WO2022135610A1 - Tetracyclic compound, pharmaceutical composition thereof and use thereof - Google Patents

Tetracyclic compound, pharmaceutical composition thereof and use thereof Download PDF

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WO2022135610A1
WO2022135610A1 PCT/CN2022/070423 CN2022070423W WO2022135610A1 WO 2022135610 A1 WO2022135610 A1 WO 2022135610A1 CN 2022070423 W CN2022070423 W CN 2022070423W WO 2022135610 A1 WO2022135610 A1 WO 2022135610A1
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compound
synthesis
mmol
alkyl
esi
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PCT/CN2022/070423
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French (fr)
Chinese (zh)
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方华祥
杨秀眉
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武汉誉祥医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetracyclic compounds, pharmaceutical compositions containing the compounds and their application in the field of medicine.
  • RAS proteins act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Activated by the guanine nucleotide exchange factor (GEF), RAS in its GTP-bound state interacts with a number of effectors. The return to an inactive state is driven by GTPase activating proteins (GAPs), which downregulate active RAS by accelerating weak intrinsic GTPase activity by up to 5 orders of magnitude.
  • GEF guanine nucleotide exchange factor
  • GAPs GTPase activating proteins
  • mutant RAS proteins require GEF activity for full activation remains to be well studied and may vary with specific mutations.
  • SOS RAS sevenless son
  • SOS1 and SOS2 The most studied protein of RAS sevenless son (SOS), two human isoforms, SOS1 and SOS2, are known.
  • SOS sevenless son
  • Fragment-based screening, rationally designed, and high-throughput screening methods led to the identification of small-molecule-addressed KRAS-SOS1 interactions, resulting in moderate micromolar affinities.
  • the SOS1 protein consists of 1333 amino acids (150 kDa).
  • SOS1 is a multi-domain protein with two tandem N-terminal histone domains (HD) followed by Dbl homology domain (DH), Pleckstrin ) homeodomain (PH), helical linker (HL), RAS exchange motif (REM), CDC25 homeodomain and C-terminal proline-rich domain (PR).
  • SOS1 has two binding sites for RAS family proteins; a catalytic site, which binds GDP-bound RAS family proteins to facilitate guanine nucleotide exchange; and an allosteric site, which binds GTP-bound RAS family protein, which leads to a further increase in the catalytic GEF function of SOS1.
  • SOS1 is critically involved in the activation of RAS family protein signaling in cancer through mechanisms other than RAS family protein mutation.
  • SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases (eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/ 3.
  • activated/phosphorylated receptor tyrosine kinases eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/ 3.
  • SOS1 is also recruited to other phosphorylated cell surface receptors, such as T cell receptor (TCR), B cell receptor (BCR), and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75).
  • TCR T cell receptor
  • BCR B cell receptor
  • monocyte colony-stimulating factor receptor SOS1 activation by RAS family proteins can also be mediated through the interaction of SOS1/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myeloid leukemia.
  • SOS1 is also a GEF for activating the GTPases RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1):125-36).
  • RAC1 Ras-related C3 botulinum toxin substrate 1
  • RAC1 has been implicated in the pathogenesis of various human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12(10):1925-34).
  • novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site and simultaneously prevent interaction with and activation of RAS family proteins. This resulted in a marked inhibition of the interaction of SOS1 with RAS family proteins, especially KRAS (with low single-digit nanomolar IC50 activity), and thus markedly reduced ERK phosphorylation in KRAS mutant cancer cell lines.
  • the selective SOS1 inhibitor compounds described herein are expected to provide pharmacological benefit to patients with cancers associated with a dependency on RAS family protein signaling.
  • Such cancers expected to be targeted by SOS1 inhibitor compounds include those that exhibit alterations (mutations, gene amplification, overexpression) in components (proteins, genes) in the RAS family protein pathway, such as KRAS , NRAS, HRAS, receptor tyrosine kinases (eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL), GAP (eg, NF1) and SOS1.
  • SOS1 inhibitor compounds are expected in other diseases associated with dysregulation of RAS family protein pathways such as neurofibromatosis, Noonan syndrome (NS), cardiofacial skin syndrome (CFC) and hereditary gingival fibromatosis type 1 Compounds will also provide pharmacological benefits.
  • NS Noonan syndrome
  • CFC cardiofacial skin syndrome
  • hereditary gingival fibromatosis type 1 Compounds will also provide pharmacological benefits.
  • the compounds disclosed herein show good solubility, excellent DMPK properties, and good selectivity for the kinases of the human kinome.
  • the present invention aims to provide a class of tetracyclic compounds with novel structures used as SOS1 inhibitors, which exhibit good inhibitory activity on tumor cells, have good druggability, and have broad prospects for drug development.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein
  • A is selected from C 6 -C 10 aryl, 5- to 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, and wherein each of the aryl, monocyclic and bicyclic heteroaryl groups optionally substituted with m independent R 4 , wherein m is independently any integer from 0 to 5;
  • X and Y are each independently selected from CR or N;
  • Z 1 and Z 2 are each independently selected from -O-, -CR 7 - or -NR 7 -;
  • L 1 , L 2 and L 3 are each independently selected from -(CH 2 ) n - or -(CH 2 ) n -O-(CH 2 ) p -O-(CH 2 ) o - or -O-( CH 2 ) q -, wherein each of n, o, p and q is independently any integer from 0 to 3;
  • R 1 and R 2 are each independently selected from hydrogen and C 1 -C 8 alkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, said alkyl and cycloalkane Each group is optionally substituted by at least 1 R 8 , and R 1 or R 2 and A ring form a 4-8 membered saturated carbocyclic or heterocyclic ring;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N(R 7 )(R 8 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C1 - C3alkoxy, and C1 - C6 haloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, and wherein The alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1 R 10 ;
  • R 8 and R 9 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 ring Alkyl, 3- to 14-membered heterocycloalkyl, C1 - C3alkoxy, C1 - C3haloalkoxy , C6 -C10aryl, 5- to 6-membered monocyclic heteroaryl or 9- to 10 membered bicyclic heteroaryl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl and bicyclic heteroaryl each is optionally substituted with at least 1 R 10 ;
  • Each R 10 is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethyl oxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
  • the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I - A specific compound shown in 3-1, I-4-1, I-5-1 or I-6-1, which is:
  • the present invention provides a pharmaceutical composition, which comprises formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1 , I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1
  • a pharmaceutical composition which comprises formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1 , I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1
  • the compound or its pharmaceutically acceptable salt, hydrate, solvate, stereo One or more of an isomer, tautomer, metabolite or prodrug.
  • the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
  • the present invention provides formulas such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I- - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof
  • a body, metabolite or prodrug or a pharmaceutical composition comprising the same in the manufacture of a medicament for the prevention and/or treatment of diseases caused by overexpression of SOS1.
  • the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I- - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof.
  • a body, a metabolite or a prodrug or a pharmaceutical composition comprising the same in the preparation of a SOS1 inhibitor medicament.
  • the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof Use of a medicament, metabolite or prodrug, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer.
  • the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.
  • the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of SOS1, comprising preventing and/or treating an effective amount of such as formula I, formula I-1, I -2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I -
  • an effective amount of such as formula I, formula I-1, I -2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I - The compound shown in 6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition comprising the same is administered to individuals in need.
  • the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of SOS1, comprising adding a preventive and/or therapeutically effective amount of 94 compounds such as compound 1 to compound 94 in total or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, to be administered to an individual in need thereof.
  • the present invention provides a series of tetracyclic compounds with novel structures. It is proved by relevant enzyme and cell activity tests that the compounds of the present invention have excellent cell proliferation inhibitory activity. In vitro experiments, the IC 50 value of cell proliferation reaches nM It can be applied well in a variety of tumors. At the same time, the compounds of the present invention have very good inhibitory effect on KRAS:SOS1 activation, which can reach nM level, and are suitable for being prepared as SOS1 inhibitors for preventing and/or treating diseases or conditions related to SOS1 activation, such as cancer (including but not limited to pancreatic cancer, colorectal cancer and lung cancer).
  • cancer including but not limited to pancreatic cancer, colorectal cancer and lung cancer.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms carbon atoms, straight and branched chain groups of 1 to 6 carbon atoms or 1 to 4 carbon atoms.
  • alkyl may be a monovalent, divalent or trivalent group.
  • Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl and various branched chain isomers, etc.
  • Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylene, propylene, propylene, butylene, butylene, and various branched chain isomers thereof.
  • alkyl may be optionally substituted or unsubstituted.
  • Alkoxy refers to a "-O-alkyl” group, wherein “alkyl” is as defined above.
  • alkenyl refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 20 carbon atoms and at least 1 carbon-carbon double bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkenyl may be a monovalent, divalent or trivalent group.
  • alkenyl may be optionally substituted or unsubstituted.
  • Alkynyl refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 20 carbon atoms and at least 1 carbon-carbon triple bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • alkynyl may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C ⁇ CH), propynyl (-C ⁇ C- CH3 ), butynyl pentynyl and various branched chain isomers.
  • Non-limiting examples also include, but are not limited to, ethynylene (-C ⁇ C-), propynylene butynylene and its various branched-chain isomers.
  • alkynyl may be optionally substituted or unsubstituted.
  • Heteroalkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 atoms, for example, may be 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, Linear and branched groups of 2 to 6 atoms or 2 to 4 atoms, wherein one or more atoms is a hetero group selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1 or 2) atoms, and the rest are carbon.
  • heteroalkyl may be a monovalent, divalent or trivalent group.
  • Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azapropyl), and various Branched chain isomers, etc.
  • heteroalkyl may be optionally substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially unsaturated, monocyclic or polycyclic, aliphatic hydrocarbon group comprising 3 to 12 ring atoms, eg, 3 to 12, 3 to 10, or 3 to 6 Ring atoms (ie, 3 to 6 membered rings).
  • monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc.
  • cycloalkyl may be optionally substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example, may be 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is 0, 1 or 2) and the remaining ring atoms are carbon.
  • Preferred heterocycloalkyl groups comprise 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 10 ring atoms, and most preferably 5 or 6 ring atoms, of which 1 to 4, Preferably 1 to 3, more preferably 1 to 2 are heteroatoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like.
  • Non-limiting examples of polycyclic heterocycloalkyl groups include, but are not limited to, spirocyclic or bridged ring heterocycloalkyl groups.
  • Halogen means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
  • Haloalkyl or “haloalkoxy” refers to an alkyl or alkoxy group substituted with one or more identical or different halogen atoms.
  • Examples of preferred alkyl or alkoxy groups include, but are not limited to: tris Fluoromethyl, trifluoroethyl, trifluoromethoxy.
  • Amino refers to the “ -NH2 " group.
  • Aryl means monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms A loop with one or more points of attachment to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6-10 or 6-7 ring atoms.
  • Heteroaryl refers to monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more selected from nitrogen, oxygen , Sulfur heteroatoms, where each ring system contains a ring of 5-7 atoms with one or more points of attachment to the rest of the molecule.
  • the term “heteroaryl” may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”. Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, quinolinyl.
  • the heteroaryl group is a ring system of 5-10 ring atoms.
  • heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not be, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted with a corresponding number of substituents.
  • “Pharmaceutically acceptable salts” refers to salts prepared from compounds of the present invention with relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting their free forms with a sufficient amount of base in neat solution or in a suitable inert solvent .
  • Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts.
  • acid addition salts can be obtained by contacting their free forms with a sufficient amount of acid in neat solution or in a suitable inert solvent .
  • Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate) , monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (such as acetate, propionate, isobutyrate, malonate, succinate , Suberate, Maleate, Fumarate, Citrate, Tartrate, Lactate, Mandelate, Benzoate, Phthalate, Mesylate, Benzene Sulfonate acid salts, p-toluenesulfonic acid salts, glucuronic acid, etc.) and amino acid salts (eg, arginine salts, etc.).
  • inorganic acid salts eg, hydrochloride, hydrobromide, hydroiodide, n
  • the pharmaceutically acceptable salt of the compound represented by formula I is an acid addition salt, preferably hydrochloride, hydrobromide, phosphate or sulfate, more preferably hydrochloride.
  • “Pharmaceutical composition” refers to a pharmaceutically acceptable composition comprising one or more compounds of Formula I or a pharmaceutically acceptable form thereof (eg, a salt, hydrate, solvate, stereoisomer isomers, tautomers, metabolites, prodrugs, etc.), and other components (eg, pharmaceutically acceptable excipients).
  • auxiliary materials refer to auxiliary materials widely used in the field of pharmaceutical production.
  • the main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in properties and/or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be The rate of dissolution, or the promotion of effective absorption of the active ingredient in the subject to which it is administered.
  • Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (eg, stabilizing the overall pH of the composition or preventing the degradation of active ingredients in the composition).
  • Non-limiting examples of pharmaceutically acceptable adjuvants include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, sizing agents, disintegrating agents, lubricants, anti-adhering agents , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, sweeteners, etc.
  • compositions of the present invention can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping and/or lyophilizing processes.
  • the purpose of using the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient, and then exert biological activity.
  • the pharmaceutical compositions of the present invention can be administered in any form, including injection (intraarterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid, oral liquid), rectal, inhalation, implant , topical (eg ocular) administration, etc.
  • oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like.
  • Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like.
  • Non-limiting examples of formulations for topical administration include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations.
  • Non-limiting examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like.
  • the pharmaceutical compositions of the present invention can also be formulated in controlled release or delayed release dosage forms (eg, liposomes or microspheres).
  • a compound of the present invention or a pharmaceutical composition comprising the same is administered orally or intravenously to an individual in need thereof.
  • other modes of administration may also be employed or even preferred.
  • transdermal administration would be a very important mode of administration.
  • the administration channel can be varied or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and medical staff, and other relevant factors.
  • the compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs or pharmaceutical compositions containing them have excellent SOS1 enzyme activity and cellular
  • the proliferation inhibitory activity can be used as an SOS1 inhibitor for preventing and/or treating diseases or conditions caused by overexpression of SOS1, and has good clinical and medical applications.
  • a non-limiting example of a disease or disorder caused by overexpression of SOS1 is cancer, including but not limited to pancreatic cancer, colorectal cancer and lung cancer.
  • the preparation of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the known starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means (for example, purchased from Shaoyuan Chemical Technology, Beijing Coupling Technology, etc.). Unless otherwise specified, the reactions were carried out in an argon atmosphere or a nitrogen atmosphere.
  • the hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times.
  • the reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • Monitoring the progress of the reaction can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate.
  • the developing solvent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent can be determined according to the polarity of the compound. adjust.
  • the separation and purification of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC) Wait.
  • Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier, and the eluent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent can be based on the compound.
  • the polarity can be adjusted, and a small amount of acidic or basic anti-tailing reagents can also be added for adjustment.
  • HPLC chromatogram was determined by Agilent1200DAD HPLC chromatograph (chromatographic column: Sunfire C18, 150 ⁇ 4.6mm, 5 ⁇ m) or Waters 2695-2996 HPLC chromatograph (chromatographic column: Gimini C18, 150 ⁇ 4.6mm, 5 ⁇ m).
  • Structural identification of the compounds of the present invention can be accomplished by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), and the like.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR spectrum was determined by Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ) or deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS), and the chemical shifts are in 10-6 (ppm).
  • MS spectra were determined using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).
  • intermediate INT-2 refers to the synthesis steps for the preparation of intermediate INT-1, wherein in the first step, S-tert-butylsulfinamide is used instead of tert-butylsulfinamide to synthesize compound intermediate INT-2.
  • the specific preparation method of compound 1 includes:
  • compound 1F 750 mg, 2.2 mmol was added to methanol (8 mL), and then 10% palladium on carbon (100 mg) was added. After the addition, the bottle mouth was covered with a hydrogen balloon, and after the gas was replaced three times, the reaction was maintained at room temperature for 12 hours in a hydrogen atmosphere. TLC showed that the reaction was completed, filtered, the solid was washed with methanol, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain compound 1G (600 mg, gray solid, yield 88%).
  • reverse phase HPLC preparation Waters Sunfire OBD 100x30mm, 5 ⁇ m,
  • the synthesis of compound 2 refers to the synthesis procedure of compound 1 in example 1, wherein compound 1B is replaced by (R)-1-Boc-3-hydroxymethylpiperazine, and (1R)-1-[3-nitro-5 -(trifluoromethyl)phenyl]ethylamine was substituted for compound INT-1, and compound 2 was synthesized.
  • the synthesis of compound 3 refers to the synthesis procedure of compound 1 in Example 1, wherein compound 1B is replaced by (S)-1-Boc-3-hydroxymethylpiperazine, and (1R)-1-[3-nitro-5 -(trifluoromethyl)phenyl]ethanamine was substituted for compound INT-1, and compound 3 was synthesized.
  • the synthesis of compound 4 refers to the synthesis steps of compound 1 in Example 1, wherein in the first step, (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B, and in the eighth step, (R)-2-( 3-(1-Aminoethyl)-2-fluorophenyl)-2,2-difluoroethane-1-ol was used to replace compound INT-1, and compound 4 was synthesized.
  • the synthesis of compound 5 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and (R)-1-(3 -(1-Aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol was substituted for compound INT-1, and compound 5 was synthesized.
  • the synthesis of compound 6 refers to the synthesis steps of compound 1 in Example 1, wherein the first step uses (R)-1-Boc-3-hydroxymethylpiperazine to replace compound 1B, and the eighth step uses (R)-1-( 3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 6 was synthesized.
  • the synthesis of compound 7 refers to the synthesis steps of compound 1 in Example 1, wherein in the first step, (S)-1-Boc-3-hydroxymethylpiperazine is used instead of compound 1B, and in the eighth step, (R)-1-( 3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 7 was synthesized.
  • the synthesis of compound 8 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and cyclopropylcarbonyl chloride is used to replace ethyl acetate in the fourth step.
  • the synthesis of compound 9 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and p-toluenesulfonyl chloride is used to replace acetyl chloride in the fourth step.
  • (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine is used to replace compound INT-1, and compound 9 is synthesized.
  • the synthesis of compound 11 refers to the synthesis steps of compound 10 in Example 10, wherein in the fourth step, paraformaldehyde is used instead of 10E to synthesize compound 11.
  • the synthesis of compound 12 refers to the synthesis steps of compound 10 in Example 10, wherein in the fourth step, tetrahydropyranone is used instead of 10E, and compound 12 is synthesized.
  • the synthesis of compound 14 refers to the synthesis procedure of compound 13 in Example 13, wherein 3-oxetanone is used instead of formaldehyde, and compound 14 is synthesized.
  • the synthesis of compound 15 refers to the synthesis procedure of compound 13 in Example 13, wherein tetrahydropyranone is used instead of formaldehyde to synthesize compound 15.
  • the synthesis of compound 16 refers to the synthesis steps of compound 13 in Example 13, wherein (S)-1-Boc-3-hydroxymethylpiperazine replaces (R)-1-Boc-3 used in the synthesis of intermediate 13A -Hydroxymethylpiperazine, compound 16 was synthesized.
  • the synthesis of compound 17 refers to the synthesis procedure of compound 13 in Example 13, wherein acetone is used instead of formaldehyde, and compound 17 is synthesized.
  • the synthesis of compound 21 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, trifluoromethyl ethanol is used instead of 20A, and compound 21 is synthesized.
  • the synthesis of compound 22 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, oxetane-3-methanol is used to replace 20A, and compound 22 is synthesized.
  • the synthesis of compound 23 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, 3-tetrahydrofuran methanol replaces 20A, and compound 23 is synthesized.
  • the synthesis of compound 24 refers to the synthesis steps of compound 20 in Example 20, wherein in the second step, bromoacetonitrile replaces 20B, and compound 24 is synthesized.
  • the synthesis of compound 26 refers to the synthesis procedure of compound 25 in Example 25, wherein in the sixth step, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine is used instead of 25H , compound 26 was synthesized.
  • the synthesis of compound 28 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (R)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 28.
  • the synthesis of compound 29 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (S)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 29.
  • the synthesis of compound 32 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methyl-3-azetidine carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 32.
  • the synthesis of compound 34 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-cyano-1-cyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 34.
  • the synthesis of compound 35 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, N-methyl-D-proline is used instead of 3-oxetane carboxylic acid to synthesize compound 35.
  • the synthesis of compound 36 refers to the synthesis steps of compound 30 in Example 30, wherein in the first step, methyl chloroformate is replaced by methylsulfonyl chloride, and compound 36 is synthesized.
  • the synthesis of compound 37 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 3-methoxypropionic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 37.
  • the synthesis of compound 38 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, pivalic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 38.
  • the synthesis of compound 39 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-fluorocyclopropane carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 39.
  • the synthesis of compound 40 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, methoxyacetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 40.
  • the synthesis of compound 41 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-(methoxymethyl)cyclopropylcarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 41.
  • the synthesis of compound 42 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, methylamine hydrochloride is used instead of dimethylamine hydrochloride to synthesize compound 42.
  • the synthesis of compound 43 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, ethylamine hydrochloride is used instead of dimethylamine hydrochloride to synthesize compound 43.
  • reaction solution was cooled to 0°C, methanol (2 mL) was added dropwise to the reaction solution, stirred until no bubbles were generated, and then ethyl acetate (100 mL) and saturated brine were added to the reaction solution (100 mL), the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL ⁇ 2), the organic phases were combined, dried, and spin-dried to give compound 44C (9.1 g, 22.4 mmol, pale yellow oil, yield 87.0 %).
  • the synthesis of compound 46 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (1S,2R)-2-fluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 46.
  • the synthesis of compound 47 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (1S,2S)-2-fluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 47.
  • the synthesis of compound 48 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2,2-difluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 48.
  • the synthesis of compound 49 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylcyclopropane-1-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 49.
  • the synthesis of compound 50 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2,2,3,3-tetramethylcyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 50.
  • the synthesis of compound 56 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2-oxetanecarboxylate is used instead of 3-oxetanecarboxylate to synthesize compound 56.
  • the synthesis of compound 57 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, cyclopropylamine is used instead of dimethylamine hydrochloride to synthesize compound 57.
  • the synthesis of compound 58 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, cyclopropanol is used instead of dimethylamine hydrochloride to synthesize compound 58.
  • the synthesis of compound 59 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, morpholine is used instead of dimethylamine hydrochloride to synthesize compound 59.
  • the synthesis of compound 60 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, tetrahydropyran-4-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 60.
  • the synthesis of compound 61 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylpiperidine-4-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 61.
  • the synthesis of compound 62 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, N-methylpiperazine is used instead of dimethylamine hydrochloride to synthesize compound 62.
  • the synthesis of compound 63 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylpyrazole-5-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 63.
  • the synthesis of compound 64 refers to the synthesis procedure of compound 27 in Example 27, wherein (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine is used in the second step Substitute (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, and in the fourth step, use cyclopropanecarboxylic acid instead of 3-oxetane carboxylic acid to synthesize Compound 64.
  • the synthesis of compound 65 refers to the synthesis procedure of compound 44 in Example 44, wherein the eighth step uses (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine In place of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, compound 65 was synthesized.
  • the synthesis of compound 68 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, (R)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 68.
  • the synthesis of compound 69 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, (S)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 69.
  • the synthesis of compound 70 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-cyano-1-cyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 70.
  • the synthesis of compound 71 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-methoxycyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 71.
  • the synthesis of compound 72 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, methyl chloroformate is used instead of dimethylamine hydrochloride to synthesize compound 72.
  • the synthesis of compound 73 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, azetidine-1-acetic acid hydrochloride is used instead of 3-oxetane carboxylic acid to synthesize compound 73.
  • the synthesis of compound 74 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, methoxyacetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 74.
  • the synthesis of compound 77 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 1-bromo-2-methoxyethane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 77.
  • the synthesis of compound 78 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, azetidine is used instead of dimethylamine hydrochloride to synthesize compound 78.
  • the synthesis of compound 79 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, nicotinic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 79.
  • the synthesis of compound 80 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, acetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 80.
