ethanol (50 mL), added with 3N hydrochloric acid solution (20 mL), and stirred at room temperature for 4 hours. After the reaction was complete, it was concentrated, and the residue was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried with ethyl acetate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain A-12b (4.4g, 79%).
1H NMR(400MHz,CDCl 3)δ7.77(d,J＝7.9Hz,1H),7.68(d,J＝7.8Hz,1H),7.39(t,J＝7.8Hz,1H),2.62(s,3H),2.57(d,J＝1.8Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.77(d, J=7.9Hz, 1H), 7.68(d, J=7.8Hz, 1H), 7.39(t, J=7.8Hz, 1H), 2.62(s ,3H),2.57(d,J=1.8Hz,3H).
步骤2：Step 2:
将A-12b(4.4g,21.8mmol)溶于四氢呋喃(50mL)，加入(R)-叔丁基亚磺酰胺(3.96g,32.6mmol)和钛酸四乙酯(14.9g,65.3mmol)。反应液80℃搅拌反应1小时。反应完成后，将反应液降至-15℃，加入甲醇(5mL)和硼氢化锂(620mg,28.3mmol)。反应液-15℃下继续搅拌反应1小时。反应完成后，加入乙酸乙酯稀释(100mL)，加少量水淬灭，接着搅拌1小时后过滤，滤液浓缩，剩余物经柱层析纯化(石油醚:乙酸乙酯＝4:1)纯化得A-12c(2.1g,31％)。A-12b (4.4g, 21.8mmol) was dissolved in tetrahydrofuran (50mL), and (R)-tert-butylsulfinamide (3.96g, 32.6mmol) and tetraethyl titanate (14.9g, 65.3mmol) were added. The reaction solution was stirred and reacted at 80° C. for 1 hour. After the reaction was completed, the reaction solution was lowered to -15°C, and methanol (5 mL) and lithium borohydride (620 mg, 28.3 mmol) were added. The reaction solution was stirred and reacted for 1 hour at -15°C. After completion of the reaction, add ethyl acetate to dilute (100 mL), add a small amount of water to quench, then stir for 1 hour and filter, the filtrate is concentrated, and the residue is purified by column chromatography (petroleum ether:ethyl acetate=4:1) to obtain A-12c (2.1 g, 31%).
1H NMR(400MHz,CDCl 3)δ7.63(dd,J＝15.7,7.9Hz,2H),7.35(t,J＝7.9Hz,1H),5.00–4.91(m,1H),2.52(d,J＝1.9Hz,3H),1.54(d,J＝6.5Hz,3H),1.28(s,9H). 1 H NMR (400MHz, CDCl 3 ) δ7.63(dd, J=15.7, 7.9Hz, 2H), 7.35(t, J=7.9Hz, 1H), 5.00–4.91(m, 1H), 2.52(d, J＝1.9Hz, 3H), 1.54(d, J＝6.5Hz, 3H), 1.28(s, 9H).
步骤3：Step 3:
将A-12c(2.1g,6.8mmol)溶于4N氯化氢/二氧六环溶液(20mL)，室温搅拌反应1小时。反应完成后，浓缩，加入石油醚/乙酸乙酯得混合溶液，室温搅拌1小时。过滤得白色固体A-12(1.28g,79％)。A-12c (2.1 g, 6.8 mmol) was dissolved in 4N hydrogen chloride/dioxane solution (20 mL), and stirred at room temperature for 1 hour. After the reaction was completed, it was concentrated, petroleum ether/ethyl acetate was added to obtain a mixed solution, and the mixture was stirred at room temperature for 1 hour. A white solid A-12 (1.28 g, 79%) was obtained by filtration.
1H NMR(400MHz,DMSO-d 6)δ8.63(s,3H),7.96(d,J＝7.9Hz,1H),7.73(d,J＝7.8Hz,1H),7.54(t,J＝7.9Hz,1H),4.74(s,1H),2.47(s,3H),1.54(d,J＝6.7Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ8.63(s, 3H), 7.96(d, J=7.9Hz, 1H), 7.73(d, J=7.8Hz, 1H), 7.54(t, J= 7.9Hz, 1H), 4.74(s, 1H), 2.47(s, 3H), 1.54(d, J=6.7Hz, 3H).
中间体实施例A-13：Intermediate Example A-13:
Figure PCTCN2022135958-appb-000099
Figure PCTCN2022135958-appb-000099
步骤1：step 1:
将二氟溴乙酸乙酯(16.9g,83mmol)和铜粉(5.3g,83mmol)溶于二甲基亚砜(70mL)，氮气保护下室温搅拌反应45分钟，加入A-13a(10g,33mmol)。反应液加热至70摄氏度反应3小时。反应完成后，冷却至室温，加水(50mL)淬灭，过滤，滤液加入乙酸乙酯(100mL*3)萃取。乙酸乙酯相干燥，过滤，浓缩，剩余物柱层析纯化得A-13b(5.95g,60％)。Dissolve ethyl difluorobromoacetate (16.9g, 83mmol) and copper powder (5.3g, 83mmol) in dimethyl sulfoxide (70mL), stir and react at room temperature for 45 minutes under nitrogen protection, add A-13a (10g, 33mmol ). The reaction solution was heated to 70° C. for 3 hours. After the reaction was completed, it was cooled to room temperature, quenched by adding water (50 mL), filtered, and the filtrate was extracted by adding ethyl acetate (100 mL*3). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain A-13b (5.95 g, 60%).
1H NMR(400MHz,CDCl 3)δ7.71(t,J＝7.3Hz,1H),7.59(t,J＝7.2Hz,1H),7.15(t,J＝7.9Hz,1H),4.37(q,J＝7.2Hz,2H),1.34(td,J＝7.1,0.9Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ7.71(t, J=7.3Hz, 1H), 7.59(t, J=7.2Hz, 1H), 7.15(t, J=7.9Hz, 1H), 4.37(q ,J=7.2Hz,2H),1.34(td,J=7.1,0.9Hz,3H).
步骤2：Step 2:
将A-13b(5.95g,20mmol)溶于四氢呋喃(70mL)，冰浴下加入甲基溴化镁(3M,20mL,60mmol)。反应液室温搅拌2小时，反应完成后加入氯化铵水溶液(50mL)淬灭，乙酸乙酯(100mL*2)萃取。乙酸乙酯相干燥，过滤，浓缩，剩余物经柱层析纯化得A-13c(5.1g,90％)。 1H NMR(400MHz,DMSO-d 6)δ7.86(ddd,J＝8.0,6.2,1.6Hz,1H),7.46(ddd,J＝8.2,6.6,1.7Hz,1H),7.30–7.21(m,1H),5.40(s,1H),1.20(d,J＝1.4Hz,6H). A-13b (5.95g, 20mmol) was dissolved in tetrahydrofuran (70mL), and methylmagnesium bromide (3M, 20mL, 60mmol) was added under ice-cooling. The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, aqueous ammonium chloride solution (50 mL) was added to quench it, and ethyl acetate (100 mL*2) was extracted. The ethyl acetate phase was dried, filtered and concentrated, and the residue was purified by column chromatography to obtain A-13c (5.1 g, 90%). 1 H NMR (400MHz, DMSO-d 6 ) δ7.86 (ddd, J＝8.0, 6.2, 1.6Hz, 1H), 7.46 (ddd, J＝8.2, 6.6, 1.7Hz, 1H), 7.30–7.21 (m ,1H),5.40(s,1H),1.20(d,J=1.4Hz,6H).
步骤3：Step 3:
将A-13c(5.1g,18mmol)、三丁基(1-乙氧基乙烯基)锡(7.8g,21.6mmol)、三乙胺(5.46g,54mmol)和双(三苯基膦)二氯化钯(1.26g,1.8mmol)溶于1,4-二氧六环(50mL)。置换氮气后，100℃搅拌反应16小时。反应完成后，冷却至室温，过滤，滤液加入乙酸乙酯(100mL)稀释，饱和碳酸氢钠水溶液和食盐水洗涤。乙酸乙酯相干燥，浓缩，剩余物溶于乙醇(50mL)，加入3N盐酸溶液(20mL)，室温搅拌反应1小时。反应完成后，浓缩，剩余物加入乙酸乙酯(200mL)稀释，饱和碳酸氢钠水溶液洗涤，饱和食盐水洗涤，乙酸乙酯相干燥，过滤，浓缩。剩余物经柱层析纯化得A-13d(3.77g,85％)。A-13c (5.1g, 18mmol), tributyl (1-ethoxyvinyl) tin (7.8g, 21.6mmol), triethylamine (5.46g, 54mmol) and bis (triphenylphosphine) di Palladium chloride (1.26 g, 1.8 mmol) was dissolved in 1,4-dioxane (50 mL). After nitrogen replacement, the reaction was stirred at 100° C. for 16 hours. After the reaction was complete, cool to room temperature, filter, add ethyl acetate (100 mL) to the filtrate to dilute, and wash with saturated aqueous sodium bicarbonate and brine. The ethyl acetate phase was dried and concentrated, and the residue was dissolved in ethanol (50 mL), added with 3N hydrochloric acid solution (20 mL), and stirred at room temperature for 1 hour. After the reaction was complete, it was concentrated, and the residue was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried with ethyl acetate, filtered, and concentrated. The residue was purified by column chromatography to obtain A-13d (3.77g, 85%).
1H NMR(400MHz,CDCl 3)δ7.94(td,J＝7.3,6.5,1.9Hz,1H),7.69–7.59(m,1H),7.29(d,J＝7.7Hz,1H),2.65(dd,J＝5.4,1.7Hz,3H),1.36(d,J＝1.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ) δ7.94 (td, J=7.3, 6.5, 1.9Hz, 1H), 7.69–7.59 (m, 1H), 7.29 (d, J=7.7Hz, 1H), 2.65( dd,J=5.4,1.7Hz,3H),1.36(d,J=1.8Hz,6H).
步骤4：Step 4:
将A-13d(3.77g,15.3mmol)溶于四氢呋喃(40mL)，加入(R)-叔丁基亚磺酰胺(2.78g,23mmol)和钛酸四乙酯(10.5g,46mmol)。反应液80℃搅拌反应12小时。反应完成后，将反应液降至-15℃，加入甲醇(3.5mL)和硼氢化锂(404mg,18.4mmol)。反应液-15℃下继续搅拌反应1小时。反应完成后，加入乙酸乙酯稀释(100mL)，加少量水淬灭，接着搅拌1小时后过滤，滤液浓缩，剩余物经柱层析纯化得A-13e(3.5g,65％)。A-13d (3.77g, 15.3mmol) was dissolved in tetrahydrofuran (40mL), and (R)-tert-butylsulfinamide (2.78g, 23mmol) and tetraethyl titanate (10.5g, 46mmol) were added. The reaction solution was stirred and reacted at 80° C. for 12 hours. After the reaction was completed, the reaction solution was lowered to -15°C, and methanol (3.5 mL) and lithium borohydride (404 mg, 18.4 mmol) were added. The reaction solution was stirred and reacted for 1 hour at -15°C. After the reaction was completed, ethyl acetate was added to dilute (100 mL), quenched by adding a small amount of water, then stirred for 1 hour and filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain A-13e (3.5 g, 65%).
步骤5：Step 5:
将A-13e(3.5g,10mmol)溶于4N氯化氢/二氧六环溶液(20mL)，室温搅拌反应2小时。反应完成后，浓缩，加入石油醚/乙酸乙酯得混合溶液，室温搅拌1小时，过滤得白色固体A-13(2.67g,95％)。 1H NMR(400MHz,DMSO-d 6)δ8.68(s,3H),7.87–7.77(m,1H),7.47(td,J＝7.5,1.7Hz,1H),7.37(t,J＝7.8Hz,1H),4.64(p,J＝6.2Hz,1H),1.53(d,J＝6.8Hz,3H),1.21(s,6H).MS(ESI)m/z[M+H] +:248.4. A-13e (3.5 g, 10 mmol) was dissolved in 4N hydrogen chloride/dioxane solution (20 mL), and stirred at room temperature for 2 hours. After the reaction was completed, it was concentrated, petroleum ether/ethyl acetate was added to obtain a mixed solution, stirred at room temperature for 1 hour, and a white solid A-13 (2.67 g, 95%) was obtained by filtration. 1 H NMR (400MHz, DMSO-d 6 ) δ8.68(s, 3H), 7.87–7.77(m, 1H), 7.47(td, J=7.5, 1.7Hz, 1H), 7.37(t, J=7.8 Hz,1H),4.64(p,J=6.2Hz,1H),1.53(d,J=6.8Hz,3H),1.21(s,6H).MS(ESI)m/z[M+H] + : 248.4.
实施例I-1：Embodiment I-1:
Figure PCTCN2022135958-appb-000100
Figure PCTCN2022135958-appb-000100
步骤1：step 1:
将I-1a(5g,20.49mmol)溶于1,4-二氧六环(50mL)，加入二氧化硒(6.82g,61.47mmol)。反应液加热至回流，搅拌反应24小时。反应完成后，过滤，滤液浓缩，剩余物经柱层析纯化得I-1b(3g,57％)。 1H NMR(400MHz,CDCl 3)δ10.27(s,1H),8.91(d,J＝2.1Hz,1H),8.22(d,J＝2.1Hz,1H),4.45(q,J＝7.1Hz,2H),1.40(t,J＝7.2Hz,3H). I-1a (5 g, 20.49 mmol) was dissolved in 1,4-dioxane (50 mL), and selenium dioxide (6.82 g, 61.47 mmol) was added. The reaction solution was heated to reflux and stirred for 24 hours. After the reaction was completed, it was filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-1b (3 g, 57%). 1 H NMR (400MHz, CDCl 3 ) δ10.27(s, 1H), 8.91(d, J=2.1Hz, 1H), 8.22(d, J=2.1Hz, 1H), 4.45(q, J=7.1Hz ,2H),1.40(t,J=7.2Hz,3H).
步骤2：Step 2:
将I-1b(500mg,1.94mmol)溶于乙醇(5mL)，加入水合肼(291mg,5.82mmol)。反应液80℃搅拌反应4小时。反应完成后，冷却至室温，加入水(10mL)，浓缩除去乙醇，反应液过滤，得到固体中间体I-1c(400mg,91％)。 1H NMR(400MHz,DMSO-d 6)δ13.09(s,1H),9.25(d,J＝2.3Hz,1H),8.73(dd,J＝2.4,0.7Hz,1H),8.44(d,J＝0.7Hz,1H). I-1b (500 mg, 1.94 mmol) was dissolved in ethanol (5 mL), and hydrazine hydrate (291 mg, 5.82 mmol) was added. The reaction solution was stirred and reacted at 80° C. for 4 hours. After the reaction was completed, cooled to room temperature, added water (10 mL), concentrated to remove ethanol, and filtered the reaction liquid to obtain solid intermediate I-1c (400 mg, 91%). 1 H NMR (400MHz, DMSO-d 6 )δ13.09(s, 1H), 9.25(d, J=2.3Hz, 1H), 8.73(dd, J=2.4, 0.7Hz, 1H), 8.44(d, J＝0.7Hz,1H).
步骤3：Step 3:
将I-1c(230mg,1.02mmol)溶于1,4-二氧六环(3mL)，加入吗啉(133mg,1.53mmol)、叔丁醇钾(240mg,2.14mmol)、2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(93mg,0.2mmol)和三(二亚苄基丙酮)二钯(91.6mg,0.1mmol)。置换氮气后，反应液回流搅拌反应12小时。反应完成后，冷却至室温， 过滤，滤液浓缩，剩余物经柱层析纯化得I-1d(200mg,85％)。Dissolve I-1c (230mg, 1.02mmol) in 1,4-dioxane (3mL), add morpholine (133mg, 1.53mmol), potassium tert-butoxide (240mg, 2.14mmol), 2-dicyclohexyl Phosphor-2',6'-diisopropoxy-1,1'-biphenyl (93 mg, 0.2 mmol) and tris(dibenzylideneacetone)dipalladium (91.6 mg, 0.1 mmol). After nitrogen replacement, the reaction solution was refluxed and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated, and the residue was purified by column chromatography to obtain I-1d (200 mg, 85%).
步骤4：Step 4:
将I-1d(55mg,0.24mmol)溶于三氯氧磷(1mL)，反应液回流搅拌反应4小时。反应完成后，浓缩，剩余物加入乙酸乙酯稀释(30mL)，加入碳酸氢钠水溶液洗涤，乙酸乙酯相干燥，过滤，浓缩。剩余物经柱层析纯化得I-1e(50mg,85％)。I-1d (55 mg, 0.24 mmol) was dissolved in phosphorus oxychloride (1 mL), and the reaction solution was refluxed and stirred for 4 hours. After the reaction was completed, it was concentrated, and the residue was diluted with ethyl acetate (30 mL), washed with aqueous sodium bicarbonate solution, dried with ethyl acetate, filtered, and concentrated. The residue was purified by column chromatography to obtain I-1e (50 mg, 85%).
步骤5：Step 5:
将I-1e(50mg,0.2mmol)和A-12(72mg,0.3mmol)溶于DMSO(1mL)，加入N,N-二异丙基乙胺(258mg,2mmol)和氟化钾(58mg,1mmol)。反应液加热至130℃搅拌反应12小时。反应完成后，冷却至室温，加入水(40mL)和乙酸乙酯(40mL)萃取，乙酸乙酯相干燥，过滤，浓缩，剩余物经柱层析纯化得I-1(25mg,30％)。Dissolve I-1e (50mg, 0.2mmol) and A-12 (72mg, 0.3mmol) in DMSO (1mL), add N,N-diisopropylethylamine (258mg, 2mmol) and potassium fluoride (58mg, 1 mmol). The reaction solution was heated to 130° C. and stirred for 12 hours. After the reaction was completed, it was cooled to room temperature, added water (40 mL) and ethyl acetate (40 mL) for extraction, the ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-1 (25 mg, 30%).
1H NMR(400MHz,DMSO-d 6)δ9.25–9.16(m,2H),8.80(d,J＝6.7Hz,1H),8.11(d,J＝2.7Hz,1H),7.75(d,J＝7.9Hz,1H),7.60(d,J＝7.8Hz,1H),7.38(t,J＝7.9Hz,1H),5.53(p,J＝6.7Hz,1H),3.84(t,J＝4.8Hz,4H),3.69(t,J＝4.9Hz,4H),2.55(s,3H),1.63(d,J＝6.8Hz,3H).MS(ESI)m/z[M+H] +:418.4. 1 H NMR (400MHz, DMSO-d 6 )δ9.25–9.16(m, 2H), 8.80(d, J=6.7Hz, 1H), 8.11(d, J=2.7Hz, 1H), 7.75(d, J=7.9Hz, 1H), 7.60(d, J=7.8Hz, 1H), 7.38(t, J=7.9Hz, 1H), 5.53(p, J=6.7Hz, 1H), 3.84(t, J= 4.8Hz, 4H), 3.69(t, J=4.9Hz, 4H), 2.55(s, 3H), 1.63(d, J=6.8Hz, 3H).MS(ESI) m/z[M+H] + :418.4.
实施例I-2：Embodiment I-2:
Figure PCTCN2022135958-appb-000101
Figure PCTCN2022135958-appb-000101
步骤1：step 1:
将I-2a(3.8g,13mmol)溶于DMF(40mL)，常温下缓慢加入碘甲烷(7.7g,54mmol)和碳酸氢钠(9.1g,108mmol)。常温搅拌反应3小时，反应完成后，将反应液倒入到冰水(50mL)中，使用乙酸乙酯(40mL*2)萃取，乙酸乙酯相用饱和食盐水(50mL*3)洗涤，过滤，干燥，浓缩。剩余物经制备色谱法纯化得黄色固体I-2b(3.9g,98％)。 1H NMR(400MHz,DMSO-d 6)δ8.74(d,J＝2.4Hz,1H),8.42(d,J＝2.4Hz,1H),3.89(s,3H). I-2a (3.8g, 13mmol) was dissolved in DMF (40mL), and methyl iodide (7.7g, 54mmol) and sodium bicarbonate (9.1g, 108mmol) were slowly added at room temperature. Stir and react at room temperature for 3 hours. After the reaction is complete, pour the reaction solution into ice water (50mL), extract with ethyl acetate (40mL*2), wash the ethyl acetate phase with saturated brine (50mL*3), and filter , dried and concentrated. The residue was purified by preparative chromatography to give I-2b (3.9 g, 98%) as a yellow solid. 1 H NMR (400MHz, DMSO-d 6 ) δ8.74(d, J=2.4Hz, 1H), 8.42(d, J=2.4Hz, 1H), 3.89(s, 3H).
MS(ESI)m/z＝295.9[M+H] +. MS(ESI)m/z=295.9[M+H] + .
步骤2：Step 2:
将I-2b(1g,3.3mmol)溶于二氧六环(10mL)，加入三乙胺(0.5g,5mmol)、三丁基(1-乙氧基乙烯)锡(1.5g,4mmol)和Pd(PPh 3) 2Cl 2(0.24g,0.33mmol)，置换氮气后，反应液升至100℃搅拌反应2小时。反应完成后，冷却至室温，加入1N盐酸溶液(30mL)，继续常温搅拌反应3小时，反应完成后，加入二氯甲烷(30mL*2)萃取。二氯甲烷相用氟化钾水溶液(30mL*2)洗涤，饱和食盐水(30mL*2)洗涤。二氯甲烷相干燥，过滤，浓缩，剩余物经制备色谱法纯化得白色固体I-2c(0.6g,69％)。 1H NMR(400MHz,DMSO-d 6)δ8.97(d,J＝2.0Hz,1H),8.44(d,J＝2.0Hz,1H),3.83(s,3H),2.60(s,3H). I-2b (1g, 3.3mmol) was dissolved in dioxane (10mL), triethylamine (0.5g, 5mmol), tributyl (1-ethoxyethylene) tin (1.5g, 4mmol) and Pd(PPh 3 ) 2 Cl 2 (0.24g, 0.33mmol), after nitrogen replacement, the reaction solution was raised to 100°C and stirred for 2 hours. After the reaction was completed, it was cooled to room temperature, 1N hydrochloric acid solution (30 mL) was added, and the reaction was continued to stir at room temperature for 3 hours. After the reaction was completed, dichloromethane (30 mL*2) was added for extraction. The dichloromethane phase was washed with potassium fluoride aqueous solution (30 mL*2), and saturated brine (30 mL*2). The dichloromethane phase was dried, filtered, concentrated, and the residue was purified by preparative chromatography to give I-2c (0.6 g, 69%) as a white solid. 1 H NMR (400MHz, DMSO-d 6 )δ8.97(d, J=2.0Hz, 1H), 8.44(d, J=2.0Hz, 1H), 3.83(s, 3H), 2.60(s, 3H) .
MS(ESI)m/z＝260.0[M+H] +. MS(ESI)m/z=260.0[M+H] + .
步骤3：Step 3:
将I-2c(5.7g,22mmol)溶于乙醇(50mL)，加入水合肼(4.2g,66mmol)。置换氮气后，反应液升至80℃搅拌反应2小时。反应完成后过滤得黄色固体I-2d(3g,57％)。 1H NMR(400MHz,DMSO-d 6)δ12.82(s,1H),9.26(d,J＝4.0Hz,1H),8.71(d,J＝4.8Hz,1H),2.52(s,3H). I-2c (5.7 g, 22 mmol) was dissolved in ethanol (50 mL), and hydrazine hydrate (4.2 g, 66 mmol) was added. After nitrogen replacement, the reaction solution was raised to 80° C. and stirred for 2 hours. After the reaction was completed, yellow solid I-2d (3 g, 57%) was obtained by filtration. 1 H NMR (400MHz,DMSO-d 6 )δ12.82(s,1H),9.26(d,J=4.0Hz,1H),8.71(d,J=4.8Hz,1H),2.52(s,3H) .
MS(ESI)m/z＝242.0[M+H] +. MS(ESI)m/z=242.0[M+H] + .
步骤4：Step 4:
将I-2d(4.5g,18.7mmol)溶于甲苯(100mL)，加入劳森试剂(9g,22.3mmol)和18-冠醚-6(500 mg,1.9mmol)。反应液升至100℃搅拌反应5小时。反应完成后，冷却至室温，过滤，滤饼用乙酸乙酯(20mL)洗涤得黄色固体I-2e(3.8g,79％)。MS(ESI)m/z＝256.0[M+H] +. I-2d (4.5 g, 18.7 mmol) was dissolved in toluene (100 mL), and Lawson's reagent (9 g, 22.3 mmol) and 18-crown-6 (500 mg, 1.9 mmol) were added. The reaction solution was raised to 100°C and stirred for 5 hours. After the reaction was completed, it was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (20 mL) to obtain a yellow solid I-2e (3.8 g, 79%). MS(ESI)m/z=256.0[M+H] + .
步骤5：Step 5:
将I-2e(3.8g,14.8mmol)溶于DMF(50mL)，冰浴下缓慢加入氢化钠(653mg,16.3mmol)。冰浴下搅拌半小时后加入碘甲烷(2.3g,16.3mmol)。反应液升至室温继续搅拌反应2小时。反应完成后，反应液加入冰水淬灭，过滤，滤饼经制备色谱法纯化得淡黄色固体I-2f(3g,75％)。 1H NMR(400MHz,CDCl 3)δ9.19(d,J＝4Hz,1H),8.54(d,J＝0Hz,1H),3.00(s,3H),2.83(s,3H). I-2e (3.8g, 14.8mmol) was dissolved in DMF (50mL), and sodium hydride (653mg, 16.3mmol) was added slowly under ice-cooling. After stirring under ice bath for half an hour, iodomethane (2.3 g, 16.3 mmol) was added. The reaction solution was raised to room temperature and continued to stir for 2 hours. After the reaction was completed, the reaction liquid was quenched by adding ice water, filtered, and the filter cake was purified by preparative chromatography to obtain light yellow solid I-2f (3 g, 75%). 1 H NMR (400MHz, CDCl 3 ) δ9.19(d, J=4Hz, 1H), 8.54(d, J=0Hz, 1H), 3.00(s, 3H), 2.83(s, 3H).
MS(ESI)m/z＝270.1[M+H] +. MS(ESI)m/z=270.1[M+H] + .
步骤6：Step 6:
将I-2f(3g,11.1mmol)溶于二氯甲烷(50mL)，-20℃下加入间氯过氧苯甲酸(2.1g,12.2mmol)。反应液在-20℃下搅拌反应1小时后升至室温继续搅拌反应2小时。反应完成后，反应液加入硫代硫酸钠水溶液淬灭，有机相用饱和食盐水(30mL*2)洗涤。有机相干燥，过滤，浓缩，剩余物经制备色谱法纯化得黄色固体I-2g(2g,63％)。 1H NMR(400MHz,CDCl 3)δ9.81(d,J＝4Hz,1H),9.30(d,J＝4Hz,1H),3.26(s,3H),3.14(s,3H). I-2f (3 g, 11.1 mmol) was dissolved in dichloromethane (50 mL), and m-chloroperoxybenzoic acid (2.1 g, 12.2 mmol) was added at -20°C. The reaction solution was stirred and reacted at -20°C for 1 hour, then raised to room temperature and continued to stir and react for 2 hours. After the reaction was completed, the reaction solution was quenched by adding sodium thiosulfate aqueous solution, and the organic phase was washed with saturated brine (30 mL*2). The organic phase was dried, filtered and concentrated, and the residue was purified by preparative chromatography to give I-2g (2g, 63%) as a yellow solid. 1 H NMR (400MHz, CDCl 3 ) δ9.81(d, J=4Hz, 1H), 9.30(d, J=4Hz, 1H), 3.26(s, 3H), 3.14(s, 3H).
MS(ESI)m/z 286.0[M+H] +. MS(ESI)m/z 286.0[M+H] + .
步骤7：Step 7:
将I-2g(500mg,1.75mmol)、A-12(461mg,1.92mmol)溶于DMSO(8mL)，加入氟化铯(239mg,1.57mmol)和吡啶(691mg,8.74mmol)。置换氮气后升温至100℃搅拌反应10小时。反应完成后，冷却至室温，加入水(20mL)淬灭，有固体析出，过滤，得到固体，将其经制备色谱法纯化得黄色固体I-2h(450mg,60％)。 1H NMR(400MHz,CDCl 3)δ9.13(d,J＝2.0Hz,1H),8.28(d,J＝2.0Hz,1H),7.63(d,J＝7.6Hz,1H),7.56(d,J＝8.0Hz,1H),7.26(t,J＝7.8Hz,1H),5.93-5.86(m,1H),5.09(d,J＝6.0Hz,3H),2.87(s,3H),2.56(s,3H),1.66(d,J＝6.4Hz,1H). I-2g (500 mg, 1.75 mmol), A-12 (461 mg, 1.92 mmol) were dissolved in DMSO (8 mL), and cesium fluoride (239 mg, 1.57 mmol) and pyridine (691 mg, 8.74 mmol) were added. After nitrogen replacement, the temperature was raised to 100°C and the reaction was stirred for 10 hours. After the reaction was completed, it was cooled to room temperature and quenched by adding water (20 mL). A solid precipitated out and was filtered to obtain a solid, which was purified by preparative chromatography to obtain a yellow solid I-2h (450 mg, 60%). 1 H NMR (400MHz, CDCl 3 ) δ9.13(d, J=2.0Hz, 1H), 8.28(d, J=2.0Hz, 1H), 7.63(d, J=7.6Hz, 1H), 7.56(d ,J=8.0Hz,1H),7.26(t,J=7.8Hz,1H),5.93-5.86(m,1H),5.09(d,J=6.0Hz,3H),2.87(s,3H),2.56 (s,3H),1.66(d,J=6.4Hz,1H).
MS(ESI)m/z＝425.1[M+H] +. MS(ESI)m/z=425.1[M+H] + .
步骤8：Step 8:
将I-2h(50mg,0.12mmol)、吗啉(21mg,0.24mmol)、RuPHOS(11mg,0.02mmol)、叔丁醇钠(11mg,0.12mmol)和三乙胺(36mg,0.36mmol)溶于1,4-二氧六环(3mL)，加入Pd 2(dba) 3(22mg,0.02mmol)，置换氮气后升至110℃搅拌反应1小时。反应完成后，冷却至室温，加入乙酸乙酯(20mL)稀释，饱和食盐水(20mL*2)洗涤。有机相干燥，过滤，浓缩，剩余物经制备色谱法纯化得白色固体I-2(15mg,27％)。 1H NMR(400MHz,Methanol-d 4)δ8.99(d,J＝2.8Hz,1H),7.97(d,J＝2.8Hz,1H),7.74(d,J＝7.8Hz,1H),7.54(d,J＝7.8Hz,1H),7.29(t,J＝7.9Hz,1H),5.77(d,J＝6.9Hz,1H),4.04–3.89(m,4H),3.63–3.50(m,4H),2.72(s,3H),2.66(s,3H),1.67(d,J＝6.9Hz,3H). Dissolve I-2h (50mg, 0.12mmol), morpholine (21mg, 0.24mmol), RuPHOS (11mg, 0.02mmol), sodium tert-butoxide (11mg, 0.12mmol) and triethylamine (36mg, 0.36mmol) in Add Pd 2 (dba) 3 (22mg, 0.02mmol) to 1,4-dioxane (3mL), replace the nitrogen gas, raise the temperature to 110°C and stir for 1 hour. After the reaction was completed, it was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated brine (20 mL*2). The organic phase was dried, filtered and concentrated, and the residue was purified by preparative chromatography to give I-2 (15 mg, 27%) as a white solid. 1 H NMR (400MHz, Methanol-d 4 ) δ8.99(d, J=2.8Hz, 1H), 7.97(d, J=2.8Hz, 1H), 7.74(d, J=7.8Hz, 1H), 7.54 (d,J=7.8Hz,1H),7.29(t,J=7.9Hz,1H),5.77(d,J=6.9Hz,1H),4.04–3.89(m,4H),3.63–3.50(m, 4H), 2.72(s, 3H), 2.66(s, 3H), 1.67(d, J=6.9Hz, 3H).
MS(ESI)m/z＝432.3[M+H] +. MS(ESI)m/z=432.3[M+H] + .
实施例I-3：Embodiment I-3:
Figure PCTCN2022135958-appb-000102
Figure PCTCN2022135958-appb-000102
参照实施例I-1制备方法，使用I-1e和A-13为原料得I-3(8mg,17％)。 1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝2.5Hz,1H),8.74(s,1H),8.01(d,J＝2.3Hz,1H),7.67(d,J＝6.8Hz,1H),7.54(t,J＝7.0Hz,1H),7.30(t,J＝6.7Hz,1H),7.17(t,J＝7.8Hz,1H),5.78(t,J＝6.9Hz,1H),5.34(s,1H),3.90–3.75(m,4H),3.53–3.43(m,4H),1.60(d,J＝7.0Hz,3H),1.23(d,J＝2.6Hz,6H). Referring to the preparation method of Example I-1, I-1e and A-13 were used as raw materials to obtain I-3 (8 mg, 17%). 1 H NMR (400MHz, DMSO-d 6 )δ9.04(d, J=2.5Hz, 1H), 8.74(s, 1H), 8.01(d, J=2.3Hz, 1H), 7.67(d, J= 6.8Hz, 1H), 7.54(t, J=7.0Hz, 1H), 7.30(t, J=6.7Hz, 1H), 7.17(t, J=7.8Hz, 1H), 5.78(t, J=6.9Hz ,1H),5.34(s,1H),3.90–3.75(m,4H),3.53–3.43(m,4H),1.60(d,J＝7.0Hz,3H),1.23(d,J＝2.6Hz, 6H).
MS(ESI)m/z 462.2[M+H] +. MS(ESI)m/z 462.2[M+H] + .