  • the synthesis of compound 81 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, 3-azetidinol is used instead of dimethylamine hydrochloride to synthesize compound 81.
  • the synthesis of compound 82 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 3-iodooxetane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 82.
  • the synthesis of compound 84 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, ammonia gas is used instead of dimethylamine hydrochloride to synthesize compound 84.
  • the synthesis of compound 85 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-methylpyrazole-5-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 85.
  • the synthesis of compound 86 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 1-bromopropane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 86.
  • the synthesis of compound 87 refers to the synthesis procedure of compound 75 in Example 75, wherein in the first step, 3-(bromomethyl)oxetane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 87.
  • the synthesis of compound 88 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, pivalic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 88.
  • the synthesis of compound 89 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 2-bromo-1,1,1-trifluoroethane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 89.
  • the synthesis of compound 90 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, bromoacetonitrile is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 90.
  • the synthesis of compound 91 refers to the synthesis steps of compound 44 in Example 44, wherein acetic acid is used instead of cyclopropanecarboxylic acid in the sixth step, and (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methane is used in the eighth step) (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was synthesized to give compound 91.
  • the synthesis of compound 92 refers to the synthesis procedure of compound 44 in Example 44, wherein the eighth step uses (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro -2-Methylpropan-2-ol was substituted for (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, and compound 92 was synthesized.
  • This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12C.
  • Lower IC50 values indicate high potency of compounds as SOS1 inhibitors in the following assay setup.
  • KRAS(G12C) protein was synthesized by Pujian Biotechnology Co., Ltd.;
  • SOS1 protein exchange human recombinant domain protein (564-1049) was purchased from Cytoskeleton;
  • Anti-6-histidine-tagged monoclonal antibody XL665 (Mab Anti 6HIS-XL665) and anti-glutathione thioltransferase-tagged europium cryptate monoclonal antibody (Mab Anti GST-Eu cryptate) were purchased from Cisbio.
  • 1X buffer preparation Hepes: 5 mM; NaCl: 150 mM; EDTA: 10 mM; Igepal: 0.0025%; KF: 100 mM; DTT: 1 mM; BSA: 005%.
  • the compounds to be tested were diluted 3-fold to the 8th concentration, ie, from 100 ⁇ M to 45.7 nM, using a row gun.
  • a mixed working solution of KRAS(G12C) (200nM) and Mab Anti GST-Eu cryptate (1ng/ ⁇ L) was prepared with 1X buffer, and the mixed working solution was placed at 25°C for 5min, and 2.5 ⁇ L/well was added to the corresponding well.
  • the raw data is converted into inhibition rate, and the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • the inhibitory activity of compound 1 prepared by the present invention and KRAS-SOS1 inhibitor BI-3406 commonly used in the art on the binding of KRAS (G12C) to SOS1 is shown in Table 1, wherein + represents >1uM, ++ represents 100nM-1uM , +++ stands for 10nM-100nM, ++++ stands for ⁇ 10nM, ND stands for not tested.
  • the compounds of the present invention have a good inhibitory effect on SOS1, and have a significant inhibitory effect on the combination of KRAS(G12C) and SOS1, and the inhibitory effect of some compounds is less than 10nM, which has a good clinical application prospect.
  • DLD-1 cells were purchased from Wuhan Prosser Life Technology Co., Ltd.; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.
  • DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37 degrees overnight;
  • Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody were diluted 20-fold with Detection buffer;
  • the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived).
  • Table 2 shows the inhibitory activity of compound 1 prepared by the present invention and KRAS-SOS1 inhibitor BI-3406 commonly used in the art on DLD-1 cell phosphorylation.
  • mice Female, 6-8 weeks old, weighing 18-22 g, were provided by Beijing Weitong Lihua Technology Co., Ltd.
  • the MIA-PaCa2 tumor cells were resuspended in PBS to prepare a cell suspension with a density of 1 ⁇ 10 7 cells/mL, and 0.2 mL of the cell suspension was subcutaneously inoculated on the right back of each mouse (Add Matrigel, volume ratio of 1:1), waiting for tumor growth. Randomization was initiated when the mean tumor volume reached approximately 150 mm3 . After administration, tumor diameters were measured with a vernier caliper twice a week, and the tumor volume was calculated as follows:
  • V 0.5a ⁇ b 2 , where a and b represent the long and short diameters of the tumor, respectively.
  • TGI tumor growth inhibition rate
  • TGI(%) [(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-at the beginning of treatment in the solvent control group Mean tumor volume)] ⁇ 100%.
  • the compound of the present invention has a more significant tumor inhibitory effect compared with the positive control BI-3406, and the TGI can reach 80% at the highest, indicating that the compound of the present invention is effective in human pancreas.
  • the cancer MIA-PaCa2 subcutaneous xenograft tumor model showed good in vivo efficacy.

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Abstract

The present invention belongs to the field of pharmaceutical chemistry, and relates to a tetracyclic compound, a pharmaceutical composition thereof and use thereof. The compound is a tetracyclic compound as shown in formula I, or a pharmaceutically acceptable salt, a hydrate, a solvate, a stereoisomer, a tautomer, a metabolite or a prodrug thereof, wherein R1-R6 and L1, L2, L3, Z1, Z2, and X and Y groups are as defined in the description. The compound and the pharmaceutical composition comprising same in the present invention have good SOS1 inhibitory activity, and therefore can be used as an SOS1 inhibitor, and can be used for preparing drugs for treating and/or preventing diseases caused by overexpression of SOS1, such as cancer, thereby being applied in the field of medicines. The tetracyclic compound in the present invention exhibits excellent biological activity and druggability, and has great prospects for drug development.

Description

四并环化合物及其药物组合物和应用Tetracyclic compounds and their pharmaceutical compositions and applications 技术领域technical field
本发明属于药物化学领域，具体涉及一类四并环化合物、包含该类化合物的药物组合物及其在医药领域中的应用。The invention belongs to the field of medicinal chemistry, and specifically relates to a class of tetracyclic compounds, pharmaceutical compositions containing the compounds and their application in the field of medicine.
背景技术Background technique
从1982年末发现RAS家族GTP酶的(其包含的成员KRAS，NRAS，和HRAS)与癌症相关开始，在人类癌症中的发生率高达20％～30％。RAS蛋白充当分子开关，其在活性的GTP结合状态和无活性的GDP结合状态之间循环。由鸟嘌呤核苷酸交换因子(GEF)激活，其GTP结合状态的RAS与许多效应子相互作用。返回无活性状态由GTP酶激活蛋白(GAPs)驱动，其通过将弱的内在GTP酶活性加速至多5个数量级来下调活性RAS。Since the discovery in late 1982 of the RAS family GTPases (which include members KRAS, NRAS, and HRAS) associated with cancer, the incidence in human cancers is as high as 20% to 30%. RAS proteins act as molecular switches that cycle between an active GTP-bound state and an inactive GDP-bound state. Activated by the guanine nucleotide exchange factor (GEF), RAS in its GTP-bound state interacts with a number of effectors. The return to an inactive state is driven by GTPase activating proteins (GAPs), which downregulate active RAS by accelerating weak intrinsic GTPase activity by up to 5 orders of magnitude.
突变RAS蛋白是否需要GEF活性才能完全激活仍有待充分研究，并且可能因特定突变而异。研究最多的RAS sevenless son(SOS)的蛋白质，已知两种人类同种型SOS1和SOS2。试图通过抑制肽模拟与纳摩尔亲和力正位SOS螺旋识别烃装订肽的RAS-SOS相互作用，但仅具有低的细胞活性。基于片段的筛选，设计合理，和高通量筛选方法导致小分子寻址KRAS-SOS1相互作用的鉴定，得到的具有中等微摩尔亲和力。Whether mutant RAS proteins require GEF activity for full activation remains to be well studied and may vary with specific mutations. The most studied protein of RAS sevenless son (SOS), two human isoforms, SOS1 and SOS2, are known. Attempted to recognize RAS-SOS interactions of hydrocarbon-bound peptides by inhibiting peptide mimicry with nanomolar affinity orthotopic SOS helices, but with only low cellular activity. Fragment-based screening, rationally designed, and high-throughput screening methods led to the identification of small-molecule-addressed KRAS-SOS1 interactions, resulting in moderate micromolar affinities.
SOS1蛋白由1333个氨基酸(150kDa)组成。SOS1是一种多结构域蛋白，所述多结构域蛋白具有两个串联的N-末端组蛋白结构域(HD)，接着是Dbl同源结构域(DH)、普列克底物蛋白(Pleckstrin)同源结构域(PH)、螺旋接头(HL)、RAS交换基序(REM)、CDC25同源结构域和C末端富脯氨酸的结构域(PR)。SOS1具有两个针对RAS家族蛋白的结合位点；催化位点，所述催化位点结合GDP结合的RAS家族蛋白以促进鸟嘌呤核苷酸交换；变构位点，所述变构位点结合GTP结合的RAS家族蛋白，这导致SOS1的催化GEF功能进一步增加。公开数据表明SOS1关键参与在癌症中的突变KRAS活化和致癌信号传导中(Jeng等人,Nat.Commun.,2012,3:1168)。消耗SOS1水平会降低携带KRAS突变的肿瘤细胞的增殖率和存活，而在KRAS野生型细胞系中没有观察到作用。SOS1丧失的影响无法通过引入催化位点突变的SOS1弥补，证明了SOS1GEF活性在KRAS突变癌细胞中的重要作用。The SOS1 protein consists of 1333 amino acids (150 kDa). SOS1 is a multi-domain protein with two tandem N-terminal histone domains (HD) followed by Dbl homology domain (DH), Pleckstrin ) homeodomain (PH), helical linker (HL), RAS exchange motif (REM), CDC25 homeodomain and C-terminal proline-rich domain (PR). SOS1 has two binding sites for RAS family proteins; a catalytic site, which binds GDP-bound RAS family proteins to facilitate guanine nucleotide exchange; and an allosteric site, which binds GTP-bound RAS family protein, which leads to a further increase in the catalytic GEF function of SOS1. Published data suggest that SOS1 is critically involved in mutant KRAS activation and oncogenic signaling in cancer (Jeng et al., Nat. Commun., 2012, 3:1168). Depleting SOS1 levels reduced the proliferation rate and survival of KRAS-mutated tumor cells, whereas no effect was observed in KRAS wild-type cell lines. The effects of SOS1 loss could not be compensated by introducing catalytic site-mutated SOS1, demonstrating the important role of SOS1GEF activity in KRAS-mutant cancer cells.
SOS1通过除RAS家族蛋白突变之外的机制关键地参与在癌症中的RAS家族蛋白信号传导的激活中。SOS1与衔接蛋白Grb2相互作用，并且所得SOS1/Grb2复合物结合于激活 的/磷酸化的受体酪氨酸激酶(例如，EGFR、ErbB2、ErbB3、ErbB4、PDGFR-A/B、FGFR1/2/3、IGF1R、INSR、ALK、ROS、TrkA、TrkB、TrkC、RET、c-MET、VEGFR1/2/3、AXL)(Pierre等人,Biochem.Pharmacol.,2011,82(9):1049-56)。SOS1还被募集到其他磷酸化的细胞表面受体，诸如T细胞受体(TCR)、B细胞受体(BCR)和单核细胞集落刺激因子受体(Salojin等人,J.Biol.Chem.2000,275(8):5966-75)。SOS1到RAS家族蛋白近端的质膜上的这种定位使SOS1能够促进RAS家族蛋白激活。RAS家族蛋白的SOS1激活也可以通过SOS1/Grb2与慢性粒细胞白血病中常见的BCR-ABL癌蛋白的相互作用来介导。SOS1 is critically involved in the activation of RAS family protein signaling in cancer through mechanisms other than RAS family protein mutation. SOS1 interacts with the adaptor protein Grb2, and the resulting SOS1/Grb2 complex binds to activated/phosphorylated receptor tyrosine kinases (eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/ 3. IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL) (Pierre et al., Biochem. Pharmacol., 2011, 82(9): 1049-56 ). SOS1 is also recruited to other phosphorylated cell surface receptors, such as T cell receptor (TCR), B cell receptor (BCR), and monocyte colony-stimulating factor receptor (Salojin et al., J. Biol. Chem. 2000, 275(8):5966-75). This localization of SOS1 to the plasma membrane proximal to RAS family proteins enables SOS1 to promote RAS family protein activation. SOS1 activation by RAS family proteins can also be mediated through the interaction of SOS1/Grb2 with the BCR-ABL oncoprotein commonly found in chronic myeloid leukemia.
SOS1也是用于激活GTP酶RAC1(Ras相关的C3肉毒杆菌毒素底物1)的GEF(Innocenti等人,J.Cell Biol.,2002,156(1):125-36)。与RAS家族蛋白一样，RAC1牵涉在多种人类癌症和其他疾病的发病机理(Bid等人,Mol.Cancer Ther.2013,12(10):1925-34)中。SOS1 is also a GEF for activating the GTPases RAC1 (Ras-related C3 botulinum toxin substrate 1) (Innocenti et al., J. Cell Biol., 2002, 156(1):125-36). Like RAS family proteins, RAC1 has been implicated in the pathogenesis of various human cancers and other diseases (Bid et al., Mol. Cancer Ther. 2013, 12(10):1925-34).
在本文中，我们描述了新型SOS1抑制剂化合物，其与SOS1催化位点结合并且同时防止与RAS家族蛋白的相互作用及其激活。这导致对SOS1与RAS家族蛋白、特别是KRAS(具有低单位数纳摩尔IC50活性)的相互作用的显著抑制作用，并且因此显著降低KRAS突变体癌细胞系中的ERK磷酸化。Herein, we describe novel SOS1 inhibitor compounds that bind to the SOS1 catalytic site and simultaneously prevent interaction with and activation of RAS family proteins. This resulted in a marked inhibition of the interaction of SOS1 with RAS family proteins, especially KRAS (with low single-digit nanomolar IC50 activity), and thus markedly reduced ERK phosphorylation in KRAS mutant cancer cell lines.
预期本文所述的选择性SOS1抑制剂化合物为患有与对RAS家族蛋白信号传导依赖性相关的癌症的患者提供药理学益处。预期被SOS1抑制剂化合物靶向的此类癌症包括展现出在RAS家族蛋白途径中的组分(蛋白质、基因)的改变(突变、基因扩增、过表达)的那些，所述组分诸如KRAS、NRAS、HRAS、受体酪氨酸激酶(例如，EGFR、ErbB2、ErbB3、ErbB4、PDGFR-A/B、FGFR1/2/3、IGF1R、INSR、ALK、ROS、TrkA、TrkB、TrkC、RET、c-MET、VEGFR1/2/3、AXL)、GAP(例如，NF1)和SOS1。另外，鉴于SOS1在RAC1激活中的作用，表现出对RAC1依赖性的癌症预期被SOS1抑制剂化合物靶向。此外，在与RAS家族蛋白途径失调相关的其他疾病诸如神经纤维瘤病、努南综合征(NS)、心面皮肤综合征(CFC)和1型遗传性牙龈纤维瘤病中，预期SOS1抑制剂化合物也将提供药理学益处。The selective SOS1 inhibitor compounds described herein are expected to provide pharmacological benefit to patients with cancers associated with a dependency on RAS family protein signaling. Such cancers expected to be targeted by SOS1 inhibitor compounds include those that exhibit alterations (mutations, gene amplification, overexpression) in components (proteins, genes) in the RAS family protein pathway, such as KRAS , NRAS, HRAS, receptor tyrosine kinases (eg, EGFR, ErbB2, ErbB3, ErbB4, PDGFR-A/B, FGFR1/2/3, IGF1R, INSR, ALK, ROS, TrkA, TrkB, TrkC, RET, c-MET, VEGFR1/2/3, AXL), GAP (eg, NF1) and SOS1. Additionally, given the role of SOS1 in RAC1 activation, cancers that exhibit RAC1 dependence are expected to be targeted by SOS1 inhibitor compounds. Furthermore, SOS1 inhibitors are expected in other diseases associated with dysregulation of RAS family protein pathways such as neurofibromatosis, Noonan syndrome (NS), cardiofacial skin syndrome (CFC) and hereditary gingival fibromatosis type 1 Compounds will also provide pharmacological benefits.
除了抑制作用和效力之外，本文公开的化合物显示出良好的溶解性、优秀的DMPK特性和对人激酶组的激酶的良好选择性。In addition to inhibition and potency, the compounds disclosed herein show good solubility, excellent DMPK properties, and good selectivity for the kinases of the human kinome.
发明内容SUMMARY OF THE INVENTION
发明要解决的问题Invention to solve problem
本发明旨在提供一类结构新颖的用作SOS1抑制剂的四并环化合物，其表现出对肿瘤 细胞很好的抑制活性，且成药性好，具有广阔的药物开发前景。The present invention aims to provide a class of tetracyclic compounds with novel structures used as SOS1 inhibitors, which exhibit good inhibitory activity on tumor cells, have good druggability, and have broad prospects for drug development.
用于解决问题的方案solution to the problem
第一方面，本发明提供了一种如式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，其中In a first aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, wherein
Figure PCTCN2022070423-appb-000001
Figure PCTCN2022070423-appb-000001
其中，in,
A选自C 6-C 10芳基、5至6元单环杂芳基或9至10元二环杂芳基，且其中所述芳基、单环杂芳基和二环杂芳基各自任选地被m个独立的R 4取代,其中m独立地为0至5中的任一整数； A is selected from C 6 -C 10 aryl, 5- to 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, and wherein each of the aryl, monocyclic and bicyclic heteroaryl groups optionally substituted with m independent R 4 , wherein m is independently any integer from 0 to 5;
X和Y各自独立地选自CR 7或N； X and Y are each independently selected from CR or N;
Z 1和Z 2各自独立地选自-O-、-CR 7-或-NR 7-； Z 1 and Z 2 are each independently selected from -O-, -CR 7 - or -NR 7 -;
L 1、L 2和L 3各自独立地独立选自-(CH 2) n-或-(CH 2) n-O-(CH 2) p-O-(CH 2) o-或-O-(CH 2) q-，其中每一个n、o、p和q各自独立地为0至3中的任一整数； L 1 , L 2 and L 3 are each independently selected from -(CH 2 ) n - or -(CH 2 ) n -O-(CH 2 ) p -O-(CH 2 ) o - or -O-( CH 2 ) q -, wherein each of n, o, p and q is independently any integer from 0 to 3;
R 1和R 2各自独立地选自氢和C 1-C 8烷基；或者R 1和R 2与其所连接的碳原子共同形成C 3-C 6环烷基，所述烷基和环烷基各自任选地被至少1个R 8取代，R 1或R 2与A环形成4-8元饱和碳环或杂环； R 1 and R 2 are each independently selected from hydrogen and C 1 -C 8 alkyl; or R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, said alkyl and cycloalkane Each group is optionally substituted by at least 1 R 8 , and R 1 or R 2 and A ring form a 4-8 membered saturated carbocyclic or heterocyclic ring;
R 3选自氢、卤素、氰基、羟基、氨基、-NH(R 7)、-C(＝O)-NH(R 7)、C 1-C 6烷基、C 2-C 4烯基、C 2-C 4炔基、C 3-C 6环烷基、3至8元杂环烷基、C 1-C 3烷氧基和C 1-C 6卤代烷基，且其中所述烷基、烯基、炔基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R 7 ), -C(=O)-NH(R 7 ), C 1 -C 6 alkyl, C 2 -C 4 alkenyl , C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 1 -C 3 alkoxy and C 1 -C 6 haloalkyl, and wherein said alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl are each optionally substituted with at least 1 R 8 ;
R 4选自氢、卤素、氰基、羟基、氨基、-NH(R 7)、-C(＝O)-NH(R 7)、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环烷基、C 1-C 3烷氧基和C 1-C 6卤代烷基，所述烷基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 4 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R 7 ), -C(=O)-NH(R 7 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkane alkyl, 3- to 8-membered heterocycloalkyl, C 1 -C 3 alkoxy and C 1 -C 6 haloalkyl, each of the alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl being any optionally substituted with at least 1 R 8 ;
R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、-N(R 7)(R 8)、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环烷基、C 1-C 3烷氧基和C 1-C 6卤代烷基，或者R 7和R 8与其所连接的氮原子共同形成5至6元杂环烷基，且其中所述烷基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 10取代； R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N(R 7 )(R 8 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C1 - C3alkoxy, and C1 - C6 haloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, and wherein The alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1 R 10 ;
R 7各自独立地选自氢、卤素、氰基、羟基、氨基、-N(R 8)(R 9)、-C(＝O)-N(R 8)(R 9)、-C(＝O)-R 8、-C(＝O)-OR 8、-S(＝O) 2-R 8、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环烷基、5-10元芳基或杂芳基、C 1-C 3烷氧基或C 1-C 6卤代烷基，或者R 8和R 9与其所连接的氮原子共同形成5至6元杂环烷基，且其中所述烷基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 7 is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -N(R 8 )(R 9 ), -C(=O)-N(R 8 )(R 9 ), -C(= O)-R 8 , -C(=O)-OR 8 , -S(=O) 2 -R 8 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocycle Alkyl, 5-10-membered aryl or heteroaryl, C1 - C3 alkoxy or C1 - C6 haloalkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 5- to 6-membered heteroalkyl group cycloalkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, alkoxy, and haloalkyl are each optionally substituted with at least 1 R;
每一个R 8和R 9各自独立地选自氢、卤素、氰基、羟基、氨基、氨基甲酰基、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 8环烷基、3至14元杂环烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 6-C 10芳基、5至6元单环杂芳基或9至10元二环杂芳基，且其中所述烷基、杂烷基、环烷基、杂环烷基、烷氧基、卤代烷氧基、芳基、单环杂芳基和二环杂芳基各自任选地被至少1个R 10取代； Each of R 8 and R 9 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 ring Alkyl, 3- to 14-membered heterocycloalkyl, C1 - C3alkoxy, C1 - C3haloalkoxy , C6 -C10aryl, 5- to 6-membered monocyclic heteroaryl or 9- to 10 membered bicyclic heteroaryl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl and bicyclic heteroaryl each is optionally substituted with at least 1 R 10 ;
R 1至R 9中所述杂烷基、杂环烷基、杂环烷氧基、杂芳基中所含的杂原子或杂原子团分别独立地选自-C(＝O)N(R 10)-、-N(R 10)-、-NH-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-和-N(R 10)C(＝O)N(R 10)-，所述杂原子或杂原子团的数目分别独立地选自1、2和3； The heteroatoms or heteroatomic groups contained in the heteroalkyl groups, heterocycloalkyl groups, heterocycloalkoxy groups, and heteroaryl groups described in R 1 to R 9 are each independently selected from -C(=O)N(R 10 )-, -N(R 10 )-, -NH-, -N=, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S) -, -S(=O)-, -S(=O) 2 - and -N(R 10 )C(=O)N(R 10 )-, the number of said heteroatoms or heteroatoms is independently selected from 1, 2 and 3;
每一个R 10各自独立地选自氢、氯、氟、氰基、羟基、氨基、异丙基、环丙基、甲基、二氟甲基、三氟甲基、甲氧基、三氟甲氧基、乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基和苯基。 Each R 10 is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethyl oxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
优选地，其为如式I-1、I-2、I-3、I-4、I-5或I-6任一所示的化合物，Preferably, it is a compound represented by any one of formulae I-1, I-2, I-3, I-4, I-5 or I-6,
Figure PCTCN2022070423-appb-000002
Figure PCTCN2022070423-appb-000002
Figure PCTCN2022070423-appb-000003
Figure PCTCN2022070423-appb-000003
更优选地，其为如式I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1任一所示的化合物，More preferably, it is a compound represented by any one of formula I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1,
Figure PCTCN2022070423-appb-000004
Figure PCTCN2022070423-appb-000004
更优选地，本发明提供了如式I、式I-1、I-2、I-3、I-4、I-5、I-6、I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1所示的具体化合物，其为：More preferably, the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I - A specific compound shown in 3-1, I-4-1, I-5-1 or I-6-1, which is:
Figure PCTCN2022070423-appb-000005
Figure PCTCN2022070423-appb-000005
Figure PCTCN2022070423-appb-000006
Figure PCTCN2022070423-appb-000006
Figure PCTCN2022070423-appb-000007
Figure PCTCN2022070423-appb-000007
Figure PCTCN2022070423-appb-000008
Figure PCTCN2022070423-appb-000008
Figure PCTCN2022070423-appb-000009
Figure PCTCN2022070423-appb-000009
Figure PCTCN2022070423-appb-000010
Figure PCTCN2022070423-appb-000010
Figure PCTCN2022070423-appb-000011
Figure PCTCN2022070423-appb-000011
Figure PCTCN2022070423-appb-000012
Figure PCTCN2022070423-appb-000012
第二方面，本发明提供了一种药物组合物，其包含如式I、式I-1、I-2、I-3、I-4、I-5、I-6、I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药的一种或多种。In the second aspect, the present invention provides a pharmaceutical composition, which comprises formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1 , I-2-1, I-3-1, I-4-1, I-5-1 or I-6-1 The compound or its pharmaceutically acceptable salt, hydrate, solvate, stereo One or more of an isomer, tautomer, metabolite or prodrug.