实施例I-4：Embodiment I-4:
Figure PCTCN2022135958-appb-000103
Figure PCTCN2022135958-appb-000103
步骤1：step 1:
将I-2d(130mg,0.6mmol)、吗啉(76mg,0.9mmol)、叔丁醇钠(167mg,1.7mmol)、RuPHOS(54mg,0.12mmol)和Pd 2(dba) 3(53mg,0.06mmol)溶于二氧六环(2mL)，置换氮气后反应液升至110℃搅拌反应6小时。反应完成后，冷却至室温，过滤，滤液加入乙酸乙酯(20mL)稀释，饱和食盐水(20mL*2)洗涤。乙酸乙酯相干燥，过滤，浓缩，剩余物经柱层析纯化得I-4a(100mg,74％)。MS(ESI)m/z 247.2[M+H] +. I-2d (130mg, 0.6mmol), morpholine (76mg, 0.9mmol), sodium tert-butoxide (167mg, 1.7mmol), RuPHOS (54mg, 0.12mmol) and Pd 2 (dba) 3 (53mg, 0.06mmol ) was dissolved in dioxane (2 mL), and the reaction solution was raised to 110° C. and stirred for 6 hours after replacing nitrogen. After the reaction was completed, cool to room temperature, filter, add ethyl acetate (20 mL) to the filtrate to dilute, and wash with saturated brine (20 mL*2). The ethyl acetate phase was dried, filtered, concentrated, and the residue was purified by column chromatography to obtain I-4a (100 mg, 74%). MS(ESI)m/z 247.2[M+H] + .
步骤2：Step 2:
将I-4a(100mg,0.43mmol)溶于三氯氧磷(3mL)，90℃下搅拌反应3小时，反应完成后，浓缩，除去三氯氧磷，剩余物加入碳酸氢钠水溶液(10mL)，乙酸乙酯(20mL*2)萃取，乙酸乙酯相干燥，过滤，浓缩，剩余物经制备色谱法纯化得I-4b(100mg,93％)。MS(ESI)m/z 265.2[M+H] +. Dissolve I-4a (100mg, 0.43mmol) in phosphorus oxychloride (3mL), stir and react at 90°C for 3 hours, after the reaction is completed, concentrate to remove phosphorus oxychloride, add sodium bicarbonate aqueous solution (10mL) to the residue , extracted with ethyl acetate (20mL*2), dried the ethyl acetate phase, filtered, concentrated, and the residue was purified by preparative chromatography to obtain I-4b (100mg, 93%). MS(ESI)m/z 265.2[M+H] + .
步骤3：Step 3:
将I-4b(50mg,0.2mmol)、A-9(41mg,0.21mmol)溶于DMSO(2mL)，加入DIPEA(74mg,0.57mmol)和氟化钾(33mg,0.6mmol)。反应液升至130℃搅拌反应16小时，反应完成后，浓缩，加入乙酸乙酯(40mL)稀释，饱和食盐水(20mL*2)洗涤。乙酸乙酯相干燥，过滤，浓缩，剩余物经柱层析纯化得黄色固体I-4(22mg,25％)。 1H NMR(400MHz,Methanol-d 4)δ8.98(d,J＝2.8Hz,1H),7.95(d,J＝2.8Hz,1H),7.59(d,J＝7.4Hz,1H),7.44–7.25(m,2H),5.56(q,J＝7.0Hz,1H),3.98–3.90(m,4H),3.61–3.51(m,4H),3.50–3.40(m,1H),3.22–3.04(m,1H),2.72(s,3H),2.66–2.55(m,2H),1.69(d,J＝7.0Hz,3H).MS(ESI)m/z 426.4[M+H] +. I-4b (50 mg, 0.2 mmol), A-9 (41 mg, 0.21 mmol) were dissolved in DMSO (2 mL), and DIPEA (74 mg, 0.57 mmol) and potassium fluoride (33 mg, 0.6 mmol) were added. The reaction solution was raised to 130°C and stirred for 16 hours. After the reaction was completed, it was concentrated, diluted with ethyl acetate (40 mL), and washed with saturated brine (20 mL*2). The ethyl acetate phase was dried, filtered and concentrated, and the residue was purified by column chromatography to obtain I-4 (22 mg, 25%) as a yellow solid. 1 H NMR (400MHz, Methanol-d 4 ) δ8.98(d, J=2.8Hz, 1H), 7.95(d, J=2.8Hz, 1H), 7.59(d, J=7.4Hz, 1H), 7.44 –7.25(m,2H),5.56(q,J＝7.0Hz,1H),3.98–3.90(m,4H),3.61–3.51(m,4H),3.50–3.40(m,1H),3.22–3.04 (m,1H),2.72(s,3H),2.66–2.55(m,2H),1.69(d,J=7.0Hz,3H). MS(ESI) m/z 426.4[M+H] + .
实施例I-5：Embodiment I-5:
Figure PCTCN2022135958-appb-000104
Figure PCTCN2022135958-appb-000104
参照实施例I-4制备方法，使用I-4b和A-1为原料得I-5(2mg,3％)。 1H NMR(400MHz,CDCl 3)δ8.94(s,1H),8.76(d,J＝2.7Hz,1H),8.24(d,J＝2.8Hz,1H),7.48(d,J＝7.3Hz,2H),7.21–7.07(m,1H),7.03–6.89(m,1H),5.22(s,1H),4.01–3.90(m,4H),3.75–3.68(m,4H),2.59(s,3H),1.72(d,J＝7.0Hz,3H)。MS(ESI)m/z 418.2[M+H] +. Referring to the preparation method of Example I-4, I-5 (2 mg, 3%) was obtained using I-4b and A-1 as raw materials. 1 H NMR (400MHz, CDCl 3 ) δ8.94(s, 1H), 8.76(d, J=2.7Hz, 1H), 8.24(d, J=2.8Hz, 1H), 7.48(d, J=7.3Hz ,2H),7.21–7.07(m,1H),7.03–6.89(m,1H),5.22(s,1H),4.01–3.90(m,4H),3.75–3.68(m,4H),2.59(s , 3H), 1.72 (d, J=7.0Hz, 3H). MS(ESI)m/z 418.2[M+H] + .
实施例I-6：Embodiment I-6:
Figure PCTCN2022135958-appb-000105
Figure PCTCN2022135958-appb-000105
参照实施例I-2步骤8的制备方法，使用I-2h和3,6-二氢-2H-吡喃-4-硼酸频哪醇酯为原料得I-6. 1H NMR(400MHz,DMSO-d 6)δ9.08(t,J＝2.0Hz,1H),8.76(dd,J＝4.0,2.1Hz,1H),7.88(t,J＝7.2Hz,1H),7.77(d,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.32(t,J＝7.8Hz,1H),6.71(d,J＝6.4Hz, 1H),5.72–5.63(m,1H),4.91–4.86(m,1H),4.11–4.01(m,2H),3.87–3.81(m,1H),2.65(s,3H),2.58(s,3H),2.34–2.24(m,1H),2.03–1.94(m,1H),1.56(d,J＝6.9Hz,3H).MS(ESI)m/z 429.1[M+H] +. 1 H NMR (400MHz, DMSO -d 6 )δ9.08(t,J=2.0Hz,1H),8.76(dd,J=4.0,2.1Hz,1H),7.88(t,J=7.2Hz,1H),7.77(d,J= 7.8Hz, 1H), 7.52(d, J=7.8Hz, 1H), 7.32(t, J=7.8Hz, 1H), 6.71(d, J=6.4Hz, 1H), 5.72–5.63(m, 1H) ,4.91–4.86(m,1H),4.11–4.01(m,2H),3.87–3.81(m,1H),2.65(s,3H),2.58(s,3H),2.34–2.24(m,1H) ,2.03–1.94(m,1H),1.56(d,J＝6.9Hz,3H).MS(ESI)m/z 429.1[M+H] + .
实施例I-7：Embodiment I-7:
Figure PCTCN2022135958-appb-000106
Figure PCTCN2022135958-appb-000106
将化合物I-6溶于甲醇，加入二氧化铂，置换氢气后，常温搅拌反应。反应完成后，过滤，滤液浓缩，剩余物经制备色谱法纯化得I-7。 1H NMR(400MHz,DMSO-d 6)δ9.10(s,1H),8.82(s,1H),7.82(d,J＝6.7Hz,1H),7.76(d,J＝7.9Hz,1H),7.53(d,J＝7.8Hz,1H),7.32(t,J＝7.9Hz,1H),5.74–5.64(m,1H),4.08–4.00(m,2H),3.57–3.48(m,2H),3.15–3.08(m,1H),2.65(s,3H),2.58(s,3H),1.93–1.82(m,4H),1.57(d,J＝6.9Hz,3H).MS(ESI)m/z 431.1[M+H] +. Compound I-6 was dissolved in methanol, platinum dioxide was added to replace the hydrogen, and the reaction was stirred at room temperature. After the reaction was completed, it was filtered, the filtrate was concentrated, and the residue was purified by preparative chromatography to obtain I-7. 1 H NMR (400MHz,DMSO-d 6 )δ9.10(s,1H),8.82(s,1H),7.82(d,J=6.7Hz,1H),7.76(d,J=7.9Hz,1H) ,7.53(d,J=7.8Hz,1H),7.32(t,J=7.9Hz,1H),5.74–5.64(m,1H),4.08–4.00(m,2H),3.57–3.48(m,2H ),3.15–3.08(m,1H),2.65(s,3H),2.58(s,3H),1.93–1.82(m,4H),1.57(d,J＝6.9Hz,3H).MS(ESI) m/z 431.1[M+H] + .
实施例I-8：Embodiment I-8:
Figure PCTCN2022135958-appb-000107
Figure PCTCN2022135958-appb-000107
参照实施例I-1步骤5的制备方法，使用I-1e和A-2为原料得I-8。 1H NMR(400MHz,DMSO-d 6)δ9.05(d,J＝2.7Hz,1H),8.75(s,1H),8.00(d,J＝2.3Hz,1H),7.74(t,J＝6.4Hz,2H),7.63(t,J＝7.4Hz,1H),7.32(t,J＝7.7Hz,1H),5.75(t,J＝7.0Hz,1H),3.92–3.75(m,4H),3.55–3.42(m,4H),1.64(d,J＝7.0Hz,3H).MS(ESI)m/z 422.0[M+H] +. Referring to the preparation method in Step 5 of Example I-1, I-1e and A-2 were used as raw materials to obtain I-8. 1 H NMR (400MHz, DMSO-d 6 )δ9.05(d, J=2.7Hz, 1H), 8.75(s, 1H), 8.00(d, J=2.3Hz, 1H), 7.74(t, J= 6.4Hz, 2H), 7.63(t, J=7.4Hz, 1H), 7.32(t, J=7.7Hz, 1H), 5.75(t, J=7.0Hz, 1H), 3.92–3.75(m, 4H) ,3.55–3.42(m,4H),1.64(d,J＝7.0Hz,3H).MS(ESI)m/z 422.0[M+H] + .
实施例I-9：Example I-9:
Figure PCTCN2022135958-appb-000108
Figure PCTCN2022135958-appb-000108
参照实施例I-1步骤5的制备方法，使用I-1e和A-9为原料得I-9。 1H NMR(400MHz,DMSO-d 6)δ9.02(d,J＝2.6Hz,1H),8.72(s,1H),7.97(d,J＝2.2Hz,1H),7.62(dd,J＝18.6,7.1Hz,2H),7.37(dt,J＝14.9,7.4Hz,2H),5.59(t,J＝7.0Hz,1H),3.90–3.68(m,4H),3.54–3.40(m,4H),3.29–3.22(m,1H),3.15(dd,J＝16.0,5.7Hz,1H),2.68–2.57(m,2H),1.60(d,J＝7.0Hz,3H).MS(ESI)m/z 412.1[M+H] +. Referring to the preparation method in Step 5 of Example I-1, I-1e and A-9 were used as raw materials to obtain I-9. 1 H NMR (400MHz, DMSO-d 6 ) δ9.02(d, J=2.6Hz, 1H), 8.72(s, 1H), 7.97(d, J=2.2Hz, 1H), 7.62(dd, J= 18.6, 7.1Hz, 2H), 7.37(dt, J＝14.9, 7.4Hz, 2H), 5.59(t, J＝7.0Hz, 1H), 3.90–3.68(m, 4H), 3.54–3.40(m, 4H ),3.29–3.22(m,1H),3.15(dd,J＝16.0,5.7Hz,1H),2.68–2.57(m,2H),1.60(d,J＝7.0Hz,3H).MS(ESI) m/z 412.1[M+H] + .
实施例I-10：Example I-10:
Figure PCTCN2022135958-appb-000109
Figure PCTCN2022135958-appb-000109
参照实施例I-2步骤8的制备方法，使用I-2h和1-甲基-6-氧代-1,6-二氢吡啶-3-硼酸频那醇酯为原料得I-10。 1H NMR(400MHz,DMSO-d 6)δ9.42(d,J＝2.0Hz,1H),9.03(d,J＝1.6Hz,1H),8.51(d,J＝2.6Hz,1H),8.11(dd,J  1＝2.8Hz,J  2＝9.6Hz,1H),7.83(d,J＝6.8Hz,1H),7.78(d,J＝7.6Hz,1H),7.53(d,J＝8.0Hz,1H),7.32(t,J＝7.8Hz,1H),6.66(t,J＝8.6Hz,1H),5.74-5.68(m,1H),3.58(s,3H),2.68(s,3H),2.59(s,3H),1.59(d,J＝6.8Hz,3H).MS(ESI)m/z 454.5[M+H] +. Referring to the preparation method in Step 8 of Example I-2, I-10 was obtained by using I-2h and 1-methyl-6-oxo-1,6-dihydropyridine-3-boronic acid pinacol ester as raw materials. 1 H NMR (400MHz, DMSO-d 6 )δ9.42(d, J=2.0Hz, 1H), 9.03(d, J=1.6Hz, 1H), 8.51(d, J=2.6Hz, 1H), 8.11 (dd, J 1 =2.8Hz, J 2 =9.6Hz, 1H), 7.83 (d, J = 6.8Hz, 1H), 7.78 (d, J = 7.6Hz, 1H), 7.53 (d, J = 8.0Hz ,1H),7.32(t,J=7.8Hz,1H),6.66(t,J=8.6Hz,1H),5.74-5.68(m,1H),3.58(s,3H),2.68(s,3H) ,2.59(s,3H),1.59(d,J=6.8Hz,3H).MS(ESI)m/z 454.5[M+H] + .
实施例I-11：Example I-11:
Figure PCTCN2022135958-appb-000110
Figure PCTCN2022135958-appb-000110
参照实施例I-1步骤5的制备方法，使用I-1e和A-1为原料得I-11。 1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝2.7Hz,1H),8.74(s,1H),8.01(d,J＝2.4Hz,1H),7.68(t,J＝15.5Hz,1H),7.61(t,J＝7.3Hz,1H),7.48(t,J＝6.7Hz,1H),7.43–6.99(m,2H),5.76(p,J＝7.0Hz,1H),3.91–3.76(m,4H),3.57–3.44(m,4H),1.62(d,J＝7.0Hz,3H).MS(ESI)m/z 404.5[M+H] +. Referring to the preparation method in Step 5 of Example I-1, I-11 was obtained using I-1e and A-1 as raw materials. 1 H NMR (400MHz, DMSO-d 6 )δ9.04(d, J=2.7Hz, 1H), 8.74(s, 1H), 8.01(d, J=2.4Hz, 1H), 7.68(t, J= 15.5Hz, 1H), 7.61(t, J=7.3Hz, 1H), 7.48(t, J=6.7Hz, 1H), 7.43–6.99(m, 2H), 5.76(p, J=7.0Hz, 1H) ,3.91–3.76(m,4H),3.57–3.44(m,4H),1.62(d,J＝7.0Hz,3H).MS(ESI)m/z 404.5[M+H] + .
实施例I-12：Example I-12:
Figure PCTCN2022135958-appb-000111
Figure PCTCN2022135958-appb-000111
参照实施例I-1步骤5的制备方法，使用I-1e和A-3为原料得I-12。 1H NMR(400MHz,DMSO-d 6)δ9.04(d,J＝2.7Hz,1H),8.74(s,1H),8.01(d,J＝2.4Hz,1H),7.68(d,J＝7.2Hz,1H),7.56(t,J＝7.1Hz,1H),7.42(t,J＝7.3Hz,1H),7.21(t,J＝7.7Hz,1H),5.78(t,J＝6.9Hz,1H),3.93–3.77(m,4H),3.54–3.43(m,4H),2.05(t,J＝19.1Hz,3H),1.62(d,J＝7.0Hz,3H).MS(ESI)m/z 418.1[M+H] +. Referring to the preparation method in Step 5 of Example I-1, I-12 was obtained using I-1e and A-3 as raw materials. 1 H NMR (400MHz, DMSO-d 6 )δ9.04(d, J=2.7Hz, 1H), 8.74(s, 1H), 8.01(d, J=2.4Hz, 1H), 7.68(d, J= 7.2Hz, 1H), 7.56(t, J=7.1Hz, 1H), 7.42(t, J=7.3Hz, 1H), 7.21(t, J=7.7Hz, 1H), 5.78(t, J=6.9Hz ,1H),3.93–3.77(m,4H),3.54–3.43(m,4H),2.05(t,J＝19.1Hz,3H),1.62(d,J＝7.0Hz,3H).MS(ESI) m/z 418.1[M+H] + .
实施例I-13：Example I-13:
Figure PCTCN2022135958-appb-000112
Figure PCTCN2022135958-appb-000112
参照实施例I-1步骤5的制备方法，使用I-1e和A-10为原料得I-13。 1H NMR(400MHz, DMSO-d 6)δ9.04(d,J＝2.7Hz,1H),8.74(s,1H),8.01(d,J＝2.5Hz,1H),7.62(d,J＝7.3Hz,1H),7.53–7.42(m,2H),7.04(t,J＝7.6Hz,1H),5.70(t,J＝7.0Hz,1H),4.89(t,J＝16.6Hz,2H),3.88–3.76(m,4H),3.53–3.42(m,4H),1.60(d,J＝7.0Hz,3H).MS(ESI)m/z 414.1[M+H] +. Referring to the preparation method in Step 5 of Example I-1, I-13 was obtained using I-1e and A-10 as raw materials. 1 H NMR (400MHz, DMSO-d 6 )δ9.04(d, J=2.7Hz, 1H), 8.74(s, 1H), 8.01(d, J=2.5Hz, 1H), 7.62(d, J= 7.3Hz, 1H), 7.53–7.42(m, 2H), 7.04(t, J=7.6Hz, 1H), 5.70(t, J=7.0Hz, 1H), 4.89(t, J=16.6Hz, 2H) ,3.88–3.76(m,4H),3.53–3.42(m,4H),1.60(d,J＝7.0Hz,3H).MS(ESI)m/z 414.1[M+H] + .
实施例I-14：Example I-14:
Figure PCTCN2022135958-appb-000113
Figure PCTCN2022135958-appb-000113
参照实施例I-2，步骤8的制备方法，使用I-2h和1-甲基-1,2,3,6-四氢吡啶-4-硼酸频哪醇酯为原料得I-14。 1H NMR(400MHz,DMSO-d 6)δ9.30(d,J＝2.1Hz,1H),8.83(d,J＝2.0Hz,1H),7.88(d,J＝6.8Hz,1H),7.76(d,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.32(t,J＝7.8Hz,1H),6.63(s,1H),5.73–5.58(m,1H),3.13(s,2H),2.78–2.61(m,7H),2.56(d,J＝18.3Hz,3H),2.33(s,3H),1.57(d,J＝6.9Hz,3H).MS(ESI)m/z 442.0[M+H] +. Referring to Example I-2, the preparation method of step 8, using I-2h and 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester as raw materials to obtain I-14. 1 H NMR (400MHz, DMSO-d 6 ) δ9.30(d, J=2.1Hz, 1H), 8.83(d, J=2.0Hz, 1H), 7.88(d, J=6.8Hz, 1H), 7.76 (d, J=7.8Hz, 1H), 7.53(d, J=7.8Hz, 1H), 7.32(t, J=7.8Hz, 1H), 6.63(s, 1H), 5.73–5.58(m, 1H) ,3.13(s,2H),2.78–2.61(m,7H),2.56(d,J＝18.3Hz,3H),2.33(s,3H),1.57(d,J＝6.9Hz,3H).MS( ESI)m/z 442.0[M+H] + .
实施例I-15Example I-15
Figure PCTCN2022135958-appb-000114
Figure PCTCN2022135958-appb-000114
步骤1：step 1:
将I-15a(250mg,0.94mmol)溶于三氟乙酸/二氯甲烷(3mL/15mL)。室温搅拌1.5小时。反应液直接浓缩，经柱层析分离得棕色固体1-15b(130mg,86％)。MS(ESI)m/z＝167.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ7.19(d,J＝0.8Hz,1H),7.09(d,J＝0.8Hz,1H),3.71(s,3H),2.78-2.75(m,4H),2.73-2.70(m,4H). I-15a (250 mg, 0.94 mmol) was dissolved in trifluoroacetic acid/dichloromethane (3 mL/15 mL). Stir at room temperature for 1.5 hours. The reaction solution was directly concentrated, and a brown solid 1-15b (130 mg, 86%) was obtained by column chromatography. MS(ESI)m/z=167.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ7.19(d,J=0.8Hz,1H),7.09(d,J=0.8Hz, 1H),3.71(s,3H),2.78-2.75(m,4H),2.73-2.70(m,4H).
步骤2：Step 2:
参照实施例I-2，步骤8制备方法，使用I-15b和I-2h为原料得I-15(28mg,46％)。MS(ESI)m/z＝511.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.06(d,J＝2.6Hz,1H),8.02(d,J＝2.6Hz,1H),7.75(d,J＝7.8Hz,1H),7.58(d,J＝6.8Hz,1H),7.52(d,J＝7.6Hz,1H),7.38(s,1H),7.32(t,J＝7.8Hz,1H),7.26(s,1H),5.71-5.64(m,1H),3.76(s,3H),3.66-3.56(m,4H),3.12-3.01(m,4H),2.59(s,3H),2.58(s,3H),1.56(d,J＝8.0Hz,3H). Referring to Example I-2, the preparation method in Step 8, I-15 (28mg, 46%) was obtained by using I-15b and I-2h as raw materials. MS(ESI)m/z=511.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.06(d,J=2.6Hz,1H),8.02(d,J=2.6Hz, 1H), 7.75(d, J=7.8Hz, 1H), 7.58(d, J=6.8Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.38(s, 1H), 7.32(t, J＝7.8Hz,1H),7.26(s,1H),5.71-5.64(m,1H),3.76(s,3H),3.66-3.56(m,4H),3.12-3.01(m,4H),2.59 (s,3H),2.58(s,3H),1.56(d,J=8.0Hz,3H).
实施例I-16：Example I-16:
Figure PCTCN2022135958-appb-000115
Figure PCTCN2022135958-appb-000115
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000116
代替吗啉，制备得到化合物I-16。 1H NMR(400MHz,DMSO-d 6)δ9.02(d,J＝2.6Hz,1H),7.98(d,J＝2.4Hz,1H),7.74(d,J＝7.7Hz,1H),7.59(d,J＝6.4Hz,1H),7.53(d,J＝7.7Hz,1H),7.32(t,J＝7.8Hz,1H),5.77–5.61(m,1H),4.80–4.66(m,4H),4.22(dd,J＝15.7,8.2Hz,1H),3.72(d,J＝5.3Hz,2H),3.50(s,4H),3.41(s,2H),2.59(s,3H),2.57(s,3H),1.56(d,J＝6.9Hz,3H).MS(ESI)m/z＝515.1[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000116
Instead of morpholine, compound 1-16 was prepared. 1 H NMR (400MHz, DMSO-d 6 )δ9.02(d, J=2.6Hz, 1H), 7.98(d, J=2.4Hz, 1H), 7.74(d, J=7.7Hz, 1H), 7.59 (d,J=6.4Hz,1H),7.53(d,J=7.7Hz,1H),7.32(t,J=7.8Hz,1H),5.77–5.61(m,1H),4.80–4.66(m, 4H), 4.22(dd, J=15.7, 8.2Hz, 1H), 3.72(d, J=5.3Hz, 2H), 3.50(s, 4H), 3.41(s, 2H), 2.59(s, 3H), 2.57(s,3H),1.56(d,J=6.9Hz,3H).MS(ESI)m/z=515.1[M+H] + .
实施例I-17：Example I-17:
Figure PCTCN2022135958-appb-000117
Figure PCTCN2022135958-appb-000117
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000118
代替吗啉，制备得到化合物I-17。 1H NMR(400MHz,DMSO-d 6)δ9.04(s,1H),8.00(d,J＝1.6Hz,1H),7.74(d,J＝7.6Hz,1H),7.60(d,J＝6.4Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.6Hz,1H),5.71–5.63(m,1H),3.91(t,J＝8.0Hz,1H),3.77–3.70(m,7H),3.55–3.45(m,5H),2.59(s,3H),2.57(s,3H),2.06(dd,J  1＝7.6Hz,J  2＝6.4Hz,1H),1.56(d,J＝6.8Hz,3H).MS(ESI)m/z＝529.3[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000118
Instead of morpholine, compound 1-17 was prepared. 1 H NMR (400MHz, DMSO-d 6 )δ9.04(s, 1H), 8.00(d, J=1.6Hz, 1H), 7.74(d, J=7.6Hz, 1H), 7.60(d, J= 6.4Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.32(t, J=7.6Hz, 1H), 5.71–5.63(m, 1H), 3.91(t, J=8.0Hz, 1H) ,3.77–3.70(m,7H),3.55–3.45(m,5H),2.59(s,3H),2.57(s,3H),2.06(dd,J 1 =7.6Hz,J 2 =6.4Hz,1H ), 1.56(d, J＝6.8Hz, 3H). MS(ESI) m/z＝529.3[M+H] + .
实施例I-18：Example I-18:
Figure PCTCN2022135958-appb-000119
Figure PCTCN2022135958-appb-000119
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000120
代替吗啉，制备得到化合物I-18。 1H NMR(400MHz,DMSO-d 6)δ9.03(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.74(d,J＝7.6Hz,1H),7.56–7.52(m,2H),7.31(t,J＝8.0Hz,1H),5.69–5.66(m,1H),3.87(d,J＝10.4Hz,2H),3.74(d,J＝2.4Hz,4H),3.51(d,J＝17.2Hz,4H),3.44-3.39(m,2H),3.00-2.95(m,1H),2.59(s,3H),2.57(s,3H),1.68–1.55(m,7H).MS(ESI)m/z＝543.2[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000120
Instead of morpholine, compound 1-18 was prepared. 1 H NMR (400MHz, DMSO-d 6 )δ9.03(d, J=2.4Hz, 1H), 7.99(d, J=2.4Hz, 1H), 7.74(d, J=7.6Hz, 1H), 7.56 –7.52(m,2H),7.31(t,J=8.0Hz,1H),5.69–5.66(m,1H),3.87(d,J=10.4Hz,2H),3.74(d,J=2.4Hz, 4H), 3.51(d, J＝17.2Hz, 4H), 3.44-3.39(m, 2H), 3.00-2.95(m, 1H), 2.59(s, 3H), 2.57(s, 3H), 1.68–1.55 (m,7H).MS(ESI)m/z＝543.2[M+H] + .
实施例I-21：Example I-21:
Figure PCTCN2022135958-appb-000121
Figure PCTCN2022135958-appb-000121
参照实施例I-1的制备方法，在步骤3中用N-甲基哌嗪代替吗啉，制备得到化合物I-21(11mg, 12％)。MS(ESI)m/z 445.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.01(d,J＝2.4Hz,1H),7.95(d,J＝2.4Hz,1H),7.74(d,J＝7.2Hz,1H),7.60-7.47(m,2H),7.31(t,J＝7.6Hz,1H),5.67(t,J＝6.8Hz,1H),3.50(s,4H),2.58-2.53(m,10H),2.28(s,3H),1.55(d,J＝6.8Hz,3H). Referring to the preparation method of Example I-1, in step 3, N-methylpiperazine was used instead of morpholine to prepare compound I-21 (11 mg, 12%). MS (ESI) m/z 445.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.01(d, J=2.4Hz, 1H), 7.95(d, J=2.4Hz, 1H ),7.74(d,J=7.2Hz,1H),7.60-7.47(m,2H),7.31(t,J=7.6Hz,1H),5.67(t,J=6.8Hz,1H),3.50(s ,4H),2.58-2.53(m,10H),2.28(s,3H),1.55(d,J＝6.8Hz,3H).
实施例I-22：Example I-22:
Figure PCTCN2022135958-appb-000122
Figure PCTCN2022135958-appb-000122
参照实施例I-1的制备方法，在步骤3中用哌嗪代替吗啉，制备得到化合物I-22。 1H NMR(400MHz,DMSO-d 6)δ8.99(d,J＝2.4Hz,1H),8.69(s,1H),7.94(d,J＝2.0Hz,1H),7.76(d,J＝7.8Hz,1H),7.70(d,J＝7.0Hz,1H),7.53(d,J＝7.6Hz,1H),7.33(t,J＝8.0Hz,1H),5.78–5.71(m,1H),3.40(t,J＝4.4Hz,4H),3.02–2.85(t,J＝4.4Hz,4H),2.58(s,3H),1.57(d,J＝8.0Hz,3H).MS(ESI)m/z＝417.1[M+H] +. Referring to the preparation method of Example I-1, piperazine was used instead of morpholine in step 3 to prepare compound I-22. 1 H NMR (400MHz, DMSO-d 6 ) δ8.99(d, J=2.4Hz, 1H), 8.69(s, 1H), 7.94(d, J=2.0Hz, 1H), 7.76(d, J= 7.8Hz, 1H), 7.70(d, J=7.0Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.33(t, J=8.0Hz, 1H), 5.78–5.71(m, 1H) ,3.40(t,J=4.4Hz,4H),3.02–2.85(t,J=4.4Hz,4H),2.58(s,3H),1.57(d,J=8.0Hz,3H).MS(ESI) m/z＝417.1[M+H] + .
实施例I-24：Example I-24:
Figure PCTCN2022135958-appb-000123
Figure PCTCN2022135958-appb-000123
参照实施例I-1的制备方法，在步骤5中用A-6代替A-12，制备得到化合物I-24。 1H NMR(400MHz,DMSO-d 6)δ9.03(d,J＝2.6Hz,1H),8.75(s,1H),8.04(d,J＝2.4Hz,1H),7.58(d,J＝7.1Hz,1H),6.70–6.60(m,1H),6.55(dt,J＝12.6,6.3Hz,1H),5.63(t,J＝7.0Hz,1H),5.09(s,2H),3.90–3.76(m,4H),3.55–3.43(m,4H),1.97(t,J＝19.0Hz,3H),1.57(d,J＝7.0Hz,3H).MS(ESI)m/z＝433.1[M+H] +. Referring to the preparation method of Example I-1, in step 5, A-6 was used instead of A-12 to prepare compound I-24. 1 H NMR (400MHz, DMSO-d 6 ) δ9.03(d, J=2.6Hz, 1H), 8.75(s, 1H), 8.04(d, J=2.4Hz, 1H), 7.58(d, J= 7.1Hz, 1H), 6.70–6.60(m, 1H), 6.55(dt, J＝12.6, 6.3Hz, 1H), 5.63(t, J＝7.0Hz, 1H), 5.09(s, 2H), 3.90– 3.76(m,4H),3.55–3.43(m,4H),1.97(t,J=19.0Hz,3H),1.57(d,J=7.0Hz,3H).MS(ESI)m/z=433.1[ M+H] + .
实施例I-25：Example I-25:
Figure PCTCN2022135958-appb-000124
Figure PCTCN2022135958-appb-000124
参照实施例I-2的制备方法，在步骤8中用哌嗪代替吗啉，制备得到化合物I-25。 1H NMR(400MHz,DMSO-d 6)δ8.99(d,J＝2.4Hz,1H),7.93(d,J＝2.8Hz,1H),7.74(d,J＝7.6Hz,1H),7.56–7.51(m,2H),7.31(t,J＝8.0Hz,1H),5.69–5.65(m,1H),3.42(d,J＝4.8Hz,4H),2.94(d,J＝3.2Hz,4H),2.58(s,6H),1.55(d,J＝7.6Hz,4H).MS(ESI)m/z＝431.1[M+H] +. Referring to the preparation method of Example I-2, piperazine was used instead of morpholine in step 8 to prepare compound I-25. 1 H NMR (400MHz, DMSO-d 6 )δ8.99(d, J=2.4Hz, 1H), 7.93(d, J=2.8Hz, 1H), 7.74(d, J=7.6Hz, 1H), 7.56 –7.51(m,2H),7.31(t,J=8.0Hz,1H),5.69–5.65(m,1H),3.42(d,J=4.8Hz,4H),2.94(d,J=3.2Hz, 4H), 2.58(s, 6H), 1.55(d, J=7.6Hz, 4H). MS(ESI) m/z=431.1[M+H] + .
实施例I-32：Example I-32:
Figure PCTCN2022135958-appb-000125
Figure PCTCN2022135958-appb-000125
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000126
代替吗啉，制备得到化合物I-32。 1H NMR(400MHz,DMSO-d 6)δ8.99(d,J＝2.6Hz,1H),7.92(d,J＝2.6Hz,1H),8.0(d,J＝7.7Hz,1H),7.52(dd,J＝7.2,3.5Hz,2H),7.32(t,J＝7.6Hz,1H),5.67(t,J＝6.9Hz,1H),3.60(dt,J＝22.5,11.4Hz,2H),3.50(t,J＝10.9Hz,2H),2.57(s,6H),1.56(dd,J＝13.3,6.0Hz,7H),1.12(s,3H).MS(ESI)m/z＝459.5[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000126
Instead of morpholine, compound 1-32 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ8.99(d, J=2.6Hz, 1H), 7.92(d, J=2.6Hz, 1H), 8.0(d, J=7.7Hz, 1H), 7.52 (dd,J=7.2,3.5Hz,2H),7.32(t,J=7.6Hz,1H),5.67(t,J=6.9Hz,1H),3.60(dt,J=22.5,11.4Hz,2H) ,3.50(t,J=10.9Hz,2H),2.57(s,6H),1.56(dd,J=13.3,6.0Hz,7H),1.12(s,3H).MS(ESI)m/z=459.5 [M+H] + .