优选地，所述药物组合物中还包含至少一种药学上可接受的辅料。Preferably, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
第三方面，本发明提供了如式I、式I-1、I-2、I-3、I-4、I-5、I-6、I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物在制备预防和/或治疗由SOS1过度表达引起的疾病的药物中的用途。In the third aspect, the present invention provides formulas such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I- - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof The use of a body, metabolite or prodrug or a pharmaceutical composition comprising the same in the manufacture of a medicament for the prevention and/or treatment of diseases caused by overexpression of SOS1.
第四方面，本发明提供了如式I、式I-1、I-2、I-3、I-4、I-5、I-6、I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物在制备SOS1抑制剂药物中的用途。In the fourth aspect, the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I- - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof The use of a body, a metabolite or a prodrug or a pharmaceutical composition comprising the same in the preparation of a SOS1 inhibitor medicament.
第五方面，本发明提供了如式I、式I-1、I-2、I-3、I-4、I-5、I-6、I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物在制备用于治疗和/或预防癌症药物中的应用。The fifth aspect, the present invention provides such as formula I, formula I-1, I-2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I - A compound represented by 3-1, I-4-1, I-5-1 or I-6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer or tautomer thereof Use of a medicament, metabolite or prodrug, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of cancer.
优选地，所述癌症为胰腺癌、结直肠癌和肺癌中的任一种或多种。Preferably, the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.
第六方面，本发明提供了一种用于预防和/或治疗由SOS1过度表达引起的疾病或病症的方法，其包括将预防和/或治疗有效量的如式I、式I-1、I-2、I-3、I-4、I-5、I-6、I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物施用于对其有需要的个体。In a sixth aspect, the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of SOS1, comprising preventing and/or treating an effective amount of such as formula I, formula I-1, I -2, I-3, I-4, I-5, I-6, I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I - The compound shown in 6-1 or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof or a pharmaceutical composition comprising the same is administered to individuals in need.
第七方面，本发明提供了一种用于预防和/或治疗由SOS1过度表达引起的疾病或病症的方法，其包括将预防和/或治疗有效量的如化合物1-化合物94共94个化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物施用于对其有需要的个体。In a seventh aspect, the present invention provides a method for preventing and/or treating a disease or condition caused by overexpression of SOS1, comprising adding a preventive and/or therapeutically effective amount of 94 compounds such as compound 1 to compound 94 in total or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or prodrug thereof, or a pharmaceutical composition comprising the same, to be administered to an individual in need thereof.
发明的效果effect of invention
本发明提供了一系列结构新颖的四并环化合物，经相关的酶和细胞活性试验证明，本发明的化合物具有优良的细胞增殖抑制活性，在体外实验中，对细胞增殖的IC 50值达到nM级别，可在多种肿瘤中获得良好的应用。同时，本发明的化合物对KRAS:SOS1激活具有非常好的抑制作用，可以达到nM级别，适于制备成SOS1抑制剂，用于预防和/或治疗与SOS1激活相关的疾病或病症，例如癌症(包括但不限于胰腺癌、结直肠癌和肺癌)。 The present invention provides a series of tetracyclic compounds with novel structures. It is proved by relevant enzyme and cell activity tests that the compounds of the present invention have excellent cell proliferation inhibitory activity. In vitro experiments, the IC 50 value of cell proliferation reaches nM It can be applied well in a variety of tumors. At the same time, the compounds of the present invention have very good inhibitory effect on KRAS:SOS1 activation, which can reach nM level, and are suitable for being prepared as SOS1 inhibitors for preventing and/or treating diseases or conditions related to SOS1 activation, such as cancer ( including but not limited to pancreatic cancer, colorectal cancer and lung cancer).
具体实施方式Detailed ways
一般术语和定义General terms and definitions
除非有相反陈述，否则在本发明中所使用的术语具有下述含义。Unless stated to the contrary, terms used in the present invention have the following meanings.
“烷基”是指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。在本发明中，“烷基”可以是一价、二价或三价基团。非限制性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基及其各种支链异构体等。非限制性实例还包括但不限于亚甲基、次甲基、亚乙基、次乙基、亚丙基、次丙基、亚丁基、次丁基及其各种支链异构体。另外，在本发明中，“烷基”可以是任选取代的或未取代的。"Alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 20 carbon atoms, for example, may be 1 to 18 carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms carbon atoms, straight and branched chain groups of 1 to 6 carbon atoms or 1 to 4 carbon atoms. In the present invention, "alkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl and various branched chain isomers, etc. Non-limiting examples also include, but are not limited to, methylene, methine, ethylene, ethylene, propylene, propylene, butylene, butylene, and various branched chain isomers thereof. In addition, in the present invention, "alkyl" may be optionally substituted or unsubstituted.
“烷氧基”是指“-O-烷基”基团，其中“烷基”的定义如上所述。"Alkoxy" refers to a "-O-alkyl" group, wherein "alkyl" is as defined above.
“烯基”是指不饱和的脂族烃基团，包括1至20个碳原子以及至少1个碳碳双键的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。在本发明中，“烯基”可以是一价、二价或三价基团。非限制性实例包括但不限于乙烯基(-CH＝CH 2)、丙烯-1-基(-CH＝CH-CH 3)、丙烯-2-基(-C(CH 3)＝CH 2)、丁烯-1-基(-CH＝CH-CH 2-CH 3)、丁烯-2-基(-C(C 2H 5)＝CH 2)、1-甲基丙烯-1-基(-C(CH 3)＝CH-CH 3)及其各种支链异构体等。非限制性实例还包括但不限于1,1-亚乙烯基(＝C＝CH 2)、1,2-亚乙烯基(-CH＝CH-)、1,1-亚丙烯基(＝C＝CH-CH 3)、1,2-亚丙烯基(-CH＝C(CH 3)-)、1,3-亚丙烯基(-CH＝CH-CH 2-)及其各种支链异构体。另外，在本发明中，“烯基”可以是任选取代的或未取代的。 "Alkenyl" refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 20 carbon atoms and at least 1 carbon-carbon double bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkenyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, vinyl (-CH=CH 2 ), propen-1-yl (-CH=CH-CH 3 ), propen-2-yl (-C(CH 3 )=CH 2 ), Buten-1-yl (-CH=CH-CH 2 -CH 3 ), buten-2-yl (-C(C 2 H 5 )=CH 2 ), 1-methylpropen-1-yl (- C(CH 3 )=CH-CH 3 ) and various branched chain isomers thereof. Non-limiting examples also include, but are not limited to, 1,1-ethenylene (=C=CH 2 ), 1,2-ethenylene (-CH=CH-), 1,1-propenylene (=C= CH-CH 3 ), 1,2-propenylene (-CH=C(CH 3 )-), 1,3-propenylene (-CH=CH-CH 2 -) and various branched isomers thereof body. In addition, in the present invention, "alkenyl" may be optionally substituted or unsubstituted.
“炔基”是指不饱和的脂族烃基团，包括1至20个碳原子以及至少1个碳碳叁键的直链和支链基团，例如可以是1至18个碳原子、1至12个碳原子、1至8个碳原子、1至6个碳原子或1至4个碳原子的直链和支链基团。在本发明中，“炔基”可以是一价、二价或三价基团。非限制性实例包括但不限于乙炔基(-C≡CH)、丙炔基(-C≡C-CH 3)、丁炔基
Figure PCTCN2022070423-appb-000013
戊炔基
Figure PCTCN2022070423-appb-000014
及其各种支链异构体等。非限制性实例还包括但不限于亚乙炔基(-C≡C-)、亚丙炔基
Figure PCTCN2022070423-appb-000015
亚丁炔基
Figure PCTCN2022070423-appb-000016
及其各种支链异构体。另外，在本发明中，“炔基”可以是任选取代的或未取代的。 "Alkynyl" refers to unsaturated aliphatic hydrocarbon groups, straight and branched chain groups comprising 1 to 20 carbon atoms and at least 1 carbon-carbon triple bond, for example, may be 1 to 18 carbon atoms, 1 to Straight and branched chain groups of 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In the present invention, "alkynyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡C- CH3 ), butynyl
Figure PCTCN2022070423-appb-000013
pentynyl
Figure PCTCN2022070423-appb-000014
and various branched chain isomers. Non-limiting examples also include, but are not limited to, ethynylene (-C≡C-), propynylene
Figure PCTCN2022070423-appb-000015
butynylene
Figure PCTCN2022070423-appb-000016
and its various branched-chain isomers. In addition, in the present invention, "alkynyl" may be optionally substituted or unsubstituted.
“杂烷基”是指饱和的脂族烃基团，包括2至20个原子的直链和支链基团，例如可以是2至18个原子、2至12个原子、2至8个原子、2至6个原子或2至4个原子的直链和支链基团，其中一个或多个原子为选自氮、氧或S(O) m(其中m为0、1或2)的杂原子，其余为碳。在本发明中，“杂烷基”可以是一价、二价或三价基团。非限制性实例包括但不限于甲氧甲基(2-氧杂丙基)、甲硫甲基(2-硫杂丙基)、甲氨甲基(2-氮杂丙基)及其各种支链异构体等。另外，在本发明中，“杂烷基”可以是任选取代的或未取代的。 "Heteroalkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 2 to 20 atoms, for example, may be 2 to 18 atoms, 2 to 12 atoms, 2 to 8 atoms, Linear and branched groups of 2 to 6 atoms or 2 to 4 atoms, wherein one or more atoms is a hetero group selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1 or 2) atoms, and the rest are carbon. In the present invention, "heteroalkyl" may be a monovalent, divalent or trivalent group. Non-limiting examples include, but are not limited to, methoxymethyl (2-oxapropyl), methylthiomethyl (2-thiapropyl), methylaminomethyl (2-azapropyl), and various Branched chain isomers, etc. In addition, in the present invention, "heteroalkyl" may be optionally substituted or unsubstituted.
“环烷基”是指饱和或部分不饱和的、单环或多环的脂族烃基团，包括3至12个环原子，例如可以是3至12个、3至10个或3至6个环原子(即3至6元环)。单环环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等。在本发明中，“环烷基”可以是任选取代的或未取代的。"Cycloalkyl" means a saturated or partially unsaturated, monocyclic or polycyclic, aliphatic hydrocarbon group comprising 3 to 12 ring atoms, eg, 3 to 12, 3 to 10, or 3 to 6 Ring atoms (ie, 3 to 6 membered rings). Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclopentyl Heptatrienyl, cyclooctyl, etc. In the present invention, "cycloalkyl" may be optionally substituted or unsubstituted.
“杂环烷基”是指饱和或部分不饱和的、单环或多环的脂族烃基团，包括3至20个环 原子，例如可以是3至16个、3至12个、3至10个或3至6个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m为0、1或2)的杂原子，其余环原子为碳。优选杂环烷基包括3至12个环原子，其中1至4个环原子是杂原子，更优选包括3至10个环原子，最优选包括5或6个环原子，其中1至4个，优选1至3个，更优选1至2个是杂原子。单环杂环烷基的非限制性实例包括但不限于吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基的非限制性实例包括但不限于螺环或桥环的杂环烷基。 "Heterocycloalkyl" refers to a saturated or partially unsaturated, monocyclic or polycyclic aliphatic hydrocarbon group comprising 3 to 20 ring atoms, for example, may be 3 to 16, 3 to 12, 3 to 10 or 3 to 6 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is 0, 1 or 2) and the remaining ring atoms are carbon. Preferred heterocycloalkyl groups comprise 3 to 12 ring atoms, of which 1 to 4 are heteroatoms, more preferably 3 to 10 ring atoms, and most preferably 5 or 6 ring atoms, of which 1 to 4, Preferably 1 to 3, more preferably 1 to 2 are heteroatoms. Non-limiting examples of monocyclic heterocycloalkyl include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Non-limiting examples of polycyclic heterocycloalkyl groups include, but are not limited to, spirocyclic or bridged ring heterocycloalkyl groups.
“卤素”是指氟、氯、溴和碘，优选氟、氯和溴。"Halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
“卤代烷基”或“卤代烷氧基”是指烷基或烷氧基基团被一个或多个相同或不同的卤素原子所取代，优选的烷基或烷氧基的实例包括但不限于：三氟甲基、三氟乙基、三氟甲氧基。"Haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more identical or different halogen atoms. Examples of preferred alkyl or alkoxy groups include, but are not limited to: tris Fluoromethyl, trifluoroethyl, trifluoromethoxy.
“氰基”是指“-CN”基团。"Cyano" refers to the "-CN" group.
“羟基”是指“-OH”基团。"Hydroxy" refers to the "-OH" group.
“氨基”是指“-NH 2”基团。 "Amino" refers to the " -NH2 " group.
“氨基甲酰基”是指“-(C＝O)-NH 2”基团。 "Carbamoyl" refers to a "-(C=O) -NH2 " group.
“芳基”是指含有6-14个环原子的单环、双环和三环的碳环体系、其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。实例包括但不限于：苯基、萘基、蒽等。优选地，所述芳基为6-10个或6-7个环原子的碳环体系。"Aryl" means monocyclic, bicyclic, and tricyclic carbocyclic ring systems containing 6-14 ring atoms, wherein at least one ring system is aromatic, wherein each ring system contains 3-7 atoms A loop with one or more points of attachment to the rest of the molecule. Examples include, but are not limited to: phenyl, naphthyl, anthracene, and the like. Preferably, the aryl group is a carbocyclic ring system of 6-10 or 6-7 ring atoms.
“杂芳基”是指含有5-14个环原子的单环、双环和三环体系，其中，至少一个环体系是芳香族的，且至少一个环体系包含一个或多个选自氮、氧、硫的杂原子，其中每一个环体系包含5-7个原子组成的环，且有一个或多个连接点与分子的其余部分相连。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。实例包括但不限于：呋喃基、咪唑基、2-吡啶基、3吡啶基、噻唑基、嘌呤基、喹啉基。优选地，所述杂芳基为5-10个环原子的环体系。"Heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more selected from nitrogen, oxygen , Sulfur heteroatoms, where each ring system contains a ring of 5-7 atoms with one or more points of attachment to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic". Examples include, but are not limited to: furyl, imidazolyl, 2-pyridyl, 3-pyridyl, thiazolyl, purinyl, quinolinyl. Preferably, the heteroaryl group is a ring system of 5-10 ring atoms.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的情形。例如，“任选被烷基取代的杂环基团”意味着烷基可以但并非必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not be, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
“取代的”是指基团中的一个或多个氢原子，优选最多5个，更优选1至3个氢原子 彼此独立地被相应数目的取代基取代。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of one another, are substituted with a corresponding number of substituents.
“药学上可接受的盐”是指由本发明中的化合物与相对无毒的酸或碱制备得到的盐。当本发明中的化合物含有相对偏酸性的官能团(例如羧基或磺酸基)时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与其游离形式接触的方式获得碱加成盐。药学上可接受的碱加成盐的非限制性实例包括但不限于钠盐、钾盐、铵盐、钙盐、镁盐、有机胺盐或类似的盐。当本发明中的化合物含有相对偏碱性的官能团(例如氨基或胍基)时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与其游离形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的非限制性实例包括但不限于无机酸盐(例如盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸盐、碳酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、亚磷酸盐、硫酸盐、硫酸氢盐等)、有机酸盐(例如乙酸盐、丙酸盐、异丁酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、马来酸盐、富马酸盐、柠檬酸盐、酒石酸盐、乳酸盐、扁桃酸盐、苯甲酸盐、邻苯二甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、葡糖醛酸等)以及氨基酸盐(例如精氨酸盐等)。药学上可接受的盐的具体形式还可参见Berge et al.,“Pharmaceutical Salts”,Journal of Pharmaceutical Science,1977,66:1-19)。本发明的某些特定化合物含有碱性和酸性的官能团，从而可以被转换成任一碱加成盐或酸加成盐。优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。根据本发明的实施例，优选如式I所示的化合物的药学上可接受的盐为酸加成盐，优选盐酸盐、氢溴酸盐、磷酸盐或硫酸盐，更优选盐酸盐。"Pharmaceutically acceptable salts" refers to salts prepared from compounds of the present invention with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups (such as carboxyl or sulfonic acid groups), base addition salts can be obtained by contacting their free forms with a sufficient amount of base in neat solution or in a suitable inert solvent . Non-limiting examples of pharmaceutically acceptable base addition salts include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, organic amine, or similar salts. When the compounds of the present invention contain relatively basic functional groups such as amino or guanidino groups, acid addition salts can be obtained by contacting their free forms with a sufficient amount of acid in neat solution or in a suitable inert solvent . Non-limiting examples of pharmaceutically acceptable acid addition salts include, but are not limited to, inorganic acid salts (eg, hydrochloride, hydrobromide, hydroiodide, nitrate, carbonate, bicarbonate, phosphate) , monohydrogen phosphate, dihydrogen phosphate, phosphite, sulfate, hydrogen sulfate, etc.), organic acid salts (such as acetate, propionate, isobutyrate, malonate, succinate , Suberate, Maleate, Fumarate, Citrate, Tartrate, Lactate, Mandelate, Benzoate, Phthalate, Mesylate, Benzene Sulfonate acid salts, p-toluenesulfonic acid salts, glucuronic acid, etc.) and amino acid salts (eg, arginine salts, etc.). See also Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66: 1-19) for specific forms of pharmaceutically acceptable salts. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts. Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of a compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents. According to embodiments of the present invention, preferably the pharmaceutically acceptable salt of the compound represented by formula I is an acid addition salt, preferably hydrochloride, hydrobromide, phosphate or sulfate, more preferably hydrochloride.
“药物组合物”是指可供药用的组合物，其包含一种或多种如式I所示的化合物或其药学上可接受的形式(例如盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物、前药等)，以及其他组分(例如药学上可接受的辅料)。"Pharmaceutical composition" refers to a pharmaceutically acceptable composition comprising one or more compounds of Formula I or a pharmaceutically acceptable form thereof (eg, a salt, hydrate, solvate, stereoisomer isomers, tautomers, metabolites, prodrugs, etc.), and other components (eg, pharmaceutically acceptable excipients).
在本发明中，“药学上可接受的辅料”是指在药物生产领域中广泛采用的辅助物料。使用辅料的主要目的在于提供一种使用安全、性质稳定和/或具有特定功能性的药物组合物，还在于提供一种方法，以便在为受试者施用药物之后，活性成分能够以所期望的速率溶出，或者促进活性成分在接受给药的受试者体内得到有效吸收。药学上可接受的辅料可以是具有惰性的填充剂，也可以是为药用组合物提供某种功能(例如稳定组合物的整体pH值或防止组合物中活性成分的降解)的功效成分。药学上可接受的辅料的非限制性实例包括但不限于粘合剂、助悬剂、乳化剂、稀释剂(或填充剂)、成粒剂、胶粘剂、崩解 剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂、甜味剂等。In the present invention, "pharmaceutically acceptable auxiliary materials" refer to auxiliary materials widely used in the field of pharmaceutical production. The main purpose of using excipients is to provide a pharmaceutical composition that is safe to use, stable in properties and/or has specific functionality, and also to provide a method so that after the drug is administered to a subject, the active ingredient can be The rate of dissolution, or the promotion of effective absorption of the active ingredient in the subject to which it is administered. Pharmaceutically acceptable excipients can be inert fillers or functional ingredients that provide a certain function for the pharmaceutical composition (eg, stabilizing the overall pH of the composition or preventing the degradation of active ingredients in the composition). Non-limiting examples of pharmaceutically acceptable adjuvants include, but are not limited to, binders, suspending agents, emulsifiers, diluents (or fillers), granulating agents, sizing agents, disintegrating agents, lubricants, anti-adhering agents , glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavors, sweeteners, etc.
本发明中的药物组合物可以使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋和/或冻干工艺。The pharmaceutical compositions of the present invention can be prepared using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, attenuating, encapsulating, entrapping and/or lyophilizing processes.
在本发明中，使用药物组合物的目的在于促进针对生物体的给药，有利于活性成分的吸收，进而发挥生物活性。本发明的药物组合物可以通过任何形式给药，包括注射(动脉内、静脉内、肌肉内、腹膜内、皮下)、粘膜、口服(口服固体制剂、口服液体制剂)、直肠、吸入、植入、局部(例如眼部)给药等。口服固体制剂的非限制性实例包括但不限于散剂、胶囊剂、锭剂、颗粒剂、片剂等。口服或粘膜给药的液体制剂的非限制性实例包括但不限于混悬剂、酊剂、酏剂、溶液剂等。局部给药制剂的非限制性实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药制剂的非限制性实例包括但不限于注射用溶液剂、注射用干粉剂、注射用悬浮液、注射用乳剂等。本发明的药物组合物还可以制成控制释放或延迟释放剂型(例如脂质体或微球)。In the present invention, the purpose of using the pharmaceutical composition is to promote the administration to the living body, facilitate the absorption of the active ingredient, and then exert biological activity. The pharmaceutical compositions of the present invention can be administered in any form, including injection (intraarterial, intravenous, intramuscular, intraperitoneal, subcutaneous), mucosal, oral (oral solid, oral liquid), rectal, inhalation, implant , topical (eg ocular) administration, etc. Non-limiting examples of oral solid formulations include, but are not limited to, powders, capsules, lozenges, granules, tablets, and the like. Non-limiting examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, tinctures, elixirs, solutions, and the like. Non-limiting examples of formulations for topical administration include, but are not limited to, creams, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Non-limiting examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry powders for injection, suspensions for injection, emulsions for injection, and the like. The pharmaceutical compositions of the present invention can also be formulated in controlled release or delayed release dosage forms (eg, liposomes or microspheres).
优选地，本发明中的化合物或包含其的药物组合物以口服或静脉内给药的方式施用于对其有需要的个体。取决于给药对象的具体情况，也可以应用甚至优选其它施用途经。例如，对于健忘或对口服药物易发怒的患者，经皮施用将是非常重要的给药方式。在本发明中，施用途经能够以任何适用的方式进行变化或调整，以满足药物的性质、患者和医务人员的便利以及其它相关因素的需求。Preferably, a compound of the present invention or a pharmaceutical composition comprising the same is administered orally or intravenously to an individual in need thereof. Depending on the particular circumstances of the subject being administered, other modes of administration may also be employed or even preferred. For example, for patients who are forgetful or irritable with oral medications, transdermal administration would be a very important mode of administration. In the present invention, the administration channel can be varied or adjusted in any suitable manner to meet the needs of the nature of the drug, the convenience of the patient and medical staff, and other relevant factors.
本发明的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药或者包含其的药物组合物具有优良的SOS1酶活性及细胞增殖抑制活性，能够作为SOS1抑制剂，用于预防和/或治疗由SOS1过度表达引起的疾病或病症，具有良好的临床应用和医药用途。优选地，由SOS1过度表达引起的疾病或病症的非限制性实例为癌症，包括但不限于胰腺癌、结直肠癌和肺癌。The compounds of the present invention or their pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, tautomers, metabolites or prodrugs or pharmaceutical compositions containing them have excellent SOS1 enzyme activity and cellular The proliferation inhibitory activity can be used as an SOS1 inhibitor for preventing and/or treating diseases or conditions caused by overexpression of SOS1, and has good clinical and medical applications. Preferably, a non-limiting example of a disease or disorder caused by overexpression of SOS1 is cancer, including but not limited to pancreatic cancer, colorectal cancer and lung cancer.
以下将结合具体实施例来阐述本发明的技术方案，下列实施例的提供旨在进一步说明本发明，而非用于限制本发明的范围。对本领域技术人员而言，在不脱离本发明的精神和范围的情况下，针对本发明的具体实施方式进行各种变化和改进将是显而易见的。The technical solutions of the present invention will be described below with reference to specific embodiments. The following embodiments are provided to further illustrate the present invention, but not to limit the scope of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present invention without departing from the spirit and scope of the invention.
本发明的化合物的制备可以通过本领域技术人员所熟知的合成方法来实现，包括但不限于下面列举的具体实施方式、其与其他化学合成方法相结合而形成的实施方式以及 本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。本发明中所使用的已知的起始原料可以提供本领域已知的方法来合成，或者通过常规的商业手段来购买(例如购自韶远化学科技、北京偶合科技等公司)。如无特殊说明，反应均在氩气氛或氮气氛下进行。氢化反应通常抽真空，充入氢气，反复操作3次。反应的温度为室温，温度范围是20℃-30℃。反应进程的监测可以通过本领域技术人员所熟知的合成方法来实现，包括但不限于薄层色谱法(TLC)。薄层层析硅胶板使用青岛海洋GF254硅胶板，展开剂体系包括但不限于A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比可以根据化合物的极性进行调节。The preparation of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention. The known starting materials used in the present invention can be synthesized by methods known in the art, or purchased by conventional commercial means (for example, purchased from Shaoyuan Chemical Technology, Beijing Coupling Technology, etc.). Unless otherwise specified, the reactions were carried out in an argon atmosphere or a nitrogen atmosphere. The hydrogenation reaction is usually evacuated and filled with hydrogen, and the operation is repeated 3 times. The reaction temperature is room temperature, and the temperature range is 20°C-30°C. Monitoring the progress of the reaction can be accomplished by synthetic methods well known to those skilled in the art, including but not limited to thin layer chromatography (TLC). The thin layer chromatography silica gel plate uses Qingdao Ocean GF254 silica gel plate. The developing solvent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system. The volume ratio of the solvent can be determined according to the polarity of the compound. adjust.
本发明的化合物的分离纯化可以通过本领域技术人员所熟知的合成方法来实现，包括但不限于柱色谱法(CC)、高效液相色谱法(HPLC)、超高效液相色谱法(UPLC)等。柱色谱法一般使用青岛海洋200-300目硅胶作为载体，洗脱剂体系包括但不限于A：二氯甲烷和甲醇体系；B：石油醚和乙酸乙酯体系，溶剂的体积比可以根据化合物的极性进行调节，也可以加入少量的酸性或碱性防拖尾试剂进行调节。HPLC图谱采用Agilent1200DAD HPLC色谱仪(色谱柱：Sunfire C18,150×4.6mm,5μm)或Waters 2695-2996 HPLC色谱仪(色谱柱：Gimini C18,150×4.6mm,5μm)测定。The separation and purification of the compounds of the present invention can be achieved by synthetic methods well known to those skilled in the art, including but not limited to column chromatography (CC), high performance liquid chromatography (HPLC), ultra-high performance liquid chromatography (UPLC) Wait. Column chromatography generally uses Qingdao Ocean 200-300 mesh silica gel as the carrier, and the eluent system includes but is not limited to A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent can be based on the compound. The polarity can be adjusted, and a small amount of acidic or basic anti-tailing reagents can also be added for adjustment. The HPLC chromatogram was determined by Agilent1200DAD HPLC chromatograph (chromatographic column: Sunfire C18, 150×4.6mm, 5μm) or Waters 2695-2996 HPLC chromatograph (chromatographic column: Gimini C18, 150×4.6mm, 5μm).
本发明的化合物的结构鉴定可以通过本领域技术人员所熟知的方法来实现，包括但不限于核磁共振(NMR)、质谱(MS)等。NMR图谱采用Bruker AVANCE-400或Varian Oxford-300核磁仪测定，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDC1 3)或氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)，化学位移以10 -6(ppm)计。MS图谱采用Agilent SQD(ESI)质谱仪(型号：6110)或Shimadzu SQD(ESI)质谱仪(型号：2020)测定。 Structural identification of the compounds of the present invention can be accomplished by methods well known to those skilled in the art, including but not limited to nuclear magnetic resonance (NMR), mass spectrometry (MS), and the like. The NMR spectrum was determined by Bruker AVANCE-400 or Varian Oxford-300 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ) or deuterated methanol (CD 3 OD), The internal standard is tetramethylsilane (TMS), and the chemical shifts are in 10-6 (ppm). MS spectra were determined using an Agilent SQD (ESI) mass spectrometer (model: 6110) or a Shimadzu SQD (ESI) mass spectrometer (model: 2020).
中间体的制备Preparation of intermediates
中间体INT-1的制备Preparation of intermediate INT-1
Figure PCTCN2022070423-appb-000017
Figure PCTCN2022070423-appb-000017
第一步：合成化合物INT-1BStep 1: Synthesis of compound INT-1B
将化合物INT-1A(25g,107mmol)溶于THF(250mL)中，室温下加入叔丁基亚磺 酰胺(19.5g,161mmol)，然后加入钛酸四乙酯(61g,267.5mmol)。加完后，将反应液升温到70℃，反应4h。TLC显示反应结束后，将反应液冷却至室温，将反应液缓慢加入到冰水中，水相用乙酸乙酯萃取(3×150mL)。有机相合并后，用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1(体积比))，得到化合物INT-1B(27.7g，淡黄色固体，产率77％)。Compound INT-1A (25 g, 107 mmol) was dissolved in THF (250 mL), tert-butylsulfinamide (19.5 g, 161 mmol) was added at room temperature, followed by tetraethyl titanate (61 g, 267.5 mmol). After the addition, the temperature of the reaction solution was raised to 70°C, and the reaction was carried out for 4h. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, the reaction solution was slowly added to ice water, and the aqueous phase was extracted with ethyl acetate (3×150 mL). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered to remove the drying agent, and desolvated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 (volume ratio)) , to obtain compound INT-1B (27.7 g, pale yellow solid, yield 77%).
MS(ESI):m/z 337[M+1] +。 MS(ESI): m/z 337[M+1] + .
第二步：合成化合物INT-1CStep 2: Synthesis of compound INT-1C
将化合物INT-1B(27g,80mmol)溶于甲醇(200mL)和水(100mL)的混合溶剂中，冷却到-20℃，然后分批加入硼氢化钠(6g,160mmol)，保持-20℃反应1h后，自然升温到室温，室温下继续反应3h。TLC显示反应结束后，减压蒸除甲醇，水相用乙酸乙酯萃取(3×150mL)。有机相合并后，用无水硫酸钠干燥，过滤除去干燥剂，减压脱溶，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1(体积比))，得到化合物INT-1C(22g，淡黄色固体，产率82％)。Compound INT-1B (27 g, 80 mmol) was dissolved in a mixed solvent of methanol (200 mL) and water (100 mL), cooled to -20 °C, then sodium borohydride (6 g, 160 mmol) was added in batches, and the reaction was maintained at -20 °C After 1 h, the temperature was naturally raised to room temperature, and the reaction was continued for 3 h at room temperature. After TLC showed that the reaction was complete, methanol was evaporated under reduced pressure, and the aqueous phase was extracted with ethyl acetate (3 x 150 mL). After the organic phases were combined, they were dried over anhydrous sodium sulfate, filtered to remove the desiccant, desolvated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1 (volume ratio)) , to obtain compound INT-1C (22 g, pale yellow solid, yield 82%).
MS(ESI):m/z 339[M+1] +。 MS(ESI): m/z 339[M+1] + .
第三步：合成化合物INT-1Step 3: Synthesis of compound INT-1
将化合物INT-1C(20g,59mmol)加入到4N HCl-乙酸乙酯溶液(200mL)中，室温反应2h。TLC显示反应结束后，析出固体，过滤，固体再用乙酸乙酯洗涤，干燥，得到化合物INT-1的盐酸盐(12.3g，淡黄色固体，产率89％)。产品无需纯化，直接用于后续反应。Compound INT-1C (20 g, 59 mmol) was added to 4N HCl-ethyl acetate solution (200 mL), and the reaction was carried out at room temperature for 2 h. TLC showed that after the completion of the reaction, a solid was precipitated, which was filtered, and the solid was washed with ethyl acetate and dried to obtain the hydrochloride salt of compound INT-1 (12.3 g, pale yellow solid, yield 89%). The product did not need to be purified and was directly used in the subsequent reaction.
MS(ESI):m/z 235[M+1] +。 MS(ESI): m/z 235[M+1] + .
中间体INT-2的制备Preparation of intermediate INT-2
Figure PCTCN2022070423-appb-000018
Figure PCTCN2022070423-appb-000018
中间体INT-2的合成参考中间体INT-1的制备的合成步骤，其中第一步用S-叔丁基亚磺酰胺代替叔丁基亚磺酰胺，合成得到化合物中间体INT-2。The synthesis of intermediate INT-2 refers to the synthesis steps for the preparation of intermediate INT-1, wherein in the first step, S-tert-butylsulfinamide is used instead of tert-butylsulfinamide to synthesize compound intermediate INT-2.
MS(ESI):m/z 235[M+1] +。 MS(ESI): m/z 235[M+1] + .
目标化合物的制备和功能验证Preparation and functional verification of target compounds
实施例1：化合物1的制备Example 1: Preparation of Compound 1
Figure PCTCN2022070423-appb-000019
Figure PCTCN2022070423-appb-000019
化合物1的合成路线为：The synthetic route of compound 1 is:
Figure PCTCN2022070423-appb-000020
Figure PCTCN2022070423-appb-000020
化合物1的具体制备方法包括：The specific preparation method of compound 1 includes:
第一步：合成化合物1CStep 1: Synthesis of Compound 1C
将化合物1A(4g,18.4mmol)和DIPEA(4.8g，36.8mmol)溶于DMF(40mL)中，冰浴下加入化合物1B 1-Boc-3-羟甲基哌嗪(4g,18.4mmol)，然后将反应液80度反应1小时。TLC显示反应结束后，将反应液过滤，滤液旋干后，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1(体积比))，得到化合物1C(5.4g，黄色油状物，产率71％)。Compound 1A (4 g, 18.4 mmol) and DIPEA (4.8 g, 36.8 mmol) were dissolved in DMF (40 mL), and compound 1B 1-Boc-3-hydroxymethylpiperazine (4 g, 18.4 mmol) was added under ice bath, The reaction solution was then reacted at 80 degrees for 1 hour. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1 (volume ratio)) to obtain compound 1C (5.4 g, yellow oil, 71% yield).
MS(ESI):m/z 414[M+1] +。 MS(ESI): m/z 414[M+1] + .
第二步：合成化合物1DStep 2: Synthesis of Compound 1D
将化合物1C(4.4g,10.6mmol)溶于DMF(40mL)中，冰浴下加入NaH(0.43g,12.7mmol)，升温到30℃反应1h。TLC显示反应结束后，倒入冰水淬灭，用乙酸乙酯萃取，盐水洗，用无水硫酸钠干燥有机相，旋干得到化合物1D(4g，黄色油状物，产率95％)。Compound 1C (4.4 g, 10.6 mmol) was dissolved in DMF (40 mL), NaH (0.43 g, 12.7 mmol) was added under ice bath, and the temperature was raised to 30° C. to react for 1 h. After TLC showed that the reaction was completed, pour into ice water to quench, extract with ethyl acetate, wash with brine, dry the organic phase with anhydrous sodium sulfate, and spin dry to obtain compound 1D (4 g, yellow oil, yield 95%).
MS(ESI):m/z 394[M+1] +。 MS(ESI): m/z 394[M+1] + .
第三步：合成化合物1EStep 3: Synthesis of Compound 1E
将化合物1D(1g,2.5mmol)加入到EA(10mL)中，冰浴下滴加8％HCl-EA(10mL)，室温反应12h。TLC显示反应结束后，旋干反应液得到化合物1E(0.7g，黄色固体，产率94％)。Compound 1D (1 g, 2.5 mmol) was added to EA (10 mL), 8% HCl-EA (10 mL) was added dropwise under ice bath, and the reaction was carried out at room temperature for 12 h. After TLC showed that the reaction was completed, the reaction solution was spin-dried to obtain compound 1E (0.7 g, yellow solid, yield 94%).
MS(ESI):m/z 294[M+1] +。 MS(ESI): m/z 294[M+1] + .
第四步：合成化合物1FStep 4: Synthesis of Compound 1F
将化合物1E(700mg,2.4mmol)加入到DCM(8mL)中，然后加入TEA(735mg,7.2mmol)和Ac2O(290mg,2.9mmol)，反应液室温反应20mins。TLC显示反应结束后，将反应液减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1(体积比))，得到化合物1F(750mg，淡黄色固体，产率93％)。Compound 1E (700 mg, 2.4 mmol) was added to DCM (8 mL), then TEA (735 mg, 7.2 mmol) and Ac2O (290 mg, 2.9 mmol) were added, and the reaction solution was reacted at room temperature for 20 mins. After TLC showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:1 (volume ratio)) to obtain compound 1F (750 mg, pale yellow) solid, 93% yield).
MS(ESI):m/z 336[M+1] +。 MS(ESI): m/z 336[M+1] + .
第五步：合成化合物1GStep 5: Synthesis of Compound 1G
室温下，将化合物1F(750mg,2.2mmol)加入到甲醇(8mL)中，然后加入质量分数为10％的钯碳(100mg)。加完后，瓶口套上氢气球，置换三次气体后，保持氢气氛围室温反应12h。TLC显示反应结束后，过滤，固体用甲醇洗涤，收集滤液，减压蒸除溶剂，得到化合物1G(600mg，灰色固体，产率88％)。At room temperature, compound 1F (750 mg, 2.2 mmol) was added to methanol (8 mL), and then 10% palladium on carbon (100 mg) was added. After the addition, the bottle mouth was covered with a hydrogen balloon, and after the gas was replaced three times, the reaction was maintained at room temperature for 12 hours in a hydrogen atmosphere. TLC showed that the reaction was completed, filtered, the solid was washed with methanol, the filtrate was collected, and the solvent was evaporated under reduced pressure to obtain compound 1G (600 mg, gray solid, yield 88%).
MS(ESI):m/z 306[M+1] +。 MS(ESI): m/z 306[M+1] + .
第六步：合成化合物1HStep 6: Synthesis of Compound 1H
室温下将化合物1G(500mg,1.6mmol)加入到含有乙腈(5mL)的闷罐中，然后加入质量分数为8％的HCl-EA(5mL)。然后加热到100度反应16h。TLC显示反应结束后，过滤，固体用EA洗涤，收集固体得到化合物1H(500mg，灰色固体，产率98％)。Compound 1G (500 mg, 1.6 mmol) was added to a stuffy tank containing acetonitrile (5 mL) at room temperature, and then 8% HCl-EA (5 mL) was added. Then heated to 100 degrees and reacted for 16h. After TLC showed that the reaction was complete, it was filtered, the solid was washed with EA, and the solid was collected to give compound 1H (500 mg, grey solid, 98% yield).
MS(ESI):m/z 273[M+1] +。 MS(ESI): m/z 273[M+1] + .
第七步：合成化合物1IStep 7: Synthesis of Compound 1I
室温下将化合物1H(550mg,2.2mmol)加入到DCM(6mL)中，然后加入TEA(400mg,6.6mmol)和Ac2O(150mg,2.6mmol)，反应液室温反应12h。TLC显示反应结束后，将反应液减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:2(体积比))得到化合物1I(400mg，淡黄色固体，产率63％)。Compound 1H (550 mg, 2.2 mmol) was added to DCM (6 mL) at room temperature, then TEA (400 mg, 6.6 mmol) and Ac2O (150 mg, 2.6 mmol) were added, and the reaction solution was reacted at room temperature for 12 h. After TLC showed that the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1:2 (volume ratio)) to obtain compound 1I (400 mg, pale yellow solid) , the yield is 63%).
MS(ESI):m/z 315[M+1] +。 MS(ESI): m/z 315[M+1] + .
第八步：合成化合物1JStep 8: Synthesis of Compound 1J
室温下将化合物1I(100mg,0.3mmol)加入到DMF(2mL)中，然后加入INT-1(120mg,0.34mmol)和DBU(150mg，0.9mmol)。然后加热到60度反应16h。TLC显示反应结束后，乙酸乙酯稀释反应液，水萃取，盐水洗，用无水硫酸钠干燥有机相，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝0:1(体积比))得到化合物1J(40mg，淡黄色固体，产率34％)。Compound II (100 mg, 0.3 mmol) was added to DMF (2 mL) at room temperature, followed by INT-1 (120 mg, 0.34 mmol) and DBU (150 mg, 0.9 mmol). Then heated to 60 degrees and reacted for 16h. After TLC showed that the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted with water, washed with brine, the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=0: 1 (volume ratio)) to obtain compound 1J (40 mg, pale yellow solid, 34% yield).
MS(ESI):m/z 531[M+1] +。 MS(ESI): m/z 531[M+1] + .
第九步：合成化合物1Step 9: Synthesis of Compound 1
室温下将化合物1J(40mg,0.07mmol)加入到EtOH(6mL)和水(1mL)中，然后加入铁粉(25mg,2.8mmol)和氯化铵(30mg，5.6mmol)。然后加热到80度反应2h。TLC显示反应结束后，乙酸乙酯稀释反应液，水萃取，盐水洗，用无水硫酸钠干燥有机相，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝0:1(体积比))，反相HPLC制备(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物1(7mg，淡黄色固体，产率19％)。Compound 1J (40 mg, 0.07 mmol) was added to EtOH (6 mL) and water (1 mL) at room temperature, followed by iron powder (25 mg, 2.8 mmol) and ammonium chloride (30 mg, 5.6 mmol). Then heated to 80 degrees and reacted for 2h. After TLC showed that the reaction was completed, the reaction solution was diluted with ethyl acetate, extracted with water, washed with brine, the organic phase was dried with anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=0: 1 (volume ratio)), reverse phase HPLC preparation (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run for 1 min, 52%-52% acetonitrile run To 10min, 95% acetonitrile run to 14min, 10% acetonitrile run to 16min end) to obtain compound 1 (7mg, pale yellow solid, yield 19%).
MS(ESI):m/z 501[M+1] +。 MS(ESI): m/z 501[M+1] + .
1H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J＝8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J＝8Hz,2H),4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H),2.09(d,J＝8Hz,3H),1.54(d,J＝8Hz,3H)。 1 H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J=8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J=8Hz,2H) ,4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H ), 2.09 (d, J=8Hz, 3H), 1.54 (d, J=8Hz, 3H).
实施例2：化合物2的制备Example 2: Preparation of Compound 2
Figure PCTCN2022070423-appb-000021
Figure PCTCN2022070423-appb-000021
化合物2的合成参考实施例1中化合物1的合成步骤，其中用(R)-1-Boc-3-羟甲基哌嗪代替化合物1B，用(1R)-1-[3-硝基-5-(三氟甲基)苯基]乙胺代替化合物INT-1，合成得到化合物2。The synthesis of compound 2 refers to the synthesis procedure of compound 1 in example 1, wherein compound 1B is replaced by (R)-1-Boc-3-hydroxymethylpiperazine, and (1R)-1-[3-nitro-5 -(trifluoromethyl)phenyl]ethylamine was substituted for compound INT-1, and compound 2 was synthesized.
MS(ESI):m/z 501[M+1] +。 MS(ESI): m/z 501[M+1] + .
1H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J＝8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J＝8Hz,2H),4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H),2.09(d,J＝8Hz,3H),1.54(d,J＝8Hz,3H)。 1 H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J=8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J=8Hz,2H) ,4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H ), 2.09 (d, J=8Hz, 3H), 1.54 (d, J=8Hz, 3H).
实施例3：化合物3的制备Example 3: Preparation of Compound 3
Figure PCTCN2022070423-appb-000022
Figure PCTCN2022070423-appb-000022
化合物3的合成参考实施例1中化合物1的合成步骤，其中用(S)-1-Boc-3-羟甲基哌嗪代替化合物1B，用(1R)-1-[3-硝基-5-(三氟甲基)苯基]乙胺代替化合物INT-1，合成得到化合物3。The synthesis of compound 3 refers to the synthesis procedure of compound 1 in Example 1, wherein compound 1B is replaced by (S)-1-Boc-3-hydroxymethylpiperazine, and (1R)-1-[3-nitro-5 -(trifluoromethyl)phenyl]ethanamine was substituted for compound INT-1, and compound 3 was synthesized.
MS(ESI):m/z 501[M+1] +。 MS(ESI): m/z 501[M+1] + .
1H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J＝8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J＝8Hz,2H),4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H),2.09(d,J＝8Hz,3H),1.54(d,J＝8Hz,3H)。 1 H-NMR(400MHz,DMSO)δ(ppm)7.96(d,J=8Hz,1H),6.85-6.84(m,1H),6.69(s,1H),5.55(d,J=8Hz,2H) ,4.46-4.42(m,2H)4.06-3.97(m,3H),3.19-3.03(m,2H),2.94-2.74(m,2H),2.68-2.61(m,1H),2.33(s,3H ), 2.09 (d, J=8Hz, 3H), 1.54 (d, J=8Hz, 3H).
实施例4：化合物4的制备Example 4: Preparation of Compound 4
Figure PCTCN2022070423-appb-000023
Figure PCTCN2022070423-appb-000023
化合物4的合成参考实施例1中化合物1的合成步骤，其中第一步用(R)-1-Boc-3-羟甲基哌嗪代替化合物1B，第八步用(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2,2-二氟乙烷-1-醇代替化合物INT-1，合成得到化合物4。The synthesis of compound 4 refers to the synthesis steps of compound 1 in Example 1, wherein in the first step, (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B, and in the eighth step, (R)-2-( 3-(1-Aminoethyl)-2-fluorophenyl)-2,2-difluoroethane-1-ol was used to replace compound INT-1, and compound 4 was synthesized.
MS(ESI):m/z 515[M+1] +。 MS(ESI): m/z 515[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.15(s,1H),8.03(d,J＝6.7Hz,1H),7.62(dd,J＝13.7,5.8Hz,2H),7.40(t,J＝7.2Hz,1H),7.23(dd,J＝20.2,12.5Hz,1H),6.84(d,J＝3.1Hz,1H),5.83-5.82(m,1H),5.78(brs,1H),4.50–4.46(m,2H),4.08–3.95(m,3H),3.36(s,1H),3.20(s,1H),3.12–3.00(m,1H),2.89–2.85(m,2H),2.75–2.62(m,1H),2.27(d,J＝1.8Hz,3H),2.09(d,J＝11.4Hz,3H),1.59(d,J＝6.9Hz,3H). 1 H NMR (400MHz, DMSO) δ (ppm) 8.15 (s, 1H), 8.03 (d, J=6.7Hz, 1H), 7.62 (dd, J=13.7, 5.8Hz, 2H), 7.40 (t, J =7.2Hz,1H),7.23(dd,J=20.2,12.5Hz,1H),6.84(d,J=3.1Hz,1H),5.83-5.82(m,1H),5.78(brs,1H),4.50 –4.46(m, 2H), 4.08 – 3.95(m, 3H), 3.36(s, 1H), 3.20(s, 1H), 3.12 – 3.00(m, 1H), 2.89 – 2.85(m, 2H), 2.75 –2.62(m,1H),2.27(d,J＝1.8Hz,3H),2.09(d,J＝11.4Hz,3H),1.59(d,J＝6.9Hz,3H).