实施例I-34：Example I-34:
Figure PCTCN2022135958-appb-000127
Figure PCTCN2022135958-appb-000127
将I-153(50mg,0.1mmol)溶于乙腈(1mL)，室温下加入甲醛水溶液(10mg,0.3mmol)和氰基硼氢化钠(20mg,0.3mmol)。反应液常温搅拌反应16小时，反应完成后，浓缩，剩余物经柱层析纯化得I-34(28mg,53％)。 1H NMR(400MHz,DMSO-d 6)δ8.42(d,J＝1.2Hz,1H),7.74(d,J＝8.0Hz,1H),7.74(d,J＝2.4Hz,1H),7.52(d,J＝7.6Hz,1H),7.44(d,J＝6.8Hz,1H),7.31(t,J＝8.0Hz,1H),5.67–5.63(m,1H),4.13(s,2H),4.03(s,2H),2.56–2.54(m,7H),2.38–2.33(m,2H),2.06–2.01(m,8H),1.54(d,J＝6.8Hz,3H).MS(ESI)m/z＝485.2[M+H] +. I-153 (50 mg, 0.1 mmol) was dissolved in acetonitrile (1 mL), and aqueous formaldehyde (10 mg, 0.3 mmol) and sodium cyanoborohydride (20 mg, 0.3 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 16 hours. After the reaction was completed, it was concentrated and the residue was purified by column chromatography to obtain I-34 (28 mg, 53%). 1 H NMR (400MHz, DMSO-d 6 ) δ8.42(d, J=1.2Hz, 1H), 7.74(d, J=8.0Hz, 1H), 7.74(d, J=2.4Hz, 1H), 7.52 (d, J=7.6Hz, 1H), 7.44(d, J=6.8Hz, 1H), 7.31(t, J=8.0Hz, 1H), 5.67–5.63(m, 1H), 4.13(s, 2H) ,4.03(s,2H),2.56–2.54(m,7H),2.38–2.33(m,2H),2.06–2.01(m,8H),1.54(d,J＝6.8Hz,3H).MS(ESI )m/z＝485.2[M+H] + .
实施例I-38：Example I-38:
Figure PCTCN2022135958-appb-000128
Figure PCTCN2022135958-appb-000128
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000129
代替吗啉，制备得到化合物I-38。 1H NMR(400MHz,MeOD-d 4)δ8.78(d,J＝2.8Hz,1H),7.71–7.68(m,2H),7.49(d,J＝8.0Hz,1H),7.24(d,J＝8.0Hz,1H),5.72(q,J＝7.2Hz,1H),3.83(d,J＝4.4Hz,2H),3.75(d,J＝6.0Hz,2H),2.85(d,J＝4.4Hz,2H),2.68-2.61(m,5H),2.61(s,3H),2.41(s,3H),2.14–2.09(m,2H),1.62(d,J＝6.8Hz,3H).MS(ESI)m/z＝459.2[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000129
Instead of morpholine, compound 1-38 was prepared. 1 H NMR (400MHz, MeOD-d 4 ) δ8.78(d, J=2.8Hz, 1H), 7.71–7.68(m, 2H), 7.49(d, J=8.0Hz, 1H), 7.24(d, J＝8.0Hz, 1H), 5.72(q, J＝7.2Hz, 1H), 3.83(d, J＝4.4Hz, 2H), 3.75(d, J＝6.0Hz, 2H), 2.85(d, J＝ 4.4Hz, 2H), 2.68-2.61(m, 5H), 2.61(s, 3H), 2.41(s, 3H), 2.14–2.09(m, 2H), 1.62(d, J=6.8Hz, 3H). MS(ESI)m/z=459.2[M+H] + .
实施例I-40：Example I-40:
Figure PCTCN2022135958-appb-000130
Figure PCTCN2022135958-appb-000130
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000131
代替吗啉，制备得到化合物I-40。 1H NMR(400MHz,DMSO-d 6)δ8.45(d,J＝2.6Hz,1H),7.73(d,J＝7.8Hz,1H),7.60(d,J＝2.6Hz,1H),7.50(dd,J＝11.8,7.2Hz,2H),7.31(t,J＝7.8Hz,1H),5.65(t,J＝6.9Hz,1H),4.78(s,4H),4.39–4.16(m,4H),2.56(s,6H),1.55(d,J＝7.0Hz,3H).MS(ESI)m/z＝444.2[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000131
Instead of morpholine, compound 1-40 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ8.45(d, J=2.6Hz, 1H), 7.73(d, J=7.8Hz, 1H), 7.60(d, J=2.6Hz, 1H), 7.50 (dd,J=11.8,7.2Hz,2H),7.31(t,J=7.8Hz,1H),5.65(t,J=6.9Hz,1H),4.78(s,4H),4.39–4.16(m, 4H), 2.56(s, 6H), 1.55(d, J=7.0Hz, 3H). MS(ESI) m/z=444.2[M+H] + .
实施例I-48：Example I-48:
Figure PCTCN2022135958-appb-000132
Figure PCTCN2022135958-appb-000132
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000133
代替吗啉，制备得到化合物I-48。 1H NMR(400MHz,DMSO-d 6)δ8.26(s,1H),7.74(d,J＝7.7Hz,1H),7.63(d,J＝2.3Hz,1H),7.50(dd,J＝16.3,7.3Hz,2H),7.31(t,J＝7.9Hz,1H),5.67(t,J＝6.8Hz,1H),3.90(dd,J＝8.5,6.5Hz,2H),3.66(dd,J＝10.8,6.8Hz,4H),3.47(d,J＝6.2Hz,2H),3.14(s,2H),2.57(s,6H),1.55(d,J＝7.0Hz,3H).MS(ESI)m/z＝458.2[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000133
Instead of morpholine, compound 1-48 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ8.26(s, 1H), 7.74(d, J=7.7Hz, 1H), 7.63(d, J=2.3Hz, 1H), 7.50(dd, J= 16.3,7.3Hz,2H),7.31(t,J=7.9Hz,1H),5.67(t,J=6.8Hz,1H),3.90(dd,J=8.5,6.5Hz,2H),3.66(dd, J=10.8,6.8Hz,4H),3.47(d,J=6.2Hz,2H),3.14(s,2H),2.57(s,6H),1.55(d,J=7.0Hz,3H).MS( ESI) m/z=458.2[M+H] + .
实施例I-62：Example I-62:
Figure PCTCN2022135958-appb-000134
Figure PCTCN2022135958-appb-000134
参照实施例I-2的制备方法，在步骤3中用
Figure PCTCN2022135958-appb-000135
代替吗啉，制备得到化合物I-62(32mg,60％)。MS(ESI)m/z 457.2[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.68(d,J＝2.4Hz,1H),7.74(d,J＝8.0Hz,1H),7.62(d,J＝2.4Hz,1H),7.52(d,J＝7.6Hz,1H),7.42(d,J＝6.4Hz,1H),7.31(t,J＝8.0Hz,1H),5.71-5.61(m,1H),4.73(s,1H),3.64(s,1H),3.50(s,2H),2.93(d,J＝9.6Hz,1H),2.56(d,J＝6.4Hz,7H),2.35(s,3H),2.02(d,J＝8.8Hz,1H),1.87(d,J＝9.2Hz,1H),1.55(d,J＝6.8Hz,3H). With reference to the preparation method of embodiment 1-2, use in step 3
Figure PCTCN2022135958-appb-000135
Instead of morpholine, compound I-62 (32 mg, 60%) was prepared. MS (ESI) m/z 457.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.68(d, J=2.4Hz, 1H), 7.74(d, J=8.0Hz, 1H ),7.62(d,J=2.4Hz,1H),7.52(d,J=7.6Hz,1H),7.42(d,J=6.4Hz,1H),7.31(t,J=8.0Hz,1H), 5.71-5.61(m,1H),4.73(s,1H),3.64(s,1H),3.50(s,2H),2.93(d,J=9.6Hz,1H),2.56(d,J=6.4Hz ,7H),2.35(s,3H),2.02(d,J=8.8Hz,1H),1.87(d,J=9.2Hz,1H),1.55(d,J=6.8Hz,3H).
实施例I-70：Example I-70:
Figure PCTCN2022135958-appb-000136
Figure PCTCN2022135958-appb-000136
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000137
代替吗啉，制备得到化合物I-70。 1H NMR(400MHz,DMSO-d 6)δ9.01(s,1H),8.27(s,2H),7.74(d,J＝7.6Hz,1H),7.59–7.47(m,2H),7.31(t,J＝7.5Hz,1H),5.66(s,1H),4.19–4.06(m,1H),3.89–3.68(m,4H),3.56(d,J＝8.6Hz,1H),3.23(s,1H),3.05(s,1H),2.57(s,6H),2.02–1.60(m,4H),1.55(d,J＝6.7Hz,3H),1.13(d,J＝6.2Hz,3H).MS(ESI)m/z 515.3[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000137
Instead of morpholine, compound 1-70 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ9.01(s, 1H), 8.27(s, 2H), 7.74(d, J=7.6Hz, 1H), 7.59–7.47(m, 2H), 7.31( t, J＝7.5Hz, 1H), 5.66(s, 1H), 4.19–4.06(m, 1H), 3.89–3.68(m, 4H), 3.56(d, J＝8.6Hz, 1H), 3.23(s ,1H),3.05(s,1H),2.57(s,6H),2.02–1.60(m,4H),1.55(d,J＝6.7Hz,3H),1.13(d,J＝6.2Hz,3H) .MS(ESI)m/z 515.3[M+H] + .
实施例I-72：Example I-72:
Figure PCTCN2022135958-appb-000138
Figure PCTCN2022135958-appb-000138
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000139
代替吗啉，制备得到化合物I-72。 1H NMR(400MHz,DMSO-d 6)δ9.21(d,J＝2.3Hz,1H),8.59(s,1H),8.07(s,1H),7.72(d,J＝8.0Hz,1H),7.58(d,J＝7.4Hz,1H),7.37(t,J＝7.7Hz,1H),5.49–5.39(m,1H),3.81(t,J＝7.1Hz,4H),3.76–3.66(m,2H),3.55(s,2H),2.71(s,3H),2.57(s,3H),1.83(t,J＝7.1Hz,2H),1.71(t,J＝5.4Hz,4H),1.61(d,J＝6.9Hz,3H).MS(ESI)m/z＝486.2[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000139
Instead of morpholine, compound 1-72 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ9.21(d, J=2.3Hz, 1H), 8.59(s, 1H), 8.07(s, 1H), 7.72(d, J=8.0Hz, 1H) ,7.58(d,J=7.4Hz,1H),7.37(t,J=7.7Hz,1H),5.49–5.39(m,1H),3.81(t,J=7.1Hz,4H),3.76–3.66( m,2H),3.55(s,2H),2.71(s,3H),2.57(s,3H),1.83(t,J=7.1Hz,2H),1.71(t,J=5.4Hz,4H), 1.61(d,J=6.9Hz,3H).MS(ESI)m/z=486.2[M+H] + .
实施例I-84：Example I-84:
Figure PCTCN2022135958-appb-000140
Figure PCTCN2022135958-appb-000140
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000141
代替吗啉，制备得到化合物I-84。 1H NMR(400MHz,DMSO-d 6)δ9.19(d,J＝2.6Hz,1H),8.54(s,1H),8.04(s,1H),7.72(d,J＝7.7Hz,1H),7.57(d,J＝7.7Hz,1H),7.37(t,J＝8.1Hz,1H),5.54–5.34(m,1H),4.58(s,1H),4.04(d,J＝13.7Hz,2H),3.51(dd,J＝29.6,17.4Hz,3H),2.68(d,J＝15.3Hz,3H),2.56(s,3H),1.72–1.56(m,6H),1.21(s,3H).MS(ESI)m/z＝460.2[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000141
Instead of morpholine, compound 1-84 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ9.19(d, J=2.6Hz, 1H), 8.54(s, 1H), 8.04(s, 1H), 7.72(d, J=7.7Hz, 1H) ,7.57(d,J=7.7Hz,1H),7.37(t,J=8.1Hz,1H),5.54–5.34(m,1H),4.58(s,1H),4.04(d,J=13.7Hz, 2H), 3.51(dd, J＝29.6, 17.4Hz, 3H), 2.68(d, J＝15.3Hz, 3H), 2.56(s, 3H), 1.72–1.56(m, 6H), 1.21(s, 3H ).MS(ESI)m/z＝460.2[M+H] + .
实施例I-142：Example I-142:
Figure PCTCN2022135958-appb-000142
Figure PCTCN2022135958-appb-000142
参照实施例I-2，步骤8的制备方法，使用I-180a与吗啉为原料制备得到化合物I-142(15mg,30％)。MS(ESI)m/z 428.0[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.03(d,J＝2.4Hz,1H),7.99(d,J＝2.8Hz,1H),7.50-7.38(m,3H),7.02(t,J＝7.6Hz,1H),5.66-5.58(m,1H),4.88(t,J＝16.4Hz,2H),3.91-3.79(m,4H),3.48(d,J＝5.2Hz,4H),2.60(s,3H),1.59(d,J＝7.2Hz,3H). Referring to Example I-2, the preparation method in step 8, compound I-142 (15 mg, 30%) was prepared using I-180a and morpholine as raw materials. MS (ESI) m/z 428.0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ9.03(d, J=2.4Hz, 1H), 7.99(d, J=2.8Hz, 1H ),7.50-7.38(m,3H),7.02(t,J＝7.6Hz,1H),5.66-5.58(m,1H),4.88(t,J＝16.4Hz,2H),3.91-3.79(m, 4H), 3.48(d, J=5.2Hz, 4H), 2.60(s, 3H), 1.59(d, J=7.2Hz, 3H).
实施例I-145：Example I-145:
Figure PCTCN2022135958-appb-000143
Figure PCTCN2022135958-appb-000143
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000144
代替吗啉，制备得到化合物I-145。 1H NMR(400MHz,DMSO-d 6)δ8.72(d,J＝2.5Hz,1H),7.74(d,J＝7.4Hz,1H),7.67(d,J＝2.5Hz,1H),7.52(d,J＝7.9Hz,1H),7.42(d,J＝6.6Hz,1H),7.31(t,J＝7.9Hz,1H),5.72–5.59(m,1H),4.98(s,1H),4.78(s,1H),3.87(d,J＝7.8Hz,1H),3.72(d,J＝7.5Hz,1H),3.66(d,J＝8.5Hz,1H),2.57(s,3H),2.56(s,3H),2.01(q,J＝9.7Hz,2H),1.55(d,J＝7.0Hz,3H).MS(ESI)m/z＝444.1[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000144
Instead of morpholine, compound 1-145 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ8.72(d, J=2.5Hz, 1H), 7.74(d, J=7.4Hz, 1H), 7.67(d, J=2.5Hz, 1H), 7.52 (d, J=7.9Hz, 1H), 7.42(d, J=6.6Hz, 1H), 7.31(t, J=7.9Hz, 1H), 5.72–5.59(m, 1H), 4.98(s, 1H) ,4.78(s,1H),3.87(d,J=7.8Hz,1H),3.72(d,J=7.5Hz,1H),3.66(d,J=8.5Hz,1H),2.57(s,3H) ,2.56(s,3H),2.01(q,J=9.7Hz,2H),1.55(d,J=7.0Hz,3H).MS(ESI)m/z=444.1[M+H] + .
实施例I-146：Example I-146:
Figure PCTCN2022135958-appb-000145
Figure PCTCN2022135958-appb-000145
参照实施例I-2的制备方法，在步骤8中用
Figure PCTCN2022135958-appb-000146
代替吗啉，制备得到化合物I-146。 1H NMR(400MHz,DMSO-d 6)δ8.73(d,J＝2.5Hz,1H),7.73(d,J＝7.6Hz,1H),7.66(d,J＝2.6Hz,1H),7.52(d,J＝7.3Hz,1H),7.39(d,J＝7.2Hz,1H),7.31(t,J＝7.6Hz,1H),5.66(t,J＝6.9Hz,1H),4.97(s,1H),4.78(s,1H),3.87(d,J＝7.5Hz,1H),3.74(d,J＝7.4Hz,1H),3.66(d,J＝9.8Hz,1H),2.57(s,6H),2.01(s,2H),1.55(d,J＝6.9Hz,3H).MS(ESI)m/z＝444.1[M+H] +. With reference to the preparation method of embodiment 1-2, use in step 8
Figure PCTCN2022135958-appb-000146
Instead of morpholine, compound 1-146 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ8.73(d, J=2.5Hz, 1H), 7.73(d, J=7.6Hz, 1H), 7.66(d, J=2.6Hz, 1H), 7.52 (d, J=7.3Hz, 1H), 7.39(d, J=7.2Hz, 1H), 7.31(t, J=7.6Hz, 1H), 5.66(t, J=6.9Hz, 1H), 4.97(s ,1H),4.78(s,1H),3.87(d,J=7.5Hz,1H),3.74(d,J=7.4Hz,1H),3.66(d,J=9.8Hz,1H),2.57(s ,6H),2.01(s,2H),1.55(d,J=6.9Hz,3H).MS(ESI)m/z=444.1[M+H] + .
实施例I-147：Example I-147:
Figure PCTCN2022135958-appb-000147
Figure PCTCN2022135958-appb-000147
参照实施例I-1的制备方法，在步骤3中用
Figure PCTCN2022135958-appb-000148
代替吗啉，制备得到化合物I-147。 1H NMR(400MHz,DMSO-d 6)δ9.00(d,J＝2.6Hz,1H),8.68(s,1H),7.94(d,J＝2.4Hz,1H),7.75(d,J＝8.0Hz,1H),7.71(d,J＝6.8Hz,1H),7.53(d,J＝8.0Hz,1H),7.33(t,J＝7.8Hz,1H),5.77-5.70(m,1H),4.54(t,J＝5.2Hz,1H),4.15(d,J＝11.6Hz,2H),3.32–3.28(m,2H),2.94(t,J＝12.4Hz,2H),2.58(s,3H),1.84(d,J＝12.0Hz,2H),1.72-1.61(m,1H),1.57(d,J＝7.2Hz,3H),δ1.30(qd,J＝12.6,3.8Hz,1H).MS(ESI)m/z＝446.1[M+H] +. With reference to the preparation method of embodiment I-1, use in step 3
Figure PCTCN2022135958-appb-000148
Instead of morpholine, compound 1-147 was prepared. 1 H NMR (400MHz, DMSO-d 6 ) δ9.00(d, J=2.6Hz, 1H), 8.68(s, 1H), 7.94(d, J=2.4Hz, 1H), 7.75(d, J= 8.0Hz, 1H), 7.71(d, J=6.8Hz, 1H), 7.53(d, J=8.0Hz, 1H), 7.33(t, J=7.8Hz, 1H), 5.77-5.70(m, 1H) ,4.54(t,J=5.2Hz,1H),4.15(d,J=11.6Hz,2H),3.32–3.28(m,2H),2.94(t,J=12.4Hz,2H),2.58(s, 3H), 1.84(d, J=12.0Hz, 2H), 1.72-1.61(m, 1H), 1.57(d, J=7.2Hz, 3H), δ1.30(qd, J=12.6, 3.8Hz, 1H ).MS(ESI)m/z＝446.1[M+H] + .
实施例I-149Example I-149
Figure PCTCN2022135958-appb-000149
Figure PCTCN2022135958-appb-000149
步骤1：step 1:
向I-149(11g,44.4mmol)的甲醇溶液(110mL)中加入对甲苯磺酸(0.43g,2.2mmol)和原甲酸三甲酯(23.6g,22.2mmol)。室温搅拌16小时。反应液经饱和碳酸氢钠水溶液处理至pH～8，经乙酸乙酯萃取，浓缩，柱层析分离后得无色油状物I-149b(8.7g,67％)。 1H NMR(400MHz,d 6-DMSO)δ7.43-7.26(m,5H),5.06(s,2H),4.09-3.93(m,3H),3.25(s,6H),2.75(s,2H),1.81-1.70(m,1H),1.62(d,J＝12.8Hz,2H),1.09(qd,J＝12.7,4.4Hz,2H). To a solution of 1-149 (11 g, 44.4 mmol) in methanol (110 mL) was added p-toluenesulfonic acid (0.43 g, 2.2 mmol) and trimethyl orthoformate (23.6 g, 22.2 mmol). Stir at room temperature for 16 hours. The reaction solution was treated with saturated aqueous sodium bicarbonate solution to pH ~ 8, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain a colorless oily substance I-149b (8.7 g, 67%). 1 H NMR (400MHz,d 6 -DMSO)δ7.43-7.26(m,5H),5.06(s,2H),4.09-3.93(m,3H),3.25(s,6H),2.75(s,2H ),1.81-1.70(m,1H),1.62(d,J=12.8Hz,2H),1.09(qd,J=12.7,4.4Hz,2H).
步骤2：Step 2:
向I-149b(8.2g,27.9mmol)的甲醇溶液(300mL)中加入氢氧化钯(820mg)。氢气氛围下搅拌16小时。将反应液过滤，滤液浓缩得无色油I-149c(4.4g,98％)。 1H NMR(400MHz,d 6-DMSO)δ3.99(d,J＝8.0Hz,1H),3.23(s,6H),2.92(d,J＝12.0Hz,2H),2.41(td,J＝12,4Hz,2H),1.68-1.49(m,3H),1.08(qd,J＝12.4,4.0Hz,2H). To a solution of 1-149b (8.2 g, 27.9 mmol) in methanol (300 mL) was added palladium hydroxide (820 mg). Stir under hydrogen atmosphere for 16 hours. The reaction liquid was filtered, and the filtrate was concentrated to obtain a colorless oil I-149c (4.4 g, 98%). 1 H NMR (400MHz, d 6 -DMSO) δ3.99(d, J=8.0Hz, 1H), 3.23(s, 6H), 2.92(d, J=12.0Hz, 2H), 2.41(td, J= 12,4Hz,2H),1.68-1.49(m,3H),1.08(qd,J＝12.4,4.0Hz,2H).
步骤3：Step 3:
参照实施例I-2，步骤8制备方法，使用I-149c和I-2h为原料得I-149(20mg,17％)。MS(ESI)m/z＝504.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.86(d,J＝2.7Hz,1H),7.82–7.69(m,2H),7.46(d,J＝7.8Hz,1H),7.17(t,J＝7.8Hz,1H),5.69–5.62(m,1H),4.19(d,J＝13.1Hz,2H),4.07(d,J＝6.5Hz,1H),3.37(s,6H),3.06–2.96(m,2H),2.77(s,3H),2.48(s,3H),1.98–1.87(m,3H),1.67(d,J＝6.8Hz,3H),1.54–1.41(m,2H). Referring to Example I-2, the preparation method in step 8, I-149 (20 mg, 17%) was obtained by using I-149c and I-2h as raw materials. MS (ESI) m/z=504.1[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.86(d, J=2.7Hz, 1H), 7.82–7.69(m, 2H), 7.46( d,J=7.8Hz,1H),7.17(t,J=7.8Hz,1H),5.69–5.62(m,1H),4.19(d,J=13.1Hz,2H),4.07(d,J=6.5 Hz,1H),3.37(s,6H),3.06–2.96(m,2H),2.77(s,3H),2.48(s,3H),1.98–1.87(m,3H),1.67(d,J= 6.8Hz, 3H), 1.54–1.41(m, 2H).
实施例I-150：Example I-150:
Figure PCTCN2022135958-appb-000150
Figure PCTCN2022135958-appb-000150
参照实施例I-1的制备方法，在步骤3中用I-149c代替吗啉，制备得到化合物I-150(20mg, 16％)。MS(ESI)m/z 490.1[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.86(d,J＝2.8Hz,1H),8.82(s,1H),7.78(d,J＝7.6Hz,2H),7.49(d,J＝8.0Hz,1H),7.20(t,J＝7.8Hz,1H),5.80-5.30(m,1H),4.18-4.11(m,2H),4.07(d,J＝6.4Hz,1H),3.37(s,6H),3.03-2.99(m,2H),2.49(s,3H),1.95-1.83(m,3H),1.71(d,J＝6.7Hz,3H),1.55-1.40(m,2H). Referring to the preparation method of Example I-1, in step 3, I-149c was used instead of morpholine to prepare compound I-150 (20 mg, 16%). MS (ESI) m/z 490.1[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.86(d, J=2.8Hz, 1H), 8.82(s, 1H), 7.78(d, J =7.6Hz, 2H), 7.49(d, J=8.0Hz, 1H), 7.20(t, J=7.8Hz, 1H), 5.80-5.30(m, 1H), 4.18-4.11(m, 2H), 4.07 (d,J=6.4Hz,1H),3.37(s,6H),3.03-2.99(m,2H),2.49(s,3H),1.95-1.83(m,3H),1.71(d,J=6.7 Hz,3H),1.55-1.40(m,2H).
实施例I-151：Example I-151:
Figure PCTCN2022135958-appb-000151
Figure PCTCN2022135958-appb-000151
将I-149(1.1g,2.0mmol)的三氟乙酸/氯仿(1/4,20mL)溶液在室温下搅拌2小时，反应液直接浓缩，用饱和碳酸氢钠水溶液中和，二氯甲烷萃取，浓缩，经反相制备色谱法纯化得黄色固体I-151(270mg,29％)。MS(ESI)m/z 458.1[M+H] +. 1H NMR(400MHz,CD 3OD)δ9.09(d,J＝2.8Hz,1H),7.98(s,1H),7.68(d,J＝8.0Hz,1H),7.53(d,J＝7.6Hz,1H),7.28(t,J＝7.6Hz,1H),5.52(q,J＝6.8Hz,1H),4.41(d,J＝11.6Hz,2H),4.32(m,1H)3.20(t,J＝12.8Hz,2H),2.78(s,3H),2.62(s,3H),2.01(d,J＝13.2Hz,2H),1.94-1.84(m 1H),1.66(d,J＝6.9Hz,3H),1.61-1.44(m,2H). A solution of I-149 (1.1g, 2.0mmol) in trifluoroacetic acid/chloroform (1/4, 20mL) was stirred at room temperature for 2 hours, the reaction solution was directly concentrated, neutralized with saturated aqueous sodium bicarbonate, and extracted with dichloromethane , concentrated, and purified by reverse phase preparative chromatography to give yellow solid I-151 (270 mg, 29%). MS(ESI) m/z 458.1[M+H] + . 1 H NMR(400MHz, CD 3 OD) δ9.09(d, J=2.8Hz, 1H), 7.98(s, 1H), 7.68(d, J=8.0Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.28(t, J=7.6Hz, 1H), 5.52(q, J=6.8Hz, 1H), 4.41(d, J= 11.6Hz, 2H), 4.32(m, 1H), 3.20(t, J=12.8Hz, 2H), 2.78(s, 3H), 2.62(s, 3H), 2.01(d, J=13.2Hz, 2H), 1.94-1.84(m 1H), 1.66(d, J=6.9Hz, 3H), 1.61-1.44(m, 2H).
实施例I-152：Example I-152:
Figure PCTCN2022135958-appb-000152
Figure PCTCN2022135958-appb-000152
参照实施例I-151的制备方法，从I-150出发，制备得到化合物I-152(72mg)。MS(ESI)m/z444.1[M+H] +. 1H NMR(400MHz,CD 3OD)δ8.95-8.85(m,1H),8.66-8.64(m,1H),7.90(t,J＝2.4Hz,1H),7.70(d,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.25(t,J＝7.6Hz,1H),5.75(dd,J＝14.0,6.8Hz,1H),4.23-3.98(m,2H),3.10-2.92(m,2H),2.65-2.56(m,3H),1.96(d,J＝12.6Hz,2H),1.79-1.42(m,6H). Referring to the preparation method of Example I-151, starting from I-150, compound I-152 (72 mg) was prepared. MS(ESI)m/z444.1[M+H] + . 1 H NMR(400MHz,CD 3 OD)δ8.95-8.85(m,1H),8.66-8.64(m,1H),7.90(t, J=2.4Hz, 1H), 7.70(d, J=7.2Hz, 1H), 7.48(t, J=7.2Hz, 1H), 7.25(t, J=7.6Hz, 1H), 5.75(dd, J= 14.0,6.8Hz,1H),4.23-3.98(m,2H),3.10-2.92(m,2H),2.65-2.56(m,3H),1.96(d,J＝12.6Hz,2H),1.79-1.42 (m,6H).
实施例I-153：Example I-153:
Figure PCTCN2022135958-appb-000153
Figure PCTCN2022135958-appb-000153
步骤1：step 1:
参照实施例I-2，步骤8的制备方法，用I-153a代替吗啉，制备得到化合物I-153b(200mg,51％)。MS(ESI)m/z 557.4[M+H] +. Referring to Example I-2, the preparation method in step 8, and using I-153a instead of morpholine, compound I-153b (200 mg, 51%) was prepared. MS(ESI)m/z 557.4[M+H] + .
步骤2：Step 2:
向I-153b(70mg,0.12mmol)的DCM(2mL)溶液中加入三氟乙酸(1mL)，室温下搅拌3小时。反应液经浓缩，薄层层析分离得黄色固体I-153(12mg,21％)。MS(ESI)m/z 457.3[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ8.42(d,J＝2.5Hz,1H),7.73(d,J＝7.8Hz,1H),7.55–7.49(m,2H),7.43(d,J＝6.8Hz,1H),7.31(d,J＝7.9Hz,1H),5.64(p,J＝6.8Hz,1H),4.11(s,2H),4.03(s,2H),3.94–3.80(m, 1H),2.58–2.54(m,6H),2.52–2.51(m,1H),2.48–2.46(m,1H),2.04–1.96(m,2H),1.54(d,J＝6.9Hz,3H). To a solution of I-153b (70 mg, 0.12 mmol) in DCM (2 mL) was added trifluoroacetic acid (1 mL), stirred at room temperature for 3 hours. The reaction solution was concentrated and separated by thin layer chromatography to obtain a yellow solid I-153 (12 mg, 21%). MS (ESI) m/z 457.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.42(d, J=2.5Hz, 1H), 7.73(d, J=7.8Hz, 1H ),7.55–7.49(m,2H),7.43(d,J=6.8Hz,1H),7.31(d,J=7.9Hz,1H),5.64(p,J=6.8Hz,1H),4.11(s ,2H),4.03(s,2H),3.94–3.80(m,1H),2.58–2.54(m,6H),2.52–2.51(m,1H),2.48–2.46(m,1H),2.04–1.96 (m,2H),1.54(d,J=6.9Hz,3H).
实施例I-154：Example I-154:
Figure PCTCN2022135958-appb-000154
Figure PCTCN2022135958-appb-000154
向I-2h(50mg,0.11mmol)、I-154a(35mg,0.13mmol)和K 2CO 3(49mg,0.33mmol)的二氧六环/水(5mL/1mL)混合物中加入Pd(dppf)Cl 2(8.6mg,0.011mmol)。氩气保护，100℃下反应1小时。反应液经乙酸乙酯稀释，饱和食盐水洗，硫酸钠干燥，浓缩，反相制备色谱法分离纯化得白色固体I-154(23mg,42％)。MS(ESI)m/z＝470.1[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ9.30(dd,J＝10.8,2.0Hz,1H),8.86(d,J＝2.0Hz,1H),7.94-7.83(m,1H),7.76(d,J＝7.8Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.8Hz,1H),6.62(s,1H),5.74-5.67(m,1H),4.25(dd,J＝19.0,2.4Hz,2H),3.77-3.72(m,2H),2.76(s,2H),2.66(s,3H),2.58(s,3H),2.10(d,J＝16.0Hz,3H),1.57(d,J＝6.8Hz,3H). To a mixture of I-2h (50 mg, 0.11 mmol), I-154a (35 mg, 0.13 mmol) and K 2 CO 3 (49 mg, 0.33 mmol) in dioxane/water (5 mL/1 mL) was added Pd(dppf) Cl2 (8.6 mg, 0.011 mmol). Under argon protection, react at 100°C for 1 hour. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated, separated and purified by reverse phase preparative chromatography to obtain white solid I-154 (23 mg, 42%). MS(ESI)m/z=470.1[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ9.30(dd,J=10.8,2.0Hz,1H),8.86(d,J=2.0 Hz,1H),7.94-7.83(m,1H),7.76(d,J=7.8Hz,1H),7.53(d,J=7.6Hz,1H),7.32(t,J=7.8Hz,1H), 6.62(s,1H),5.74-5.67(m,1H),4.25(dd,J＝19.0,2.4Hz,2H),3.77-3.72(m,2H),2.76(s,2H),2.66(s, 3H), 2.58(s, 3H), 2.10(d, J=16.0Hz, 3H), 1.57(d, J=6.8Hz, 3H).
实施例I-155：Example I-155:
Figure PCTCN2022135958-appb-000155
Figure PCTCN2022135958-appb-000155
向I-154(50mg,0.11mmol)的甲醇(20mL)溶液中加入Pd/C(25mg)。氢气氛围下，室温搅拌30分钟。将反应液通过硅藻土过滤，滤液浓缩，经反相制备色谱法分离纯化得白色固体I-155(19mg,38％)。MS(ESI)m/z＝472.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.10(d,J＝1.2Hz,1H),8.77(s,1H),7.81-7.78(m,1H),7.75(d,J＝8.0Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),5.68(t,J＝6.8Hz,1H),4.64(d,J＝14.0Hz,1H),4.02(d,J＝13.6Hz,1H),3.21(t,J＝12.0Hz,1H),3.11(t,J＝12.2Hz,1H),2.69-2.64(m,4H),2.58(s,3H),2.07(s,3H),2.02-1.88(m,2H),1.78-1.63(m,2H),1.56(d,J＝6.6Hz,3H). To a solution of 1-154 (50 mg, 0.11 mmol) in methanol (20 mL) was added Pd/C (25 mg). Under hydrogen atmosphere, stir at room temperature for 30 minutes. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, separated and purified by reverse phase preparative chromatography to obtain a white solid I-155 (19 mg, 38%). MS(ESI)m/z=472.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.10(d,J=1.2Hz,1H),8.77(s,1H),7.81- 7.78(m, 1H), 7.75(d, J=8.0Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.32(t, J=8.0Hz, 1H), 5.68(t, J=6.8 Hz, 1H), 4.64(d, J=14.0Hz, 1H), 4.02(d, J=13.6Hz, 1H), 3.21(t, J=12.0Hz, 1H), 3.11(t, J=12.2Hz, 1H), 2.69-2.64(m, 4H), 2.58(s, 3H), 2.07(s, 3H), 2.02-1.88(m, 2H), 1.78-1.63(m, 2H), 1.56(d, J= 6.6Hz, 3H).
实施例I-156：Example I-156:
Figure PCTCN2022135958-appb-000156
Figure PCTCN2022135958-appb-000156
步骤1：step 1:
向I-156a(5g,20mmol)的DMF(50mL)溶液中加入NaHCO 3(13.66g,160mmol)和碘甲烷(11.5g,80mmol)。室温搅拌16小时。反应液经水稀释，乙酸乙酯萃取，浓缩，柱层析分离得白色固体I-156b(1.8g,34％)。MS(ESI)m/z＝261.0[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.07(s,1H),7.44(s,2H),3.91(s,3H),3.78(s,3H). To a solution of I-156a (5 g, 20 mmol) in DMF (50 mL) was added NaHCO 3 (13.66 g, 160 mmol) and iodomethane (11.5 g, 80 mmol). Stir at room temperature for 16 hours. The reaction solution was diluted with water, extracted with ethyl acetate, concentrated, and separated by column chromatography to obtain a white solid I-156b (1.8 g, 34%). MS(ESI)m/z=261.0[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.07(s,1H),7.44(s,2H),3.91(s,3H), 3.78(s,3H).
步骤2：Step 2:
向I-156b(4.1g,15.76mmol)的二溴甲烷溶液中加入四丁基溴化铵(20.3g,63mmol)和叔丁基亚硝酯(16.3g,157.6mmol)。室温搅拌16小时。二氯甲烷稀释，水洗，有机相干燥浓缩，柱层析分离得白色固体I-156c(3.9g,76％)。MS(ESI)m/z＝325.9[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.38(d,J＝1.6Hz,1H),4.00(s,3H),3.85(s,3H). To a solution of 1-156b (4.1 g, 15.76 mmol) in dibromomethane was added tetrabutylammonium bromide (20.3 g, 63 mmol) and tert-butylnitrosate (16.3 g, 157.6 mmol). Stir at room temperature for 16 hours. Diluted with dichloromethane, washed with water, dried and concentrated the organic phase, and separated by column chromatography to obtain a white solid I-156c (3.9 g, 76%). MS (ESI) m/z=325.9[M+H] + . 1 H NMR (400MHz,d 6 -DMSO) δ8.38(d,J=1.6Hz,1H),4.00(s,3H),3.85( s,3H).
步骤3：Step 3:
向I-156c(3.9g,12mmol)和三丁基(1-乙氧烯基)锡的二氧六环(40mL)溶液中加入三乙胺(1.83g,18mmol)和Pd(PPh 3) 2Cl 2(0.84g,1.2mmol)。氮气保护，100℃下反应2小时。冷却至室温，反应液用1N盐酸处理，室温搅拌3小时。二氯甲烷萃取。有机相用饱和氟化钾水溶液处理，干燥，浓缩，柱层析分离得白色固体I-156d(2.6g,76％)。MS(ESI)m/z＝288.0[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.39(d,J＝1.2Hz,1H),4.04(s,3H),3.80(s,3H),2.56(s,3H). To a solution of I-156c (3.9 g, 12 mmol) and tributyl(1-ethoxyl)tin in dioxane (40 mL) was added triethylamine (1.83 g, 18 mmol) and Pd(PPh 3 ) 2 Cl2 (0.84g, 1.2mmol). Under nitrogen protection, react at 100°C for 2 hours. After cooling to room temperature, the reaction solution was treated with 1N hydrochloric acid and stirred at room temperature for 3 hours. dichloromethane extraction. The organic phase was treated with saturated potassium fluoride aqueous solution, dried, concentrated, and separated by column chromatography to obtain a white solid I-156d (2.6 g, 76%). MS (ESI) m/z=288.0[M+H] + . 1 H NMR (400MHz,d 6 -DMSO) δ8.39(d,J=1.2Hz,1H),4.04(s,3H),3.80( s,3H),2.56(s,3H).
步骤4：Step 4:
向I-156d(2.8g,9.7mmol)的乙醇(30mL)溶液中加入一水合肼(1.83g,29.3mmol)，80℃下搅拌2小时。冷却到室温后，反应液直接过滤得白色固体I-156e(2.1g,80％)。MS(ESI)m/z＝270[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ12.70(s,1H),8.62(s,1H),4.13(s,3H),2.51(s,3H). Hydrazine monohydrate (1.83 g, 29.3 mmol) was added to a solution of I-156d (2.8 g, 9.7 mmol) in ethanol (30 mL), and stirred at 80° C. for 2 hours. After cooling to room temperature, the reaction solution was directly filtered to obtain white solid I-156e (2.1 g, 80%). MS(ESI)m/z=270[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ12.70(s,1H),8.62(s,1H),4.13(s,3H), 2.51(s,3H).
步骤5：Step 5:
向I-156e(2.1g,7.8mmol)的甲苯(50mL)溶液中加入Lawessen试剂(2.8g,6.86mmol)，110℃下搅拌3小时。冷却到室温后，反应液直接过滤得黄色固体I-156f(2.8g)。MS(ESI)m/z＝288.0[M +,Br 79,81]. Lawessen's reagent (2.8 g, 6.86 mmol) was added to a solution of I-156e (2.1 g, 7.8 mmol) in toluene (50 mL), and stirred at 110° C. for 3 hours. After cooling to room temperature, the reaction solution was directly filtered to obtain a yellow solid I-156f (2.8 g). MS(ESI)m/z=288.0[M + ,Br 79,81 ].
步骤6：Step 6:
0℃下，向I-156f(2.8g,9.8mmol)的DMF(30mL)溶液中加入NaH(0.6g,14.7mmol)，搅拌30分钟后，加入碘甲烷(2.1g,14.7mmol)，室温搅拌2小时。加水，过滤得粉色固体I-156g(1.7g,58％)。MS(ESI)m/z＝301.9[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.60(s,1H),4.16(s,3H),2.82(s,3H),2.74(s,3H). At 0°C, add NaH (0.6g, 14.7mmol) to a solution of I-156f (2.8g, 9.8mmol) in DMF (30mL), stir for 30 minutes, add iodomethane (2.1g, 14.7mmol), and stir at room temperature 2 hours. Water was added and filtered to obtain a pink solid I-156g (1.7g, 58%). MS(ESI)m/z=301.9[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.60(s,1H),4.16(s,3H),2.82(s,3H), 2.74(s,3H).
步骤7：Step 7:
-20℃下，向I-156g(1.7g,5.6mmol)的二氯甲烷(85mL)溶液中加入间氯过氧化苯甲酸(1.18g,6.8mmol)，搅拌30分钟后，升至室温，继续搅拌2小时。反应液经饱和亚硫酸钠水溶液处理，二 氯甲烷萃取，干燥，浓缩得粉色固体I-156h(1.3g,72％)。MS(ESI)m/z＝317.9[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.59(s,1H),4.20(s,3H),3.14(s,3H),2.95(s,3H). At -20°C, m-chloroperoxybenzoic acid (1.18g, 6.8mmol) was added to a solution of 1-156g (1.7g, 5.6mmol) in dichloromethane (85mL), and after stirring for 30 minutes, it was raised to room temperature and continued Stir for 2 hours. The reaction solution was treated with saturated aqueous sodium sulfite, extracted with dichloromethane, dried, and concentrated to give I-156h (1.3 g, 72%) as a pink solid. MS(ESI)m/z=317.9[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.59(s,1H),4.20(s,3H),3.14(s,3H), 2.95(s,3H).
步骤8：Step 8:
向I-156h(100mg,0.317mmol)和A-12(97mg,0.476mmol)的DMSO(3mL)溶液中加入氟化铯(43mg,0.285mmol)和吡啶(226mg,2.85mmol)，在100℃下反应8小时。水处理，二氯甲烷萃取，浓缩，薄层层析分离得I-156i(14mg,10％)。MS(ESI)m/z＝457.0[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.26(s,1H),7.74(t,J＝8.0Hz,2H),7.52(d,J＝7.6Hz,1H),7.32(t,J＝7.2Hz,1H),5.70-5.57(m,1H),4.10(s,3H),2.59(d,J＝13.6Hz,6H),1.53(d,J＝6.8Hz,3H). Add cesium fluoride (43 mg, 0.285 mmol) and pyridine (226 mg, 2.85 mmol) to a solution of I-156h (100 mg, 0.317 mmol) and A-12 (97 mg, 0.476 mmol) in DMSO (3 mL), at 100 ° C React for 8 hours. Treated with water, extracted with dichloromethane, concentrated, and separated by thin layer chromatography to obtain I-156i (14 mg, 10%). MS (ESI) m/z=457.0[M+H] + . 1 H NMR (400MHz, d 6 -DMSO) δ9.26(s, 1H), 7.74(t, J=8.0Hz, 2H), 7.52( d,J=7.6Hz,1H),7.32(t,J=7.2Hz,1H),5.70-5.57(m,1H),4.10(s,3H),2.59(d,J=13.6Hz,6H), 1.53(d,J=6.8Hz,3H).
步骤9：Step 9:
向I-156i(44mg,0.096mmol)和I-156j(24mg,0.116mmol)的二氧六环(3mL)溶液中加入碳酸钾(33mg,0.24mmol)和Pd(dppf)Cl 2(7mg,2.85mmol)，氮气保护，在100℃下反应1小时。乙酸乙酯稀释，水洗，浓缩，薄层层析分离得到I-156(19mg,43％)。MS(ESI)m/z＝459.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.67(s,1H),7.76(d,J＝7.2Hz,2H),7.52(d,J＝6.8Hz,1H),7.32(t,J＝8.0Hz,1H),6.31(s,1H),5.67(d,J＝6.0Hz,1H),4.29(s,2H),4.05(s,3H),3.85(d,J＝5.2Hz,2H),2.59(d,J＝15.6Hz,7H),1.54(d,J＝6.8Hz,3H),1.23(s,1H). To a solution of I-156i (44 mg, 0.096 mmol) and I-156j (24 mg, 0.116 mmol) in dioxane (3 mL) was added potassium carbonate (33 mg, 0.24 mmol) and Pd(dppf)Cl 2 (7 mg, 2.85 mmol), under nitrogen protection, reacted at 100°C for 1 hour. Diluted with ethyl acetate, washed with water, concentrated, and separated by thin layer chromatography to obtain I-156 (19 mg, 43%). MS (ESI) m/z=459.1[M+H] + . 1 H NMR (400MHz, d 6 -DMSO) δ8.67(s, 1H), 7.76(d, J=7.2Hz, 2H), 7.52( d,J=6.8Hz,1H),7.32(t,J=8.0Hz,1H),6.31(s,1H),5.67(d,J=6.0Hz,1H),4.29(s,2H),4.05( s,3H),3.85(d,J=5.2Hz,2H),2.59(d,J=15.6Hz,7H),1.54(d,J=6.8Hz,3H),1.23(s,1H).
实施例I-157：Example I-157:
Figure PCTCN2022135958-appb-000157
Figure PCTCN2022135958-appb-000157
参照实施例I-154制备方法，使用I-180a和I-156j为原料得I-157(12mg,22％)。MS(ESI)m/z＝425.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.34(d,J＝2.1Hz,1H),8.86(d,J＝2.1Hz,1H),7.76(d,J＝7.2Hz,1H),7.49(dd,J＝11.5,7.6Hz,2H),7.02(t,J＝7.6Hz,1H),6.74(s,1H),5.67(dd,J＝13.9,6.9Hz,1H),4.89(t,J＝16.8Hz,2H),4.35(d,J＝2.8Hz,2H),3.93(t,J＝5.4Hz,2H),2.67(s,5H),1.60(d,J＝7.0Hz,3H). Referring to the preparation method of Example I-154, I-157 (12 mg, 22%) was obtained using I-180a and I-156j as raw materials. MS(ESI)m/z=425.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.34(d,J=2.1Hz,1H),8.86(d,J=2.1Hz, 1H), 7.76(d, J=7.2Hz, 1H), 7.49(dd, J=11.5, 7.6Hz, 2H), 7.02(t, J=7.6Hz, 1H), 6.74(s, 1H), 5.67( dd, J=13.9, 6.9Hz, 1H), 4.89(t, J=16.8Hz, 2H), 4.35(d, J=2.8Hz, 2H), 3.93(t, J=5.4Hz, 2H), 2.67( s,5H),1.60(d,J=7.0Hz,3H).
实施例I-158：Example I-158:
Figure PCTCN2022135958-appb-000158
Figure PCTCN2022135958-appb-000158
参照实施例I-155制备方法，使用I-157为原料得I-158(6.7mg,16％)。MS(ESI)m/z＝427.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.12(d,J＝2.0Hz,1H),8.84(d,J＝1.6Hz,1H),7.70(d,J＝7.2Hz,1H),7.48(t,J＝8.4Hz,2H),7.09-6.96(m,1H),5.64(t,J＝7.0Hz,1H),4.89(t,J＝16.8Hz,2H),4.05(d,J＝10.6Hz,2H),3.62-3.46(m,2H),3.21-3.03(m,1H),2.66(s,3H),2.02-1.78(m,4H),1.60(d,J＝7.0Hz,3H). Referring to the preparation method of Example I-155, I-158 (6.7 mg, 16%) was obtained by using I-157 as a raw material. MS(ESI)m/z=427.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.12(d,J=2.0Hz,1H),8.84(d,J=1.6Hz, 1H), 7.70(d, J=7.2Hz, 1H), 7.48(t, J=8.4Hz, 2H), 7.09-6.96(m, 1H), 5.64(t, J=7.0Hz, 1H), 4.89( t,J=16.8Hz,2H),4.05(d,J=10.6Hz,2H),3.62-3.46(m,2H),3.21-3.03(m,1H),2.66(s,3H),2.02-1.78 (m,4H),1.60(d,J=7.0Hz,3H).
实施例I-159：Example I-159:
Figure PCTCN2022135958-appb-000159
Figure PCTCN2022135958-appb-000159
参照实施例I-172制备方法，在第三步中使用环丙基羧酸为原料得到I-159(2mg,8％)。MS(ESI)m/z＝496.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.32(s,1H),8.87(d,J＝2Hz,1H),7.88(d,J＝6.8Hz,1H),7.77(d,J＝7.2Hz,1H),7.54(d,J＝7.6Hz,1H),7.33(t,J＝7.6Hz,1H),6.65-6.63(m,1H),5.72-5.69(m,1H),4.52(m,1H),4.26(m,1H),4.00(m,1H),3.79(m,1H),2.80(m,1H),2.69(m,4H),2.59(s,3H),2.00-1.59(m,1H),1.58(d,J＝7.2Hz,3H),0.80-0.78(m,4H). Referring to the preparation method of Example I-172, cyclopropylcarboxylic acid was used as a raw material in the third step to obtain I-159 (2 mg, 8%). MS(ESI)m/z=496.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.32(s,1H),8.87(d,J=2Hz,1H),7.88(d ,J=6.8Hz,1H),7.77(d,J=7.2Hz,1H),7.54(d,J=7.6Hz,1H),7.33(t,J=7.6Hz,1H),6.65-6.63(m ,1H),5.72-5.69(m,1H),4.52(m,1H),4.26(m,1H),4.00(m,1H),3.79(m,1H),2.80(m,1H),2.69( m,4H),2.59(s,3H),2.00-1.59(m,1H),1.58(d,J＝7.2Hz,3H),0.80-0.78(m,4H).
实施例I-160：Example I-160:
Figure PCTCN2022135958-appb-000160
Figure PCTCN2022135958-appb-000160
参照实施例I-155制备方法，使用I-211为原料得I-160(3.3mg,33％)。MS(ESI)m/z＝461.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.66(s,1H),7.75-7.69(m,2H),7.53(d,J＝7.4Hz,1H),7.33(t,J＝7.6Hz,1H),5.66(t,J＝6.8Hz,1H),4.13-3.95(m,5H),3.51(td,J＝11.6,2.0Hz,2H),3.24-3.13(m,1H),2.60(s,3H),2.58(s,3H),1.90-1.77(m,4H),1.55(d,J＝6.8Hz,3H). Referring to the preparation method of Example I-155, I-160 (3.3 mg, 33%) was obtained by using I-211 as a raw material. MS(ESI)m/z=461.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.66(s,1H),7.75-7.69(m,2H),7.53(d,J =7.4Hz, 1H), 7.33(t, J=7.6Hz, 1H), 5.66(t, J=6.8Hz, 1H), 4.13-3.95(m, 5H), 3.51(td, J=11.6, 2.0Hz ,2H),3.24-3.13(m,1H),2.60(s,3H),2.58(s,3H),1.90-1.77(m,4H),1.55(d,J＝6.8Hz,3H).
实施例I-161：Example I-161:
Figure PCTCN2022135958-appb-000161
Figure PCTCN2022135958-appb-000161
参照实施例I-155制备方法，使用I-159为原料得I-161(5mg,16％)。MS(ESI)m/z＝498.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.11(d,J＝2.0Hz,1H),8.79(s,1H),7.84(d,J＝6.0Hz,1H),7.75(d,J＝7.9Hz,1H),7.53(d,J＝8.0Hz,1H),7.32(t,J＝7.6Hz,1H),5.75-5.61(m,1H),4.70-4.61(m,1H),4.51-4.45(m,1H),3.15(t,J＝12.0Hz,1H),2.72-2.65(m,4H),2.58(s,3H),2.18-1.87(m,3H),1.73(s,2H),1.56(d,J＝7.2Hz,3H),0.79-0.73(d,J＝7.8Hz,4H). Referring to the preparation method of Example I-155, I-161 (5 mg, 16%) was obtained by using I-159 as a raw material. MS(ESI)m/z=498.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.11(d,J=2.0Hz,1H),8.79(s,1H),7.84( d, J=6.0Hz, 1H), 7.75(d, J=7.9Hz, 1H), 7.53(d, J=8.0Hz, 1H), 7.32(t, J=7.6Hz, 1H), 5.75-5.61( m,1H),4.70-4.61(m,1H),4.51-4.45(m,1H),3.15(t,J＝12.0Hz,1H),2.72-2.65(m,4H),2.58(s,3H) ,2.18-1.87(m,3H),1.73(s,2H),1.56(d,J=7.2Hz,3H),0.79-0.73(d,J=7.8Hz,4H).
实施例I-162：Example I-162:
Figure PCTCN2022135958-appb-000162
Figure PCTCN2022135958-appb-000162
参照实施例I-2，步骤8制备方法，使用8-氧杂-3-氮杂二环[3,2,1]辛烷盐酸盐和I-2h为原料得I-162(7mg,12％)。MS(ESI)m/z＝458.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.93(d,J＝2.4Hz,1H),7.84(d,J＝2.4Hz,1H),7.74(d,J＝7.2Hz,1H),7.52(d,J＝8.4Hz,2H),7.31(t,J＝7.8Hz,1H),5.67(t,J＝6.8Hz,1H),4.55(s,1H),3.77(dd,J＝11.6,4.8Hz,2H),3.09(d,J＝12.6Hz,2H),2.57(s,6H),1.89(d,J＝9.0Hz,4H),1.55(d,J＝6.8Hz,3H). Referring to Example I-2, step 8 preparation method, using 8-oxa-3-azabicyclo[3,2,1]octane hydrochloride and I-2h as raw materials to obtain I-162 (7mg, 12 %). MS(ESI)m/z=458.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.93(d,J=2.4Hz,1H),7.84(d,J=2.4Hz, 1H), 7.74(d, J=7.2Hz, 1H), 7.52(d, J=8.4Hz, 2H), 7.31(t, J=7.8Hz, 1H), 5.67(t, J=6.8Hz, 1H) ,4.55(s,1H),3.77(dd,J=11.6,4.8Hz,2H),3.09(d,J=12.6Hz,2H),2.57(s,6H),1.89(d,J=9.0Hz, 4H), 1.55(d, J＝6.8Hz, 3H).
实施例I-163：Example I-163:
Figure PCTCN2022135958-appb-000163
Figure PCTCN2022135958-appb-000163
参照实施例I-2，步骤8制备方法，使用4-甲氧基哌啶和I-2h为原料得I-163(30mg,29％)。MS(ESI)m/z＝460.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝2.8Hz,1H),7.95(d,J＝2.7Hz,1H),7.74(d,J＝7.7Hz,1H),7.53(t,J＝7.2Hz,2H),7.31(t,J＝7.8Hz,1H),5.67(t,J＝6.9Hz,1H),3.82(d,J＝12.7Hz,2H),3.53-3.39(m,1H),3.31(s,3H),3.26(dd,J＝13.0,9.9Hz,2H),2.57(s,6H),2.01(d,J＝12.3Hz,2H),1.61(d,J＝11.2Hz,2H),1.55(d,J＝7.0Hz,3H). Referring to Example I-2, the preparation method in Step 8, using 4-methoxypiperidine and I-2h as raw materials, I-163 (30mg, 29%) was obtained. MS(ESI)m/z=460.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.00(d,J=2.8Hz,1H),7.95(d,J=2.7Hz, 1H), 7.74(d, J=7.7Hz, 1H), 7.53(t, J=7.2Hz, 2H), 7.31(t, J=7.8Hz, 1H), 5.67(t, J=6.9Hz, 1H) ,3.82(d,J=12.7Hz,2H),3.53-3.39(m,1H),3.31(s,3H),3.26(dd,J=13.0,9.9Hz,2H),2.57(s,6H), 2.01(d, J=12.3Hz, 2H), 1.61(d, J=11.2Hz, 2H), 1.55(d, J=7.0Hz, 3H).
实施例I-164：Example I-164:
Figure PCTCN2022135958-appb-000164
Figure PCTCN2022135958-appb-000164
步骤1：step 1:
参照实施例I-154制备方法，使用I-156j和I-2h为原料得I-164a(450mg,86％)。MS(ESI)m/z＝429.0[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.33(d,J＝2.0Hz,1H),8.84(d,J＝1.9Hz,1H),7.89(d,J＝6.8Hz,1H),7.76(d,J＝7.7Hz,1H),7.53(d,J＝7.7Hz,1H),7.32(t,J＝7.8Hz,1H),6.73(s,1H),5.70(p,J＝6.7Hz,1H),4.35(d,J＝2.7Hz,2H),3.93(t,J＝5.4Hz,2H),2.66(s,5H),2.56(d,J＝15.8Hz,3H),1.57(d,J＝6.9Hz,3H). Referring to the preparation method of Example I-154, I-164a (450 mg, 86%) was obtained by using I-156j and I-2h as raw materials. MS(ESI)m/z=429.0[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.33(d,J=2.0Hz,1H),8.84(d,J=1.9Hz, 1H), 7.89(d, J=6.8Hz, 1H), 7.76(d, J=7.7Hz, 1H), 7.53(d, J=7.7Hz, 1H), 7.32(t, J=7.8Hz, 1H) ,6.73(s,1H),5.70(p,J=6.7Hz,1H),4.35(d,J=2.7Hz,2H),3.93(t,J=5.4Hz,2H),2.66(s,5H) ,2.56(d,J=15.8Hz,3H),1.57(d,J=6.9Hz,3H).
步骤2：Step 2:
参照实施例I-201制备方法，使用I-164a为原料得I-164(60mg,67％)。MS(ESI)m/z＝447.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.34(d,J＝2.0Hz,1H),8.97(d,J＝2.0Hz,1H),7.97(d,J＝6.8Hz,1H),7.77(d,J＝7.8Hz,1H),7.53(d,J＝7.7Hz,1H),7.33(t,J＝7.8Hz,1H),5.69(t,J＝6.8Hz,1H),5.58(s,1H),3.93-3.75(m,4H),2.66(s,3H),2.57(d,J＝15.7Hz,3H),2.20(s,2H),1.72(t,J＝12.8Hz,2H),1.57(d,J＝6.9Hz,3H). Referring to the preparation method of Example I-201, I-164 (60 mg, 67%) was obtained by using I-164a as a raw material. MS(ESI)m/z=447.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.34(d,J=2.0Hz,1H),8.97(d,J=2.0Hz, 1H), 7.97(d, J=6.8Hz, 1H), 7.77(d, J=7.8Hz, 1H), 7.53(d, J=7.7Hz, 1H), 7.33(t, J=7.8Hz, 1H) ,5.69(t,J=6.8Hz,1H),5.58(s,1H),3.93-3.75(m,4H),2.66(s,3H),2.57(d,J=15.7Hz,3H),2.20( s,2H),1.72(t,J=12.8Hz,2H),1.57(d,J=6.9Hz,3H).
实施例I-165：Example I-165:
Figure PCTCN2022135958-appb-000165
Figure PCTCN2022135958-appb-000165
参照实施例I-2，步骤8制备方法，使用3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐和I-2h为原料得I-165(15mg,28％)。MS(ESI)m/z＝458.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.91(d,J＝2.4Hz,1H),7.89(d,J＝2.8Hz,1H),7.72(d,J＝7.6Hz,1H),7.52(d,J＝8Hz,1H),7.40(d,J＝6.8Hz,1H),7.32(t,J＝7.6Hz,1H),5.66(t,J＝6.8Hz,1H),4.57(s,2H),3.76(dd,J＝11.1,5.2Hz,2H),3.58(d,J＝10.8Hz,2H),2.55(s,6H),2.04(m,4H),1.55(d,J＝6.8Hz,3H). Referring to Example I-2, step 8 preparation method, using 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and I-2h as raw materials to obtain I-165 (15 mg, 28%). MS(ESI)m/z=458.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.91(d,J=2.4Hz,1H),7.89(d,J=2.8Hz, 1H), 7.72(d, J=7.6Hz, 1H), 7.52(d, J=8Hz, 1H), 7.40(d, J=6.8Hz, 1H), 7.32(t, J=7.6Hz, 1H), 5.66(t, J=6.8Hz, 1H), 4.57(s, 2H), 3.76(dd, J=11.1, 5.2Hz, 2H), 3.58(d, J=10.8Hz, 2H), 2.55(s, 6H ),2.04(m,4H),1.55(d,J＝6.8Hz,3H).
实施例I-166：Example I-166:
Figure PCTCN2022135958-appb-000166
Figure PCTCN2022135958-appb-000166
步骤1：step 1:
参照实施例I-154制备方法，使用I-196a和I-156j为原料得I-166a(40mg,80％)。 1H NMR(400MHz,d 6-DMSO)δ9.34(d,J＝2.0Hz,1H),8.86(d,J＝2.0Hz,1H),7.85(d,J＝6.9Hz,1H),7.62(t,J＝7.3Hz,1H),7.48(t,J＝7.3Hz,1H),7.43-7.07(m,2H),6.74(s,1H),5.72(t,J＝6.9Hz,1H),4.35(d,J＝2.6Hz,2H),4.00-3.87(m,2H),2.67(s,5H),1.63(d,J＝7.0Hz,3H). Referring to the preparation method of Example I-154, using I-196a and I-156j as raw materials, I-166a (40 mg, 80%) was obtained. 1 H NMR (400MHz, d 6 -DMSO) δ9.34 (d, J = 2.0Hz, 1H), 8.86 (d, J = 2.0Hz, 1H), 7.85 (d, J = 6.9Hz, 1H), 7.62 (t,J=7.3Hz,1H),7.48(t,J=7.3Hz,1H),7.43-7.07(m,2H),6.74(s,1H),5.72(t,J=6.9Hz,1H) ,4.35(d,J=2.6Hz,2H),4.00-3.87(m,2H),2.67(s,5H),1.63(d,J=7.0Hz,3H).
步骤2：Step 2:
参照实施例I-155制备方法，使用I-166a为原料得I-166(15mg,30％)。MS(ESI)m/z＝417.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.12(d,J＝1.9Hz,1H),8.83(d,J＝1.9Hz,1H),7.78(d,J＝ 6.8Hz,1H),7.62(t,J＝7.4Hz,1H),7.48(t,J＝6.9Hz,1H),7.41-7.05(m,2H),5.71(dd,J＝14.2,7.1Hz,1H),4.05(d,J＝10.7Hz,2H),3.59-3.45(m,2H),3.17-3.07(m,1H),2.66(s,3H),2.04-1.77(m,4H),1.62(d,J＝7.0Hz,3H). Referring to the preparation method of Example I-155, I-166 (15 mg, 30%) was obtained by using I-166a as a raw material. MS(ESI)m/z=417.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.12(d,J=1.9Hz,1H),8.83(d,J=1.9Hz, 1H), 7.78(d, J=6.8Hz, 1H), 7.62(t, J=7.4Hz, 1H), 7.48(t, J=6.9Hz, 1H), 7.41-7.05(m, 2H), 5.71( dd,J=14.2,7.1Hz,1H),4.05(d,J=10.7Hz,2H),3.59-3.45(m,2H),3.17-3.07(m,1H),2.66(s,3H),2.04 -1.77(m,4H),1.62(d,J＝7.0Hz,3H).
实施例I-167：Example I-167:
Figure PCTCN2022135958-appb-000167
Figure PCTCN2022135958-appb-000167
向I-176b(180mg,0.41mmol)的甲醇溶液中加入NaBH 4(17mg,0.45mmol)，室温搅拌1小时。水淬灭，乙酸乙酯萃取。有机相浓缩后经反相制备色谱法分离得黄色固体I-167(55mg,30％)。MS(ESI)m/z＝443.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.26(d,J＝1.6Hz,1H),8.82(d,J＝2.0Hz,1H),7.87(d,J＝6.4Hz,1H),7.76(d,J＝7.6Hz,1H),7.53(d,J＝7.8Hz,1H),7.32(t,J＝7.8Hz,1H),6.47(s,1H),5.80-5.58(m,1H),4.78(d,J＝4.0Hz,1H),3.89(s,1H),2.81-2.69(m,1H),2.65(s,3H),2.58(s,5H),2.21-2.14(m,1H),1.95(s,1H),1.73(d,J＝4.8Hz,1H),1.56(d,J＝6.8Hz,3H). NaBH 4 (17 mg, 0.45 mmol) was added to a methanol solution of I-176b (180 mg, 0.41 mmol), and stirred at room temperature for 1 hour. Quenched with water and extracted with ethyl acetate. The organic phase was concentrated and separated by reverse phase preparative chromatography to give I-167 (55 mg, 30%) as a yellow solid. MS(ESI)m/z=443.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.26(d,J=1.6Hz,1H),8.82(d,J=2.0Hz, 1H), 7.87(d, J=6.4Hz, 1H), 7.76(d, J=7.6Hz, 1H), 7.53(d, J=7.8Hz, 1H), 7.32(t, J=7.8Hz, 1H) ,6.47(s,1H),5.80-5.58(m,1H),4.78(d,J＝4.0Hz,1H),3.89(s,1H),2.81-2.69(m,1H),2.65(s,3H ),2.58(s,5H),2.21-2.14(m,1H),1.95(s,1H),1.73(d,J=4.8Hz,1H),1.56(d,J=6.8Hz,3H).
实施例I-168：Example I-168:
Figure PCTCN2022135958-appb-000168
Figure PCTCN2022135958-appb-000168
向I-168a(129mg,0.3mmol)和I-2h(93mg,0.45mmol)在甲苯/水(15mL/1.5mL)的混合物中加入碳酸铯(294mg,0.9mmol)和ataCXium A Pd G3(12mg,0.015mmol)，氩气保护，110℃下反应16小时。反应液直接浓缩，水处理，二氯甲烷萃取，浓缩，薄层层析分离得黄色固体I-168(90mg)。MS(ESI)m/z 443.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.11(d,J＝2.0Hz,1H),8.70(d,J＝2.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.76(d,J＝7.6Hz,1H),7.53(d J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),5.68(t,J＝6.8Hz,1H),4.05-4.09(m,1H),3.88-3.91(m,1H),3.56-3.61(m,1H),3.47-3.53(m,1H),2.64(s,3H),2.58(s,3H),2.18-2.21(m,2H),1.62-1.70(m,1H),1.57(d,J＝7.2Hz,3H),1.28-1.34(m,1H),1.08-1.11(m,1H). To a mixture of I-168a (129 mg, 0.3 mmol) and I-2h (93 mg, 0.45 mmol) in toluene/water (15 mL/1.5 mL) was added cesium carbonate (294 mg, 0.9 mmol) and ataCXium A Pd G3 (12 mg, 0.015 mmol), under argon protection, reacted at 110°C for 16 hours. The reaction solution was directly concentrated, treated with water, extracted with dichloromethane, concentrated, and separated by thin layer chromatography to obtain a yellow solid I-168 (90 mg). MS(ESI)m/z 443.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.11(d,J=2.0Hz,1H),8.70(d,J=2.0Hz,1H ),7.84(d,J=8.0Hz,1H),7.76(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.32(t,J=8.0Hz,1H),5.68 (t,J=6.8Hz,1H),4.05-4.09(m,1H),3.88-3.91(m,1H),3.56-3.61(m,1H),3.47-3.53(m,1H),2.64(s ,3H),2.58(s,3H),2.18-2.21(m,2H),1.62-1.70(m,1H),1.57(d,J=7.2Hz,3H),1.28-1.34(m,1H), 1.08-1.11(m,1H).
实施例I-169：Example I-169:
Figure PCTCN2022135958-appb-000169
Figure PCTCN2022135958-appb-000169
参照实施例I-213制备方法，使用I-213a和I-2h为原料经4步得I-169(94mg)。MS(ESI)m/z＝461.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.31(d,J＝1.8Hz,1H),8.92(d,J＝1.7Hz,1H),7.97(d,J＝6.5Hz,1H),7.77(d,J＝7.8Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.8Hz,1H),5.68(t,J＝6.9Hz,1H),5.30(s,1H),4.60(d,J＝4.6Hz,1H),3.58(d,J＝5.0Hz,1H),2.65(s,3H),2.58(s,3H),2.01 -1.88(m,2H),1.85-1.70(m,6H),1.57(d,J＝6.9Hz,3H). Referring to the preparation method of Example I-213, I-169 (94 mg) was obtained in 4 steps using I-213a and I-2h as raw materials. MS(ESI)m/z=461.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.31(d,J=1.8Hz,1H),8.92(d,J=1.7Hz, 1H), 7.97(d, J=6.5Hz, 1H), 7.77(d, J=7.8Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.32(t, J=7.8Hz, 1H) ,5.68(t,J=6.9Hz,1H),5.30(s,1H),4.60(d,J=4.6Hz,1H),3.58(d,J=5.0Hz,1H),2.65(s,3H) ,2.58(s,3H),2.01-1.88(m,2H),1.85-1.70(m,6H),1.57(d,J＝6.9Hz,3H).