实施例5：化合物5的制备Example 5: Preparation of Compound 5
Figure PCTCN2022070423-appb-000024
Figure PCTCN2022070423-appb-000024
化合物5的合成参考实施例1中化合物1的合成步骤，其中第一步用(R)-1-Boc-3-羟甲基哌嗪代替化合物1B，八步用(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1,1-二氟-2-甲基丙烷-2-醇代替化合物INT-1，合成得到化合物5。The synthesis of compound 5 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and (R)-1-(3 -(1-Aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methylpropan-2-ol was substituted for compound INT-1, and compound 5 was synthesized.
MS(ESI):m/z 544[M+1] +。 MS(ESI): m/z 544[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.10(d,J＝34.7Hz,1H),7.77–7.73(m,1H),7.37- 7.33(m,1H),7.26-7.04(m,1H),7.05(d,J＝8.0Hz,1H),5.97-5.91(m,1H),5.35(s,1H),4.56–4.52(m,2H),4.22(dd,J＝28.7,12.1Hz,1H),4.14–3.95(m,2H),3.62–3.58(m,1H),3.20–3.04(m,2H),3.01–2.64(m,2H),2.45(d,J＝7.5Hz,3H),2.08(s,3H),1.68(dd,J＝6.7,4.0Hz,3H),1.23–1.19(m,6H) 1 H NMR (400 MHz, DMSO) δ (ppm) 8.10 (d, J=34.7 Hz, 1H), 7.77-7.73 (m, 1H), 7.37-7.33 (m, 1H), 7.26-7.04 (m, 1H) ,7.05(d,J＝8.0Hz,1H),5.97-5.91(m,1H),5.35(s,1H),4.56-4.52(m,2H),4.22(dd,J＝28.7,12.1Hz,1H ), 4.14–3.95 (m, 2H), 3.62–3.58 (m, 1H), 3.20–3.04 (m, 2H), 3.01–2.64 (m, 2H), 2.45 (d, J=7.5Hz, 3H), 2.08(s, 3H), 1.68(dd, J=6.7, 4.0Hz, 3H), 1.23–1.19(m, 6H)
实施例6：化合物6的制备Example 6: Preparation of Compound 6
Figure PCTCN2022070423-appb-000025
Figure PCTCN2022070423-appb-000025
化合物6的合成参考实施例1中化合物1的合成步骤，其中第一步用(R)-1-Boc-3-羟甲基哌嗪代替化合物1B，第八步用(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺代替化合物INT-1，合成得到化合物6。The synthesis of compound 6 refers to the synthesis steps of compound 1 in Example 1, wherein the first step uses (R)-1-Boc-3-hydroxymethylpiperazine to replace compound 1B, and the eighth step uses (R)-1-( 3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 6 was synthesized.
MS(ESI):m/z 486[M+1] +。 MS(ESI): m/z 486[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.03(d,J＝4.0Hz,1H),7.70–7.59(m,2H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝56.0Hz,1H),6.84(d,J＝3.2Hz,1H),5.83-5.78(m,1H),4.62–4.37(m,2H),4.06–3.98(m,3H),3.23–3.02(m,1H),2.95–2.85(m,1H),2.68(dd,J＝10.0,2.3Hz,1H),2.50–2.35(m,1H),2.26(d,J＝1.4Hz,3H),2.10(d,J＝11.3Hz,3H),1.60(d,J＝6.8Hz,3H).1H NMR(400MHz,DMSO)δ(ppm)8.03(d,J=4.0Hz,1H),7.70-7.59(m,2H),7.49(t,J=6.9Hz,1H),7.29(t,J= 7.7Hz, 1H), 7.23 (t, J=56.0Hz, 1H), 6.84 (d, J=3.2Hz, 1H), 5.83-5.78 (m, 1H), 4.62–4.37 (m, 2H), 4.06– 3.98 (m, 3H), 3.23–3.02 (m, 1H), 2.95–2.85 (m, 1H), 2.68 (dd, J=10.0, 2.3Hz, 1H), 2.50–2.35 (m, 1H), 2.26 ( d, J=1.4Hz, 3H), 2.10 (d, J=11.3Hz, 3H), 1.60 (d, J=6.8Hz, 3H).
实施例7：化合物7的制备Example 7: Preparation of Compound 7
Figure PCTCN2022070423-appb-000026
Figure PCTCN2022070423-appb-000026
化合物7的合成参考实施例1中化合物1的合成步骤，其中第一步用(S)-1-Boc-3-羟甲基哌嗪代替化合物1B，第八步用(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺代替化合物INT-1，合成得到化合物7。The synthesis of compound 7 refers to the synthesis steps of compound 1 in Example 1, wherein in the first step, (S)-1-Boc-3-hydroxymethylpiperazine is used instead of compound 1B, and in the eighth step, (R)-1-( 3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 7 was synthesized.
MS(ESI):m/z 486[M+1] +。 MS(ESI): m/z 486[M+1] + .
1H NMR(300MHz,DMSO)δ(ppm)8.00(d,J＝7.4Hz,1H),7.65–7.61(m,2H),7.48(t,J＝6.9Hz,1H),7.27(t,J＝7.7Hz,1H),7.23(t,J＝54.0Hz,1H),6.84(d,J＝2.0Hz,1H),5.83-5.79(m,1H),4.59–4.43(m,2H),4.09–3.96(m,3H),3.31-3.20(m,1H),2.90–2.86(m,1H),2.71-2.67(m 1H),2.48–2.35(m,1H),2.26(s,3H),2.10(d,J＝8.5Hz,3H),1.60(d,J＝7.1Hz,3H). 1 H NMR(300MHz,DMSO)δ(ppm)8.00(d,J=7.4Hz,1H),7.65-7.61(m,2H),7.48(t,J=6.9Hz,1H),7.27(t,J =7.7Hz,1H),7.23(t,J=54.0Hz,1H),6.84(d,J=2.0Hz,1H),5.83-5.79(m,1H),4.59-4.43(m,2H),4.09 –3.96(m, 3H), 3.31-3.20(m, 1H), 2.90–2.86(m, 1H), 2.71-2.67(m, 1H), 2.48–2.35(m, 1H), 2.26(s, 3H), 2.10(d,J=8.5Hz,3H),1.60(d,J=7.1Hz,3H).
实施例8：化合物8的制备Example 8: Preparation of Compound 8
Figure PCTCN2022070423-appb-000027
Figure PCTCN2022070423-appb-000027
化合物8的合成参考实施例1中化合物1的合成步骤，其中第一步用(R)-1-Boc-3-羟甲基哌嗪代替化合物1B，第四步用环丙基甲酰氯代替乙酰氯，第八步用((R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺代替化合物INT-1，合成得到化合物8。The synthesis of compound 8 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and cyclopropylcarbonyl chloride is used to replace ethyl acetate in the fourth step. Acid chloride, in the eighth step, ((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine was used to replace compound INT-1, and compound 8 was synthesized.
MS(ESI):m/z 512[M+1] +。 MS(ESI): m/z 512[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.03(d,J＝8.0Hz,1H),7.66-7.63(m,2H),7.49(t,J＝6.8Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝56.0Hz,1H),6.84(s,1H),5.84–5.76(m,1H),4.58–4.40(m,3H),4.05(s,2H),3.06–2.72(m,4H),2.26(s,3H),1.60(d,J＝7.0Hz,3H),1.54–1.42(m,1H),0.78–0.76(m,4H). 1 H NMR(400MHz,DMSO)δ(ppm)8.03(d,J=8.0Hz,1H),7.66-7.63(m,2H),7.49(t,J=6.8Hz,1H),7.28(t,J =7.7Hz,1H),7.23(t,J=56.0Hz,1H),6.84(s,1H),5.84-5.76(m,1H),4.58-4.40(m,3H),4.05(s,2H) , 3.06–2.72 (m, 4H), 2.26 (s, 3H), 1.60 (d, J=7.0Hz, 3H), 1.54–1.42 (m, 1H), 0.78–0.76 (m, 4H).
实施例9：化合物9的制备Example 9: Preparation of Compound 9
Figure PCTCN2022070423-appb-000028
Figure PCTCN2022070423-appb-000028
化合物9的合成参考实施例1中化合物1的合成步骤，其中第一步用(R)-1-Boc-3-羟甲基哌嗪代替化合物1B，第四步用对甲苯磺酰氯代替乙酰氯，第八步用(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺代替化合物INT-1，合成得到化合物9。The synthesis of compound 9 refers to the synthesis steps of compound 1 in Example 1, wherein (R)-1-Boc-3-hydroxymethylpiperazine is used to replace compound 1B in the first step, and p-toluenesulfonyl chloride is used to replace acetyl chloride in the fourth step. In the eighth step, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine is used to replace compound INT-1, and compound 9 is synthesized.
MS(ESI):m/z 598[M+1] +。 MS(ESI): m/z 598[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.38(s,1H),7.70–7.66(m,4H),7.52–7.47(m,3H),7.30(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.84(s,1H),5.83–5.75(m,1H),4.42(dd,J＝10.9,2.7Hz,1H),4.15(d,J＝12.4Hz,1H),4.01–3.98(m,1H),3.88–3.72(m,2H),2.98-2.92(m,2H),2.44(d,J＝2.6Hz,1H),2.41(s,3H),2.35–2.31(m,1H),2.28(s,3H),1.60(d,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO) δ (ppm) 8.38 (s, 1H), 7.70–7.66 (m, 4H), 7.52–7.47 (m, 3H), 7.30 (t, J=7.7Hz, 1H), 7.23 (t, J=52.0Hz, 1H), 6.84 (s, 1H), 5.83–5.75 (m, 1H), 4.42 (dd, J=10.9, 2.7Hz, 1H), 4.15 (d, J=12.4Hz, 1H), 4.01–3.98 (m, 1H), 3.88–3.72 (m, 2H), 2.98–2.92 (m, 2H), 2.44 (d, J=2.6Hz, 1H), 2.41 (s, 3H), 2.35 –2.31(m, 1H), 2.28(s, 3H), 1.60(d, J=7.0Hz, 3H).
实施例10：化合物10的制备Example 10: Preparation of Compound 10
Figure PCTCN2022070423-appb-000029
Figure PCTCN2022070423-appb-000029
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000030
Figure PCTCN2022070423-appb-000030
制备方法：Preparation:
第一步：合成化合物10AStep 1: Synthesis of Compound 10A
将化合物10A(1.0g，3.2mmol,合成参考实施例1中中间体1I的合成，用(R)-1-Boc-3-羟甲基哌嗪代替1B(1-Boc-3-羟甲基哌嗪)合成得到10A)溶于DCE(10mL)中，向反应液中加入三苯基膦(1.68g，6.4mmol)和四氯化碳(1.48g，9.6mmol)，然后氮气保护下，把反应加热到70℃搅拌反应2h。TLC显示反应结束后，把反应液冷却到室温后，加入到饱和碳酸氢钠溶液中(100mL),然后用二氯甲烷萃取(25mL×3)，合并有机相，并用无水硫酸钠干燥，然后旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/异丙醇＝10:1)，得到化合物10A(0.5g，黄色油状物，产率47.2％)。Synthesis of compound 10A (1.0 g, 3.2 mmol, synthetic reference Example 1 for the synthesis of intermediate 1I, replace 1B (1-Boc-3-hydroxymethylpiperazine) with (R)-1-Boc-3-hydroxymethylpiperazine Piperazine) was synthesized to obtain 10A), which was dissolved in DCE (10 mL), triphenylphosphine (1.68 g, 6.4 mmol) and carbon tetrachloride (1.48 g, 9.6 mmol) were added to the reaction solution, and then under nitrogen protection, the The reaction was heated to 70°C and stirred for 2h. After TLC showed that the reaction was over, the reaction solution was cooled to room temperature, added to saturated sodium bicarbonate solution (100 mL), then extracted with dichloromethane (25 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, then Spin to dryness, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/isopropanol=10:1) to obtain compound 10A (0.5 g, yellow oil, yield 47.2%).
MS(ESI):m/z 333[M+1] +。 MS(ESI): m/z 333[M+1] + .
第二步：合成化合物10CStep 2: Synthesis of compound 10C
将化合物10A(0.5g，1.5mmol)溶于DMF(125mL)中，再加入INT-2(401mg，1.71mmol)，然后加DIEA(580mg，5.155mmol)，然后将反应液加热到80℃下回流过夜，TLC显示反应结束后，把反应液中加到饱和NaCl溶液(50mL)中,然后用乙酸乙酯萃取(25mL×3)，合并有机相，并用无水硫酸钠干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10/1)，得到化合物10C(0.5g，类白色固体，62.5％)。Compound 10A (0.5 g, 1.5 mmol) was dissolved in DMF (125 mL), INT-2 (401 mg, 1.71 mmol) was added, then DIEA (580 mg, 5.155 mmol) was added, and the reaction solution was heated to reflux at 80 °C Overnight, after TLC showed that the reaction was over, the reaction solution was added to saturated NaCl solution (50 mL), then extracted with ethyl acetate (25 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, spin-dried, and the residue was Purification by silica gel column chromatography (eluent: ethyl acetate/methanol=10/1) gave compound 10C (0.5 g, off-white solid, 62.5%).
MS(ESI):m/z 531[M+1] +。 MS(ESI): m/z 531[M+1] + .
第三步：合成化合物10DStep 3: Synthesis of Compound 10D
将化合物10C(0.5g，0.94mmol)溶于乙醇(5mL)中，再加浓盐酸(1mL)，加完后，将反应液加热至80℃搅拌反应16h。TLC显示反应结束后，将反应液旋干后，得到化合物10D(0.5g类白色固体，产率100.0％)。Compound 10C (0.5 g, 0.94 mmol) was dissolved in ethanol (5 mL), and concentrated hydrochloric acid (1 mL) was added. After the addition, the reaction solution was heated to 80 °C and stirred for 16 h. After TLC showed that the reaction was completed, the reaction solution was spun dry to obtain compound 10D (0.5 g off-white solid, yield 100.0%).
MS(ESI):m/z 489[M+1] +。 MS(ESI): m/z 489[M+1] + .
第四步：合成化合物10FStep 4: Synthesis of Compound 10F
将化合物10D(200mg，0.41mmol)溶于DCE(2ml)中，再加10E(118mg，1.64mmol)，再滴3滴AcOH，然后将反应液放到室温搅拌1h，然后再加NaBH 3CN(38.7mg，0.614mmol)然后再将反应液放到室温下搅拌1h。TLC显示反应结束后，加氨水调PH值到8-9，然后旋干，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10：1)，得到化合物10F(130mg，产率58.41％)。 Compound 10D (200 mg, 0.41 mmol) was dissolved in DCE (2 ml), 10E (118 mg, 1.64 mmol) was added, 3 drops of AcOH were added, and the reaction solution was stirred at room temperature for 1 h, and then NaBH 3 CN ( 38.7 mg, 0.614 mmol) and then the reaction solution was stirred at room temperature for 1 h. After TLC showed that the reaction was over, ammonia water was added to adjust the pH to 8-9, then spin-dried, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain compound 10F (130 mg, yield 58.41%).
MS(ESI):m/z 545[M+1] +。 MS(ESI): m/z 545[M+1] + .
第五步：合成化合物10Step 5: Synthesis of Compound 10
将化合物10F(130mg，0.24mmol)溶于乙醇/水(2mL/0.5mL)中，再加氯化铵(103.2mg，1.91mmol)，然后加铁粉(53.5mg，0.995mmol)，然后将反应液加热到80℃下回流1h，TLC显示反应结束后，将反应液过滤，滤液旋干，反相HPLC制备(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物10(80mg，淡黄色固体，产率65.0％)。Compound 10F (130 mg, 0.24 mmol) was dissolved in ethanol/water (2 mL/0.5 mL), ammonium chloride (103.2 mg, 1.91 mmol) was added, and iron powder (53.5 mg, 0.995 mmol) was added, and the reaction was The solution was heated to 80°C and refluxed for 1 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, prepared by reverse-phase HPLC (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: Acetonitrile, gradient: 10% acetonitrile run for 1 min, 52%-52% acetonitrile run to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to obtain compound 10 (80 mg, pale yellow solid, yield 65.0%) ).
MS(ESI):m/z 515[M+1] +。 MS(ESI): m/z 515[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)7.90(d,J＝7.9Hz,1H),7.55(s,1H),6.86(d,J＝9.5Hz,2H),6.82(s,1H),6.70(s,1H),5.61–5.55(m,1H),5.54(s,2H),4.64–4.44(m,4H),4.34(dd,J＝10.7,2.7Hz,1H),4.01-3.96(m,2H),3.54–3.42(m,1H),3.18(t,J＝9.8Hz,1H),3.01–2.71(m,3H),2.31(s,3H),2.17–2.01(m,1H),1.67(t,J＝10.6Hz,1H),1.53(d,J＝7.0Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)7.90(d,J=7.9Hz,1H),7.55(s,1H),6.86(d,J=9.5Hz,2H),6.82(s,1H), 6.70(s,1H),5.61-5.55(m,1H),5.54(s,2H),4.64-4.44(m,4H),4.34(dd,J=10.7,2.7Hz,1H),4.01-3.96( m, 2H), 3.54–3.42 (m, 1H), 3.18 (t, J=9.8Hz, 1H), 3.01–2.71 (m, 3H), 2.31 (s, 3H), 2.17–2.01 (m, 1H) ,1.67(t,J=10.6Hz,1H),1.53(d,J=7.0Hz,3H).
实施例11：化合物11的制备Example 11: Preparation of Compound 11
Figure PCTCN2022070423-appb-000031
Figure PCTCN2022070423-appb-000031
化合物11的合成参考实施例10中化合物10的合成步骤，其中第四步用多聚甲醛代替10E，合成得到化合物11。The synthesis of compound 11 refers to the synthesis steps of compound 10 in Example 10, wherein in the fourth step, paraformaldehyde is used instead of 10E to synthesize compound 11.
MS(ESI):m/z 473[M+1] +。 MS(ESI): m/z 473[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)7.90(d,J＝7.8Hz,1H),7.54(s,1H),6.89–6.79(m,3H),6.69(s,1H),5.59-5.54(m,3H),4.33(dd,J＝10.7,2.8Hz,1H),4.01-3.93(m,2H),3.16(dd,J＝13.3,6.4Hz,1H),2.98(d,J＝11.2Hz,1H),2.84–2.77(m,2H),2.35–2.28(m,3H),2.24(d,J＝8.8Hz,3H),2.16–2.14(m,1H),1.71(t,J＝10.7Hz,1H),1.52(d,J＝12.0Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)7.90(d,J=7.8Hz,1H),7.54(s,1H),6.89-6.79(m,3H),6.69(s,1H),5.59-5.54 (m, 3H), 4.33 (dd, J=10.7, 2.8Hz, 1H), 4.01-3.93 (m, 2H), 3.16 (dd, J=13.3, 6.4Hz, 1H), 2.98 (d, J=11.2 Hz, 1H), 2.84–2.77 (m, 2H), 2.35–2.28 (m, 3H), 2.24 (d, J=8.8Hz, 3H), 2.16–2.14 (m, 1H), 1.71 (t, J= 10.7Hz, 1H), 1.52(d, J=12.0Hz, 3H).
实施例12：化合物12的制备Example 12: Preparation of Compound 12
Figure PCTCN2022070423-appb-000032
Figure PCTCN2022070423-appb-000032
化合物12的合成参考实施例10中化合物10的合成步骤，其中第四步用四氢吡喃酮代替10E，合成得到化合物12。The synthesis of compound 12 refers to the synthesis steps of compound 10 in Example 10, wherein in the fourth step, tetrahydropyranone is used instead of 10E, and compound 12 is synthesized.
MS(ESI):m/z 543[M+1] +。 MS(ESI): m/z 543[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)7.92(d,J＝7.3Hz,1H),7.54(s,1H),6.92–6.77(m,3H),6.69(s,1H),5.59-5.54(m,3H),4.35(dd,J＝10.6,2.7Hz,1H),4.04–3.95(m,2H),3.91(dd,J＝11.0,2.9Hz,2H),3.33-3.25(m,2H),3.15–3.04(m,2H),3.01(d,J＝10.4Hz,1H),2.78–2.66(m,1H),2.46(d,J＝11.3Hz,1H),2.37-2.34(m,1H),2.31(s,3H),1.91(t,J＝10.6Hz,1H),1.76-1.72(m 2H),1.51(dd,J＝18.0,5.4Hz,3H),1.49–1.37(m,2H). 1 H NMR (400MHz, DMSO) δ(ppm) 7.92(d, J=7.3Hz, 1H), 7.54(s, 1H), 6.92-6.77(m, 3H), 6.69(s, 1H), 5.59-5.54 (m, 3H), 4.35 (dd, J=10.6, 2.7Hz, 1H), 4.04-3.95 (m, 2H), 3.91 (dd, J=11.0, 2.9Hz, 2H), 3.33-3.25 (m, 2H) ), 3.15–3.04 (m, 2H), 3.01 (d, J=10.4Hz, 1H), 2.78–2.66 (m, 1H), 2.46 (d, J=11.3Hz, 1H), 2.37–2.34 (m, 1H), 2.31(s, 3H), 1.91(t, J=10.6Hz, 1H), 1.76-1.72(m 2H), 1.51(dd, J=18.0, 5.4Hz, 3H), 1.49-1.37(m, 2H).
实施例13：化合物13的制备Example 13: Preparation of Compound 13
Figure PCTCN2022070423-appb-000033
Figure PCTCN2022070423-appb-000033
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000034
Figure PCTCN2022070423-appb-000034
制备方法：Preparation:
将化合物13A(181mg，0.41mmol,合成参考实施例10中中间体10D的合成，用(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺代替INT-2合成得到13A)溶于DCE(2ml)中，再加入质量分数为30％到35％甲醛水溶液(150mg，1.64mmol)，再滴3滴AcOH，然后将反应液放到室温搅拌1h，然后再加NaBH3CN(38.7mg，0.614mmol)然后再将反应液放到室温下搅拌1h。TLC显示反应结束后，加氨水调PH＝8-9，然后浓缩旋干，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10：1)，得到化合物13(130mg，产率58.41％)。Compound 13A (181 mg, 0.41 mmol, synthetic reference Example 10 for the synthesis of intermediate 10D was synthesized with (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine Instead of INT-2, 13A was synthesized and dissolved in DCE (2ml), then 30% to 35% aqueous formaldehyde solution (150mg, 1.64mmol) was added, and 3 drops of AcOH were added, and then the reaction solution was stirred at room temperature for 1h , and then add NaBH3CN (38.7 mg, 0.614 mmol) and then the reaction solution was stirred at room temperature for 1 h. After TLC showed that the reaction was over, ammonia water was added to adjust the pH to 8-9, then concentrated and spin-dried, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain compound 13 (130 mg, yield 58.41%).
MS(ESI):m/z 458[M+1] +。 MS(ESI): m/z 458[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)7.97(d,J＝7.2Hz,1H),7.65(t,J＝7.2Hz,1H),7.58(s,1H),7.48(t,J＝6.8Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝56.0Hz,1H),6.81(s,1H),5.79(m,1H),4.33(dd,J＝10.7,2.7Hz,1H),4.01-3.96(m,2H),3.17(t,J＝9.9Hz,1H),2.99(d,J＝10.8Hz,1H),2.90–2.71(m,2H),2.26(d,J＝3.9Hz,6H),2.22–2.13(m,1H),1.72(t,J＝10.7Hz,1H),1.59(d,J＝7.1Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)7.97(d,J=7.2Hz,1H),7.65(t,J=7.2Hz,1H),7.58(s,1H),7.48(t,J=6.8 Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=56.0Hz, 1H), 6.81(s, 1H), 5.79(m, 1H), 4.33(dd, J=10.7 ,2.7Hz,1H),4.01-3.96(m,2H),3.17(t,J=9.9Hz,1H),2.99(d,J=10.8Hz,1H),2.90–2.71(m,2H),2.26 (d, J=3.9Hz, 6H), 2.22–2.13 (m, 1H), 1.72 (t, J=10.7Hz, 1H), 1.59 (d, J=7.1Hz, 3H).