实施例I-170：Example I-170:
Figure PCTCN2022135958-appb-000170
Figure PCTCN2022135958-appb-000170
参照实施例I-2制备方法，使用(3R)-3-甲基吗啉和I-2h为原料得I-170(11mg,10％)。MS(ESI)m/z＝446.1[M+H] +.1H NMR(400MHz,d 6-DMSO)δ8.96(d,J＝2.4Hz,1H),7.90(d,J＝2.4Hz,1H),7.74(d,J＝7.6Hz,1H),7.53(m,2H),7.32(t,J＝7.6Hz,1H),5.67(t,J＝6.8Hz,1H),4.34(d,J＝6.8Hz,1H),4.05(d,J＝8Hz,1H),3.80(s,2H),3.63(d,J＝7.6Hz,2H),3.23(dd,J＝12.8,9.6Hz,1H),2.61-2.54(m,6H),1.55(d,J＝6.8Hz,3H),1.16(d,J＝6.4Hz,3H). Referring to the preparation method of Example I-2, I-170 (11 mg, 10%) was obtained using (3R)-3-methylmorpholine and I-2h as raw materials. MS(ESI)m/z=446.1[M+H] + .1H NMR(400MHz,d 6 -DMSO)δ8.96(d,J=2.4Hz,1H),7.90(d,J=2.4Hz,1H ),7.74(d,J=7.6Hz,1H),7.53(m,2H),7.32(t,J=7.6Hz,1H),5.67(t,J=6.8Hz,1H),4.34(d,J =6.8Hz,1H),4.05(d,J=8Hz,1H),3.80(s,2H),3.63(d,J=7.6Hz,2H),3.23(dd,J=12.8,9.6Hz,1H) ,2.61-2.54(m,6H),1.55(d,J=6.8Hz,3H),1.16(d,J=6.4Hz,3H).
实施例I-171：Example I-171:
Figure PCTCN2022135958-appb-000171
Figure PCTCN2022135958-appb-000171
参照实施例I-2制备方法，使用
Figure PCTCN2022135958-appb-000172
和I-2h为原料得I-171(18mg,17％)。MS(ESI)m/z＝460.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.03(d,J＝2.4Hz,1H),7.92(d,J＝2.4Hz,1H),7.75(d,J＝7.6Hz,1H),7.52(d,J＝7.2Hz,2H),7.32(t,J＝8Hz,1H),5.68(t,J＝6.8Hz,1H),4.05-3.92(m,2H),3.78(s,2H),2.62-2.54(m,8H),1.57(d,J＝6.8Hz,3H),1.24(d,J＝6.0Hz,6H). With reference to the preparation method of Example 1-2, use
Figure PCTCN2022135958-appb-000172
and I-2h as raw materials to obtain I-171 (18mg, 17%). MS(ESI)m/z=460.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.03(d,J=2.4Hz,1H),7.92(d,J=2.4Hz, 1H), 7.75(d, J=7.6Hz, 1H), 7.52(d, J=7.2Hz, 2H), 7.32(t, J=8Hz, 1H), 5.68(t, J=6.8Hz, 1H), 4.05-3.92(m,2H),3.78(s,2H),2.62-2.54(m,8H),1.57(d,J=6.8Hz,3H),1.24(d,J=6.0Hz,6H).
实施例I-172：Example I-172:
Figure PCTCN2022135958-appb-000173
Figure PCTCN2022135958-appb-000173
步骤1：step 1:
参照实施例I-154制备方法，使用I-172a和I-2h为原料得I-172b(200mg,80％)。MS(ESI)m/z＝528.2[M+H] +. Referring to the preparation method of Example I-154, I-172b (200 mg, 80%) was obtained by using I-172a and I-2h as raw materials. MS(ESI)m/z=528.2[M+H] + .
步骤2：Step 2:
向I-172b(200mg,0.47mmol)的二氧六环(5mL)溶液中加入氯化氢/二氧六环(1N,5mL)。室温搅拌2小时。反应液直接浓缩得黄色固体I-172c(150mg,95％)。MS(ESI)m/z＝428.2[M+H] +. To a solution of 1-172b (200 mg, 0.47 mmol) in dioxane (5 mL) was added hydrogen chloride/dioxane (1 N, 5 mL). Stir at room temperature for 2 hours. The reaction solution was directly concentrated to obtain a yellow solid I-172c (150 mg, 95%). MS(ESI)m/z=428.2[M+H] + .
步骤3：Step 3:
向I-172c(150mg,0.35mmol)和羟基乙酸(53mg,0.7mmol)的DMF(3mL)溶液中加入DIPEA(225mg,1.75mmol)和HATU(199mg,0.525mmol)。室温搅拌16小时。反应液经乙酸乙酯稀释，饱和食盐水洗，硫酸钠干燥，浓缩，薄层层析分离得黄色固体I-172(87mg,41％)。MS(ESI)m/z＝486.0[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.31(s,1H),8.86(s,1H),7.91(s,1H),7.76(d,J＝7.9Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.9Hz,1H),6.63(d,J＝17.1Hz,1H),5.74-5.62(m,1H),4.68(d,J＝37.3Hz,1H),4.31-4.09(m,4H),3.80(s,1H),3.67(s,1H),2.72(d,J＝27.2Hz,2H),2.66(s,3H),2.58(s,3H),1.57(d,J＝6.9Hz,3H). To a solution of I-172c (150 mg, 0.35 mmol) and glycolic acid (53 mg, 0.7 mmol) in DMF (3 mL) was added DIPEA (225 mg, 1.75 mmol) and HATU (199 mg, 0.525 mmol). Stir at room temperature for 16 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, concentrated, and separated by thin layer chromatography to obtain a yellow solid I-172 (87 mg, 41%). MS(ESI)m/z=486.0[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.31(s,1H),8.86(s,1H),7.91(s,1H), 7.76(d, J=7.9Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.32(t, J=7.9Hz, 1H), 6.63(d, J=17.1Hz, 1H), 5.74- 5.62(m,1H),4.68(d,J=37.3Hz,1H),4.31-4.09(m,4H),3.80(s,1H),3.67(s,1H),2.72(d,J=27.2Hz ,2H),2.66(s,3H),2.58(s,3H),1.57(d,J=6.9Hz,3H).
实施例I-173：Example I-173:
Figure PCTCN2022135958-appb-000174
Figure PCTCN2022135958-appb-000174
参照实施例I-2，步骤8制备方法，使用(3S)-3-甲基吗啉和I-2h为原料得I-173。MS(ESI)m/z＝446.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.98(d,J＝2.8Hz,1H),7.89(d,J＝2.8Hz,1H),7.74(d,J＝8.0Hz,1H),7.53(t,J＝6.8Hz,2H),7.32(t,J＝8Hz,1H),5.68(t,J＝7.2Hz,1H),4.35(s,1H),4.07(d,J＝10.8Hz,1H),3.80(s,2H),3.64(dd,J＝16.8,11.6Hz,2H),3.22(d,J＝12.4Hz,1H),2.58(d,J＝1.6Hz,6H),1.56(d,J＝7.2Hz,3H),1.16(d,J＝6.4Hz,3H). Referring to Example I-2, step 8 preparation method, use (3S)-3-methylmorpholine and I-2h as raw materials to obtain I-173. MS(ESI)m/z=446.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.98(d,J=2.8Hz,1H),7.89(d,J=2.8Hz, 1H), 7.74(d, J=8.0Hz, 1H), 7.53(t, J=6.8Hz, 2H), 7.32(t, J=8Hz, 1H), 5.68(t, J=7.2Hz, 1H), 4.35(s,1H),4.07(d,J=10.8Hz,1H),3.80(s,2H),3.64(dd,J=16.8,11.6Hz,2H),3.22(d,J=12.4Hz,1H ), 2.58(d, J=1.6Hz, 6H), 1.56(d, J=7.2Hz, 3H), 1.16(d, J=6.4Hz, 3H).
实施例I-174：Example I-174:
Figure PCTCN2022135958-appb-000175
Figure PCTCN2022135958-appb-000175
参照实施例I-172，步骤3制备方法，使用四氢呋喃-3-甲酸和I-172c为原料得I-174。MS(ESI)m/z＝526.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.37-9.22(m,1H),8.86(d,J＝2.0Hz,1H),7.88(t,J＝6.0Hz,1H),7.76(d,J＝8.0Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.8Hz,1H),6.63(s,1H),5.70(t,J＝6.8Hz,1H),4.35(s,1H),4.25(s,1H),3.99-3.88(m,1H),3.82-3.69(m,5H),3.56-3.38(m,1H),2.75(s,1H),2.66(s,4H),2.58(s,3H),2.09(dd,J＝14.6,7.4Hz,2H),1.57(d,J＝6.8Hz,3H). Referring to Example I-172, the preparation method in step 3, tetrahydrofuran-3-carboxylic acid and I-172c were used as raw materials to obtain I-174. MS(ESI)m/z=526.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.37-9.22(m,1H),8.86(d,J=2.0Hz,1H), 7.88(t, J=6.0Hz, 1H), 7.76(d, J=8.0Hz, 1H), 7.53(d, J=7.6Hz, 1H), 7.32(t, J=7.8Hz, 1H), 6.63( s,1H),5.70(t,J=6.8Hz,1H),4.35(s,1H),4.25(s,1H),3.99-3.88(m,1H),3.82-3.69(m,5H),3.56 -3.38(m,1H),2.75(s,1H),2.66(s,4H),2.58(s,3H),2.09(dd,J=14.6,7.4Hz,2H),1.57(d,J=6.8 Hz,3H).
实施例I-175：Example I-175:
Figure PCTCN2022135958-appb-000176
Figure PCTCN2022135958-appb-000176
参照实施例I-155制备方法，使用I-174为原料得I-175(35mg,39％)。MS(ESI)m/z＝528.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.12(s,1H),8.76(s,1H),7.81-7.73(m,2H),7.51(t,J＝11.0Hz,1H),7.32(t,J＝7.8Hz,1H),5.71-5.64(m,1H),4.67(d,J＝14.0Hz,1H),4.17(d,J＝11.6Hz,1H),3.98-3.62(m,4H),3.43(s,1H),3.13(t,J＝12.4Hz,2H),2.79-2.62(m,4H),2.59(d,J＝8.6Hz,3H),2.16-1.89(m,4H),1.81-1.61(m,2H),1.57(t,J＝8.6Hz,3H). Referring to the preparation method of Example I-155, I-174 was used as a raw material to obtain I-175 (35 mg, 39%). MS(ESI)m/z＝528.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.12(s,1H),8.76(s,1H),7.81-7.73(m,2H ), 7.51(t, J=11.0Hz, 1H), 7.32(t, J=7.8Hz, 1H), 5.71-5.64(m, 1H), 4.67(d, J=14.0Hz, 1H), 4.17(d ,J=11.6Hz,1H),3.98-3.62(m,4H),3.43(s,1H),3.13(t,J=12.4Hz,2H),2.79-2.62(m,4H),2.59(d, J＝8.6Hz, 3H), 2.16-1.89(m, 4H), 1.81-1.61(m, 2H), 1.57(t, J＝8.6Hz, 3H).
实施例I-176：Example I-176:
Figure PCTCN2022135958-appb-000177
Figure PCTCN2022135958-appb-000177
步骤1：step 1:
参照实施例I-154和I-155制备方法，使用I-176a与I-2h为原料经两步得I-176c。MS(ESI)m/z＝443.0[M+H] +. Referring to the preparation methods of Examples I-154 and I-155, I-176c was obtained in two steps using I-176a and I-2h as raw materials. MS(ESI)m/z=443.0[M+H] + .
步骤2：Step 2:
0℃下，向I-176c(120mg,0.27mmol)的水无四氢呋喃溶液中加入甲基溴化镁的四氢呋喃溶液(3M,0.3mL,0.9mmol)。室温搅拌5小时。饱和氯化铵水溶液萃灭，乙酸乙酯萃取。有机相经浓缩，薄层层析分离后得到白色固体异构体A(18.7mg,15％)和异构体B(2.9mg,2.9％)。To a solution of I-176c (120 mg, 0.27 mmol) in water without THF was added methylmagnesium bromide in THF (3M, 0.3 mL, 0.9 mmol) at 0°C. Stir at room temperature for 5 hours. Saturated ammonium chloride aqueous solution was extracted, and ethyl acetate extracted. The organic phase was concentrated, and Isomer A (18.7 mg, 15%) and Isomer B (2.9 mg, 2.9%) were obtained as white solids after separation by thin layer chromatography.
经SFC(柱型号：SunFire C18 5um 4.6x150mm 25C；流动相A：水(含0.03％的三氟乙酸)；流动相B：乙腈(含0.03％三氟乙酸)；流速：1mL/min；波长：254nm)，异构体A(t R＝10.96min)和异构体B(t R＝7.07min)。 After SFC (column model: SunFire C18 5um 4.6x150mm 25C; mobile phase A: water (containing 0.03% trifluoroacetic acid); mobile phase B: acetonitrile (containing 0.03% trifluoroacetic acid); flow rate: 1mL/min; wavelength: 254 nm), isomer A (t R =10.96 min) and isomer B (t R =7.07 min).
异构体A：MS(ESI)m/z＝459.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.05(s,1H),8.77(s,1H),7.97(d,J＝6.4Hz,1H),7.76(d,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.32(t,J＝7.9Hz,1H),5.77-5.59(m,1H),4.18(s,1H),2.76(t,J＝12.6Hz,1H),2.64(s,3H),2.58(s,3H),2.08-1.94(m,2H),1.70(t,J＝14.6Hz,4H),1.61-1.44(m,5H),1.22(d,J＝13.4Hz,3H). Isomer A: MS (ESI) m/z = 459.1 [M+H] + . 1 H NMR (400MHz, d 6 -DMSO) δ9.05 (s, 1H), 8.77 (s, 1H), 7.97 ( d, J=6.4Hz, 1H), 7.76(d, J=7.8Hz, 1H), 7.52(d, J=7.8Hz, 1H), 7.32(t, J=7.9Hz, 1H), 5.77-5.59( m, 1H), 4.18(s, 1H), 2.76(t, J=12.6Hz, 1H), 2.64(s, 3H), 2.58(s, 3H), 2.08-1.94(m, 2H), 1.70(t ,J=14.6Hz,4H),1.61-1.44(m,5H),1.22(d,J=13.4Hz,3H).
异构体B：MS(ESI)m/z＝459.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.11(s,1H),8.72(s,1H),7.77(dd,J＝12.2,7.3Hz,2H),7.53(d,J＝7.7Hz,1H),7.32(t,J＝7.9Hz,1H),5.80-5.59(m,1H),4.45(s,1H),2.80(d,J＝11.9Hz,1H),2.64(s,3H),2.55(d,J＝21.3Hz,3H),1.89(d,J＝8.8Hz,2H),1.72(d,J＝11.0Hz,4H),1.59(dd,J＝17.0,10.4Hz,5H),1.27(s,3H). Isomer B: MS (ESI) m/z = 459.3 [M+H] + . 1 H NMR (400MHz, d 6 -DMSO) δ9.11 (s, 1H), 8.72 (s, 1H), 7.77 ( dd,J=12.2,7.3Hz,2H),7.53(d,J=7.7Hz,1H),7.32(t,J=7.9Hz,1H),5.80-5.59(m,1H),4.45(s,1H ),2.80(d,J=11.9Hz,1H),2.64(s,3H),2.55(d,J=21.3Hz,3H),1.89(d,J=8.8Hz,2H),1.72(d,J =11.0Hz,4H),1.59(dd,J=17.0,10.4Hz,5H),1.27(s,3H).
实施例I-178：Example I-178:
Figure PCTCN2022135958-appb-000178
Figure PCTCN2022135958-appb-000178
步骤1：step 1:
参照实施例I-172，步骤3的制备方法，使用1-三氟甲基环丙烷-1-羧酸和I-172c为原料得I-178a(40mg,31％)。MS(ESI)m/z＝564.1[M+H] +. Referring to Example I-172, the preparation method in Step 3, using 1-trifluoromethylcyclopropane-1-carboxylic acid and I-172c as raw materials, I-178a (40 mg, 31%) was obtained. MS(ESI)m/z=564.1[M+H] + .
步骤2：Step 2:
参照实施例I-155制备方法，使用I-178a为原料制得I-178(3mg,18％)；。MS(ESI)m/z＝566.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.12(s,1H),8.75(s,1H),7.81(d,J＝6.6Hz,1H),7.75(d,J＝7.7Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.8Hz,1H),5.76-5.59(m,1H),4.48(s,2H),3.22-3.05(m,1H),2.65(s,3H),2.58(s,3H),2.02(d,J＝11.5Hz,2H),1.73(d,J＝10.6Hz,2H),1.56(d,J＝6.8Hz,3H),1.35(s,2H),1.24(s,4H). Referring to the preparation method of Example I-155, I-178 (3 mg, 18%) was prepared using I-178a as a raw material; MS(ESI)m/z=566.3[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.12(s,1H),8.75(s,1H),7.81(d,J=6.6 Hz,1H),7.75(d,J=7.7Hz,1H),7.53(d,J=7.6Hz,1H),7.32(t,J=7.8Hz,1H),5.76-5.59(m,1H), 4.48(s,2H),3.22-3.05(m,1H),2.65(s,3H),2.58(s,3H),2.02(d,J=11.5Hz,2H),1.73(d,J=10.6Hz ,2H),1.56(d,J=6.8Hz,3H),1.35(s,2H),1.24(s,4H).
实施例I-179：Example I-179:
Figure PCTCN2022135958-appb-000179
Figure PCTCN2022135958-appb-000179
参照实施例I-2，步骤8的制备方法，使用3,3-二氟吡咯烷和I-2h为原料得I-179(17mg,24％)。MS(ESI)m/z＝452.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.70(d,J＝2.8Hz,1H),7.75(d,J＝8.0Hz,1H),7.68(d,J＝2.4Hz,1H),7.52(d,J＝7.6Hz,1H),7.47(d,J＝6.8Hz,1H),7.31(t,J＝7.6Hz,1H),5.74-5.62(m,1H),4.00(dd,J＝16.4,12.8Hz,2H),3.78(dd,J＝12.2,7.2Hz,2H),2.58(d,J＝3.6Hz,8H),1.56(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method of Step 8, using 3,3-difluoropyrrolidine and I-2h as raw materials, I-179 (17mg, 24%) was obtained. MS(ESI)m/z=452.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.70(d,J=2.8Hz,1H),7.75(d,J=8.0Hz, 1H), 7.68(d, J=2.4Hz, 1H), 7.52(d, J=7.6Hz, 1H), 7.47(d, J=6.8Hz, 1H), 7.31(t, J=7.6Hz, 1H) ,5.74-5.62(m,1H),4.00(dd,J=16.4,12.8Hz,2H),3.78(dd,J=12.2,7.2Hz,2H),2.58(d,J=3.6Hz,8H), 1.56(d,J=6.8Hz,3H).
实施例I-180：Example I-180:
Figure PCTCN2022135958-appb-000180
Figure PCTCN2022135958-appb-000180
步骤1：step 1:
向I-2g(150mg,0.52mmol)和A-10(185mg,0.78mmol)的DMSO(2mL)溶液中加入吡啶(373mg,4.73mmol)和氟化铯(71mg,0.47mmol)，120℃下搅拌8小时。将反应液用乙酸乙酯稀释，饱和食盐水洗，浓缩，反相制备色谱法分离得I-180a(100mg,45％)。MS(ESI)m/z＝421.0[M+H] +. Add pyridine (373mg, 4.73mmol) and cesium fluoride (71mg, 0.47mmol) to a solution of I-2g (150mg, 0.52mmol) and A-10 (185mg, 0.78mmol) in DMSO (2mL), and stir at 120°C 8 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, concentrated, and separated by reverse-phase preparative chromatography to obtain I-180a (100 mg, 45%). MS(ESI)m/z=421.0[M+H] + .
步骤2：Step 2:
参照实施例I-2，步骤8的制备方法，使用3-氧杂-8-氮杂双环[3.2.1]辛烷和I-180a为原料得I-180(24mg,47％)。MS(ESI)m/z＝454.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.92(d,J＝2.8Hz,1H),7.91(d,J＝2.4Hz,1H),7.46(d,J＝7.6Hz,2H),7.27(d,J＝7.2Hz,1H),7.02(t,J＝7.6Hz,1H),5.61(t,J＝7.2Hz,1H),4.88(t,J＝16.8Hz,2H),4.58(s,2H),3.83-3.70(m,2H),3.58(d,J＝11.2Hz,2H),2.58(s,3H),2.12-1.99(m,4H),1.60(t,J＝10.2Hz,3H). Referring to Example I-2, the preparation method of Step 8, using 3-oxa-8-azabicyclo[3.2.1]octane and I-180a as raw materials, I-180 (24 mg, 47%) was obtained. MS(ESI)m/z=454.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.92(d,J=2.8Hz,1H),7.91(d,J=2.4Hz, 1H), 7.46(d, J=7.6Hz, 2H), 7.27(d, J=7.2Hz, 1H), 7.02(t, J=7.6Hz, 1H), 5.61(t, J=7.2Hz, 1H) ,4.88(t,J=16.8Hz,2H),4.58(s,2H),3.83-3.70(m,2H),3.58(d,J=11.2Hz,2H),2.58(s,3H),2.12- 1.99(m,4H),1.60(t,J=10.2Hz,3H).
实施例I-181：Example I-181:
Figure PCTCN2022135958-appb-000181
Figure PCTCN2022135958-appb-000181
参照实施例I-2，步骤8的制备方法，使用4-羟基哌啶和I-2h为原料得I-181(5mg,9％)。MS(ESI)m/z＝446.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.02(s,1H),7.95(s,1H),7.74(d,J＝7.9Hz,1H),7.63(s,1H),7.53(d,J＝7.5Hz,1H),7.32(t,J＝7.9Hz,1H),5.64(t,J＝6.5Hz,1H),4.80(d,J＝4.2Hz,1H),3.89(s,2H),3.78(s,1H),3.23(s,2H),2.58(d,J＝4.1Hz,6H),1.90(s,2H),1.56(d,J＝6.8Hz,5H). Referring to Example I-2, the preparation method of Step 8, using 4-hydroxypiperidine and I-2h as raw materials, I-181 (5 mg, 9%) was obtained. MS(ESI)m/z=446.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.02(s,1H),7.95(s,1H),7.74(d,J=7.9 Hz, 1H), 7.63(s, 1H), 7.53(d, J=7.5Hz, 1H), 7.32(t, J=7.9Hz, 1H), 5.64(t, J=6.5Hz, 1H), 4.80( d,J=4.2Hz,1H),3.89(s,2H),3.78(s,1H),3.23(s,2H),2.58(d,J=4.1Hz,6H),1.90(s,2H), 1.56(d,J=6.8Hz,5H).
实施例I-182：Example I-182:
Figure PCTCN2022135958-appb-000182
Figure PCTCN2022135958-appb-000182
参照实施例I-2，步骤8的制备方法，使用(S)-3-羟基吡咯烷和I-2h为原料得I-182(4mg,7％)。MS(ESI)m/z＝432.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.64(d,J＝2.7Hz,1H),7.74(d,J＝8.0Hz,1H),7.54(dd,J＝14.3,5.1Hz,3H),7.31(t,J＝7.8Hz,1H),5.66(t,J＝7.0Hz,1H),5.12(d,J＝3.9Hz,1H),4.51(s,1H),3.60(dt,J＝18.0,6.6Hz,3H),3.40(d,J＝11.2Hz,1H),2.57(s,6H),2.20-2.08(m,1H),2.02(s,1H),1.55(d,J＝7.0Hz,3H). Referring to Example I-2, the preparation method of Step 8, using (S)-3-hydroxypyrrolidine and I-2h as raw materials, I-182 (4 mg, 7%) was obtained. MS(ESI)m/z=432.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.64(d,J=2.7Hz,1H),7.74(d,J=8.0Hz, 1H), 7.54(dd, J=14.3, 5.1Hz, 3H), 7.31(t, J=7.8Hz, 1H), 5.66(t, J=7.0Hz, 1H), 5.12(d, J=3.9Hz, 1H), 4.51(s, 1H), 3.60(dt, J=18.0, 6.6Hz, 3H), 3.40(d, J=11.2Hz, 1H), 2.57(s, 6H), 2.20-2.08(m, 1H ),2.02(s,1H),1.55(d,J=7.0Hz,3H).
实施例I-183：Example I-183:
Figure PCTCN2022135958-appb-000183
Figure PCTCN2022135958-appb-000183
参照实施例I-2，步骤8的制备方法，使用(S)-3-甲氧基吡咯烷和I-2h为原料得I-182(20mg,27％)。MS(ESI)m/z＝446.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.64(d,J＝2.4Hz,1H),7.75(d,J＝8.0Hz,1H),7.56(d,J＝2.4Hz,1H),7.51(d,J＝7.2Hz,1H),7.43(d,J＝7.0Hz,1H),7.31(t,J＝8.0Hz,1H),5.70-5.63(m,1H),4.21(s,1H),3.66-3.54(m,3H),3.49(dd,J＝17.0,9.2Hz,1H),3.32(s,3H),2.57(s,3H),2.56(s,3H),2.16(t,J＝8.4Hz,2H),1.55(d,J＝7.0Hz,3H). Referring to Example I-2, the preparation method of Step 8, using (S)-3-methoxypyrrolidine and I-2h as raw materials, I-182 (20mg, 27%) was obtained. MS(ESI)m/z=446.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.64(d,J=2.4Hz,1H),7.75(d,J=8.0Hz, 1H), 7.56(d, J=2.4Hz, 1H), 7.51(d, J=7.2Hz, 1H), 7.43(d, J=7.0Hz, 1H), 7.31(t, J=8.0Hz, 1H) ,5.70-5.63(m,1H),4.21(s,1H),3.66-3.54(m,3H),3.49(dd,J＝17.0,9.2Hz,1H),3.32(s,3H),2.57(s ,3H),2.56(s,3H),2.16(t,J=8.4Hz,2H),1.55(d,J=7.0Hz,3H).
实施例I-184：Example I-184:
Figure PCTCN2022135958-appb-000184
Figure PCTCN2022135958-appb-000184
参照实施例I-2，步骤8的制备方法，使用(R)-3-甲氧基吡咯烷和I-2h为原料得I-182(3mg,5％)。MS(ESI)m/z＝446.2[M+H] +. 1H NMR(400MHz,CDCl 3)δ8.54(s,1H),8.07(s,1H),7.80(d,J＝7.6Hz,1H),7.39(d,J＝8.0Hz,1H),7.08(t,J＝7.6Hz,1H),5.33(d,J＝6.0Hz,1H),4.14(s,1H),4.00-3.62(m,4H),3.36(s,3H),2.78(s,3H),2.45(s,3H),2.30(s,1H),2.11(d,J＝9.8Hz,1H),1.65(d,J＝6.4Hz,3H). Referring to Example I-2, the preparation method in Step 8, using (R)-3-methoxypyrrolidine and I-2h as raw materials, I-182 (3 mg, 5%) was obtained. MS(ESI)m/z=446.2[M+H] + . 1 H NMR(400MHz, CDCl 3 )δ8.54(s, 1H), 8.07(s, 1H), 7.80(d, J=7.6Hz, 1H), 7.39(d, J=8.0Hz, 1H), 7.08(t, J=7.6Hz, 1H), 5.33(d, J=6.0Hz, 1H), 4.14(s, 1H), 4.00-3.62( m,4H),3.36(s,3H),2.78(s,3H),2.45(s,3H),2.30(s,1H),2.11(d,J＝9.8Hz,1H),1.65(d,J =6.4Hz,3H).
实施例I-185：Example I-185:
Figure PCTCN2022135958-appb-000185
Figure PCTCN2022135958-appb-000185
参照实施例I-2，步骤8的制备方法，使用1-氧杂-7-氮杂螺[4.4]壬烷和I-2h为原料得I-185(16mg,29％)。MS(ESI)m/z＝474.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.61(d,J＝2.4Hz,1H),7.75(d,J＝8.0Hz,1H),7.51(d,J＝7.6Hz,2H),7.42(d,J＝4.8Hz,1H),7.31(t,J＝7.6Hz,1H),5.74–5.61(m,1H),3.82(d,J＝6.4Hz,2H),3.70–3.46(m,4H),2.57(d,J＝4.8Hz,6H),2.22–1.90(m,6H),1.55(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method of Step 8, using 1-oxa-7-azaspiro[4.4]nonane and I-2h as raw materials, I-185 (16 mg, 29%) was obtained. MS(ESI)m/z=474.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.61(d,J=2.4Hz,1H),7.75(d,J=8.0Hz, 1H), 7.51(d, J=7.6Hz, 2H), 7.42(d, J=4.8Hz, 1H), 7.31(t, J=7.6Hz, 1H), 5.74–5.61(m, 1H), 3.82( d,J=6.4Hz,2H),3.70–3.46(m,4H),2.57(d,J=4.8Hz,6H),2.22–1.90(m,6H),1.55(d,J=6.8Hz,3H ).
实施例I-186：Example I-186:
Figure PCTCN2022135958-appb-000186
Figure PCTCN2022135958-appb-000186
参照实施例I-2，步骤8的制备方法，使用(S)-3-(甲氧基甲基)吗啉盐酸盐和I-2h为原料得I-186(15mg,27％)。MS(ESI)m/z＝476.3[M+H] +.1H NMR(400MHz,d 6-DMSO)δ9.01(d,J＝2.8Hz,1H),7.88(d,J＝2.8Hz,1H),7.74(d,J＝7.6Hz,1H),7.53(d,J＝7.2Hz,2H),7.32(t,J＝7.6Hz,1H),5.68(t,J＝6.8Hz,1H),4.44(s,1H),4.03(dd,J＝19.6,11.4Hz,2H),3.68(dt,J＝18.3,10.6Hz,4H),3.46(dd,J＝9.6,6.2Hz,1H),3.35-3.25(m,3H),2.60-2.53(m,6H),1.56(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method of Step 8, using (S)-3-(methoxymethyl)morpholine hydrochloride and I-2h as raw materials, I-186 (15 mg, 27%) was obtained. MS(ESI)m/z=476.3[M+H] + .1H NMR(400MHz,d 6 -DMSO)δ9.01(d,J=2.8Hz,1H),7.88(d,J=2.8Hz,1H ),7.74(d,J=7.6Hz,1H),7.53(d,J=7.2Hz,2H),7.32(t,J=7.6Hz,1H),5.68(t,J=6.8Hz,1H), 4.44(s,1H),4.03(dd,J=19.6,11.4Hz,2H),3.68(dt,J=18.3,10.6Hz,4H),3.46(dd,J=9.6,6.2Hz,1H),3.35 -3.25(m,3H),2.60-2.53(m,6H),1.56(d,J＝6.8Hz,3H).
实施例I-187：Example I-187:
Figure PCTCN2022135958-appb-000187
Figure PCTCN2022135958-appb-000187
参照实施例I-2，步骤8的制备方法，使用(R)-3-(甲氧基甲基)吗啉盐酸盐和I-2h为原料得I-187(12mg,21％)。MS(ESI)m/z＝476.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.01(d,J＝2.8Hz,1H),7.88(d,J＝2.8Hz,1H),7.74(d,J＝7.6Hz,1H),7.53(d,J＝7.2Hz,2H),7.32(t,J＝7.6Hz,1H),5.68(t,J＝6.8Hz,1H),4.44(s,1H),4.03(dd,J＝19.6,11.4Hz,2H),3.68(dt,J＝18.3,10.6Hz,4H),3.46(dd,J＝9.6,6.2Hz,1H),3.35-3.25(m,3H),2.60-2.53(m,6H),1.56(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method of Step 8, using (R)-3-(methoxymethyl)morpholine hydrochloride and I-2h as raw materials, I-187 (12 mg, 21%) was obtained. MS(ESI)m/z=476.3[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.01(d,J=2.8Hz,1H),7.88(d,J=2.8Hz, 1H), 7.74(d, J=7.6Hz, 1H), 7.53(d, J=7.2Hz, 2H), 7.32(t, J=7.6Hz, 1H), 5.68(t, J=6.8Hz, 1H) ,4.44(s,1H),4.03(dd,J=19.6,11.4Hz,2H),3.68(dt,J=18.3,10.6Hz,4H),3.46(dd,J=9.6,6.2Hz,1H), 3.35-3.25(m,3H),2.60-2.53(m,6H),1.56(d,J＝6.8Hz,3H).
实施例I-188：Example I-188:
Figure PCTCN2022135958-appb-000188
Figure PCTCN2022135958-appb-000188
参照实施例I-2，步骤8的制备方法，使用(R)-2-(甲氧基甲基)吡咯烷和I-2h为原料得I-188(8mg,15％)。MS(ESI)m/z＝460.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.74(d,J＝2.5Hz,1H),7.74(d,J＝7.6Hz,1H),7.60(d,J＝2.4Hz,1H),7.51(d,J＝7.5Hz,2H),7.30(t,J＝7.6Hz,1H),5.66(t,J＝6.9Hz,1H),4.37(s,1H),3.63(t,J＝8.0Hz,1H),3.48-3.37(m,3H),3.29(s,3H),2.57(d,J＝2.7Hz,6H),2.08(dd,J＝31.9,11.3Hz,4H),1.55(d,J＝6.9Hz,3H). Referring to Example I-2, the preparation method in Step 8, using (R)-2-(methoxymethyl)pyrrolidine and I-2h as raw materials, I-188 (8 mg, 15%) was obtained. MS(ESI)m/z=460.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.74(d,J=2.5Hz,1H),7.74(d,J=7.6Hz, 1H), 7.60(d, J=2.4Hz, 1H), 7.51(d, J=7.5Hz, 2H), 7.30(t, J=7.6Hz, 1H), 5.66(t, J=6.9Hz, 1H) ,4.37(s,1H),3.63(t,J=8.0Hz,1H),3.48-3.37(m,3H),3.29(s,3H),2.57(d,J=2.7Hz,6H),2.08( dd,J=31.9,11.3Hz,4H),1.55(d,J=6.9Hz,3H).
实施例I-189：Example I-189:
Figure PCTCN2022135958-appb-000189
Figure PCTCN2022135958-appb-000189
参照实施例I-2，步骤8的制备方法，使用D-脯氨醇和I-2h为原料得I-189(10mg,19％)。MS(ESI)m/z＝446.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.76(d,J＝2.5Hz,1H),7.75(d,J＝8.0Hz,1H),7.54(dd,J＝17.3,5.0Hz,3H),7.31(t,J＝7.7Hz,1H),5.77-5.55(m,1H),4.89(t,J＝5.7Hz,1H),4.18(s,1H),3.61-3.51(m,2H),3.47-3.37(m,2H),2.57(s,6H),2.18-1.94(m,4H),1.55(d,J＝7.0Hz,3H). Referring to Example I-2, the preparation method of Step 8, using D-prolinol and I-2h as raw materials, I-189 (10 mg, 19%) was obtained. MS(ESI)m/z=446.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.76(d,J=2.5Hz,1H),7.75(d,J=8.0Hz, 1H), 7.54(dd, J=17.3, 5.0Hz, 3H), 7.31(t, J=7.7Hz, 1H), 5.77-5.55(m, 1H), 4.89(t, J=5.7Hz, 1H), 4.18(s,1H),3.61-3.51(m,2H),3.47-3.37(m,2H),2.57(s,6H),2.18-1.94(m,4H),1.55(d,J＝7.0Hz, 3H).
实施例I-190：Example I-190:
Figure PCTCN2022135958-appb-000190
Figure PCTCN2022135958-appb-000190
参照实施例I-2，步骤8的制备方法，使用(R)-3-吡咯烷醇和I-2h为原料得I-190(6mg,12％)。MS(ESI)m/z＝432.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.65(d,J＝2.6Hz,1H),7.74(d,J＝8.0Hz,1H),7.54(dd,J＝18.5,5.1Hz,3H),7.31(t,J＝7.7Hz,1H),5.74-5.53(m,1H),5.12(d,J＝3.7Hz,1H),4.51(s,1H),3.71-3.48(m,3H),3.38(d,J＝11.1Hz,1H),2.58(s,6H),2.12(dt,J＝17.5,6.7Hz,1H),2.03(s,1H),1.56(d,J＝6.9Hz,3H). Referring to Example I-2, the preparation method in step 8, using (R)-3-pyrrolidinol and I-2h as raw materials, I-190 (6 mg, 12%) was obtained. MS(ESI)m/z=432.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.65(d,J=2.6Hz,1H),7.74(d,J=8.0Hz, 1H), 7.54(dd, J=18.5, 5.1Hz, 3H), 7.31(t, J=7.7Hz, 1H), 5.74-5.53(m, 1H), 5.12(d, J=3.7Hz, 1H), 4.51(s,1H),3.71-3.48(m,3H),3.38(d,J=11.1Hz,1H),2.58(s,6H),2.12(dt,J=17.5,6.7Hz,1H),2.03 (s,1H),1.56(d,J=6.9Hz,3H).
实施例I-191：Example I-191:
Figure PCTCN2022135958-appb-000191
Figure PCTCN2022135958-appb-000191
参照实施例I-2，步骤8的制备方法，使用L-脯氨醇和I-2h为原料得I-191(12mg,16％)。MS(ESI)m/z＝446.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.74(d,J＝2.6Hz,1H),7.74(d,J＝7.6Hz,1H),7.57(d,J＝2.6Hz,1H),7.50(t,J＝6.4Hz,2H),7.30(t,J＝7.8Hz,1H),5.70-5.63(m,1H),4.89(t,J＝5.6Hz,1H),4.20(d,J＝4.8Hz,1H),3.62(t,J＝8.8Hz,1H),3.55-3.50(m,1H),3.47-3.37(m,1H),3.30(s,1H),2.57(s,3H),2.56(s,3H),2.17-1.92(m,4H),1.55(d,J＝7.0Hz,3H). Referring to Example I-2, the preparation method in Step 8, using L-prolinol and I-2h as raw materials, I-191 (12 mg, 16%) was obtained. MS(ESI)m/z=446.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.74(d,J=2.6Hz,1H),7.74(d,J=7.6Hz, 1H), 7.57(d, J=2.6Hz, 1H), 7.50(t, J=6.4Hz, 2H), 7.30(t, J=7.8Hz, 1H), 5.70-5.63(m, 1H), 4.89( t, J=5.6Hz, 1H), 4.20(d, J=4.8Hz, 1H), 3.62(t, J=8.8Hz, 1H), 3.55-3.50(m, 1H), 3.47-3.37(m, 1H ),3.30(s,1H),2.57(s,3H),2.56(s,3H),2.17-1.92(m,4H),1.55(d,J=7.0Hz,3H).
实施例I-192：Example I-192:
Figure PCTCN2022135958-appb-000192
Figure PCTCN2022135958-appb-000192
参照实施例I-2，步骤8的制备方法，使用(R)-3-羟甲基吗啉盐酸盐和I-2h为原料得I-192(2mg,2％)。MS(ESI)m/z＝462.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.98(s,1H),7.86(s,1H),7.74(d,J＝7.2Hz,1H),7.52(d,J＝7.2Hz,2H),7.32(t,J＝7.2Hz,1H),5.67(t,J＝4Hz,1H),4.85(t,J＝5.6Hz,1H),4.26-4.01(m,3H),3.68(dd,J＝23.5,9.8Hz,4H),3.51(d,J＝10.6Hz,1H),2.58(s,6H),1.55(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method of Step 8, using (R)-3-hydroxymethylmorpholine hydrochloride and I-2h as raw materials, I-192 (2 mg, 2%) was obtained. MS(ESI)m/z=462.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.98(s,1H),7.86(s,1H),7.74(d,J=7.2 Hz, 1H), 7.52(d, J=7.2Hz, 2H), 7.32(t, J=7.2Hz, 1H), 5.67(t, J=4Hz, 1H), 4.85(t, J=5.6Hz, 1H ),4.26-4.01(m,3H),3.68(dd,J=23.5,9.8Hz,4H),3.51(d,J=10.6Hz,1H),2.58(s,6H),1.55(d,J= 6.8Hz, 3H).
实施例I-193：Example I-193:
Figure PCTCN2022135958-appb-000193
Figure PCTCN2022135958-appb-000193
参照实施例I-2，步骤8的制备方法，使用(S)-3-羟甲基吗啉盐酸盐和I-2h为原料得I-193(2mg,2％)。MS(ESI)m/z＝462.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.00(s,1H),7.86(s,1H),7.73(d, J＝7.4Hz,1H),7.60(s,1H),7.53(d,J＝7.7Hz,1H),7.32(t,J＝7.6Hz,1H),5.70-5.60(m,1H),4.85(t,J＝5.2Hz,1H),4.22(s,1H),4.06(t,J＝11.6Hz,2H),3.79-3.57(m,4H),3.57-3.48(m,1H),3.29(s,1H),2.59(s,3H),2.57(s,3H),1.55(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method of Step 8, using (S)-3-hydroxymethylmorpholine hydrochloride and I-2h as raw materials, I-193 (2mg, 2%) was obtained. MS(ESI)m/z=462.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.00(s,1H),7.86(s,1H),7.73(d, J=7.4 Hz,1H),7.60(s,1H),7.53(d,J=7.7Hz,1H),7.32(t,J=7.6Hz,1H),5.70-5.60(m,1H),4.85(t,J =5.2Hz,1H),4.22(s,1H),4.06(t,J=11.6Hz,2H),3.79-3.57(m,4H),3.57-3.48(m,1H),3.29(s,1H) ,2.59(s,3H),2.57(s,3H),1.55(d,J=6.8Hz,3H).
实施例I-194：Example I-194:
Figure PCTCN2022135958-appb-000194
Figure PCTCN2022135958-appb-000194
参照实施例I-2，步骤8的制备方法，使用1,4-二氧杂-7-氮杂螺[4.4]壬烷和I-2h为原料得I-194(16mg,29％)。MS(ESI)m/z＝474.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.64(d,J＝2.7Hz,1H),7.74(d,J＝7.7Hz,1H),7.58(d,J＝2.7Hz,1H),7.49(dd,J＝18.9,7.2Hz,2H),7.31(t,J＝7.8Hz,1H),5.65(dd,J＝13.8,6.9Hz,1H),4.04-3.95(m,4H),3.64(dd,J＝12.9,7.2Hz,2H),3.57(t,J＝7.6Hz,2H),2.57(s,6H),2.24(t,J＝7.2Hz,2H),1.55(d,J＝7.0Hz,3H). Referring to Example I-2, the preparation method of Step 8, using 1,4-dioxa-7-azaspiro[4.4]nonane and I-2h as raw materials, I-194 (16 mg, 29%) was obtained. MS(ESI)m/z=474.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.64(d,J=2.7Hz,1H),7.74(d,J=7.7Hz, 1H), 7.58(d, J=2.7Hz, 1H), 7.49(dd, J=18.9, 7.2Hz, 2H), 7.31(t, J=7.8Hz, 1H), 5.65(dd, J=13.8, 6.9 Hz, 1H), 4.04-3.95(m, 4H), 3.64(dd, J=12.9, 7.2Hz, 2H), 3.57(t, J=7.6Hz, 2H), 2.57(s, 6H), 2.24(t ,J=7.2Hz,2H),1.55(d,J=7.0Hz,3H).
实施例I-195：Example I-195:
Figure PCTCN2022135958-appb-000195
Figure PCTCN2022135958-appb-000195
参照实施例I-172，步骤3的制备方法，使用2-氟乙酸和I-172c为原料得I-195(30mg,61％)。MS(ESI)m/z＝488.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.31(d,J＝10.2Hz,1H),8.86(s,1H),7.89(s,1H),7.76(d,J＝8.0Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.7Hz,1H),6.62(d,J＝16.3Hz,1H),5.71(dd,J＝18.3,11.8Hz,1H),5.24(dd,J＝46.7,22.7Hz,2H),4.24(s,1H),4.14(s,1H),3.79(s,1H),3.60(s,1H),2.76(s,2H),2.66(s,3H),2.58(s,3H),1.57(d,J＝6.9Hz,3H). Referring to Example I-172, the preparation method in step 3, using 2-fluoroacetic acid and I-172c as raw materials, I-195 (30 mg, 61%) was obtained. MS(ESI)m/z=488.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.31(d,J=10.2Hz,1H),8.86(s,1H),7.89( s,1H),7.76(d,J=8.0Hz,1H),7.53(d,J=7.6Hz,1H),7.32(t,J=7.7Hz,1H),6.62(d,J=16.3Hz, 1H), 5.71(dd, J＝18.3, 11.8Hz, 1H), 5.24(dd, J＝46.7, 22.7Hz, 2H), 4.24(s, 1H), 4.14(s, 1H), 3.79(s, 1H ),3.60(s,1H),2.76(s,2H),2.66(s,3H),2.58(s,3H),1.57(d,J=6.9Hz,3H).
实施例I-196：Example I-196:
Figure PCTCN2022135958-appb-000196
Figure PCTCN2022135958-appb-000196
步骤1：step 1:
参照实施例I-2，步骤7的制备方法，使用I-2g和A-1为原料得I-196a。Referring to Example I-2, the preparation method of step 7, using I-2g and A-1 as raw materials to obtain I-196a.
步骤2：Step 2:
参照实施例I-2，步骤8的制备方法，使用L-脯氨醇和I-196a为原料得I-196(15mg,30％)。MS(ESI)m/z＝432.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.75(d,J＝2.7Hz,1H),7.57(t,J＝5.6Hz,2H),7.45(t,J＝9.0Hz,2H),7.40-7.07(m,2H),5.70(t,J＝7.2Hz,1H),4.89(t,J＝5.7Hz,1H),4.20(d,J＝5.0Hz,1H),3.62(t,J＝8.9Hz,1H),3.53(dt,J＝9.8,4.8Hz,1H),3.47-3.38(m,1H),3.29(d,J＝6.8Hz,1H),2.56(s,3H),2.18-1.90(m,4H),1.61(d,J＝7.1Hz,3H). Referring to Example I-2, the preparation method in Step 8, using L-prolinol and I-196a as raw materials, I-196 (15 mg, 30%) was obtained. MS(ESI)m/z=432.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.75(d,J=2.7Hz,1H),7.57(t,J=5.6Hz, 2H), 7.45(t, J=9.0Hz, 2H), 7.40-7.07(m, 2H), 5.70(t, J=7.2Hz, 1H), 4.89(t, J=5.7Hz, 1H), 4.20( d,J=5.0Hz,1H),3.62(t,J=8.9Hz,1H),3.53(dt,J=9.8,4.8Hz,1H),3.47-3.38(m,1H),3.29(d,J =6.8Hz,1H),2.56(s,3H),2.18-1.90(m,4H),1.61(d,J=7.1Hz,3H).
实施例I-197：Example I-197:
Figure PCTCN2022135958-appb-000197
Figure PCTCN2022135958-appb-000197
参照实施例I-196，步骤2的制备方法，使用(S)-3-甲基吗啉和I-196a为原料得I-197(16mg,31％)。MS(ESI)m/z＝432.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.98(d,J＝2.8Hz,1H),7.89(d,J＝2.8Hz,1H),7.58(t,J＝8.0Hz,1H),7.46(dd,J＝12.0,6.4Hz,2H),7.23(t,J＝4.4Hz,1H),5.75-5.63(m,1H),4.35(s,1H),4.06(d,J＝11.2Hz,1H),3.80(s,2H),3.64(t,J＝14.8Hz,2H),3.27(s,1H),2.58(s,4H),1.60(d,J＝6.8Hz,3H),1.15(d,J＝6.4Hz,3H). Referring to Example I-196, the preparation method in Step 2, using (S)-3-methylmorpholine and I-196a as raw materials, I-197 (16 mg, 31%) was obtained. MS(ESI)m/z=432.3[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.98(d,J=2.8Hz,1H),7.89(d,J=2.8Hz, 1H), 7.58(t, J=8.0Hz, 1H), 7.46(dd, J=12.0, 6.4Hz, 2H), 7.23(t, J=4.4Hz, 1H), 5.75-5.63(m, 1H), 4.35(s,1H),4.06(d,J=11.2Hz,1H),3.80(s,2H),3.64(t,J=14.8Hz,2H),3.27(s,1H),2.58(s,4H ), 1.60(d, J=6.8Hz, 3H), 1.15(d, J=6.4Hz, 3H).
实施例I-198：Example I-198:
Figure PCTCN2022135958-appb-000198
Figure PCTCN2022135958-appb-000198
参照实施例I-196，步骤2的制备方法，使用(R)-3-甲基吗啉和I-196a为原料得I-198(7mg,14％)。MS(ESI)m/z＝432.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.98(d,J＝2.8Hz,1H),7.89(d,J＝2.8Hz,1H),7.58(t,J＝8.0Hz,1H),7.46(dd,J＝12.0,6.4Hz,2H),7.23(t,J＝4.4Hz,1H),5.75-5.63(m,1H),4.35(s,1H),4.06(d,J＝11.2Hz,1H),3.80(s,2H),3.64(t,J＝14.8Hz,2H),3.27(s,1H),2.58(s,4H),1.60(d,J＝6.8Hz,3H),1.15(d,J＝6.4Hz,3H). Referring to Example I-196, the preparation method in Step 2, using (R)-3-methylmorpholine and I-196a as raw materials, I-198 (7mg, 14%) was obtained. MS(ESI)m/z=432.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.98(d,J=2.8Hz,1H),7.89(d,J=2.8Hz, 1H), 7.58(t, J=8.0Hz, 1H), 7.46(dd, J=12.0, 6.4Hz, 2H), 7.23(t, J=4.4Hz, 1H), 5.75-5.63(m, 1H), 4.35(s,1H),4.06(d,J=11.2Hz,1H),3.80(s,2H),3.64(t,J=14.8Hz,2H),3.27(s,1H),2.58(s,4H ), 1.60(d, J=6.8Hz, 3H), 1.15(d, J=6.4Hz, 3H).
实施例I-199：Example I-199:
Figure PCTCN2022135958-appb-000199
Figure PCTCN2022135958-appb-000199
参照实施例I-196，步骤2的制备方法，使用3-氧杂-8-氮杂双环[3.2.1]辛烷盐酸盐和I-196a为原料得I-198(7mg,14％)。MS(ESI)m/z＝444.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.92(d,J＝2.4Hz,1H),7.90(d,J＝2.4Hz,1H),7.58(t,J＝7.2Hz,1H),7.46(t,J＝6.4Hz,1H),7.40-7.32(m,1H),7.24(t,J＝3.6Hz,1H),5.75-5.62(m,1H),4.58(s,2H),3.83-3.71(m,2H),3.59(d,J＝10.8Hz,2H),3.28(s,1H),2.58(s,3H),2.11-1.97(m,4H),1.60(d,J＝7.2Hz,3H). Referring to Example I-196, the preparation method of step 2, using 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride and I-196a as raw materials to obtain I-198 (7mg, 14%) . MS(ESI)m/z=444.3[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.92(d,J=2.4Hz,1H),7.90(d,J=2.4Hz, 1H), 7.58(t, J=7.2Hz, 1H), 7.46(t, J=6.4Hz, 1H), 7.40-7.32(m, 1H), 7.24(t, J=3.6Hz, 1H), 5.75- 5.62(m,1H),4.58(s,2H),3.83-3.71(m,2H),3.59(d,J＝10.8Hz,2H),3.28(s,1H),2.58(s,3H),2.11 -1.97(m,4H),1.60(d,J＝7.2Hz,3H).
实施例I-200：Example I-200:
Figure PCTCN2022135958-appb-000200
Figure PCTCN2022135958-appb-000200
参照实施例I-154制备方法，使用3,6-二氢-2H-吡喃-4-硼酸频哪醇酯和I-196a为原料得I-200(37mg,29％)。MS(ESI)m/z＝415.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.35(d,J＝2.0Hz,1H),8.86(d,J＝2.0Hz,1H),7.87(d,J＝6.8Hz,1H),7.62(t,J＝7.2Hz,1H),7.48(t,J＝6.8Hz,1H),7.12-7.39(m,2H),6.75(s,1H),5.70-5.73(m,1H),4.34-4.35(m,2H),3.94(t,J＝5.2Hz,2H),2.67(s,5H),1.62(d,J＝6.8Hz,3H). Referring to the preparation method of Example I-154, 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester and I-196a were used as raw materials to obtain I-200 (37 mg, 29%). MS(ESI)m/z=415.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.35(d,J=2.0Hz,1H),8.86(d,J=2.0Hz, 1H), 7.87(d, J=6.8Hz, 1H), 7.62(t, J=7.2Hz, 1H), 7.48(t, J=6.8Hz, 1H), 7.12-7.39(m, 2H), 6.75( s,1H),5.70-5.73(m,1H),4.34-4.35(m,2H),3.94(t,J＝5.2Hz,2H),2.67(s,5H),1.62(d,J＝6.8Hz ,3H).
实施例I-201：Example I-201:
Figure PCTCN2022135958-appb-000201
Figure PCTCN2022135958-appb-000201
将I-200(40mg,0.097mmol)、Mn(TMHD) 3(12mg,0.019mmol)和PhSiH 3(21mg,0.19mmol)在无水二氯甲烷/异丙醇(0.5mL/5mL)中的溶液，在氧气氛围下，室温搅拌16小时。反应液经二氯甲烷稀释，饱和食盐水洗，硫酸钠干燥，浓缩，薄板层析分离得白色固体I-201(15mg,37％)。MS(ESI)m/z＝433.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.35(s,1H),8.98(s,1H),7.94(d,J＝6.5Hz,1H),7.62(t,J＝7.5Hz,1H),7.48(t,J＝6.8Hz,1H),7.42-7.06(m,2H),5.70(dd,J＝14.2,7.1Hz,1H),5.60(s,1H),3.96-3.73(m,4H),2.67(s,3H),2.21(s,2H),1.71(d,J＝13.0Hz,2H),1.62(d,J＝7.0Hz,3H). A solution of I-200 (40 mg, 0.097 mmol), Mn(TMHD) 3 (12 mg, 0.019 mmol) and PhSiH 3 (21 mg, 0.19 mmol) in anhydrous dichloromethane/isopropanol (0.5 mL/5 mL) , under an oxygen atmosphere, stirred at room temperature for 16 hours. The reaction solution was diluted with dichloromethane, washed with saturated brine, dried over sodium sulfate, concentrated, and separated by thin-plate chromatography to obtain white solid I-201 (15 mg, 37%). MS(ESI)m/z=433.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.35(s,1H),8.98(s,1H),7.94(d,J=6.5 Hz, 1H), 7.62(t, J=7.5Hz, 1H), 7.48(t, J=6.8Hz, 1H), 7.42-7.06(m, 2H), 5.70(dd, J=14.2, 7.1Hz, 1H ),5.60(s,1H),3.96-3.73(m,4H),2.67(s,3H),2.21(s,2H),1.71(d,J＝13.0Hz,2H),1.62(d,J＝ 7.0Hz, 3H).
实施例I-202：Example I-202:
Figure PCTCN2022135958-appb-000202
Figure PCTCN2022135958-appb-000202
参照实施例I-168备方法，使用
Figure PCTCN2022135958-appb-000203
和I-196a为原料得I-202(34mg,27％)。MS(ESI)m/z＝429.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.13(d,J＝2.0Hz,1H),8.72(d,J＝2.0Hz,1H),7.82(d,J＝8.5Hz,1H),7.62(t,J＝7.2Hz,1H),7.47(t,J＝7.2Hz,1H),7.12-7.25(m,2H),5.68-5.71(m,1H),4.05-4.10(m,1H),3.89-3.92(m,1H),3.56-3.62(m,1H),3.47-3.53(m,1H),2.65(s,3H),2.20(t,J＝5.2Hz,2H),1.60-1.69(m,4H),1.29-1.35(m,1H),1.09-1.12(m,1H). Prepare method with reference to embodiment I-168, use
Figure PCTCN2022135958-appb-000203
and I-196a as raw materials to obtain I-202 (34mg, 27%). MS(ESI)m/z=429.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.13(d,J=2.0Hz,1H),8.72(d,J=2.0Hz, 1H), 7.82(d, J=8.5Hz, 1H), 7.62(t, J=7.2Hz, 1H), 7.47(t, J=7.2Hz, 1H), 7.12-7.25(m, 2H), 5.68- 5.71(m,1H),4.05-4.10(m,1H),3.89-3.92(m,1H),3.56-3.62(m,1H),3.47-3.53(m,1H),2.65(s,3H), 2.20(t, J=5.2Hz, 2H), 1.60-1.69(m, 4H), 1.29-1.35(m, 1H), 1.09-1.12(m, 1H).
实施例I-203：Example I-203:
Figure PCTCN2022135958-appb-000204
Figure PCTCN2022135958-appb-000204
参照实施例I-196，步骤2的制备方法，使用(R)-3-羟甲基吗啉盐酸盐和I-196a为原料得I-203(3mg,2％)。MS(ESI)m/z＝448.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝2.4Hz,1H),7.86(s,1H),7.59(d,J＝7.6Hz,1H),7.47(s,2H),7.24(d,J＝6.8Hz,2H),5.68(t,J＝7.2Hz,1H),4.20(s,1H),4.06(t,J＝12.0Hz,2H),3.80-3.59(m,4H),3.52(d,J＝6.0Hz,1H),3.27–3.18(m,1H),2.58(s,4H),1.60(d,J＝6.8Hz,3H). Referring to Example I-196, the preparation method in Step 2, using (R)-3-hydroxymethylmorpholine hydrochloride and I-196a as raw materials, I-203 (3 mg, 2%) was obtained. MS (ESI) m/z=448.3[M+H] + . 1 H NMR (400MHz, d 6 -DMSO) δ9.00 (d, J=2.4Hz, 1H), 7.86(s, 1H), 7.59( d,J=7.6Hz,1H),7.47(s,2H),7.24(d,J=6.8Hz,2H),5.68(t,J=7.2Hz,1H),4.20(s,1H),4.06( t, J＝12.0Hz, 2H), 3.80-3.59(m, 4H), 3.52(d, J＝6.0Hz, 1H), 3.27–3.18(m, 1H), 2.58(s, 4H), 1.60(d ,J＝6.8Hz,3H).
实施例I-204：Example I-204:
Figure PCTCN2022135958-appb-000205
Figure PCTCN2022135958-appb-000205
参照实施例I-196，步骤2的制备方法，使用1-氧杂-7-氮杂螺[4.4]壬烷盐酸盐和I-196a为原料 得I-204(13mg,23％)。MS(ESI)m/z＝458.3[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.63(d,J＝2.4Hz,1H),7.57(dd,J＝15.2,7.6Hz,2H),7.43(dd,J＝14,6.8Hz,2H),7.27-7.16(m,1H),5.75-5.62(m,1H),3.88-3.76(m,2H),3.70-3.45(m,4H),2.57(s,3H),2.19-1.94(m,7H),1.60(d,J＝6.8Hz,3H). Referring to Example I-196, the preparation method in Step 2, using 1-oxa-7-azaspiro[4.4]nonane hydrochloride and I-196a as raw materials, I-204 (13 mg, 23%) was obtained. MS(ESI)m/z=458.3[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.63(d,J=2.4Hz,1H),7.57(dd,J=15.2,7.6 Hz,2H),7.43(dd,J＝14,6.8Hz,2H),7.27-7.16(m,1H),5.75-5.62(m,1H),3.88-3.76(m,2H),3.70-3.45( m,4H),2.57(s,3H),2.19-1.94(m,7H),1.60(d,J＝6.8Hz,3H).
实施例I-205：Example I-205:
Figure PCTCN2022135958-appb-000206
Figure PCTCN2022135958-appb-000206
参照实施例I-196，步骤2的制备方法，使用(S)-3-(甲氧基甲基)吗啉盐酸盐和I-196a为原料得I-205(9mg,16％)。MS(ESI)m/z＝462.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝2.8Hz,1H),7.89(d,J＝2.8Hz,1H),7.58(t,J＝7.2Hz,1H),7.49-7.45(m,2H),7.38-7.11(m,2H),5.71-5.68(m,1H),4.44(s,1H),4.07-3.99(m,2H),3.62-3.71(m,4H),3.49-3.45(m,1H),3.21(s,3H),2.59(s,3H),1.61(d,J＝7.2Hz,3H). Referring to Example I-196, the preparation method in Step 2, using (S)-3-(methoxymethyl)morpholine hydrochloride and I-196a as raw materials, I-205 (9 mg, 16%) was obtained. MS(ESI)m/z=462.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.00(d,J=2.8Hz,1H),7.89(d,J=2.8Hz, 1H), 7.58(t, J=7.2Hz, 1H), 7.49-7.45(m, 2H), 7.38-7.11(m, 2H), 5.71-5.68(m, 1H), 4.44(s, 1H), 4.07 -3.99(m,2H),3.62-3.71(m,4H),3.49-3.45(m,1H),3.21(s,3H),2.59(s,3H),1.61(d,J＝7.2Hz,3H ).
实施例I-206：Example I-206:
Figure PCTCN2022135958-appb-000207
Figure PCTCN2022135958-appb-000207
参照实施例I-196，步骤2的制备方法，使用D-脯氨醇和I-196a为原料得I-206(11mg,22％)。MS(ESI)m/z＝432.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.77(d,J＝2.6Hz,1H),7.59(dd,J＝8.8,5.1Hz,2H),7.46(s,2H),7.40-7.04(m,2H),5.69(t,J＝7.0Hz,1H),4.90(t,J＝5.7Hz,1H),4.17(d,J＝4.2Hz,1H),3.56(d t,J＝10.1,6.4Hz,2H),3.47-3.33(m,2H),2.57(s,3H),2.15-1.91(m,4H),1.61(d,J＝7.0Hz,3H). Referring to Example I-196, the preparation method in Step 2, using D-prolinol and I-196a as raw materials, I-206 (11 mg, 22%) was obtained. MS(ESI)m/z=432.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.77(d,J=2.6Hz,1H),7.59(dd,J=8.8,5.1 Hz, 2H), 7.46(s, 2H), 7.40-7.04(m, 2H), 5.69(t, J=7.0Hz, 1H), 4.90(t, J=5.7Hz, 1H), 4.17(d, J =4.2Hz, 1H), 3.56(d t, J=10.1, 6.4Hz, 2H), 3.47-3.33(m, 2H), 2.57(s, 3H), 2.15-1.91(m, 4H), 1.61(d, J=7.0Hz,3H).
实施例I-207：Example I-207:
Figure PCTCN2022135958-appb-000208
Figure PCTCN2022135958-appb-000208
参照实施例I-196，步骤2的制备方法，使用(S)-3-吡咯烷醇和I-196a为原料得I-207(11mg,22％)。MS(ESI)m/z＝418.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.65(d,J＝2.6Hz,1H),7.66-7.54(m,2H),7.46(s,2H),7.38-7.06(m,2H),5.68(t,J＝7.0Hz,1H),5.12(d,J＝3.9Hz,1H),4.52(s,1H),3.61(dd,J＝15.7,4.9Hz,3H),3.41(d,J＝10.5Hz,1H),2.58(s,3H),2.13(dd,J＝8.4,4.3Hz,1H),2.03(s,1H),1.61(d,J＝7.0Hz,3H). Referring to Example I-196, the preparation method in Step 2, using (S)-3-pyrrolidinol and I-196a as raw materials, I-207 (11 mg, 22%) was obtained. MS(ESI)m/z=418.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.65(d,J=2.6Hz,1H),7.66-7.54(m,2H), 7.46(s,2H),7.38-7.06(m,2H),5.68(t,J=7.0Hz,1H),5.12(d,J=3.9Hz,1H),4.52(s,1H),3.61(dd ,J=15.7,4.9Hz,3H),3.41(d,J=10.5Hz,1H),2.58(s,3H),2.13(dd,J=8.4,4.3Hz,1H),2.03(s,1H) ,1.61(d,J=7.0Hz,3H).
实施例I-208：Example I-208:
Figure PCTCN2022135958-appb-000209
Figure PCTCN2022135958-appb-000209
参照实施例I-172，步骤3的制备方法，使用3-呋喃甲酸和I-172c为原料得I-208(21mg,42％)。MS(ESI)m/z＝512.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.33(d,J＝6.8Hz,1H),8.88(s,1H),7.88(s,1H),7.62(t,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.42-7.05(m,2H),6.65(s,1H),5.80-5.63(m,1H),4.31(d,J＝38.4Hz,2H),4.01-3.66(m,6H),3.59-3.37(m,1H),2.72(d,J＝37.9Hz,5H), 2.09(dd,J＝14.9,7.5Hz,2H),1.63(d,J＝7.0Hz,3H). Referring to Example I-172, the preparation method in Step 3, using 3-furancarboxylic acid and I-172c as raw materials, I-208 (21 mg, 42%) was obtained. MS(ESI)m/z=512.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.33(d,J=6.8Hz,1H),8.88(s,1H),7.88( s,1H),7.62(t,J=7.2Hz,1H),7.48(t,J=7.2Hz,1H),7.42-7.05(m,2H),6.65(s,1H),5.80-5.63(m ,1H),4.31(d,J＝38.4Hz,2H),4.01-3.66(m,6H),3.59-3.37(m,1H),2.72(d,J＝37.9Hz,5H), 2.09(dd, J=14.9,7.5Hz,2H),1.63(d,J=7.0Hz,3H).
实施例I-209：Example I-209:
Figure PCTCN2022135958-appb-000210
Figure PCTCN2022135958-appb-000210
参照实施例I-196，步骤2的制备方法，使用(S)-3-羟甲基吗啉和I-196a为原料得I-209(6mg,5％)。MS(ESI)m/z＝448.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.00(d,J＝2.5Hz,1H),7.86(d,J＝2.4Hz,1H),7.58(t,J＝7.2Hz,1H),7.47(d,J＝7.0Hz,2H),7.41-7.06(m,2H),5.69(t,J＝6.9Hz,1H),4.85(t,J＝5.6Hz,1H),4.21(s,1H),4.07(t,J＝11.2Hz,2H),3.82-3.58(m,4H),3.57-3.43(m,1H),3.27-3.21(m,1H),2.63(s,3H),1.60(d,J＝7.0Hz,3H). Referring to Example I-196, the preparation method in Step 2, using (S)-3-hydroxymethylmorpholine and I-196a as raw materials, I-209 (6 mg, 5%) was obtained. MS(ESI)m/z=448.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.00(d,J=2.5Hz,1H),7.86(d,J=2.4Hz, 1H), 7.58(t, J=7.2Hz, 1H), 7.47(d, J=7.0Hz, 2H), 7.41-7.06(m, 2H), 5.69(t, J=6.9Hz, 1H), 4.85( t,J=5.6Hz,1H),4.21(s,1H),4.07(t,J=11.2Hz,2H),3.82-3.58(m,4H),3.57-3.43(m,1H),3.27-3.21 (m,1H),2.63(s,3H),1.60(d,J=7.0Hz,3H).
实施例I-210：Example I-210:
Figure PCTCN2022135958-appb-000211
Figure PCTCN2022135958-appb-000211
参照实施例I-155制备方法，使用I-208为原料得I-210(47mg,39％)。MS(ESI)m/z＝514.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.12(s,1H),8.78(s,1H),7.77(s,1H),7.61(t,J＝7.3Hz,1H),7.47(t,J＝6.8Hz,1H),7.42-7.07(m,2H),5.69(p,J＝6.8Hz,1H),4.67(d,J＝12.3Hz,1H),4.18(d,J＝13.4Hz,1H),3.91(dd,J＝15.6,7.7Hz,1H),3.86-3.64(m,3H),3.49-3.38(m,1H),3.16(dd,J＝27.4,15.0Hz,2H),2.79-2.62(m,4H),2.20-1.88(m,4H),1.81-1.53(m,5H). Referring to the preparation method of Example I-155, I-210 (47 mg, 39%) was obtained by using I-208 as a raw material. MS(ESI)m/z=514.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.12(s,1H),8.78(s,1H),7.77(s,1H), 7.61(t,J=7.3Hz,1H),7.47(t,J=6.8Hz,1H),7.42-7.07(m,2H),5.69(p,J=6.8Hz,1H),4.67(d,J =12.3Hz,1H),4.18(d,J=13.4Hz,1H),3.91(dd,J=15.6,7.7Hz,1H),3.86-3.64(m,3H),3.49-3.38(m,1H) ,3.16(dd,J=27.4,15.0Hz,2H),2.79-2.62(m,4H),2.20-1.88(m,4H),1.81-1.53(m,5H).