实施例14：化合物14的制备Example 14: Preparation of Compound 14
Figure PCTCN2022070423-appb-000035
Figure PCTCN2022070423-appb-000035
化合物14的合成参考实施例13中化合物13的合成步骤，其中用3-氧杂环丁酮代替甲醛，合成得到化合物14。The synthesis of compound 14 refers to the synthesis procedure of compound 13 in Example 13, wherein 3-oxetanone is used instead of formaldehyde, and compound 14 is synthesized.
MS(ESI):m/z 500[M+1] +。 MS(ESI): m/z 500[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)7.98(d,J＝7.2Hz,1H),7.65(t,J＝7.7Hz,1H),7.59(s,1H),7.49(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝56.0Hz,1H),6.82(s,1H),5.86–5.73(m,1H),4.60(dd,J＝15.8,6.5Hz,2H),4.55–4.47(m,2H),4.34(d,J＝8.1Hz,1H),4.00(dd,J＝18.7,9.1Hz,2H),3.55–3.44(m,1H),3.25–3.13(m,1H),2.96(d,J＝10.1Hz,1H),2.87-2.83(m,2H),2.25(s,3H),2.17–2.08(m,1H),1.69(t,J＝10.8Hz,1H),1.59(d,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 7.98 (d, J=7.2Hz, 1H), 7.65 (t, J=7.7Hz, 1H), 7.59 (s, 1H), 7.49 (t, J= 7.0Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=56.0Hz, 1H), 6.82(s, 1H), 5.86–5.73(m, 1H), 4.60(dd, J=15.8, 6.5Hz, 2H), 4.55–4.47 (m, 2H), 4.34 (d, J=8.1Hz, 1H), 4.00 (dd, J=18.7, 9.1Hz, 2H), 3.55–3.44 (m ,1H),3.25-3.13(m,1H),2.96(d,J=10.1Hz,1H),2.87-2.83(m,2H),2.25(s,3H),2.17-2.08(m,1H), 1.69(t, J=10.8Hz, 1H), 1.59(d, J=7.0Hz, 3H).
实施例15：化合物15的制备Example 15: Preparation of Compound 15
Figure PCTCN2022070423-appb-000036
Figure PCTCN2022070423-appb-000036
化合物15的合成参考实施例13中化合物13的合成步骤，其中用四氢吡喃酮代替甲醛，合成得到化合物15。The synthesis of compound 15 refers to the synthesis procedure of compound 13 in Example 13, wherein tetrahydropyranone is used instead of formaldehyde to synthesize compound 15.
MS(ESI):m/z 528[M+1] +。 MS(ESI): m/z 528[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)7.97(d,J＝7.3Hz,1H),7.65(t,J＝7.3Hz,1H),7.57(s,1H),7.48(t,J＝6.5Hz,1H),7.28(t,J＝7.6Hz,1H),7.23(t,J＝56.0Hz,1H),6.81(s,1H),5.87–5.73(m,1H),4.35(dd,J＝10.6,2.5Hz,1H),4.12–3.86(m,5H),3.14(dd,J＝20.8,7.8Hz,4H),3.01(d,J＝10.8Hz,1H),2.75(t,J＝10.3Hz,1H),2.39(t,J＝9.9Hz,1H),2.25(s,3H),1.92(t,J＝10.7Hz,1H),1.75(d,J＝11.5Hz,2H),1.59(d,J＝7.0Hz,3H),1.45(s,2H). 1 H NMR (400MHz, DMSO): δ (ppm) 7.97 (d, J=7.3Hz, 1H), 7.65 (t, J=7.3Hz, 1H), 7.57 (s, 1H), 7.48 (t, J= 6.5Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23(t, J=56.0Hz, 1H), 6.81(s, 1H), 5.87–5.73(m, 1H), 4.35(dd, J=10.6, 2.5Hz, 1H), 4.12–3.86 (m, 5H), 3.14 (dd, J=20.8, 7.8Hz, 4H), 3.01 (d, J=10.8Hz, 1H), 2.75 (t, J ＝10.3Hz, 1H), 2.39(t, J＝9.9Hz, 1H), 2.25(s, 3H), 1.92(t, J＝10.7Hz, 1H), 1.75(d, J＝11.5Hz, 2H), 1.59(d, J=7.0Hz, 3H), 1.45(s, 2H).
实施例16：化合物16的制备Example 16: Preparation of Compound 16
Figure PCTCN2022070423-appb-000037
Figure PCTCN2022070423-appb-000037
化合物16的合成参考实施例13中化合物13的合成步骤，其中(S)-1-Boc-3-羟甲基哌嗪代替中间体13A合成中要用到的(R)-1-Boc-3-羟甲基哌嗪，合成得到化合物16。The synthesis of compound 16 refers to the synthesis steps of compound 13 in Example 13, wherein (S)-1-Boc-3-hydroxymethylpiperazine replaces (R)-1-Boc-3 used in the synthesis of intermediate 13A -Hydroxymethylpiperazine, compound 16 was synthesized.
MS(ESI):m/z 458[M+1] +。 MS(ESI): m/z 458[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)7.98(d,J＝7.4Hz,1H),7.63(t,J＝7.4Hz,1H),7.58(s,1H),7.48(t,J＝7.0Hz,1H),7.27(t,J＝7.6Hz,1H),7.23(t,J＝54.0Hz,1H),6.81(s,1H),5.87–5.71(m,1H),4.34(dd,J＝10.7,2.5Hz,1H),3.99-3.94(m,2H),3.17(t,J＝9.7Hz,1H),3.00(d,J＝11.0Hz,1H),2.86(d,J＝10.3Hz,1H),2.78(t,J＝10.3Hz,1H),2.26(s,3H),2.25(s,3H),2.18(t,J＝10.2Hz,1H),1.71(t,J＝10.8Hz,1H),1.60(d,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 7.98 (d, J=7.4Hz, 1H), 7.63 (t, J=7.4Hz, 1H), 7.58 (s, 1H), 7.48 (t, J= 7.0Hz, 1H), 7.27(t, J=7.6Hz, 1H), 7.23(t, J=54.0Hz, 1H), 6.81(s, 1H), 5.87–5.71(m, 1H), 4.34(dd, J=10.7, 2.5Hz, 1H), 3.99-3.94(m, 2H), 3.17(t, J=9.7Hz, 1H), 3.00(d, J=11.0Hz, 1H), 2.86(d, J=10.3 Hz, 1H), 2.78(t, J＝10.3Hz, 1H), 2.26(s, 3H), 2.25(s, 3H), 2.18(t, J＝10.2Hz, 1H), 1.71(t, J＝10.8 Hz,1H),1.60(d,J＝7.0Hz,3H).
实施例17：化合物17的制备Example 17: Preparation of Compound 17
Figure PCTCN2022070423-appb-000038
Figure PCTCN2022070423-appb-000038
化合物17的合成参考实施例13中化合物13的合成步骤，其中用丙酮代替甲醛，合成得到化合物17。The synthesis of compound 17 refers to the synthesis procedure of compound 13 in Example 13, wherein acetone is used instead of formaldehyde, and compound 17 is synthesized.
MS(ESI):m/z 486[M+1] +。 MS(ESI): m/z 486[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)7.99(d,J＝7.3Hz,1H),7.65(t,J＝7.5Hz,1H),7.57(s,1H),7.49(t,J＝6.8Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.81(s,1H),5.87-5.71(m,1H),4.35(dd,J＝10.6,2.7Hz,1H),4.04-3.91(m,2H),3.090(t,J＝9.8Hz,1H),3.00(d,J＝10.7Hz,1H),2.90(d,J＝10.5Hz,1H),2.80-2.69(m,2H),2.41-2.40(m,1H),2.25(s,3H),1.92(t,J＝10.6Hz,1H),1.59(d,J＝7.1Hz,3H),1.03(t,J＝6.5Hz,6H). 1 H NMR (400MHz, DMSO): δ (ppm) 7.99 (d, J=7.3Hz, 1H), 7.65 (t, J=7.5Hz, 1H), 7.57 (s, 1H), 7.49 (t, J= 6.8Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.81(s, 1H), 5.87-5.71(m, 1H), 4.35(dd, J=10.6, 2.7Hz, 1H), 4.04-3.91(m, 2H), 3.090(t, J=9.8Hz, 1H), 3.00(d, J=10.7Hz, 1H), 2.90(d, J=10.5 Hz, 1H), 2.80-2.69(m, 2H), 2.41-2.40(m, 1H), 2.25(s, 3H), 1.92(t, J=10.6Hz, 1H), 1.59(d, J=7.1Hz ,3H),1.03(t,J＝6.5Hz,6H).
实施例18：化合物18的制备Example 18: Preparation of Compound 18
Figure PCTCN2022070423-appb-000039
Figure PCTCN2022070423-appb-000039
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000040
Figure PCTCN2022070423-appb-000040
制备方法：Preparation:
将化合物13A(181mg，0.41mmol)溶于乙腈(2ml)中，室温下再加入碳酸钾(113mg，0.82mmol)，再加入化合物18A(108mg，0.82mmol)，然后将反应液升温到60℃搅拌2h。TLC显示反应结束后，将反应液冷却到室温，然后旋干，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝10：1)，得到化合物18(116mg，产率52.4％)。Compound 13A (181 mg, 0.41 mmol) was dissolved in acetonitrile (2 ml), potassium carbonate (113 mg, 0.82 mmol) was added at room temperature, compound 18A (108 mg, 0.82 mmol) was added, and the reaction solution was heated to 60 °C and stirred 2h. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, then spin-dried, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol=10:1) to obtain compound 18 (116 mg, yield 52.4 %).
MS(ESI):m/z 540[M+1] +。 MS(ESI): m/z 540[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.54(s,2H),8.04(d,J＝7.2Hz,1H),7.69-7.63(m,2H),7.49(t,J＝6.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.85(s,1H),5.83-5.76(m,1H),4.70(dd,J＝36.1,12.3Hz,2H),4.51(dd,J＝10.8,2.7Hz,1H),4.21-4.01(m,2H),3.26-3.18(m,2H),2.90-2.85(m,1H),2.80-2.70(m,1H),2.26(s,3H),1.60(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.54 (s, 2H), 8.04 (d, J=7.2Hz, 1H), 7.69-7.63 (m, 2H), 7.49 (t, J=6.9Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.85(s, 1H), 5.83-5.76(m, 1H), 4.70(dd, J=36.1 ,12.3Hz,2H),4.51(dd,J=10.8,2.7Hz,1H),4.21-4.01(m,2H),3.26-3.18(m,2H),2.90-2.85(m,1H),2.80- 2.70(m, 1H), 2.26(s, 3H), 1.60(d, J=7.1Hz, 3H).
实施例19：化合物19的制备Example 19: Preparation of Compound 19
Figure PCTCN2022070423-appb-000041
Figure PCTCN2022070423-appb-000041
化合物19的合成参考实施例18中化合物18的合成步骤，其中2-溴乙基甲基醚代替18A，合成得到化合物19。Synthesis of compound 19 Referring to the synthesis procedure of compound 18 in Example 18, wherein 2-bromoethyl methyl ether was used instead of 18A, compound 19 was synthesized.
MS(ESI):m/z 502[M+1] +。 MS(ESI): m/z 502[M+1] + .
1H-NMR(400MHz,DMSO):δ(ppm)7.99(d,J＝4.0Hz,1H),7.65(dd,J＝14.4,7.1Hz, 1H),7.58(s,1H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.82(s,1H),5.81-5.78(m,1H),4.35(dd,J＝10.7,2.7Hz,1H),4.01-3.96(m,2H),3.51-3.49(m,2H),3.3(s,3H),3.13–3.09(m,2H),2.97(d,J＝6.0Hz,1H),2.80-2.76(m,1H),2.59-2.49(m,2H),2.29-2.25(m,1H),2.24(s,3H),1.82(t,J＝6.0Hz,1H),1.59(d,J＝7.1Hz,3H). 1 H-NMR (400MHz, DMSO): δ(ppm) 7.99(d, J=4.0Hz, 1H), 7.65(dd, J=14.4, 7.1Hz, 1H), 7.58(s, 1H), 7.49(t , J=6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.82(s, 1H), 5.81-5.78(m, 1H), 4.35 (dd,J＝10.7,2.7Hz,1H),4.01-3.96(m,2H),3.51-3.49(m,2H),3.3(s,3H),3.13-3.09(m,2H),2.97(d , J=6.0Hz, 1H), 2.80-2.76(m, 1H), 2.59-2.49(m, 2H), 2.29-2.25(m, 1H), 2.24(s, 3H), 1.82(t, J=6.0 Hz,1H),1.59(d,J=7.1Hz,3H).
实施例20：化合物20的制备Example 20: Preparation of Compound 20
Figure PCTCN2022070423-appb-000042
Figure PCTCN2022070423-appb-000042
制备方法：Preparation:
第一步：合成化合物20BStep 1: Synthesis of Compound 20B
将化合物20A(500mg,4.23mmol)溶于DCM(5mL)溶液中，然后加入吡啶(762mg,8.46mmol)和DMAP(52mg,0.423mmol)，再加入对甲苯磺酰氯(1.2g,6.34mmol)，加完后，室温搅拌2小时，TLC显示反应结束后，将反应液加入到饱和碳酸氢钠水溶液中(50mL)，分出有机层，水相再用DCM萃取(25mL×3)，合并有机相，无水硫酸钠干燥,旋干溶剂，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5:1(体积比))，得到化合物20B(1.1g，淡黄色固体，产率93.2％)。Compound 20A (500 mg, 4.23 mmol) was dissolved in DCM (5 mL) solution, then pyridine (762 mg, 8.46 mmol) and DMAP (52 mg, 0.423 mmol) were added, followed by p-toluenesulfonyl chloride (1.2 g, 6.34 mmol), After the addition, the mixture was stirred at room temperature for 2 hours. After TLC showed that the reaction was over, the reaction solution was added to saturated aqueous sodium bicarbonate solution (50 mL), the organic layer was separated, and the aqueous phase was extracted with DCM (25 mL×3), and the organic phases were combined. , dried over anhydrous sodium sulfate, spin-dried the solvent, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5:1 (volume ratio)) to obtain compound 20B (1.1 g, pale yellow solid) , yield 93.2%).
第二步：合成化合物20Step 2: Synthesis of Compound 20
将化合物13A(181mg，0.41mmol)溶于乙腈(2ml)中，室温下再加入碳酸钾(113mg，0.82mmol)，再加入化合物20B(155mg，0.82mmol)，然后将反应液升温到60℃搅拌2h。TLC显示反应结束后，将反应液冷却到室温，然后旋干，残余物pre-TLC纯化(展 开剂：乙酸乙酯/甲醇＝10：1)，得到化合物20(106mg)。Compound 13A (181 mg, 0.41 mmol) was dissolved in acetonitrile (2 ml), potassium carbonate (113 mg, 0.82 mmol) was added at room temperature, compound 20B (155 mg, 0.82 mmol) was added, and the reaction solution was heated to 60 °C and stirred 2h. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, then spin-dried, and the residue was purified by pre-TLC (developing solvent: ethyl acetate/methanol = 10:1) to obtain compound 20 (106 mg).
MS(ESI):m/z 544[M+1] +。 MS(ESI): m/z 544[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.26(d,J＝19.0Hz,1H),7.68(t,J＝7.4Hz,1H),7.64(s,1H),7.50(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.0Hz,1H),6.84(s,1H),5.86-5.78(m,1H),5.75(s,1H),4.37-4.32(m,1H),3.99-3.96(m,2H),3.81-3.69(m,4H),3.67-3.55(m,4H),3.27-2.91(m,4H),2.44-2.32(m,2H),2.29(s,3H),1.61(d,J＝7.0Hz,3H). 1 H NMR (400 MHz, DMSO): δ (ppm) 8.26 (d, J=19.0 Hz, 1H), 7.68 (t, J=7.4 Hz, 1H), 7.64 (s, 1H), 7.50 (t, J= 6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.0Hz, 1H), 6.84(s, 1H), 5.86-5.78(m, 1H), 5.75(s, 1H), 4.37-4.32(m, 1H), 3.99-3.96(m, 2H), 3.81-3.69(m, 4H), 3.67-3.55(m, 4H), 3.27-2.91(m, 4H), 2.44- 2.32(m, 2H), 2.29(s, 3H), 1.61(d, J=7.0Hz, 3H).
实施例21：化合物21的制备Example 21: Preparation of Compound 21
Figure PCTCN2022070423-appb-000043
Figure PCTCN2022070423-appb-000043
化合物21的合成参考实施例20中化合物20的合成步骤，其中第一步用三氟甲基乙醇代替20A，合成得到化合物21。The synthesis of compound 21 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, trifluoromethyl ethanol is used instead of 20A, and compound 21 is synthesized.
MS(ESI):m/z 526[M+1] +。 MS(ESI): m/z 526[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.00(d,J＝7.2Hz,1H),7.65-7.49(m,1H),7.60(s,1H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.82(s,1H),5.83-5.76(m,J＝7.0Hz,1H),4.35(dd,J＝10.7,2.7Hz,1H),3.98(dd,J＝12.5,7.0Hz,2H),3.31-3.10(m,5H),3.02(d,J＝10.6Hz,1H),2.84(dd,J＝12.0,9.2Hz,1H),2.67(t,J＝10.5Hz,1H),2.26-2.20(m,3H),1.59(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.00 (d, J=7.2Hz, 1H), 7.65-7.49 (m, 1H), 7.60 (s, 1H), 7.49 (t, J=6.9Hz, 1H), 7.29(t, J＝7.7Hz, 1H), 7.23(t, J＝52.0Hz, 1H), 6.82(s, 1H), 5.83-5.76(m, J＝7.0Hz, 1H), 4.35( dd,J＝10.7,2.7Hz,1H),3.98(dd,J＝12.5,7.0Hz,2H),3.31-3.10(m,5H),3.02(d,J＝10.6Hz,1H),2.84(dd , J=12.0, 9.2Hz, 1H), 2.67(t, J=10.5Hz, 1H), 2.26-2.20(m, 3H), 1.59(d, J=7.1Hz, 3H).
实施例22：化合物22的制备Example 22: Preparation of Compound 22
Figure PCTCN2022070423-appb-000044
Figure PCTCN2022070423-appb-000044
化合物22的合成参考实施例20中化合物20的合成步骤，其中第一步用氧杂环丁烷-3-甲醇代替20A，合成得到化合物22。The synthesis of compound 22 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, oxetane-3-methanol is used to replace 20A, and compound 22 is synthesized.
MS(ESI):m/z 514[M+1] +。 MS(ESI): m/z 514[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.03(d,J＝7.3Hz,1H),7.66(t,J＝7.2Hz,1H),7.60(s,1H),7.48(t,J＝6.8Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.81(s,1H),5.84-5.76(m,1H),4.69-4.65(m,2H),4.37-4.26(m,3H),4.05-3.96(m,2H),3.26-3.25(m,1H),3.18-3.06(m,1H),2.97(d,J＝10.9Hz,1H),2.84(d,J＝10.2Hz,1H),2.79-2.64(m,3H),2.25(s,3H),2.21(d,J＝11.6Hz,1H),1.75(t,J＝10.6Hz,1H),1.59(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.03 (d, J=7.3Hz, 1H), 7.66 (t, J=7.2Hz, 1H), 7.60 (s, 1H), 7.48 (t, J= 6.8Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.81(s, 1H), 5.84-5.76(m, 1H), 4.69-4.65( m, 2H), 4.37-4.26(m, 3H), 4.05-3.96(m, 2H), 3.26-3.25(m, 1H), 3.18-3.06(m, 1H), 2.97(d, J=10.9Hz, 1H), 2.84(d, J＝10.2Hz, 1H), 2.79-2.64(m, 3H), 2.25(s, 3H), 2.21(d, J＝11.6Hz, 1H), 1.75(t, J＝10.6 Hz,1H),1.59(d,J=7.1Hz,3H).
实施例23：化合物23的制备Example 23: Preparation of Compound 23
Figure PCTCN2022070423-appb-000045
Figure PCTCN2022070423-appb-000045
化合物23的合成参考实施例20中化合物20的合成步骤，其中第一步3-四氢呋喃甲醇代替20A，合成得到化合物23。The synthesis of compound 23 refers to the synthesis steps of compound 20 in Example 20, wherein in the first step, 3-tetrahydrofuran methanol replaces 20A, and compound 23 is synthesized.
MS(ESI):m/z 528[M+1] +。 MS(ESI): m/z 528[M+1] + .
1H-NMR(400MHz,DMSO):δ(ppm)8.10(d,J＝5.3Hz,1H),7.66(t,J＝7.2Hz,1H),7.60(s,1H),7.49(t,J＝6.9Hz,1H),7.28(dd,J＝16.5,8.9Hz,1H),7.23(t,J＝52.0Hz,1H),6.82(s,1H),5.85-5.77(m,1H),4.35(dd,J＝10.6,2.7Hz,1H),4.05-3.95(m,2H),3.81-3.69(m,2H),3.63(dd,J＝15.4,7.5Hz,1H),3.43-3.40(m,2H),3.13(d,J＝10.3Hz,1H),3.09-2.92(m,2H),2.83-2.74(m,1H),2.37-2.32(m,2H),2.26(s,3H),2.23-2.18(m,1H),2.03-1.90(m,1H),1.77–1.70(m,1H),1.60(d,J＝7.1Hz,3H),1.56-1.52(m,1H). 1 H-NMR (400MHz, DMSO): δ(ppm) 8.10(d, J=5.3Hz, 1H), 7.66(t, J=7.2Hz, 1H), 7.60(s, 1H), 7.49(t, J ＝6.9Hz,1H),7.28(dd,J＝16.5,8.9Hz,1H),7.23(t,J＝52.0Hz,1H),6.82(s,1H),5.85-5.77(m,1H),4.35 (dd,J=10.6,2.7Hz,1H),4.05-3.95(m,2H),3.81-3.69(m,2H),3.63(dd,J=15.4,7.5Hz,1H),3.43-3.40(m ,2H),3.13(d,J＝10.3Hz,1H),3.09-2.92(m,2H),2.83-2.74(m,1H),2.37-2.32(m,2H),2.26(s,3H), 2.23-2.18(m, 1H), 2.03-1.90(m, 1H), 1.77-1.70(m, 1H), 1.60(d, J=7.1Hz, 3H), 1.56-1.52(m, 1H).
实施例24：化合物24的制备Example 24: Preparation of Compound 24
Figure PCTCN2022070423-appb-000046
Figure PCTCN2022070423-appb-000046
化合物24的合成参考实施例20中化合物20的合成步骤，其中第二步溴乙腈代替20B，合成得到化合物24。The synthesis of compound 24 refers to the synthesis steps of compound 20 in Example 20, wherein in the second step, bromoacetonitrile replaces 20B, and compound 24 is synthesized.
MS(ESI):m/z 483[M+1] +。 MS(ESI): m/z 483[M+1] + .
1H NMR(400MHz,CDCl 3):δ(ppm)7.51-7.46(m,2H),7.26(s,1H),7.18(t,J＝7.7Hz,1H),7.10(s,1H),6.92(t,J＝56.0Hz,1H),6.85(s,1H),5.85-5.66(m,1H),4.29(dd,J＝10.7,2.7Hz,1H),4.12(t,J＝9.9Hz,1H),3.89(d,J＝10.0Hz,1H),3.63(s,2H),3.32(dd,J＝13.3,6.4Hz,1H),3.00-2.97(m,2H),2.83-2.65(m,2H),2.49(s,3H),2.28(t,J＝10.6Hz,1H),1.71(d,J＝6.7Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) 7.51-7.46 (m, 2H), 7.26 (s, 1H), 7.18 (t, J=7.7Hz, 1H), 7.10 (s, 1H), 6.92 (t, J＝56.0Hz, 1H), 6.85(s, 1H), 5.85-5.66(m, 1H), 4.29(dd, J＝10.7, 2.7Hz, 1H), 4.12(t, J＝9.9Hz, 1H), 3.89(d, J=10.0Hz, 1H), 3.63(s, 2H), 3.32(dd, J=13.3, 6.4Hz, 1H), 3.00-2.97(m, 2H), 2.83-2.65(m , 2H), 2.49(s, 3H), 2.28(t, J=10.6Hz, 1H), 1.71(d, J=6.7Hz, 3H).