实施例I-211：Example I-211:
Figure PCTCN2022135958-appb-000212
Figure PCTCN2022135958-appb-000212
步骤1：step 1:
0℃下，向I-211a(10g,60mmol)的氯仿(400mL)溶液中加入NBS(11.7g,66mmol)，室温搅拌4小时。冰水淬灭，乙酸乙酯萃取，浓缩，用石油醚/乙酸乙酯打浆过滤得I-211b(5g,34％)。MS(ESI)m/z＝246.1[M+H] +. To a solution of I-211a (10 g, 60 mmol) in chloroform (400 mL) was added NBS (11.7 g, 66 mmol) at 0° C., and stirred at room temperature for 4 hours. Quenched with ice water, extracted with ethyl acetate, concentrated, and filtered with petroleum ether/ethyl acetate to obtain I-211b (5 g, 34%). MS(ESI)m/z=246.1[M+H] + .
步骤2：Step 2:
向I-211b(5g,20mmol)的甲苯(100mL)溶液中加入碳酸银(8.4g,30mmol)和碘甲烷(4.3g,30 mmol)。100℃下搅拌10小时。冷却，冰水处理，过滤，滤饼用乙酸乙酯/石油醚(1/1)洗，干燥得黄色固体I-211c(2.5g,47％)。MS(ESI)m/z 260.1[M+H] +. To a solution of 1-211b (5 g, 20 mmol) in toluene (100 mL) was added silver carbonate (8.4 g, 30 mmol) and iodomethane (4.3 g, 30 mmol). Stir at 100°C for 10 hours. Cool, treat with ice water, filter, wash the filter cake with ethyl acetate/petroleum ether (1/1), and dry to obtain a yellow solid I-211c (2.5 g, 47%). MS(ESI)m/z 260.1[M+H] + .
步骤3：Step 3:
向I-211c(4g,15mmol)的四氯化碳(60mL)溶液中加入NBS(6.7g,37mmol)和AIBN(0.3g,2mmol)。将反应在90℃下搅拌12小时。将反应液冷却，乙酸乙酯稀释，饱和食盐水洗。有机相用硫酸钠干燥后，浓缩后经柱层析分离得白色固体I-211d(4g,62％)。MS(ESI)m/z 417.9[M+H] +. To a solution of I-211c (4 g, 15 mmol) in carbon tetrachloride (60 mL) was added NBS (6.7 g, 37 mmol) and AIBN (0.3 g, 2 mmol). The reaction was stirred at 90 °C for 12 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed with saturated brine. The organic phase was dried over sodium sulfate, concentrated and separated by column chromatography to obtain a white solid I-211d (4 g, 62%). MS(ESI)m/z 417.9[M+H] + .
步骤4：Step 4:
0℃下，向I-211d(4.0g,9mmol)的乙醇溶液中加入一水合肼(2.2g,45mmol)。80℃下搅拌4小时。将反应液冷却，过滤，滤饼用甲醇/水(10/1)打浆，过滤得黄色固体I-211e(2.1g,85％)。MS(ESI)m/z 256.1[M+H] +. To a solution of I-211d (4.0 g, 9 mmol) in ethanol was added hydrazine monohydrate (2.2 g, 45 mmol) at 0°C. Stir at 80°C for 4 hours. The reaction solution was cooled and filtered, and the filter cake was slurried with methanol/water (10/1), and filtered to obtain a yellow solid I-211e (2.1 g, 85%). MS(ESI)m/z 256.1[M+H] + .
步骤5：Step 5:
向I-211e(1.0g,4mmol)的甲苯(30mL)溶液中加入Lawessen试剂(1.9g,4.8mmol)和18-冠-6(105mg,0.4mmol)。100℃下搅拌4小时。反应液直接浓缩，加入四氢呋喃，并研磨，过滤，滤饼经反相制备色谱法分离得黄色固体I-211f(300mg,28％)。MS(ESI)m/z 272.0[M+H] +. To a solution of 1-211e (1.0 g, 4 mmol) in toluene (30 mL) was added Lawessen's reagent (1.9 g, 4.8 mmol) and 18-crown-6 (105 mg, 0.4 mmol). Stir at 100°C for 4 hours. The reaction solution was directly concentrated, added THF, triturated, filtered, and the filter cake was separated by reverse-phase preparative chromatography to obtain a yellow solid I-211f (300 mg, 28%). MS(ESI)m/z 272.0[M+H] + .
步骤6：Step 6:
0℃下，向I-211f(1.5g,6mmol)的DMF(50mL)溶液中加入氢化钠(260mg,6.6mmol)。0℃下搅拌半小时，加入碘甲烷(900mg,6.6mmol)，室温搅拌2小时。冰水处理，过滤，滤饼经柱层析分离得黄色固体I-211g(1.3g,82％)。MS(ESI)m/z 286.0[M+H] +. To a solution of I-211f (1.5 g, 6 mmol) in DMF (50 mL) was added sodium hydride (260 mg, 6.6 mmol) at 0°C. Stir at 0°C for half an hour, add iodomethane (900 mg, 6.6 mmol), and stir at room temperature for 2 hours. Treated with ice water, filtered, and the filter cake was separated by column chromatography to obtain a yellow solid I-211g (1.3g, 82%). MS(ESI)m/z 286.0[M+H] + .
步骤7：Step 7:
-20℃下，向I-211g(286mg,1mmol)的二氯甲烷(15mL)溶液中加入mCPBA(190mg,1.1mmol)。将反应室温搅拌2小时，饱和亚硫酸钠萃灭，水洗。有机相干燥后，浓缩，柱层析分离得I-211h(100mg,31％)。MS(ESI)m/z 302.0[M+H] +. To a solution of I-211 g (286 mg, 1 mmol) in dichloromethane (15 mL) was added mCPBA (190 mg, 1.1 mmol) at -20°C. The reaction was stirred at room temperature for 2 hours, extracted with saturated sodium sulfite, and washed with water. The organic phase was dried, concentrated, and separated by column chromatography to obtain I-211h (100 mg, 31%). MS(ESI)m/z 302.0[M+H] + .
步骤8：Step 8:
向I-211h(100mg,0.33mmol)和I-156j(139mg,0.66mmol)的二氧六环(5mL)/水(1mL)溶液中加入碳酸钾(182mg,0.66mmol)和Pd(dppf)Cl 2(21mg,0.03mmol)。氩气保护，100℃下搅拌1小时。冷却，水处理，二氯甲烷萃取。有机相浓缩，柱层析分离后得到黄色固体I-211i(60mg,59％)。MS(ESI)m/z 306.1[M+H] +. To a solution of I-211h (100 mg, 0.33 mmol) and I-156j (139 mg, 0.66 mmol) in dioxane (5 mL)/water (1 mL) was added potassium carbonate (182 mg, 0.66 mmol) and Pd(dppf)Cl 2 (21 mg, 0.03 mmol). Under argon protection, stir at 100°C for 1 hour. Cooling, water treatment, dichloromethane extraction. The organic phase was concentrated and separated by column chromatography to obtain I-211i (60 mg, 59%) as a yellow solid. MS(ESI)m/z 306.1[M+H] + .
步骤9：Step 9:
向I-211i(70mg,0.2mmol)和A-2(82mg,0.3mmol)的DMSO(1.5mL)溶液中加入氟化铯(31mg,0.2mmol)和吡啶(142mg,1.8mmol)。氩气保护，100℃下反应16小时。将反应液冷却，水稀释，二氯甲烷萃取，浓缩，反相制备色谱法分离得白色固体I-211(5mg,5％)。MS(ESI)m/z 445.1.[M+H] +. To a solution of I-211i (70 mg, 0.2 mmol) and A-2 (82 mg, 0.3 mmol) in DMSO (1.5 mL) was added cesium fluoride (31 mg, 0.2 mmol) and pyridine (142 mg, 1.8 mmol). Under argon protection, react at 100°C for 16 hours. The reaction solution was cooled, diluted with water, extracted with dichloromethane, concentrated, and separated by reverse-phase preparative chromatography to obtain a white solid I-211 (5 mg, 5%). MS (ESI) m/z 445.1.[M+H] + .
1H NMR(400MHz,MeOD-d 4)δ8.70(s,1H),7.71(d,J＝8.0Hz,1H),7.50(d,J＝7.6Hz,1H),7.26(t,J＝8.0Hz,1H),6.28(s,1H),5.81-5.68(m,1H),4.35(s,2H),4.11(s,3H),3.93(t,J＝5.6Hz,2H),2.62(s,5H),1.62(d,J＝6.8Hz,3H). 1 H NMR (400MHz, MeOD-d 4 )δ8.70(s, 1H), 7.71(d, J=8.0Hz, 1H), 7.50(d, J=7.6Hz, 1H), 7.26(t, J= 8.0Hz, 1H), 6.28(s, 1H), 5.81-5.68(m, 1H), 4.35(s, 2H), 4.11(s, 3H), 3.93(t, J=5.6Hz, 2H), 2.62( s,5H),1.62(d,J=6.8Hz,3H).
实施例I-212：Example I-212:
Figure PCTCN2022135958-appb-000213
Figure PCTCN2022135958-appb-000213
参照实施例I-196，步骤2制备方法，使用(R)-3-吡咯烷醇和I-196a为原料得I-212(5.5mg,10％)。MS(ESI)m/z＝418.1[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ8.64(d,J＝2.5Hz,1H),7.57(dd,J＝12.7,4.8Hz,2H),7.43(dt,J＝22.6,7.2Hz,2H),7.39-7.07(m,2H),5.69(t,J＝7.0Hz,1H),5.12(d,J＝3.8Hz,1H),4.51(s,1H),3.61(ddd,J＝22.3,11.8,4.4Hz,3H),3.37(d,J＝11.4Hz,1H),2.57(s,3H),2.19-1.94(m,2H),1.61(d,J＝7.0Hz,3H). Referring to Example I-196, the preparation method in step 2, using (R)-3-pyrrolidinol and I-196a as raw materials, I-212 (5.5 mg, 10%) was obtained. MS(ESI)m/z=418.1[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ8.64(d,J=2.5Hz,1H),7.57(dd,J=12.7,4.8 Hz, 2H), 7.43(dt, J=22.6, 7.2Hz, 2H), 7.39-7.07(m, 2H), 5.69(t, J=7.0Hz, 1H), 5.12(d, J=3.8Hz, 1H ),4.51(s,1H),3.61(ddd,J=22.3,11.8,4.4Hz,3H),3.37(d,J=11.4Hz,1H),2.57(s,3H),2.19-1.94(m, 2H), 1.61(d, J=7.0Hz, 3H).
实施例I-213：Example I-213:
Figure PCTCN2022135958-appb-000214
Figure PCTCN2022135958-appb-000214
步骤1：step 1:
参照实施例I-154制备方法，使用I-213a和I-196a为原料得I-213b(300mg,87％)。 1H NMR(400MHz,d 6-DMSO)δ9.28(d,J＝2.1Hz,1H),8.86(d,J＝2.0Hz,1H),7.83(d,J＝7.0Hz,1H),7.62(t,J＝7.4Hz,1H),7.47(t,J＝7.0Hz,1H),7.42-7.08(m,2H),6.45(s,1H),5.79-5.63(m,1H),3.97(s,4H),3.17(d,J＝5.3Hz,1H),2.78(q,J＝19.2Hz,2H),2.66(s,3H),1.92(t,J＝6.4Hz,2H),1.62(d,J＝7.0Hz,3H). Referring to the preparation method of Example I-154, I-213b (300 mg, 87%) was obtained by using I-213a and I-196a as raw materials. 1 H NMR (400MHz, d 6 -DMSO) δ9.28 (d, J = 2.1Hz, 1H), 8.86 (d, J = 2.0Hz, 1H), 7.83 (d, J = 7.0Hz, 1H), 7.62 (t,J=7.4Hz,1H),7.47(t,J=7.0Hz,1H),7.42-7.08(m,2H),6.45(s,1H),5.79-5.63(m,1H),3.97( s,4H),3.17(d,J=5.3Hz,1H),2.78(q,J=19.2Hz,2H),2.66(s,3H),1.92(t,J=6.4Hz,2H),1.62( d,J=7.0Hz,3H).
步骤2：Step 2:
参照实施例I-201制备方法，使用I-213b为原料得I-213c(230mg,79％)。 1H NMR(400MHz,d 6-DMSO)δ9.34(d,J＝1.9Hz,1H),8.91(d,J＝1.9Hz,1H),8.01(d,J＝6.9Hz,1H),7.62(t,J＝7.1Hz,1H),7.48(t,J＝6.9Hz,1H),7.41-7.04(m,2H),5.73(dd,J＝16.4,9.3Hz,1H),5.48(s,1H),3.94(s,4H),3.18(d,J＝5.3Hz,2H),2.67(s,3H),2.20-1.95(m,4H),1.86(d,J＝12.5Hz,2H),1.63(d,J＝7.1Hz,3H). Referring to the preparation method of Example I-201, I-213c (230 mg, 79%) was obtained by using I-213b as a raw material. 1 H NMR (400MHz, d 6 -DMSO) δ9.34 (d, J = 1.9Hz, 1H), 8.91 (d, J = 1.9Hz, 1H), 8.01 (d, J = 6.9Hz, 1H), 7.62 (t,J=7.1Hz,1H),7.48(t,J=6.9Hz,1H),7.41-7.04(m,2H),5.73(dd,J=16.4,9.3Hz,1H),5.48(s, 1H), 3.94(s, 4H), 3.18(d, J=5.3Hz, 2H), 2.67(s, 3H), 2.20-1.95(m, 4H), 1.86(d, J=12.5Hz, 2H), 1.63(d,J=7.1Hz,3H).
步骤3：Step 3:
向I-213c(100mg,0.2mmol)的丙酮(2mL)溶液中加入盐酸(6N)，室温搅拌16小时。反应液用水稀释，饱和碳酸氢钠水溶液中和，二氯甲烷萃取，浓缩，薄层层析分离得黄色固体I-213d(33mg,33％)。MS(ESI)m/z＝445.2[M+H] +. To a solution of I-213c (100 mg, 0.2 mmol) in acetone (2 mL) was added hydrochloric acid (6N) and stirred at room temperature for 16 hours. The reaction solution was diluted with water, neutralized with saturated aqueous sodium bicarbonate, extracted with dichloromethane, concentrated, and separated by thin layer chromatography to obtain a yellow solid I-213d (33 mg, 33%). MS(ESI)m/z=445.2[M+H] + .
步骤4：Step 4:
向I-213d(33mg,0.074mmol)的甲醇(1mL)溶液中加入硼氢化钠(3mg,0.0814mmol)，室温搅拌1小时。反应液用饱和氯化铵水溶液处理，二氯甲烷萃取，浓缩，薄层层析分离得黄色固体I-213(9mg,29％)。MS(ESI)m/z＝447.2[M+H] +. 1H NMR(400MHz,d 6-DMSO)δ9.32(d,J＝1.9Hz,1H),8.93(d,J＝1.8Hz,1H),7.92(d,J＝6.6Hz,1H),7.62(t,J＝7.5Hz,1H),7.47(t,J＝6.9Hz,1H),7.40-7.07(m,2H),5.71(t,J＝7.0Hz,1H),5.31(s,1H),4.61(d,J＝4.6Hz,1H),3.58(d,J＝4.8Hz,1H),2.66(s,3H),2.04-1.87(m,2H),1.87-1.68(m,6H),1.62(d,J＝7.0Hz,3H). Sodium borohydride (3 mg, 0.0814 mmol) was added to a solution of I-213d (33 mg, 0.074 mmol) in methanol (1 mL), and stirred at room temperature for 1 hour. The reaction solution was treated with saturated aqueous ammonium chloride, extracted with dichloromethane, concentrated, and separated by thin layer chromatography to obtain a yellow solid I-213 (9 mg, 29%). MS(ESI)m/z=447.2[M+H] + . 1 H NMR(400MHz,d 6 -DMSO)δ9.32(d,J=1.9Hz,1H),8.93(d,J=1.8Hz, 1H), 7.92(d, J=6.6Hz, 1H), 7.62(t, J=7.5Hz, 1H), 7.47(t, J=6.9Hz, 1H), 7.40-7.07(m, 2H), 5.71( t,J=7.0Hz,1H),5.31(s,1H),4.61(d,J=4.6Hz,1H),3.58(d,J=4.8Hz,1H),2.66(s,3H),2.04- 1.87(m,2H),1.87-1.68(m,6H),1.62(d,J=7.0Hz,3H).
实施例I-214：Example I-214:
Figure PCTCN2022135958-appb-000215
Figure PCTCN2022135958-appb-000215
参照实施例I-2，步骤8的制备方法，使用3-吗啉酮为原料得I-214(7.4mg,13％)。MS(ESI)m/z＝446.3[M+H] +1H NMR(400MHz,d 6-DMSO)δ9.27(d,J＝2.0Hz,1H),8.91(d,J＝2.4Hz,1H), 7.82(d,J＝6.4Hz,1H),7.76(d,J＝7.6Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝7.6Hz,1H),5.69(t,J＝7.2Hz,1H),4.34(s,2H),4.10(t,J＝5.2Hz,2H),4.05–3.93(m,2H),2.67(s,3H),2.58(s,3H),1.56(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method in Step 8, using 3-morpholinone as a raw material, I-214 (7.4 mg, 13%) was obtained. MS(ESI)m/z=446.3[M+H] +1H NMR(400MHz,d 6 -DMSO)δ9.27(d,J=2.0Hz,1H),8.91(d,J=2.4Hz,1H ), 7.82(d, J＝6.4Hz, 1H), 7.76(d, J＝7.6Hz, 1H), 7.53(d, J＝7.6Hz, 1H), 7.32(t, J＝7.6Hz, 1H), 5.69(t, J=7.2Hz, 1H), 4.34(s, 2H), 4.10(t, J=5.2Hz, 2H), 4.05–3.93(m, 2H), 2.67(s, 3H), 2.58(s ,3H),1.56(d,J=6.8Hz,3H).
实施例I-215：Example I-215:
Figure PCTCN2022135958-appb-000216
Figure PCTCN2022135958-appb-000216
参照实施例I-2，步骤8的制备方法，使用4-乙酰基哌嗪-2-酮为原料得I-215(4.5mg,8％)。MS(ESI)m/z＝487.3[M+H] +1H NMR(400MHz,d 6-DMSO)δ9.22(d,J＝5.6Hz,1H),8.87(s,1H),7.83(s,1H),7.75(d,J＝7.6Hz,1H),7.53(d,J＝7.6Hz,1H),7.32(t,J＝8.4Hz,1H),5.74–5.63(m,1H),4.40(s,1H),4.30(s,1H),4.04(s,1H),3.93(s,2H),2.67(s,3H),2.57(s,4H),2.12(d,J＝12.8Hz,3H),1.56(d,J＝6.8Hz,3H). Referring to Example I-2, the preparation method in Step 8, using 4-acetylpiperazin-2-one as a raw material, I-215 (4.5 mg, 8%) was obtained. MS(ESI)m/z=487.3[M+H] + 1H NMR(400MHz,d 6 -DMSO)δ9.22(d,J=5.6Hz,1H),8.87(s,1H),7.83(s ,1H),7.75(d,J=7.6Hz,1H),7.53(d,J=7.6Hz,1H),7.32(t,J=8.4Hz,1H),5.74–5.63(m,1H),4.40 (s,1H),4.30(s,1H),4.04(s,1H),3.93(s,2H),2.67(s,3H),2.57(s,4H),2.12(d,J＝12.8Hz, 3H), 1.56(d, J＝6.8Hz, 3H).
实施例I-216：Example I-216:
Figure PCTCN2022135958-appb-000217
Figure PCTCN2022135958-appb-000217
步骤1：step 1:
参照实施例I-2，步骤7的制备方法，用A-14代替A-12，制备得到化合物I-216a(200mg,50％)。MS(ESI)m/z＝384.1[M+H] + Referring to Example I-2, the preparation method in step 7, A-14 was used instead of A-12 to prepare compound I-216a (200 mg, 50%). MS(ESI)m/z=384.1[M+H] +
步骤2：Step 2:
参照实施例I-2，步骤8的制备方法，使用I-216a和3,6-二氢-2H-吡喃-4-硼酸频哪醇酯为原料得I-216(40mg,80％)。MS(ESI)m/z＝386.2[M+H] +1H NMR(400MHz,d 6-DMSO)δ9.33(d,J＝1.8Hz,1H),8.82(d,J＝1.6Hz,1H),7.89(d,J＝6.8Hz,1H),7.76(d,J＝7.8Hz,1H),7.62(d,J＝7.6Hz,1H),7.32(t,J＝7.8Hz,1H),6.72(s,1H),5.59(t,J＝6.8Hz,1H),4.34(d,J＝2.9Hz,2H),3.92(t,J＝5.4Hz,2H),2.68(s,3H),2.66(s,4H),1.57(d,J＝7.2Hz,3H). Referring to Example I-2, the preparation method in Step 8, I-216a (40 mg, 80%) was obtained by using I-216a and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester as raw materials. MS(ESI)m/z=386.2[M+H] +1H NMR(400MHz,d 6 -DMSO)δ9.33(d,J=1.8Hz,1H),8.82(d,J=1.6Hz,1H ),7.89(d,J=6.8Hz,1H),7.76(d,J=7.8Hz,1H),7.62(d,J=7.6Hz,1H),7.32(t,J=7.8Hz,1H), 6.72(s,1H),5.59(t,J=6.8Hz,1H),4.34(d,J=2.9Hz,2H),3.92(t,J=5.4Hz,2H),2.68(s,3H), 2.66(s,4H),1.57(d,J=7.2Hz,3H).
实施例I-217：Example I-217:
Figure PCTCN2022135958-appb-000218
Figure PCTCN2022135958-appb-000218
参照实施例I-168的制备方法，使用
Figure PCTCN2022135958-appb-000219
和I-216a为原料得I-217(10mg,6％)。MS(ESI)m/z＝400.2[M+H] +1H NMR(400MHz,d 6-DMSO)δ9.11(d,J＝2.0Hz,1H),8.68(d,J＝2.4Hz,1H),7.84(d,J＝6.4Hz,1H),7.76(d,J＝8.0Hz,1H),7.62(d,J＝7.2Hz,1H),7.32(t,J＝7.8Hz,1H),5.57(t,J＝6.6Hz,1H),4.14–4.00(m,1H),3.90(d,J＝11.2Hz,1H),3.58(d,J＝7.4Hz,1H),3.55–3.45(m,1H), 2.67(s,3H),2.64(s,3H),2.20–2.17(m,2H),1.69–1.62(m,1H),1.56(d,J＝7.0Hz,3H),1.30(td,J＝9.6,4.4Hz,1H),1.11–1.07(m,1H). With reference to the preparation method of Example I-168, use
Figure PCTCN2022135958-appb-000219
and I-216a as raw materials to obtain I-217 (10 mg, 6%). MS(ESI)m/z=400.2[M+H] +1H NMR(400MHz,d 6 -DMSO)δ9.11(d,J=2.0Hz,1H),8.68(d,J=2.4Hz,1H ),7.84(d,J=6.4Hz,1H),7.76(d,J=8.0Hz,1H),7.62(d,J=7.2Hz,1H),7.32(t,J=7.8Hz,1H), 5.57(t, J＝6.6Hz, 1H), 4.14–4.00(m, 1H), 3.90(d, J＝11.2Hz, 1H), 3.58(d, J＝7.4Hz, 1H), 3.55–3.45(m ,1H), 2.67(s,3H),2.64(s,3H),2.20–2.17(m,2H),1.69–1.62(m,1H),1.56(d,J＝7.0Hz,3H),1.30( td,J＝9.6,4.4Hz,1H),1.11–1.07(m,1H).
实施例I-218：Example I-218:
Figure PCTCN2022135958-appb-000220
Figure PCTCN2022135958-appb-000220
参照实施例I-2，步骤8的制备方法，使用1,1-二氧化硫代吗啉和I-216a为原料得I-218(34mg,30％)。 1H NMR(400MHz,d 6-DMSO)δ9.06(d,J＝2.7Hz,1H),8.05(d,J＝2.8Hz,1H),7.73(d,J＝7.7Hz,1H),7.61(d,J＝7.4Hz,1H),7.54(d,J＝6.7Hz,1H),7.32(t,J＝7.8Hz,1H),5.65–5.46(m,1H),4.09(s,4H),3.29(s,4H),2.67(s,3H),2.59(s,3H),1.56(d,J＝7.0Hz,3H).MS(ESI)m/z＝437.1[M+H] + Referring to Example I-2, the preparation method in Step 8, using 1,1-thiomorpholine dioxide and I-216a as raw materials, I-218 (34 mg, 30%) was obtained. 1 H NMR (400MHz, d 6 -DMSO) δ9.06 (d, J = 2.7Hz, 1H), 8.05 (d, J = 2.8Hz, 1H), 7.73 (d, J = 7.7Hz, 1H), 7.61 (d, J=7.4Hz, 1H), 7.54(d, J=6.7Hz, 1H), 7.32(t, J=7.8Hz, 1H), 5.65–5.46(m, 1H), 4.09(s, 4H) ,3.29(s,4H),2.67(s,3H),2.59(s,3H),1.56(d,J=7.0Hz,3H).MS(ESI)m/z=437.1[M+H] +
实施例I-219：Example I-219:
Figure PCTCN2022135958-appb-000221
Figure PCTCN2022135958-appb-000221
参照实施例I-2，步骤8的制备方法，使用1,1-二氧化硫代吗啉和I-196a为原料得I-219(36mg,40％)。 1H NMR(400MHz,CDCl 3)δ8.89(d,J＝2.8Hz,1H),7.67(s,1H),7.58(t,J＝7.1Hz,1H),7.38(t,J＝6.9Hz,1H),7.26–7.22(m,1H),7.10(t,J＝7.6Hz,1H),6.79(t,J＝55.1Hz,1H),5.68(q,J＝7.2Hz,1H),4.10–3.99(m,4H),3.17(s,4H),2.80(s,3H),1.63(d,J＝6.9Hz,3H).MS(ESI)m/z＝466.1[M+H] + Referring to Example I-2, the preparation method in Step 8, using 1,1-thiomorpholine dioxide and I-196a as raw materials, I-219 (36 mg, 40%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ8.89(d, J=2.8Hz, 1H), 7.67(s, 1H), 7.58(t, J=7.1Hz, 1H), 7.38(t, J=6.9Hz ,1H),7.26–7.22(m,1H),7.10(t,J=7.6Hz,1H),6.79(t,J=55.1Hz,1H),5.68(q,J=7.2Hz,1H),4.10 –3.99(m,4H),3.17(s,4H),2.80(s,3H),1.63(d,J=6.9Hz,3H).MS(ESI)m/z=466.1[M+H] +
生物学测试biological test
实验例1.Experimental example 1.
使用KRAS-G12C/SOS1结合测定试剂盒(Cisbio#63ADK000CB16PEG)进行测试。将待测化合物的起始浓度设置为10μM(0.5％DMSO)，1:10稀释，设置7个浓度梯度，每个浓度设置2复孔。选用白色384孔板(Corning#3572)，每孔加2μL待测化合物，4μL的SOS1、4μL的KRAS-G12C蛋白(按测定试剂盒说明用稀释缓冲液稀释100倍)，室温孵育15min。再分别加入5μL的anti-Tag1-Tb(按测定试剂盒说明用检测缓冲液稀释100倍)和5μL的anti-Tag2-XL665(按测定试剂盒说明用检测缓冲液稀释25倍)，4℃孵育3h，测定TRF(620nm，665nm，延迟100us，积分200us)。同时设置不加KRAS-G12C蛋白的阴性对照孔与不加化合物的阳性对照孔。Testing was performed using the KRAS-G12C/SOS1 Binding Assay Kit (Cisbio #63ADK000CB16PEG). The initial concentration of the compound to be tested was set at 10 μM (0.5% DMSO), diluted 1:10, 7 concentration gradients were set, and 2 replicate wells were set for each concentration. Select a white 384-well plate (Corning#3572), add 2 μL of the compound to be tested, 4 μL of SOS1, and 4 μL of KRAS-G12C protein (diluted 100 times with dilution buffer according to the instructions of the assay kit) to each well, and incubate at room temperature for 15 minutes. Add 5 μL of anti-Tag1-Tb (diluted 100 times with detection buffer according to the instructions of the assay kit) and 5 μL of anti-Tag2-XL665 (dilute 25 times with detection buffer according to the instructions of the assay kit), and incubate at 4 °C 3h, measure TRF (620nm, 665nm, delay 100us, integration 200us). At the same time, negative control wells without KRAS-G12C protein and positive control wells without compound were set.
IC 50数据处理：统计化合物处理组RFU665/RFU620的比值，应用GraphPad Prism 7.0软件，使用非线性回归模型绘制S型剂量-抑制率曲线，拟合并计算IC 50值。 IC 50 data processing: The ratio of RFU665/RFU620 in the compound treatment group was counted, and the GraphPad Prism 7.0 software was used to draw a sigmoid dose-inhibition rate curve using a nonlinear regression model, and the IC 50 value was fitted and calculated.
结果如下表中所示。The results are shown in the table below.
Figure PCTCN2022135958-appb-000222
Figure PCTCN2022135958-appb-000222
Figure PCTCN2022135958-appb-000223
Figure PCTCN2022135958-appb-000223
实验例2.Experimental example 2.
取处于对数生长期的HCC827细胞进行消化、离心、重悬、计数。以适合的细胞密度铺到96孔板中(30000个/孔)，每孔180μL，周围用PBS进行水封，37℃培养箱过夜。将待测化合物的起始浓度设置为10μM，1:5稀释，设置9个浓度梯度，每个浓度设置3复孔。向96孔板中加入20μL待测化合物；另外设置DMSO对照组与空白组。HCC827 cells in the logarithmic growth phase were digested, centrifuged, resuspended, and counted. Spread the cells in a 96-well plate (30,000 cells/well) at a suitable cell density, 180 μL per well, seal the cells with PBS, and incubate overnight at 37°C. The initial concentration of the compound to be tested was set at 10 μM, diluted 1:5, 9 concentration gradients were set, and 3 replicate wells were set for each concentration. 20 μL of the compound to be tested was added to the 96-well plate; in addition, a DMSO control group and a blank group were set.
化合物作用1h后，弃培养基，用PBST漂洗2次。用150μL/孔4％的多聚甲醛固定细胞，室温孵育20min。弃固定液，用PBST漂洗2次。每孔加入150μL专用封闭液(含0.1％Triton-X100)，室温封闭2h。弃封闭液，每孔加入50μL用含0.033％Triton-X 100的专用封闭液以1:2000稀释的pERK-抗体，4℃过夜孵育(空白组不加一抗)。用PBST漂洗2次，每孔加入50μL含0.033％Triton-X 100的专用封闭液以1:2000稀释的抗兔IgG(H+L)(DyLight TM800)和1:10000稀释的DRAQ5(空白组不加DRAQ5)，室温孵育2h后PBST漂洗2遍，PBS漂洗1遍。用Li-COR Odyssey双色近红外激光成像仪检测700nm和800nm的荧光信号。 After the compound was reacted for 1 h, the culture medium was discarded and rinsed twice with PBST. Cells were fixed with 150 μL/well of 4% paraformaldehyde and incubated at room temperature for 20 min. Discard the fixative and rinse twice with PBST. Add 150 μL of special blocking solution (containing 0.1% Triton-X100) to each well, and block for 2 hours at room temperature. The blocking solution was discarded, and 50 μL of pERK-antibody diluted 1:2000 with a special blocking solution containing 0.033% Triton-X 100 was added to each well, and incubated overnight at 4°C (no primary antibody was added to the blank group). Rinse twice with PBST, add 50 μL anti-rabbit IgG (H+L) (DyLight TM 800) diluted 1:2000 in special blocking solution containing 0.033% Triton-X 100 to each well and DRAQ5 (blank group) diluted 1:10000 DRAQ5 was not added), incubated at room temperature for 2 hours, then rinsed twice with PBST and once with PBS. Fluorescent signals at 700nm and 800nm were detected with a Li-COR Odyssey two-color near-infrared laser imager.
EC 50数据处理：A＝700nm检测数据-空白组数据，B＝800nm检测数据-空白组数据，C＝B/A，抑制率(％)＝(1-C/D)*100％，D为DMSO对照组的B/A。应用GraphPad Prism 7.0软件，使用非线性回归模型绘制S型剂量-抑制率曲线，拟合并计算EC 50值。 EC50 data processing: A=700nm detection data-blank group data, B=800nm detection data-blank group data, C=B/A, inhibition rate (%)=(1-C/D)*100%, D is B/A of the DMSO control group. Using GraphPad Prism 7.0 software, a sigmoid dose-inhibition rate curve was drawn using a nonlinear regression model, and the EC 50 value was fitted and calculated.
结果如下表所示：The results are shown in the table below:
Figure PCTCN2022135958-appb-000224
Figure PCTCN2022135958-appb-000224
Figure PCTCN2022135958-appb-000225
Figure PCTCN2022135958-appb-000225
实验例3. 3D细胞增殖抑制Experimental example 3. 3D cell proliferation inhibition
采用CCL检测方法评价本申请中化合物对人非小细胞肺癌细胞株NCI-H358、人胰腺癌细胞株KP-4、人结直肠腺癌细胞株SW620和人肺腺癌细胞株HCC827的抗增殖活性。取上述生长正常的细胞，用胰酶细胞消化液进行消化，离心，计数，以适合的细胞密度铺到96孔板中(6000个/孔)，每孔100μL。细胞铺板后第二天进行给药，每孔加不同浓度梯度的化合物，每个浓度点设三个复孔，另外设置相应的DMSO阴性处理对照组。药物处理5天后，于培养箱中取出待测细胞培养 板，待CCL溶液和96孔板恢复室温后，每孔加入100μL CCL溶液，震荡10min后静置10min，将待测液体转移至全白96孔培养板中，稳定发光后用酶标仪检测化学发光。每孔数值减去本底值后，计算抑制率。Inhibition Rate(％)＝(1-Sample/Vehicle)*100。Sample为药物处理组的发光值，Vehicle为DMSO对照组的发光值。应用GraphPad Prism 7.0软件，使用非线性回归模型绘制S型剂量-存活率曲线并计算IC 50值。 CCL detection method was used to evaluate the anti-proliferative activity of the compounds in this application on human non-small cell lung cancer cell line NCI-H358, human pancreatic cancer cell line KP-4, human colorectal adenocarcinoma cell line SW620 and human lung adenocarcinoma cell line HCC827 . The above normal growing cells were taken, digested with trypsin cell digestion solution, centrifuged, counted, and plated in a 96-well plate at a suitable cell density (6000 cells/well), 100 μL per well. The administration was carried out on the second day after the cells were plated, and compounds with different concentration gradients were added to each well, and three replicate wells were set at each concentration point, and a corresponding DMSO negative treatment control group was also set. After 5 days of drug treatment, take out the cell culture plate to be tested in the incubator, and after the CCL solution and the 96-well plate return to room temperature, add 100 μL of CCL solution to each well, shake for 10 minutes and then let it stand for 10 minutes, then transfer the liquid to be tested to Quanbai 96 Well culture plate, after stable luminescence, detect chemiluminescence with a microplate reader. After subtracting the background value from the value of each well, the inhibition rate was calculated. Inhibition Rate (%)=(1-Sample/Vehicle)*100. Sample is the luminescence value of the drug treatment group, and Vehicle is the luminescence value of the DMSO control group. Using GraphPad Prism 7.0 software, a sigmoid dose-survival curve was drawn using a nonlinear regression model and IC 50 values were calculated.