实施例25：化合物25的制备Example 25: Preparation of Compound 25
Figure PCTCN2022070423-appb-000047
Figure PCTCN2022070423-appb-000047
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000048
Figure PCTCN2022070423-appb-000048
制备方法：Preparation:
第一步：合成化合物25CStep 1: Synthesis of compound 25C
将化合物25A(12.5g，57.57mmol)溶于DMF(125ml)中，再加入25B(7.42g，63.33mmol)，然后滴加DIEA(23.4g，181.4mmol)，加完后将反应液加热到80℃搅拌 16h。TLC显示反应结束后，把反应液倒入乙酸乙酯(200ml)和饱和NaCl溶液(500ml)中，分出有机层,水相再用乙酸乙酯萃取(150ml×3)，合并有机相，用无水硫酸钠干燥，然后旋干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1)，得到化合物25C(15.6g，黄色液体，产率86.22％)。Compound 25A (12.5 g, 57.57 mmol) was dissolved in DMF (125 ml), 25B (7.42 g, 63.33 mmol) was added, DIEA (23.4 g, 181.4 mmol) was added dropwise, and the reaction solution was heated to 80 °C °C stirred for 16h. After TLC showed that the reaction was over, the reaction solution was poured into ethyl acetate (200ml) and saturated NaCl solution (500ml), the organic layer was separated, the aqueous phase was extracted with ethyl acetate (150ml×3), the organic phases were combined, and the Dry over anhydrous sodium sulfate, then spin dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain compound 25C (15.6 g, yellow liquid, yield 86.22%) .
MS(ESI):m/z 315.09[M+1] +。 MS(ESI): m/z 315.09[M+1] + .
第二步：合成化合物25DStep 2: Synthesis of Compound 25D
将化合物25C(15.6g，49.64mmol)溶于DMF(125mL)中，在0℃下分批加入NaH(2g，49.64mmol)，然后升温到30℃搅拌2h。TLC显示反应结束后，把反应液中加到饱和NaCl溶液(500mL)中，用乙酸乙酯萃取(150ml×3)，合并有机相，用无水硫酸钠干燥，然后旋干，得到化合物25D(14.1g,黄色油状，产率96.53％)。无需继续纯化，直接用于下一步。Compound 25C (15.6 g, 49.64 mmol) was dissolved in DMF (125 mL), NaH (2 g, 49.64 mmol) was added in portions at 0 °C, and then the temperature was raised to 30 °C and stirred for 2 h. After TLC showed that the reaction was over, the reaction solution was added to saturated NaCl solution (500 mL), extracted with ethyl acetate (150 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried to obtain compound 25D ( 14.1 g, yellow oil, 96.53% yield). It was used directly in the next step without further purification.
MS(ESI):m/z 295[M+1] +。 MS(ESI): m/z 295[M+1] + .
第三步：合成化合物25EStep 3: Synthesis of Compound 25E
将化合物25D(14.1g，47.92mmol)溶于甲醇(140mL)中，再加质量分数为10％的Pb/C(1.4g，0.1eq)，加完后，瓶口套上氢气球，置换三次气体后，保持氢气氛围室温反应5h。TLC显示反应结束后，将反应液过滤，滤液旋干后，得到化合物25E(12g，灰色固体，产率94.76％)。无需继续纯化，直接用于下一步。Compound 25D (14.1 g, 47.92 mmol) was dissolved in methanol (140 mL), and Pb/C (1.4 g, 0.1 eq) with a mass fraction of 10% was added. After the addition, the bottle was covered with a hydrogen balloon and replaced three times. After degassing, keep the hydrogen atmosphere at room temperature for 5h. After TLC showed that the reaction was completed, the reaction solution was filtered, and the filtrate was spin-dried to obtain compound 25E (12 g, gray solid, yield 94.76%). It was used directly in the next step without further purification.
MS(ESI):m/z 265[M+1] +。 MS(ESI): m/z 265[M+1] + .
第四步：合成化合物25FStep 4: Synthesis of Compound 25F
将化合物25E(5g，18.92mmol)溶于乙腈(5ml)中，再加4％HCl-MeCN(50mL)，然后把反应液放到110℃下反应过夜。TLC显示反应结束后，将反应液冷却到室温，析出大量固体，过滤固体，并用冰的乙腈洗涤多次，然后干燥，得到化合物25F(3.6g，白色固体，产率69.63％)。Compound 25E (5 g, 18.92 mmol) was dissolved in acetonitrile (5 ml), 4% HCl-MeCN (50 mL) was added, and the reaction solution was placed at 110° C. for overnight reaction. After TLC showed that the reaction was completed, the reaction solution was cooled to room temperature, and a large amount of solid was precipitated. The solid was filtered, washed with ice-cold acetonitrile several times, and then dried to obtain compound 25F (3.6 g, white solid, yield 69.63%).
MS(ESI):m/z 274[M+1] +。 MS(ESI): m/z 274[M+1] + .
第五步：合成化合物25GStep 5: Synthesis of Compound 25G
将化合物25F(2g，7.32mmol)溶于POCl 3(23mL)中，再加DMF(3滴)，然后将反应加热到100℃下反应。TLC显示反应结束后，将反应液旋干，然后用饱和碳酸氢钠水溶液在调成弱碱性(PH＝8-9)，再加水稀释(100mL)，所得到的水相用用乙酸乙酯萃取(150ml×3)，合并有机相，用无水硫酸钠干燥，然后旋干，残余物用硅胶柱层析纯化(洗 脱剂：乙酸乙酯/异丙醇＝10:1)，得到化合物25G(1.6g，淡黄色粉末，74.94％)。 Compound 25F (2 g, 7.32 mmol) was dissolved in POCl3 (23 mL), followed by DMF (3 drops), and the reaction was heated to 100 °C. After TLC showed that the reaction was completed, the reaction solution was spin-dried, and then adjusted to weakly alkaline (PH=8-9) with saturated aqueous sodium bicarbonate solution, and then diluted with water (100 mL), and the obtained aqueous phase was washed with ethyl acetate Extraction (150ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, and then spin-dried. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/isopropanol=10:1) to obtain the compound 25G (1.6 g, pale yellow powder, 74.94%).
MS(ESI):m/z 292[M+1] +。 MS(ESI): m/z 292[M+1] + .
第六步：合成化合物25IStep 6: Synthesis of Compound 25I
将化合物25G(500mg，1.71mmol)溶于DMF(5mL)中，再加25H(401mg，1.71mmol)，然后加DIEA(665mg，5.16mmol)，然后将反应液加热到80℃下反应16h，TLC显示反应结束后，将反应液旋干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3:1)，得到化合物25I(200mg，淡黄色油状，23.84％)Compound 25G (500 mg, 1.71 mmol) was dissolved in DMF (5 mL), 25H (401 mg, 1.71 mmol) was added, then DIEA (665 mg, 5.16 mmol) was added, and the reaction solution was heated to 80 °C for 16 h. TLC After the completion of the reaction, the reaction solution was spun dry, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3:1) to obtain compound 25I (200 mg, pale yellow oil, 23.84%)
MS(ESI):m/z 490[M+1] +。 MS(ESI): m/z 490[M+1] + .
第七步：合成化合物25Step 7: Synthesis of Compound 25
将化合物25I(200mg，408.62mmol)溶于乙醇/水(1.6mL/0.4mL)中，再加氯化铵(176.7mg，3.11mmol)，然后加入铁粉(91.6mg，1.636mmol)，将反应液加热到80℃下回流1h，TLC显示反应结束后，将反应液过滤，滤液旋干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1)，得到化合物25(325mg，淡黄色固体)。Compound 25I (200 mg, 408.62 mmol) was dissolved in ethanol/water (1.6 mL/0.4 mL), ammonium chloride (176.7 mg, 3.11 mmol) was added, and iron powder (91.6 mg, 1.636 mmol) was added to the reaction. The solution was heated to 80°C and refluxed for 1 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:1) to obtain Compound 25 (325 mg, pale yellow solid).
MS(ESI):m/z 460[M+1] +。 MS(ESI): m/z 460[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)7.95(d,J＝7.8Hz,1H),7.55(s,1H),6.87-6.84(m,3H),6.70(s,1H),5.61–5.55(m,1H),5.54(s,2H),4.32(dd,J＝10.7,2.0Hz,1H),4.08(dd,J＝11.3,2.9Hz,1H),3.96–3.90(m,2H),3.83(d,J＝11.6Hz,1H),3.68–3.35(m,1H),3.24–3.17(m,2H),2.85–2.82(m,1H),2.32(s,3H),1.54(d,J＝7.1Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)7.95(d,J=7.8Hz,1H),7.55(s,1H),6.87-6.84(m,3H),6.70(s,1H),5.61-5.55 (m,1H),5.54(s,2H),4.32(dd,J=10.7,2.0Hz,1H),4.08(dd,J=11.3,2.9Hz,1H),3.96–3.90(m,2H), 3.83(d,J=11.6Hz,1H),3.68-3.35(m,1H),3.24-3.17(m,2H),2.85-2.82(m,1H),2.32(s,3H),1.54(d, J=7.1Hz, 3H).
实施例26：化合物26的制备Example 26: Preparation of Compound 26
Figure PCTCN2022070423-appb-000049
Figure PCTCN2022070423-appb-000049
化合物26的合成参考实施例25中化合物25的合成步骤，其中第六步用(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺代替25H，合成得到化合物26。The synthesis of compound 26 refers to the synthesis procedure of compound 25 in Example 25, wherein in the sixth step, (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine is used instead of 25H , compound 26 was synthesized.
MS(ESI):m/z 445[M+1] +。 MS(ESI): m/z 445[M+1] + .
1H-NMR(400MHz,DMSO)δ(ppm)7.99(d,J＝7.2Hz,1H),7.65(t,J＝7.3Hz,1H),7.59(s,1H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.24(t,J＝72Hz,1H)6.84(s,1H), 5.80(m,1H),4.33(dd,J＝10.8,2.0Hz,1H),4.17–4.05(m,1H),4.02–3.79(m,3H),3.70(dd,J＝11.8,9.3Hz,1H),3.26–3.18(m,2H),2.86(n,1H),2.27(s,3H),1.60(d,J＝7.1Hz,3H). 1 H-NMR(400MHz,DMSO)δ(ppm)7.99(d,J=7.2Hz,1H),7.65(t,J=7.3Hz,1H),7.59(s,1H),7.49(t,J= 6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.24(t, J=72Hz, 1H), 6.84(s, 1H), 5.80(m, 1H), 4.33(dd, J=10.8, 2.0Hz, 1H), 4.17–4.05 (m, 1H), 4.02–3.79 (m, 3H), 3.70 (dd, J=11.8, 9.3Hz, 1H), 3.26–3.18 (m, 2H), 2.86 (n ,1H),2.27(s,3H),1.60(d,J=7.1Hz,3H).
实施例27：化合物27的制备Example 27: Preparation of Compound 27
Figure PCTCN2022070423-appb-000050
Figure PCTCN2022070423-appb-000050
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000051
Figure PCTCN2022070423-appb-000051
制备方法：Preparation:
第一步：合成化合物27AStep 1: Synthesis of compound 27A
向化合物10A(4.42g，14.1mmol)中加入1，2-二氯乙烷(50mL)中，再加四氯化碳(1.73g，11.3mmol)，然后加入三苯基膦(1.48g，5.64mmol，4.0eq)，加完后，用氮气置换三次气体，然后氮气保护下将反应液加热到80℃下搅拌2h。TLC显示反应结束后，旋干，得到粗品化合物27A(5.2g，深棕色油状)，无需进一步纯化，直接用于下一步。To compound 10A (4.42 g, 14.1 mmol) was added 1,2-dichloroethane (50 mL), followed by carbon tetrachloride (1.73 g, 11.3 mmol), followed by triphenylphosphine (1.48 g, 5.64 g) mmol, 4.0 eq), after the addition, the gas was replaced with nitrogen three times, and then the reaction solution was heated to 80° C. and stirred for 2 h under nitrogen protection. After TLC showed that the reaction was over, it was spin-dried to obtain the crude compound 27A (5.2 g, dark brown oil), which was used in the next step without further purification.
MS(ESI):m/z 333.3[M+1] +。 MS(ESI): m/z 333.3[M+1] + .
第二步：合成化合物27BStep 2: Synthesis of Compound 27B
向上一步得到的粗品化合物27A(5.2g)中加入NMP(50mL)，再加(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(2.84g，15.0mmol，1.0eq)和DIEA(3.8g，30.0mmol)，加完后，将反应液加热到100℃下搅拌3h。TLC显示反应结束后，向反应液中加入乙酸乙酯(100mL)和饱和食盐水(100mL)，分出有机层，水相用乙酸乙酯(100mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂为二氯甲烷：甲醇＝20：1(体积比))，得到化合物27B(5.5g，淡黄色固体，两步产率80.2％)。NMP (50 mL) was added to the crude compound 27A (5.2 g) obtained in the previous step, followed by (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (2.84 g). g, 15.0 mmol, 1.0 eq) and DIEA (3.8 g, 30.0 mmol), after the addition, the reaction solution was heated to 100 °C and stirred for 3 h. After TLC showed that the reaction was over, ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (100 mL×2), the organic phases were combined and dried , spin dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20: 1 (volume ratio)) to obtain compound 27B (5.5 g, pale yellow solid, two-step yield 80.2%) .
MS(ESI):m/z 486.2[M+1] +。 MS(ESI): m/z 486.2[M+1] + .
第三步：合成化合物27CThe third step: synthesis of compound 27C
将化合物27B(5.0g,10.3mmol)加入到乙醇(50mL)中，再加入浓盐酸(10mL)，然后升温到90℃，反应12小时，TLC显示反应结束，旋干得到化合物27C的盐酸盐粗品(5.7g,白色固体)，无需进一步纯化，直接用于下一步。Compound 27B (5.0 g, 10.3 mmol) was added to ethanol (50 mL), then concentrated hydrochloric acid (10 mL) was added, then the temperature was raised to 90 ° C, and the reaction was carried out for 12 hours. The crude product (5.7 g, white solid) was used in the next step without further purification.
第四步：合成化合物27Step 4: Synthesis of Compound 27
将化合物27C的粗品盐酸盐(0.57g)和化合物3-氧杂环丁烷羧酸(175mg，1.72mmol)加入到DMF(5.5mL)中，将反应液冷却到0℃，向反应液中逐滴滴加T3P(712mg，2.24mmol)，再逐滴滴加三乙胺(0.52g，5.16mmol)，滴加完毕，将反应液升温至25℃下反应1h。TLC显示反应结束后，再向反应液中加入乙酸乙酯(20mL)和饱和食盐水(20mL)，分出有机层，水相用乙酸乙酯(20mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20：1(体积比))，柱层析纯化的产物再用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物27(0.34g，灰白色固体，两步产率63.2％)。The crude hydrochloride of compound 27C (0.57 g) and compound 3-oxetane carboxylic acid (175 mg, 1.72 mmol) were added to DMF (5.5 mL), the reaction solution was cooled to 0° C., and added to the reaction solution. T3P (712 mg, 2.24 mmol) was added dropwise, and then triethylamine (0.52 g, 5.16 mmol) was added dropwise. After the dropwise addition was completed, the reaction solution was heated to 25° C. and reacted for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, Dry, spin dry, the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20:1 (volume ratio)), and the product purified by column chromatography is purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min to end ) to give compound 27 (0.34 g, off-white solid, 63.2% yield for two steps).
MS(ESI):m/z 528.2[M+1] +。 MS(ESI): m/z 528.2[M+1] + .
1H NMR(300MHz,DMSO):δ(ppm)8.05-7.97(m,1H),7.68-7.59(m,2H),7.49(t,J＝7.2Hz,1H),7.29(t,J＝7.6Hz,1H),7.24(d,J＝54.0Hz,1H),6.84(s,1H),5.85-5.74(m,1H),4.80-4.69(m,3H),4.68-4.36(m,3H),4.30-4.15(m,1H),4.13-3.95(m,2H),3.64-3.50(m,1H),3.28-3.04(m,2H),2.94-2.83(m,1H),2.79-2.66(m,1H),2.26(s,3H),1.60(d,J＝7.2Hz,3H). 1 H NMR (300MHz, DMSO): δ (ppm) 8.05-7.97 (m, 1H), 7.68-7.59 (m, 2H), 7.49 (t, J=7.2Hz, 1H), 7.29 (t, J=7.6 Hz, 1H), 7.24(d, J＝54.0Hz, 1H), 6.84(s, 1H), 5.85-5.74(m, 1H), 4.80-4.69(m, 3H), 4.68-4.36(m, 3H) ,4.30-4.15(m,1H),4.13-3.95(m,2H),3.64-3.50(m,1H),3.28-3.04(m,2H),2.94-2.83(m,1H),2.79-2.66( m, 1H), 2.26(s, 3H), 1.60(d, J=7.2Hz, 3H).
实施例28：化合物28的制备Example 28: Preparation of Compound 28
Figure PCTCN2022070423-appb-000052
Figure PCTCN2022070423-appb-000052
化合物28的合成参考实施例27中化合物27的合成步骤，其中第四步用(R)-四氢-3-呋喃甲酸代替3-氧杂环丁烷羧酸，合成得到化合物28。The synthesis of compound 28 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (R)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 28.
MS(ESI):m/z 542.2[M+1] +。 MS(ESI): m/z 542.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)9.62(s,1H),7.83(s,1H),7.71(t,J＝7.3Hz,1H),7.57(t,J＝7.1Hz,1H),7.37(t,J＝7.7Hz,1H),7.23(t,J＝54.3Hz,1H),6.97(s,1H),5.98-5.87(m,1H),4.66-4.45(m,2H),4.26-4.07(m,2H),4.01(d,J＝12.1Hz,1H),3.96-3.87(m,1H),3.80-3.61(m,3H),3.55-3.38(m,2H),3.25-3.12(m,1H),2.99-2.79(m,2H),2.52(s,3H),2.13-1.92(m,2H),1.69(d,J＝6.8Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 9.62 (s, 1H), 7.83 (s, 1H), 7.71 (t, J=7.3Hz, 1H), 7.57 (t, J=7.1Hz, 1H) ,7.37(t,J＝7.7Hz,1H),7.23(t,J＝54.3Hz,1H),6.97(s,1H),5.98-5.87(m,1H),4.66-4.45(m,2H), 4.26-4.07(m, 2H), 4.01(d, J=12.1Hz, 1H), 3.96-3.87(m, 1H), 3.80-3.61(m, 3H), 3.55-3.38(m, 2H), 3.25- 3.12(m, 1H), 2.99-2.79(m, 2H), 2.52(s, 3H), 2.13-1.92(m, 2H), 1.69(d, J=6.8Hz, 3H).
实施例29：化合物29的制备Example 29: Preparation of Compound 29
Figure PCTCN2022070423-appb-000053
Figure PCTCN2022070423-appb-000053
化合物29的合成参考实施例27中化合物27的合成步骤，其中第四步用(S)-四氢-3-呋喃甲酸代替3-氧杂环丁烷羧酸，合成得到化合物29。The synthesis of compound 29 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (S)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 29.
MS(ESI):542.2[M+1] +。 MS(ESI): 542.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)9.69-9.57(m,1H),7.83(s,1H),7.72(t,J＝7.3Hz,1H),7.57(t,J＝6.9Hz,1H),7.37(t,J＝7.7Hz,1H),7.23(t,J＝54.2Hz,1H),6.97(s,1H),5.97-5.89(m,1H),4.64-4.53(m,2H),4.26-4.08(m,2H),4.01(d,J＝11.9Hz,1H),3.96-3.88(m,1H),3.78-3.68(m,3H),3.56-3.38(m,2H),3.27-3.18(m,1H),3.01-2.76(m,2H),2.52(s,3H),2.15-1.91(m,3H),1.69(d,J＝6.8Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 9.69-9.57 (m, 1H), 7.83 (s, 1H), 7.72 (t, J=7.3Hz, 1H), 7.57 (t, J=6.9Hz, 1H), 7.37(t, J=7.7Hz, 1H), 7.23(t, J=54.2Hz, 1H), 6.97(s, 1H), 5.97-5.89(m, 1H), 4.64-4.53(m, 2H) ), 4.26-4.08(m, 2H), 4.01(d, J=11.9Hz, 1H), 3.96-3.88(m, 1H), 3.78-3.68(m, 3H), 3.56-3.38(m, 2H), 3.27-3.18(m, 1H), 3.01-2.76(m, 2H), 2.52(s, 3H), 2.15-1.91(m, 3H), 1.69(d, J=6.8Hz, 3H).
实施例30：化合物30的制备Example 30: Preparation of Compound 30
Figure PCTCN2022070423-appb-000054
Figure PCTCN2022070423-appb-000054
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000055
Figure PCTCN2022070423-appb-000055
制备方法：Preparation:
第一步：合成化合物30Step 1: Synthesis of Compound 30
将化合物27C的粗品盐酸盐(0.57g,1.03mmol)和加入到DMF(5.5mL)中，将反应液冷却到0℃，再逐滴滴加三乙胺(0.52g，5.16mmol)，再然后逐滴滴加氯甲酸甲酯(162mg,1.72mmol),将反应液升温至25℃下反应1h。TLC显示反应结束后，再向反应液中加入乙酸乙酯(20mL)和饱和食盐水(20mL)，分出有机层，水相用乙酸乙酯(20mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20：1(体积比))，柱层析纯化的产物再用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物30(142mg，灰白色固体，产率28.2％)。The crude hydrochloride of compound 27C (0.57 g, 1.03 mmol) was added to DMF (5.5 mL), the reaction solution was cooled to 0 °C, and triethylamine (0.52 g, 5.16 mmol) was added dropwise, followed by Then methyl chloroformate (162 mg, 1.72 mmol) was added dropwise, and the reaction solution was heated to 25 °C for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, Dry, spin dry, the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20:1 (volume ratio)), and the product purified by column chromatography is purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min to end ) to give compound 30 (142 mg, off-white solid, 28.2% yield).
MS(ESI):m/z 502.2[M+1] +。 MS(ESI): m/z 502.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.05(d,J＝7.2Hz,1H),7.71-7.62(m,2H),7.49(t,J＝6.8Hz,1H),7.28(t,J＝7.6Hz,1H),7.23(d,J＝54.0Hz,1H),6.84(s,1H),5.80(q,J＝7.2Hz,1H),4.44(dd,J＝10.8,2.4Hz,1H),4.14(d,J＝12.8Hz,1H),4.07(d,J＝12.0Hz, 2H),4.03-3.95(m,1H),3.66(s,3H),3.20-3.11(m,2H),2.84-2.65(m,2H),2.26(s,3H),1.60(d,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.05 (d, J=7.2Hz, 1H), 7.71-7.62 (m, 2H), 7.49 (t, J=6.8Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.23(d, J=54.0Hz, 1H), 6.84(s, 1H), 5.80(q, J=7.2Hz, 1H), 4.44(dd, J=10.8, 2.4Hz, 1H), 4.14(d, J=12.8Hz, 1H), 4.07(d, J=12.0Hz, 2H), 4.03-3.95(m, 1H), 3.66(s, 3H), 3.20-3.11(m, 2H) ), 2.84-2.65(m, 2H), 2.26(s, 3H), 1.60(d, J=7.2Hz, 3H).