结果显示本申请化合物具有良好的抗癌细胞增殖活性。The results show that the compound of the present application has good anti-proliferation activity of cancer cells.
实验例4.hERGExperimental example 4.hERG
将HEK293细胞在含有10％胎牛血清及0.8mg/mL G418的DMEM培养基中培养，培养温度为37℃，CO 2浓度为5％。细胞用TrypLE TMExpress消化后离心，调整细胞密度为2×106cells/mL，然后用室温平衡摇床轻混细胞15-20min，上机进行膜片钳检测。将制备好的细胞的培养基置换为细胞外液。从液体池中吸取细胞内、外液分别加到QPlate芯片的细胞内液池、细胞与受试物池中。全细胞膜片钳记录全细胞hERG钾电流的电压刺激，并将试验数据由Qpatch进行采集并储存。化合物以30μM起始，3倍稀释，设置6个浓度点，每个药物浓度设定为两次给药，时间至少为5分钟。将每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组，每个浓度至少使用两个细胞独立重复检测两次。所有电生理试验在室温下进行。 HEK293 cells were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a culture temperature of 37°C and a CO concentration of 5%. The cells were digested with TrypLE TM Express and then centrifuged to adjust the cell density to 2×106cells/mL. Then, the cells were gently mixed with a room temperature balance shaker for 15-20min, and the patch clamp detection was carried out on the machine. The culture medium of the prepared cells was replaced with extracellular fluid. The intracellular and extracellular fluids are sucked from the liquid pool and added to the intracellular pool, cell and test substance pool of the QPlate chip respectively. The whole-cell patch clamp records the voltage stimulation of the whole-cell hERG potassium current, and the experimental data is collected and stored by Qpatch. The compound was started at 30 μM, diluted 3 times, and 6 concentration points were set, and each drug concentration was set to be administered twice, and the time was at least 5 minutes. The current detected by each cell in the external fluid without the compound was used as its own control group, and at least two cells were used for each concentration to repeat the detection twice independently. All electrophysiological experiments were performed at room temperature.
数据分析，首先将每一个药物浓度作用后的电流和空白对照电流标准化
Figure PCTCN2022135958-appb-000226
然后计算每一个药物浓度对应的抑制率
Figure PCTCN2022135958-appb-000227
对每一个浓度计算平均数和标准误，并计算每种化合物的半抑制浓度： For data analysis, first normalize the current after each drug concentration and the blank control current
Figure PCTCN2022135958-appb-000226
Then calculate the inhibition rate corresponding to each drug concentration
Figure PCTCN2022135958-appb-000227
Calculate the mean and standard error for each concentration, and calculate the half-inhibitory concentration for each compound:
Figure PCTCN2022135958-appb-000228
用以上方程对剂量依赖效应进行非线性拟合，其中Y代表抑制率、C代表受试物浓度，IC 50为半抑制浓度，HillSlope代表希尔系数。曲线拟合以及IC 50的计算利用Graphpad软件完成。
Figure PCTCN2022135958-appb-000228
Use the above equation to perform nonlinear fitting on the dose-dependent effect, where Y represents the inhibition rate, C represents the concentration of the test substance, IC 50 is the half-inhibition concentration, and HillSlope represents the Hill coefficient. Curve fitting and IC 50 calculations were performed using Graphpad software.
结果显示，本申请化合物没有明显hERG抑制活性。The results show that the compound of the present application has no obvious hERG inhibitory activity.
实验例5.肝微粒体代谢稳定性(MMS)Experimental Example 5. Liver Microsome Metabolic Stability (MMS)
分别配置100mM pH 7.4的磷酸缓冲液、NADPH再生***(1mM NADP、1mM氯化镁、6mM ISO和1unit/mL IDH)、0.56mg/mL肝微粒体溶液(100mM pH 7.4的磷酸缓冲液稀释)、终止液为含有内标的乙腈。Prepare 100mM pH 7.4 phosphate buffer, NADPH regeneration system (1mM NADP, 1mM magnesium chloride, 6mM ISO and 1unit/mL IDH), 0.56mg/mL liver microsome solution (diluted in 100mM pH 7.4 phosphate buffer), stop solution Acetonitrile with internal standard.
准备8块孵育板，分别命名为T0、T5、T15、T30、T45、T60、Blank60和NCF60。前6块板对应反应时间点分别为0、5、15、30、45和60分钟。Blank60板中不加入供试品或对照化合物，并在孵育60分钟后取样。NCF60板中用磷酸钾盐缓冲液代替NADPH再生体系溶液进行孵育60分钟。所有条件样品为三个平行。将微粒体和供试品或对照化合物混合，然后将除T0和NCF60外的孵育板Blank60、T5、T15、T30、T45和T60放置于37℃水浴锅中预孵育大约10分钟。孵育板T0中先加入终止液后再添加NADPH再生体系工作液，孵育板NCF60每个样品孔内添加98μL磷酸钾盐缓冲液以启动反应。Prepare 8 incubation plates and name them T0, T5, T15, T30, T45, T60, Blank60 and NCF60 respectively. The first 6 plates correspond to reaction time points of 0, 5, 15, 30, 45 and 60 minutes, respectively. No test or control compounds were added to Blank60 plates, and samples were taken after 60 minutes of incubation. In the NCF60 plate, potassium phosphate buffer was used to replace the NADPH regeneration system solution and incubated for 60 minutes. All conditional samples were run in triplicate. Mix the microsomes with the test or control compound, and then pre-incubate the incubation plates Blank60, T5, T15, T30, T45 and T60 in a 37°C water bath for about 10 minutes except for T0 and NCF60. Add the stop solution first to the incubation plate T0 and then add the NADPH regeneration system working solution. Add 98 μL potassium phosphate buffer solution to each sample well of the incubation plate NCF60 to start the reaction.
孵育板Blank60、T5、T15、T30、T45和T60预孵育结束后，每个样品孔内添加98μL NADPH再生体系工作液以启动反应。反应的温度为37±1℃，反应的最终体积是200μL，反应体系中包括0.5mg/mL的微粒体、1.0μM的底物、1mM NADP、6mM ISO和1unit/mL IDH。分别在5、15、30、45和60分钟时，将含有内标的冷的终止液加入到反应板中以终止反应。将终止后的所有反应板摇匀，并在4℃，3220×g下离心20分钟。将上清液稀释一定比例后进行LC-MS/MS 分析。After pre-incubation of Blank60, T5, T15, T30, T45 and T60 incubation plates, add 98 μL NADPH regeneration system working solution to each sample well to start the reaction. The temperature of the reaction was 37±1°C, the final volume of the reaction was 200 μL, and the reaction system included 0.5 mg/mL microsomes, 1.0 μM substrate, 1 mM NADP, 6 mM ISO and 1 unit/mL IDH. At 5, 15, 30, 45 and 60 minutes, cold stop solution containing an internal standard was added to the reaction plate to stop the reaction. Shake all reaction plates after termination and centrifuge at 3220 x g for 20 min at 4°C. The supernatant was diluted to a certain ratio for LC-MS/MS analysis.
结果显示本申请化合物具有良好的肝微粒体代谢稳定性。The results show that the compound of the present application has good metabolic stability of liver microsomes.
实验例6.细胞色素氧化酶P450抑制Experimental Example 6. Cytochrome Oxidase P450 Inhibition
1)缓冲液的配制：1) Preparation of buffer:
100mM K-Buffer：将9.5mL原液A混合到40.5mL原液B中，用超纯水将总体积调至500mL，用KOH或H 3PO 4滴定缓冲液至pH 7.4。 100mM K-Buffer: Mix 9.5mL stock solution A into 40.5mL stock solution B, adjust the total volume to 500mL with ultrapure water, and titrate the buffer with KOH or H 3 PO 4 to pH 7.4.
原料A(1M磷酸二氢钾):136.5g磷酸二氢钾在1L水中；Raw material A (1M potassium dihydrogen phosphate): 136.5g potassium dihydrogen phosphate in 1L water;
储备B(1M磷酸二氢钾):174.2g磷酸二氢钾在1L水。Stock B (1M Potassium Monobasic Phosphate): 174.2g Potassium Monobasic Phosphate in 1L of water.
2)受试物的配制2) Preparation of test substance
受试物粉末用DMSO或其他的有机溶剂配制成一定浓度的储备液，然后用合适的有机溶剂进行进一步的稀释。The powder of the test substance is prepared into a stock solution of a certain concentration with DMSO or other organic solvents, and then further diluted with a suitable organic solvent.
3)体外孵育3) In vitro incubation
CYP450酶代谢表型研究的肝微粒体体外孵育体系，是由制备的肝微粒体辅以氧化还原型辅酶，再加入酶特异的选择性抑制剂，在模拟生理温度及生理环境的条件下进行的生化反应。The in vitro incubation system of liver microsomes for CYP450 enzyme metabolic phenotype research is carried out by preparing liver microsomes supplemented with redox-type coenzymes, and then adding enzyme-specific selective inhibitors, under the conditions of simulating physiological temperature and physiological environment biochemical reaction.
4)原型药物或代谢产物的检测4) Detection of prototype drugs or metabolites
采用LC-MS/MS测定温孵液中原型药物或其代谢产物的浓度。The concentration of the original drug or its metabolites in the incubation solution was determined by LC-MS/MS.
结果显示本申请化合物没有明显细胞色素氧化酶抑制活性。The results show that the compound of the present application has no obvious cytochrome oxidase inhibitory activity.
实验例7.化合物药代动力学研究Experimental example 7. Compound pharmacokinetic research
取6-8周只雄性Balb/c小鼠。IV组动物通过尾静脉分别给予相应化合物，PO组动物通过强饲法分别给予相应化合物。IV组动物自由饮食饮水，PO组动物给药前禁食过夜，给药4h后喂食，整个试验中，动物自由饮水。分别于给药后0.083(仅IV组)、0.25、0.5、1、2、4、8和24h采集血浆样品。动物眼眶取血约100μL于1.5mL抗凝离心管中，以8000rpm在4℃条件下离心10分钟，移取上层血浆样品至EP管中。血浆样品保存于-80℃冰箱直至样品分析。Take 6-8 weeks old male Balb/c mice. Animals in group IV were given corresponding compounds through tail vein, and animals in group PO were given corresponding compounds by gavage. Animals in group IV were given free access to food and water. Animals in group PO were fasted overnight before administration and fed 4 hours after administration. During the entire experiment, animals were given free access to water. Plasma samples were collected at 0.083 (group IV only), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, respectively. About 100 μL of blood was taken from the orbit of the animal and placed in a 1.5 mL anticoagulant centrifuge tube, centrifuged at 8000 rpm for 10 minutes at 4 °C, and the upper plasma sample was transferred to an EP tube. Plasma samples were stored in a -80°C freezer until sample analysis.
根据药物浓度-时间数据计算药物的药动学参数，包括达峰浓度Cmax、达峰时间Tmax、清除率CL、稳态表观分布容积Vss、药-时曲线下面积AUC、消除半衰期t1/2、生物利用度等。低于80％定量下限的数据不参与药动学参数的计算。Calculate the pharmacokinetic parameters of the drug based on the drug concentration-time data, including peak concentration Cmax, peak time Tmax, clearance rate CL, steady-state apparent volume of distribution Vss, area under the drug-time curve AUC, and elimination half-life t1/2 , bioavailability, etc. Data below the 80% lower limit of quantitation were not involved in the calculation of pharmacokinetic parameters.
结果显示本申请化合物具有良好的药代动力学性质。The results show that the compound of the present application has good pharmacokinetic properties.
实验例8.Experimental example 8.
药效学研究Pharmacodynamic study
SPF级雌性BALB/C裸小鼠(来源：江苏集萃药康生物科技有限公司)右后背细胞皮下接种5x10 6个NCI-H358细胞。待肿瘤平均体积达到85mm 3左右时，将动物分成给药组和对照组。分组当天为d0天，d1天开始灌胃给药，每天给药2次。对照组给予溶媒。连续给药21天，每周测2-3次瘤体积，同时称鼠重，记录数据：每日观察并记录小鼠一般表现。试验结束后称取瘤重并拍照。 SPF-grade female BALB/C nude mice (source: Jiangsu Jicui Yaokang Biotechnology Co., Ltd.) were subcutaneously inoculated with 5x106 NCI-H358 cells on the right back. When the average volume of the tumor reached about 85 mm 3 , the animals were divided into a drug-administered group and a control group. The day of grouping was d0 day, d1 day began to gavage administration, twice a day. The control group was given vehicle. The administration was continued for 21 days, the tumor volume was measured 2-3 times a week, and the mice were weighed at the same time, and the data was recorded: observe and record the general performance of the mice every day. After the experiment, the tumors were weighed and photographed.
相对肿瘤抑制率，TGI(％)，计算公式如下：TGI％＝(1-治疗组瘤重量/对照组瘤重量)*100％；Relative tumor inhibition rate, TGI (%), the calculation formula is as follows: TGI%=(1-treatment group tumor weight/control group tumor weight)*100%;
结果显示本申请化合物具有良好的体内药效活性。The results show that the compound of the present application has good pharmacodynamic activity in vivo.
除本文中描述的那些外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, journal articles, books, and any other publications, is hereby incorporated by reference in its entirety.

Claims (15)

  1. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(I)的结构：Compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein the compound has the formula ( I) Structure:
    Figure PCTCN2022135958-appb-100001
    Figure PCTCN2022135958-appb-100001
    其中：in:
    Figure PCTCN2022135958-appb-100002
    表示单键或双键，条件是，当其表示双键时，R 3和R 4’不存在；
    Figure PCTCN2022135958-appb-100002
    represents a single bond or a double bond, with the proviso that, when it represents a double bond, R 3 and R 4' are absent;
    环A为C 6-10芳环或5-14元杂芳环； Ring A is a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
    L为直接键、-C 1-6亚烷基-、-C(＝O)-、-NR a-、-O-(CH 2) m-、-S-(CH 2) m-、-S(＝O)-(CH 2) m-、-S(＝O) 2-(CH 2) m-或-C(＝O)NR a-； L is a direct bond, -C 1-6 alkylene-, -C(=O)-, -NR a -, -O-(CH 2 ) m -, -S-(CH 2 ) m -, -S (=O)-(CH 2 ) m -, -S(=O) 2 -(CH 2 ) m - or -C(=O)NR a -;
    R 1在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； Each occurrence of R 1 is independently selected from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-14 membered heteroaryl group, C 6-12 aralkyl group, -C(=O)R a , -OC(= O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S(=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S( =O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene-NR a R b and - OC 1-6 alkylene-NR a R b ;
    当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成C 3-6烃环、3-10元杂环、C 6-10芳环或5-14元杂芳环； When n>1, two adjacent R 1 together with the group they are connected to optionally form a C 3-6 hydrocarbon ring, a 3-10 membered heterocycle, a C 6-10 aromatic ring or a 5-14 membered Heteroaromatic ring;
    R 2选自C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； R 2 is selected from C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
    R 3、R 4、R 4’和R 5各自独立地选自H、卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R a、-OC(＝O)R a、-C(＝O)OR a、-OR a、-SR a、-S(＝O)R a、-S(＝O) 2R a、-S(＝O) 2NR aR b、-NR aR b、-C(＝O)NR aR b、-NR a-C(＝O)R b、-NR a-C(＝O)OR b、-NR a-S(＝O) 2-R b、-NR a-C(＝O)-NR aR b、-C 1-6亚烷基-OR a、-C 1-6亚烷基-NR aR b和-O-C 1-6亚烷基-NR aR b； R 3 , R 4 , R 4' and R 5 are each independently selected from H, halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O) R a , -OC(=O)R a , -C(=O)OR a , -OR a , -SR a , -S(=O)R a , -S(=O) 2 R a , -S (=O) 2 NR a R b , -NR a R b , -C(=O)NR a R b , -NR a -C(=O)R b , -NR a -C(=O)OR b , -NR a -S(=O) 2 -R b , -NR a -C(=O)-NR a R b , -C 1-6 alkylene-OR a , -C 1-6 alkylene -NR a R b and -OC 1-6 alkylene-NR a R b ;
    或者R 4和R 4’连同其所连接的碳原子共同构成
    Figure PCTCN2022135958-appb-100003
    条件是此时，
    Figure PCTCN2022135958-appb-100004
    表示单键；     Or R 4 and R 4' together with the carbon atom to which they are attached form
    Figure PCTCN2022135958-appb-100003
    The condition is that at this time,
    Figure PCTCN2022135958-appb-100004
    Indicates a single key;
    R a和R b在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； R a and R b are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
    m为0、1、2或3的整数；m is an integer of 0, 1, 2 or 3;
    n为0、1、2、3或4的整数；n is an integer of 0, 1, 2, 3 or 4;
    上述烷基、亚烷基、烯基、炔基、环烃基、烃环、杂环基、杂环、芳基、芳环、杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-C(＝O)R c、-OC(＝O)R c、-C(＝O)OR c、-OR c、-SR c、-S(＝O)R c、-S(＝O) 2R c、-S(＝O) 2NR cR d、-NR cR d、-C(＝O)NR cR d、-NR c-C(＝O)R d、-NR c-C(＝O)OR d、-NR c-S(＝O) 2-R d、-NR c-C(＝O)-NR cR d、-C 1- 6亚烷基-OR c、-C 1-6亚烷基-NR cR d和-O-C 1-6亚烷基-NR cR d，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-O-C 1-6烷基和-C 1-6亚烷基-O-C 1-6烷基，优选地，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃 基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基和-C 1-6亚烷基-O-C 1-6烷基；并且 The above-mentioned alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, hydrocarbon ring, heterocyclyl, heterocycle, aryl, aromatic ring, heteroaryl, heteroaryl ring and aralkyl are each Optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -C(=O)R c , -OC(=O)R c , -C(=O)OR c , -OR c , -SR c , -S(=O)R c , -S(=O) 2 R c , -S(=O) 2 NR c R d , -NR c R d , -C(=O)NR c R d , -NR c -C(=O)R d , -NR c -C(=O)OR d , -NR c -S(=O) 2 - R d , -NR c -C(=O)-NR c R d , -C 1-6 alkylene-OR c , -C 1-6 alkylene-NR c R d and -OC 1-6 alkylene Alkyl-NR c R d , said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from the following: halogen , -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl , 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl, -OC 1-6 alkyl and -C 1-6 alkylene-OC 1-6 alkyl, preferably, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more substituents independently selected from the following: Halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 ring Hydrocarbyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl and -C 1-6 alkylene-OC 1-6 alkyl; and
    R c和R d在每次出现时各自独立地选自H、C 1-6烷基、C 3-10环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 3-6环烃基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6- 12芳烷基和-C 1-6亚烷基-O-C 1-6烷基。 R c and R d are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl, said alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are further optionally substituted by one or more independently selected from the following Substitution: halogen, -OH, =O, -C(=O)O-tert-butyl, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3 -6 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl, C 6-12 aralkyl and -C 1-6 alkylene - OC 1-6 alkane base.
  2. 权利要求1的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物具有式(II)、(III)或(IV)的结构：The compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or prodrug thereof, wherein said Compounds have the structure of formula (II), (III) or (IV):
    Figure PCTCN2022135958-appb-100005
    Figure PCTCN2022135958-appb-100005
  3. 权利要求1或2的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中环A为苯环或吡啶环，优选为苯环。The compound of claim 1 or 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein Ring A is a benzene ring or a pyridine ring, preferably a benzene ring.
  4. 权利要求1-3中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中L为直接键、-CH 2-、-C(＝O)-、-NH-、-O-、-S-、-S(＝O) 2-、-C(＝O)N(CH 3)-或-O-CH 2-。 The compound of any one of claims 1-3, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrugs, wherein L is a direct bond, -CH 2 -, -C(=O)-, -NH-, -O-, -S-, -S(=O) 2 -, -C(=O)N (CH 3 )- or -O-CH 2 -.
  5. 权利要求1-4中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 1在每次出现时各自独立地选自卤素、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 3-6环烃基、3-10元杂环基、-C(＝O)R a、-C(＝O)OR a、-OR a、-S(＝O) 2R a、-NR aR b、-C(＝O)NR aR b、-C 1-6亚烷基-OR a和-C 1-6亚烷基-NR aR b；上述烷基、亚烷基、环烃基和杂环基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH 2、-CN、C 1-6烷基、C 3-6环烃基和3-10元杂环基； The compound of any one of claims 1-4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrugs, wherein R 1 is each independently selected from halogen, -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 3-6 cycloalkyl, 3-10 membered Heterocyclyl, -C(=O)R a , -C(=O)OR a , -OR a , -S(=O) 2 R a , -NR a R b , -C(=O)NR a R b , -C 1-6 alkylene-OR a and -C 1-6 alkylene-NR a R b ; the above-mentioned alkyl, alkylene, cyclohydrocarbyl and heterocyclyl are each optional at each occurrence is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -NH 2 , -CN, C 1-6 alkyl, C 3-6 cycloalkyl, and 3-10 membered Heterocyclyl;
    优选地，R 1选自-F、-Cl、-Br、-I、-OH、-NH 2、-CN、-NO 2、-CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 3、-CH 2CF 3、-CF 2CH 3、-CF 2CN、-CH 2NHCH 3、-CF 2CH 2NH 2、-CH(CH 3)OH、-C(CH 3) 2OH、-CF 2CH 2OH、-CF 2C(CH 3) 2OH、-CF 2OCH 3、-CF 2CH 2OCH 3、-CF 2O-(环丙基)、环丙基、
    Figure PCTCN2022135958-appb-100006
    -C(＝O)CH 3、-C(＝O)OCH 3、-OCH 3、-S(＝O) 2CH 3和-C(＝O)NH 2。     Preferably, R 1 is selected from -F, -Cl, -Br, -I, -OH, -NH 2 , -CN, -NO 2 , -CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 3 , -CH 2 CF 3 , -CF 2 CH 3 , -CF 2 CN, -CH 2 NHCH 3 , -CF 2 CH 2 NH 2 , -CH(CH 3 )OH, -C(CH 3 ) 2 OH, -CF 2 CH 2 OH, -CF 2 C(CH 3 ) 2 OH, -CF 2 OCH 3 , -CF 2 CH 2 OCH 3 , -CF 2 O-(cyclopropyl), cyclopropyl ,
    Figure PCTCN2022135958-appb-100006
    -C(=O) CH3 , -C(=O) OCH3 , -OCH3 , -S(= O ) 2CH3 , and -C(=O) NH2 .
  6. 权利要求1-5中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中：The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrugs, of which:
    当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成C 3-6烃环、3-10元杂环或5-14元杂芳环；所述烃环、杂环和杂芳环各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、C 1-6烷基和-C 1-6亚烷基-OR c； When n>1, two adjacent R 1 together with the group it is connected to optionally jointly form a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring or a 5-14 membered heteroaromatic ring; the hydrocarbon Each ring, heterocycle and heteroaromatic ring is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH, =O, C 1-6 alkyl and -C 1-6 alkylene -OR c ;
    优选地，当n>1时，两个相邻的R 1连同其所连接的基团任选地共同形成
    Figure PCTCN2022135958-appb-100007
    Figure PCTCN2022135958-appb-100008
    Preferably, when n>1, two adjacent R 1 together with the groups to which they are connected optionally jointly form
    Figure PCTCN2022135958-appb-100007
    Figure PCTCN2022135958-appb-100008
  7. 权利要求1-6中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中
    Figure PCTCN2022135958-appb-100009
    选自
    Figure PCTCN2022135958-appb-100010
    The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrugs, of which
    Figure PCTCN2022135958-appb-100009
    selected from
    Figure PCTCN2022135958-appb-100010
    Figure PCTCN2022135958-appb-100011
    Figure PCTCN2022135958-appb-100011
    Figure PCTCN2022135958-appb-100012
    Figure PCTCN2022135958-appb-100012
  8. 权利要求1-7中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中-L-R 2选自
    Figure PCTCN2022135958-appb-100013
    Figure PCTCN2022135958-appb-100014
    The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrug, wherein -LR 2 is selected from
    Figure PCTCN2022135958-appb-100013
    Figure PCTCN2022135958-appb-100014
    Figure PCTCN2022135958-appb-100015
    Figure PCTCN2022135958-appb-100015
    Figure PCTCN2022135958-appb-100016
    Figure PCTCN2022135958-appb-100016
    Figure PCTCN2022135958-appb-100017
    Figure PCTCN2022135958-appb-100017
    Figure PCTCN2022135958-appb-100018
    Figure PCTCN2022135958-appb-100018
    Figure PCTCN2022135958-appb-100019
    Figure PCTCN2022135958-appb-100019
    Figure PCTCN2022135958-appb-100020
    Figure PCTCN2022135958-appb-100021
    甲氧基、
    Figure PCTCN2022135958-appb-100022
    Figure PCTCN2022135958-appb-100020
    Figure PCTCN2022135958-appb-100021
    Methoxy,
    Figure PCTCN2022135958-appb-100022
    Figure PCTCN2022135958-appb-100023
    Figure PCTCN2022135958-appb-100023
    Figure PCTCN2022135958-appb-100024
    Figure PCTCN2022135958-appb-100024
  9. 权利要求1-8中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3、R 4、R 4’和R 5各自独立地选自H、F、Cl、Br、甲基、二氟甲基、三氟甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、
    Figure PCTCN2022135958-appb-100025
    Figure PCTCN2022135958-appb-100026
    The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrug, wherein R 3 , R 4 , R 4′ and R 5 are each independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl, ethyl, n-propyl, iso Propyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
    Figure PCTCN2022135958-appb-100025
    Figure PCTCN2022135958-appb-100026
  10. 权利要求1-9中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、 多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 3选自H、卤素、C 1-6烷基、C 3-6环烃基、-OR a和-C 1-6亚烷基-OR a；所述烷基、亚烷基和环烃基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH和-CN； The compound of any one of claims 1-9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrug, wherein R 3 is selected from H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a and -C 1-6 alkylene-OR a ; said alkyl, alkylene and cycloalkyl are each optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH and -CN;
    优选地，R 3选自H、F、Cl、Br、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、
    Figure PCTCN2022135958-appb-100027
    Preferably, R is selected from H, F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl,
    Figure PCTCN2022135958-appb-100027
    更优选地，R 3选自H、甲基、乙基和
    Figure PCTCN2022135958-appb-100028
    最优选地，R 3选自H和甲基。     More preferably, R is selected from H, methyl, ethyl and
    Figure PCTCN2022135958-appb-100028
    Most preferably, R3 is selected from H and methyl.
  11. 权利要求1-10中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 4和R 4’各自独立地选自H、卤素、C 1-6烷基、C 3-6环烃基、-OR a、-NR aR b和-C 1-6亚烷基-OR a；所述烷基和环烃基各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH和-CN； The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrug, wherein R 4 and R 4' are each independently selected from H, halogen, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a , -NR a R b and -C 1-6 alkylene The group -OR a ; each of the alkyl and cycloalkyl is optionally substituted by one or more substituents independently selected from the group consisting of halogen, -OH and -CN;
    R 4和R 4’各自独立地选自H、F、Cl、Br、甲基、二氟甲基、三氟甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、
    Figure PCTCN2022135958-appb-100029
    Figure PCTCN2022135958-appb-100030
    R and R are each independently selected from H, F, Cl, Br, methyl, difluoromethyl, trifluoromethyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, cyclopropyl,
    Figure PCTCN2022135958-appb-100029
    Figure PCTCN2022135958-appb-100030
    优选地，R 4和R 4’各自独立地选自H、F、甲基、二氟甲基、三氟甲基、异丙基、叔丁基、
    Figure PCTCN2022135958-appb-100031
    Preferably, R4 and R4 ' are each independently selected from H, F, methyl, difluoromethyl, trifluoromethyl, isopropyl, tert-butyl,
    Figure PCTCN2022135958-appb-100031
  12. 权利要求1-11中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中R 5为H、C 1-6烷基、C 3-6环烃基、-OR a、-SR a、-NR aR b或-C 1-6亚烷基-NR aR b，优选为H、甲基、乙基、异丙基、环丙基、
    Figure PCTCN2022135958-appb-100032
    The compound of any one of claims 1-11 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or Prodrug, wherein R 5 is H, C 1-6 alkyl, C 3-6 cycloalkyl, -OR a , -SR a , -NR a R b or -C 1-6 alkylene-NR a R b , preferably H, methyl, ethyl, isopropyl, cyclopropyl,
    Figure PCTCN2022135958-appb-100032
  13. 化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，其中所述化合物选自Compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotopically labeled compound or prodrug thereof, wherein said compound is selected from
    Figure PCTCN2022135958-appb-100033
    Figure PCTCN2022135958-appb-100033
    Figure PCTCN2022135958-appb-100034
    Figure PCTCN2022135958-appb-100034
    Figure PCTCN2022135958-appb-100035
    Figure PCTCN2022135958-appb-100035
    Figure PCTCN2022135958-appb-100036
    Figure PCTCN2022135958-appb-100036
    Figure PCTCN2022135958-appb-100037
    Figure PCTCN2022135958-appb-100037
    Figure PCTCN2022135958-appb-100038
    Figure PCTCN2022135958-appb-100038
    Figure PCTCN2022135958-appb-100039
    Figure PCTCN2022135958-appb-100039
    Figure PCTCN2022135958-appb-100040
    Figure PCTCN2022135958-appb-100040
    Figure PCTCN2022135958-appb-100041
    Figure PCTCN2022135958-appb-100041
    Figure PCTCN2022135958-appb-100042
    Figure PCTCN2022135958-appb-100042
    Figure PCTCN2022135958-appb-100043
    Figure PCTCN2022135958-appb-100043
    Figure PCTCN2022135958-appb-100044
    Figure PCTCN2022135958-appb-100044
    Figure PCTCN2022135958-appb-100045
    Figure PCTCN2022135958-appb-100045
    Figure PCTCN2022135958-appb-100046
    Figure PCTCN2022135958-appb-100046
    Figure PCTCN2022135958-appb-100047
    Figure PCTCN2022135958-appb-100047
    Figure PCTCN2022135958-appb-100048
    Figure PCTCN2022135958-appb-100048
    Figure PCTCN2022135958-appb-100049
    Figure PCTCN2022135958-appb-100049
    Figure PCTCN2022135958-appb-100050
    Figure PCTCN2022135958-appb-100050
    Figure PCTCN2022135958-appb-100051
    Figure PCTCN2022135958-appb-100051
    Figure PCTCN2022135958-appb-100052
    Figure PCTCN2022135958-appb-100052
    Figure PCTCN2022135958-appb-100053
    Figure PCTCN2022135958-appb-100053
    Figure PCTCN2022135958-appb-100054
    Figure PCTCN2022135958-appb-100054
    Figure PCTCN2022135958-appb-100055
    Figure PCTCN2022135958-appb-100055
  14. 药物组合物，其包含预防或治疗有效量的权利要求1-13中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药，以及药学上可接受的载体，所述药物组合物优选为固体制剂、半固体制剂、液体制剂或气态制剂。A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, Solvate, metabolite, isotope-labeled compound or prodrug, and a pharmaceutically acceptable carrier, the pharmaceutical composition is preferably a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  15. 权利要求1-13中任一项的化合物或其药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂合物、代谢物、同位素标记的化合物或前药或者权利要求14的药物组合物在制备用作SOS1抑制剂的药物中的用途，优选地，所述药物用于预防或治疗癌症(例如胰腺癌、肺癌、结直肠癌、胆管癌、多发性骨髓瘤、黑素瘤、子宫癌、子宫内膜癌、甲状腺癌、急性髓性白血病、膀胱癌、尿路上皮癌、胃癌、***、头颈部鳞状细胞癌、弥漫性大B细胞淋巴瘤、食道癌、慢性淋巴细胞白血病、肝细胞癌、乳腺癌、卵巢癌、***癌、胶质母细胞瘤、肾癌和肉瘤)、RAS病(例如1型神经纤维瘤病(NF1)、努南综合征(NS)、伴有多斑的努南综合征(NSML)、毛细血管畸形-动静脉畸形综合征(CM-AVM)、科斯特洛综合征(CS)、心-面-皮肤综合症(CFC)、莱格斯综合征和遗传性牙龈纤维瘤病)。The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite, isotope-labeled compound or The purposes of prodrug or the pharmaceutical composition of claim 14 in the preparation of the medicine that is used as SOS1 inhibitor, preferably, described medicine is used for preventing or treating cancer (such as pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple Myeloma, Melanoma, Uterine Cancer, Endometrial Cancer, Thyroid Cancer, Acute Myeloid Leukemia, Bladder Cancer, Urothelial Cancer, Gastric Cancer, Cervical Cancer, Head and Neck Squamous Cell Carcinoma, Diffuse Large B Cell Carcinoma Lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma), RAS disorders (such as neurofibromatosis type 1 (NF1), Noonan Syndrome (NS), Noonan Syndrome with Mottling (NSML), Capillary Malformation-Arteriovenous Malformation Syndrome (CM-AVM), Costello Syndrome (CS), Heart-Face-Skin Syndrome (CFC), Legers syndrome, and hereditary gingival fibromatosis).
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WO2003066630A2 (en) * 2002-02-07 2003-08-14 Amgen Inc. Quinolinone derivatives for treating cell proliferation related disorders
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