实施例31：化合物31的制备Example 31: Preparation of Compound 31
Figure PCTCN2022070423-appb-000056
Figure PCTCN2022070423-appb-000056
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000057
Figure PCTCN2022070423-appb-000057
制备方法：Preparation:
第一步：合成化合物31Step 1: Synthesis of Compound 31
将化合物27C的粗品盐酸盐(0.29g，0.5mmol)加入到DCM(2mL)中，然后向反应液中加入三乙胺(100mg，1.0mmol)，将反应液冷却到0℃，分批加入三光气(296mg，1.0mmol)，加完后，0℃反应30min。TLC显示反应结束后，再加入二甲胺盐酸盐(81.5mg，1.0mmol)，并补加三乙胺(100mg，1.0mmol)，加完后，将反应液升温到室温搅拌反应1h。TLC显示反应结束后，向反应液中加入水(50mL)，分出有机层，水相用乙酸乙酯(5mL×2)萃取两次，合并有机相，干燥，旋干，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物31(108mg,白色固体，产率42.0％)。The crude hydrochloride of compound 27C (0.29 g, 0.5 mmol) was added to DCM (2 mL), then triethylamine (100 mg, 1.0 mmol) was added to the reaction solution, the reaction solution was cooled to 0 °C, and added in batches Triphosgene (296 mg, 1.0 mmol) was added and reacted at 0°C for 30 min. After TLC showed that the reaction was completed, dimethylamine hydrochloride (81.5 mg, 1.0 mmol) was added, and triethylamine (100 mg, 1.0 mmol) was added. After the addition, the reaction solution was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was over, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 mL×2), the organic phases were combined, dried, and spun to dry, and the residue was prepared by HPLC Purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile was run to the end of 16 min) to give compound 31 (108 mg, white solid, 42.0% yield).
MS(ESI):m/z 515.2[M+1] +。 MS(ESI): m/z 515.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)9.97(s,1H),8.10(s,1H),7.87(t,J＝7.3Hz,1H),7.54(t,J＝6.9Hz,1H),7.34(t,J＝7.7Hz,1H),7.23(t,J＝54.3Hz,1H),7.07(s,1H),6.01- 5.91(m,1H),4.53(dd,J＝10.9,2.8Hz,1H),4.16(d,J＝11.8Hz,1H),4.09(t,J＝10.0Hz,1H),3.70(d,J＝12.1Hz,2H),3.63(d,J＝12.3Hz,1H),3.26(dd,J＝13.1,6.7Hz,1H),3.04-2.95(m,2H),2.93-2.84(m,4H),2.82(s,6H),2.61-2.54(m,1H),2.49(s,3H),1.71(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 9.97 (s, 1H), 8.10 (s, 1H), 7.87 (t, J=7.3Hz, 1H), 7.54 (t, J=6.9Hz, 1H) ,7.34(t,J=7.7Hz,1H),7.23(t,J=54.3Hz,1H),7.07(s,1H),6.01- 5.91(m,1H),4.53(dd,J=10.9,2.8 Hz, 1H), 4.16(d, J＝11.8Hz, 1H), 4.09(t, J＝10.0Hz, 1H), 3.70(d, J＝12.1Hz, 2H), 3.63(d, J＝12.3Hz, 1H), 3.26(dd, J＝13.1, 6.7Hz, 1H), 3.04-2.95(m, 2H), 2.93-2.84(m, 4H), 2.82(s, 6H), 2.61-2.54(m, 1H) ,2.49(s,3H),1.71(d,J=7.1Hz,3H).
实施例32：化合物32的制备Example 32: Preparation of Compound 32
Figure PCTCN2022070423-appb-000058
Figure PCTCN2022070423-appb-000058
化合物32的合成参考实施例27中化合物27的合成步骤，其中第四步用1-甲基-3-氮杂丁烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物32。The synthesis of compound 32 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methyl-3-azetidine carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 32.
MS(ESI):541.2[M+1] +。 MS(ESI): 541.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.19(s,1H),8.02(d,J＝7.0Hz,1H),7.68-7.61(m,1H),7.50(t,J＝7.1Hz,1H),7.28(t,J＝7.1Hz,1H),7.23(t,J＝54.4Hz,1H),6.84(s,1H),5.85-5.75(m,1H),4.57-4.40(m,3H),4.10-3.97(m,2H),3.79-3.61(m,4H),3.43-3.25(m,2H),3.18-3.02(m,1H),2.96-2.81(m,1H),2.78-2.65(m,1H),2.33(s,3H),2.26(s,3H),1.60(d,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.19 (s, 1H), 8.02 (d, J=7.0Hz, 1H), 7.68-7.61 (m, 1H), 7.50 (t, J=7.1Hz, 1H), 7.28(t, J＝7.1Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.84(s, 1H), 5.85-5.75(m, 1H), 4.57-4.40(m, 3H) ), 4.10-3.97(m, 2H), 3.79-3.61(m, 4H), 3.43-3.25(m, 2H), 3.18-3.02(m, 1H), 2.96-2.81(m, 1H), 2.78-2.65 (m, 1H), 2.33(s, 3H), 2.26(s, 3H), 1.60(d, J=7.0Hz, 3H).
实施例33：化合物33的制备Example 33: Preparation of Compound 33
Figure PCTCN2022070423-appb-000059
Figure PCTCN2022070423-appb-000059
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000060
Figure PCTCN2022070423-appb-000060
制备方法：Preparation:
第一步：合成化合物33Step 1: Synthesis of Compound 33
将化合物27C的粗品盐酸盐(0.29g，0.5mmol)和2-溴-N,N-二甲基乙酰胺(166mg,1.0mmol)加入到DMF(5.0mL)中，然后加入碳酸钾(138mg，1.0mmol)，室温反应过夜，TLC显示还有部分原料没有反应完，继续补加2-溴-N,N-二甲基乙酰胺(166mg,1.0mmol)和碳酸钾(138mg，1.0mmol)，反应3小时，TLC显示反应结束，向反应液中加入水(50mL)，分出有机层，水相用乙酸乙酯(15mL×2)萃取两次，合并有机相，干燥，旋干，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物33(87.3mg,白色固体，产率33.0％)。The crude hydrochloride salt of compound 27C (0.29 g, 0.5 mmol) and 2-bromo-N,N-dimethylacetamide (166 mg, 1.0 mmol) were added to DMF (5.0 mL) followed by potassium carbonate (138 mg) , 1.0mmol), reacted at room temperature overnight, TLC showed that some raw materials were not reacted, continued to add 2-bromo-N,N-dimethylacetamide (166mg, 1.0mmol) and potassium carbonate (138mg, 1.0mmol) , reacted for 3 hours, TLC showed that the reaction was over, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (15 mL×2), the organic phases were combined, dried, and spun to dry, the residual The compound was preparatively purified by HPLC (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile run for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile Run to 14min, 10% acetonitrile run to 16min end) to give compound 33 (87.3 mg, white solid, 33.0% yield).
MS(ESI):m/z 529.3[M+1] +。 MS(ESI): m/z 529.3[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)7.98(d,J＝7.2Hz,1H),7.65(t,J＝7.2Hz,1H),7.59(s,1H),7.49(t,J＝6.8Hz,1H),7.28(t,J＝7.6Hz,1H),7.23(d,J＝54.0Hz,1H),6.82(s,1H),5.80(q,J＝6.8Hz,1H),4.34(dd,J＝10.8,2.8Hz,1H),4.03-3.91(m,2H),3.30(s,1H),3.21(d,J＝14.4Hz,1H),3.15(d,J＝9.6Hz,1H),3.08(d,J＝10.8Hz,1H),3.03(s,3H),2.95(d,J＝10.4Hz,1H),2.87-2.76(m,4H),2.47-2.38(m,1H),2.26(s,3H),1.97(t,J＝10.8Hz,1H),1.59(d,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 7.98 (d, J=7.2Hz, 1H), 7.65 (t, J=7.2Hz, 1H), 7.59 (s, 1H), 7.49 (t, J= 6.8Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23(d, J=54.0Hz, 1H), 6.82(s, 1H), 5.80(q, J=6.8Hz, 1H), 4.34 (dd,J=10.8,2.8Hz,1H),4.03-3.91(m,2H),3.30(s,1H),3.21(d,J=14.4Hz,1H),3.15(d,J=9.6Hz, 1H), 3.08(d, J=10.8Hz, 1H), 3.03(s, 3H), 2.95(d, J=10.4Hz, 1H), 2.87-2.76(m, 4H), 2.47-2.38(m, 1H) ), 2.26(s, 3H), 1.97(t, J=10.8Hz, 1H), 1.59(d, J=7.2Hz, 3H).
实施例34：化合物34的制备Example 34: Preparation of Compound 34
Figure PCTCN2022070423-appb-000061
Figure PCTCN2022070423-appb-000061
化合物34的合成参考实施例27中化合物27的合成步骤，其中第四步用1-氰基-1-环丙烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物34。The synthesis of compound 34 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-cyano-1-cyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 34.
MS(ESI):537.2[M+1] +。 MS(ESI): 537.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.04(d,J＝7.2Hz,1H),7.72-7.59(m,2H),7.49(t,J＝6.8Hz,1H),7.28(t,J＝7.6Hz,1H),7.24(d,J＝54.0Hz,1H),6.86(s,1H),5.79(q,J＝6.89Hz,1H),4.57-4.42(m,2H),4.37(d,J＝12.4Hz,1H),4.18-4.03(m,2H),3.32-3.13(m,2H),2.98-2.79(m,2H),2.26(s,3H),1.74-1.47(m,7H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.04 (d, J=7.2Hz, 1H), 7.72-7.59 (m, 2H), 7.49 (t, J=6.8Hz, 1H), 7.28 (t, J=7.6Hz, 1H), 7.24(d, J=54.0Hz, 1H), 6.86(s, 1H), 5.79(q, J=6.89Hz, 1H), 4.57-4.42(m, 2H), 4.37( d, J＝12.4Hz, 1H), 4.18-4.03(m, 2H), 3.32-3.13(m, 2H), 2.98-2.79(m, 2H), 2.26(s, 3H), 1.74-1.47(m, 7H).
实施例35：化合物35的制备Example 35: Preparation of Compound 35
Figure PCTCN2022070423-appb-000062
Figure PCTCN2022070423-appb-000062
化合物35的合成参考实施例27中化合物27的合成步骤，其中第四步用N-甲基-D-脯氨酸代替3-氧杂环丁烷羧酸，合成得到化合物35。The synthesis of compound 35 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, N-methyl-D-proline is used instead of 3-oxetane carboxylic acid to synthesize compound 35.
MS(ESI):555.2[M+1] +。 MS(ESI): 555.2[M+1] + .
1H NMR(400MHz,DMSO):δ(ppm)8.02(d,J＝7.2Hz,1H),7.65(d,J＝8.5Hz,2H),7.49(t,J＝6.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.85(s,1H),5.86–5.75(m,1H),4.66–4.28(m,5H),4.10–4.03(m,2H),3.51-3.49(m,1H),3.13–3.08(m,1H),2.95-2.92(m,1H),2.75-2.67(m,1H),2.33-2.31(m,4H),2.26(s,3H),2.19-2.16(m,1H),1.86-1.73(m,3H),1.60(d,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO): δ (ppm) 8.02 (d, J=7.2Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 7.49 (t, J=6.9Hz, 1H), 7.28 (t, J=7.7Hz, 1H), 7.23 (t, J=52.0Hz, 1H), 6.85 (s, 1H), 5.86–5.75 (m, 1H), 4.66–4.28 (m, 5H), 4.10– 4.03(m, 2H), 3.51-3.49(m, 1H), 3.13-3.08(m, 1H), 2.95-2.92(m, 1H), 2.75-2.67(m, 1H), 2.33-2.31(m, 4H ), 2.26(s, 3H), 2.19-2.16(m, 1H), 1.86-1.73(m, 3H), 1.60(d, J=7.0Hz, 3H).
实施例36：化合物36的制备Example 36: Preparation of Compound 36
Figure PCTCN2022070423-appb-000063
Figure PCTCN2022070423-appb-000063
化合物36的合成参考实施例30中化合物30的合成步骤，其中第一步用甲基磺酰氯代替氯甲酸甲酯，合成得到化合物36。The synthesis of compound 36 refers to the synthesis steps of compound 30 in Example 30, wherein in the first step, methyl chloroformate is replaced by methylsulfonyl chloride, and compound 36 is synthesized.
MS(ESI):522.2[M+1] +。 MS(ESI): 522.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.04(d,J＝7.2Hz,1H),7.69(s,1H),7.65(t,J＝7.2Hz,1H),7.49(t,J＝6.8Hz,1H),7.29(t,J＝7.6Hz,1H),7.23(d,J＝54.0Hz,1H),6.86(s,1H),5.80(q,J＝6.8Hz,1H),4.46(dd,J＝10.8,2.4Hz,1H),4.20(d,J＝12.0Hz,1H),4.03(dd,J＝10.8,8.8Hz,1H),3.70(dd,J＝19.6,11.2Hz,2H),3.33-3.27(m,1H),3.10-2.87(m,5H),2.63(t,J＝11.2Hz,1H),2.26(s,3H),1.60(d,J＝7.2Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.04(d,J=7.2Hz,1H),7.69(s,1H),7.65(t,J=7.2Hz,1H),7.49(t,J=6.8 Hz, 1H), 7.29(t, J＝7.6Hz, 1H), 7.23(d, J＝54.0Hz, 1H), 6.86(s, 1H), 5.80(q, J＝6.8Hz, 1H), 4.46( dd,J＝10.8,2.4Hz,1H),4.20(d,J＝12.0Hz,1H),4.03(dd,J＝10.8,8.8Hz,1H),3.70(dd,J＝19.6,11.2Hz,2H) ),3.33-3.27(m,1H),3.10-2.87(m,5H),2.63(t,J=11.2Hz,1H),2.26(s,3H),1.60(d,J=7.2Hz,3H) .
实施例37：化合物37的制备Example 37: Preparation of Compound 37
Figure PCTCN2022070423-appb-000064
Figure PCTCN2022070423-appb-000064
化合物37的合成参考实施例27中化合物27的合成步骤，其中第四步用3-甲氧基丙酸代替3-氧杂环丁烷羧酸，合成得到化合物37。The synthesis of compound 37 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 3-methoxypropionic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 37.
MS(ESI):530.2[M+1] +。 MS(ESI): 530.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.00(t,J＝6.0Hz,1H),7.69-7.61(m,2H),7.49(t,J＝6.8Hz,1H),7.28(t,J＝7.67Hz,1H),7.23(d,J＝54.4Hz,1H),6.84(s,1H),5.85-5.74(s,1H),4.54(dd,J＝35.2,12.8Hz,1H),4.44(d,J＝10.4Hz,1H),4.19-3.96(m,3H),3.59(dd,J＝10.4,5.6Hz,2H),3.24(s,3H),3.11(dt,J＝17.6,9.6Hz,1H),2.94-2.82(m,1H),2.82-2.58(m,3H),2.47-2.37(m,1H),2.26(s,3H),1.60(d,J＝7.2Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.00(t,J=6.0Hz,1H),7.69-7.61(m,2H),7.49(t,J=6.8Hz,1H),7.28(t,J ＝7.67Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.84(s, 1H), 5.85-5.74(s, 1H), 4.54(dd, J＝35.2, 12.8Hz, 1H), 4.44 (d, J=10.4Hz, 1H), 4.19-3.96 (m, 3H), 3.59 (dd, J=10.4, 5.6Hz, 2H), 3.24 (s, 3H), 3.11 (dt, J=17.6, 9.6 Hz, 1H), 2.94-2.82(m, 1H), 2.82-2.58(m, 3H), 2.47-2.37(m, 1H), 2.26(s, 3H), 1.60(d, J=7.2Hz, 3H) .
实施例38：化合物38的制备Example 38: Preparation of Compound 38
Figure PCTCN2022070423-appb-000065
Figure PCTCN2022070423-appb-000065
化合物38的合成参考实施例27中化合物27的合成步骤，其中第四步用特戊酸代替3-氧杂环丁烷羧酸，合成得到化合物38。The synthesis of compound 38 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, pivalic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 38.
MS(ESI):528.2[M+1] +。 MS(ESI): 528.2[M+1] + .
1H NMR(300MHz,DMSO)δ(ppm)8.02(d,J＝7.3Hz,1H),7.69-7.58(m,2H),7.49(t,J＝7.2Hz,1H),7.28(t,J＝7.8Hz,1H),7.24(t,J＝54.3Hz,1H),6.84(s,1H),5.86-5.73(m,1H),4.59-4.47(m,2H),4.41(d,J＝13.4Hz,1H),4.09-3.94(m,2H),3.21-3.04(m,2H),2.73(dd,J＝22.5,10.3Hz,2H),2.26(s,3H),1.60(d,J＝7.1Hz,3H),1.26(s,9H). 1 H NMR(300MHz,DMSO)δ(ppm)8.02(d,J=7.3Hz,1H),7.69-7.58(m,2H),7.49(t,J=7.2Hz,1H),7.28(t,J ＝7.8Hz, 1H), 7.24(t, J＝54.3Hz, 1H), 6.84(s, 1H), 5.86-5.73(m, 1H), 4.59-4.47(m, 2H), 4.41(d, J＝ 13.4Hz, 1H), 4.09-3.94(m, 2H), 3.21-3.04(m, 2H), 2.73(dd, J=22.5, 10.3Hz, 2H), 2.26(s, 3H), 1.60(d, J =7.1Hz,3H),1.26(s,9H).
实施例39：化合物39的制备Example 39: Preparation of Compound 39
Figure PCTCN2022070423-appb-000066
Figure PCTCN2022070423-appb-000066
化合物39的合成参考实施例27中化合物27的合成步骤，其中第四步用1-氟环丙烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物39。The synthesis of compound 39 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-fluorocyclopropane carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 39.
MS(ESI):530.2[M+1] +。 MS(ESI): 530.2[M+1] + .
1H NMR(300MHz,DMSO)δ(ppm)8.03(d,J＝7.2Hz,1H),7.64(d,J＝8.4Hz,2H),7.49(t,J＝7.0Hz,1H),7.28(t,J＝7.7Hz,1H),7.24(t,J＝54.3Hz,1H),6.86(s,1H),5.88-5.72(m,1H),4.56-4.27(m,3H),4.08(dd,J＝17.0,8.1Hz,2H),3.28-3.12(m,2H),2.94-2.79(m,2H),2.26(s,3H),1.60(d,J＝7.0Hz,3H),1.43-1.14(m,4H). 1 H NMR(300MHz,DMSO)δ(ppm)8.03(d,J=7.2Hz,1H),7.64(d,J=8.4Hz,2H),7.49(t,J=7.0Hz,1H),7.28( t, J＝7.7Hz, 1H), 7.24(t, J＝54.3Hz, 1H), 6.86(s, 1H), 5.88-5.72(m, 1H), 4.56-4.27(m, 3H), 4.08(dd , J=17.0, 8.1Hz, 2H), 3.28-3.12(m, 2H), 2.94-2.79(m, 2H), 2.26(s, 3H), 1.60(d, J=7.0Hz, 3H), 1.43- 1.14(m,4H).
实施例40：化合物40的制备Example 40: Preparation of Compound 40
Figure PCTCN2022070423-appb-000067
Figure PCTCN2022070423-appb-000067
化合物40的合成参考实施例27中化合物27的合成步骤，其中第四步用甲氧基乙酸代替3-氧杂环丁烷羧酸，合成得到化合物40。The synthesis of compound 40 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, methoxyacetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 40.
MS(ESI):516.2[M+1] +。 MS(ESI): 516.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.01(d,J＝7.3Hz,1H),7.65(d,J＝7.7Hz,2H),7.49(t,J＝6.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.84(s,1H),5.80(q,J＝6.8Hz,1H),4.62-4.35(m,2H),4.31-3.85(m,5H),3.33(s,3H),3.15(d,J＝42.7Hz,1H),3.00-2.69(m,2H),2.48-2.43(m,1H),2.26(s,3H),1.60(d,J＝7.0Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.01(d,J=7.3Hz,1H),7.65(d,J=7.7Hz,2H),7.49(t,J=6.9Hz,1H),7.28( t, J＝7.7Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.84(s, 1H), 5.80(q, J＝6.8Hz, 1H), 4.62-4.35(m, 2H), 4.31-3.85(m, 5H), 3.33(s, 3H), 3.15(d, J=42.7Hz, 1H), 3.00-2.69(m, 2H), 2.48-2.43(m, 1H), 2.26(s, 3H),1.60(d,J=7.0Hz,3H).
实施例41：化合物41的制备Example 41: Preparation of Compound 41
Figure PCTCN2022070423-appb-000068
Figure PCTCN2022070423-appb-000068
化合物41的合成参考实施例27中化合物27的合成步骤，其中第四步用1-(甲氧基甲基)环丙基甲酸代替3-氧杂环丁烷羧酸，合成得到化合物41。The synthesis of compound 41 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-(methoxymethyl)cyclopropylcarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 41.
MS(ESI):556.2[M+1] +。 MS(ESI): 556.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.15(s,1H),8.02(d,J＝7.3Hz,1H),7.66(d,J＝9.0Hz,2H),7.49(t,J＝6.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.85(s,1H),5.87-5.73(m,1H),4.53-4.45(m,2H),4.39(d,J＝12.4Hz,1H),4.12-4.98(m,2H),3.38-3.28(m,3H),3.25(s,3H),3.17-3.06(m,2H),2.82-2.70(m,1H),2.26(s,3H),1.60(d,J＝7.0Hz,3H),0.90(t,J＝6.1Hz,2H),0.76(t,J＝5.2Hz,2H). 1 H NMR(400MHz, DMSO)δ8.15(s,1H),8.02(d,J=7.3Hz,1H),7.66(d,J=9.0Hz,2H),7.49(t,J=6.9Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.85(s, 1H), 5.87-5.73(m, 1H), 4.53-4.45(m, 2H) ), 4.39(d, J＝12.4Hz, 1H), 4.12-4.98(m, 2H), 3.38-3.28(m, 3H), 3.25(s, 3H), 3.17-3.06(m, 2H), 2.82- 2.70(m, 1H), 2.26(s, 3H), 1.60(d, J=7.0Hz, 3H), 0.90(t, J=6.1Hz, 2H), 0.76(t, J=5.2Hz, 2H).
实施例42：化合物42的制备Example 42: Preparation of Compound 42
Figure PCTCN2022070423-appb-000069
Figure PCTCN2022070423-appb-000069
化合物42的合成参考实施例31中化合物31的合成步骤，其中第一步用甲胺盐酸盐代替二甲胺盐酸盐，合成得到化合物42。The synthesis of compound 42 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, methylamine hydrochloride is used instead of dimethylamine hydrochloride to synthesize compound 42.
MS(ESI):501.2[M+1] +。 MS(ESI): 501.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.00(d,J＝7.3Hz,1H),7.70-7.59(m,2H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.83(s,1H),6.64(d,J＝4.3Hz,1H),5.80(q,J＝6.9Hz,1H),4.37(dd,J＝10.8,2.7Hz,1H),4.12(d,J＝13.1Hz,1H),4.02(dd,J＝21.9,11.5Hz,3H),3.08(t,J＝9.9Hz,1H),2.99(dd,J＝12.4,9.9Hz,1H),2.77-2.66(m,1H),2.62(d,J＝4.2Hz,3H),2.63-2.46(m,1H),2.26(s,3H),1.60(d,J＝7.1Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.00(d,J=7.3Hz,1H),7.70-7.59(m,2H),7.49(t,J=6.9Hz,1H),7.29(t,J =7.7Hz,1H),7.23(t,J=54.4Hz,1H),6.83(s,1H),6.64(d,J=4.3Hz,1H),5.80(q,J=6.9Hz,1H), 4.37(dd,J＝10.8,2.7Hz,1H),4.12(d,J＝13.1Hz,1H),4.02(dd,J＝21.9,11.5Hz,3H),3.08(t,J＝9.9Hz,1H) ), 2.99(dd, J=12.4, 9.9Hz, 1H), 2.77-2.66(m, 1H), 2.62(d, J=4.2Hz, 3H), 2.63-2.46(m, 1H), 2.26(s, 3H),1.60(d,J=7.1Hz,3H).
实施例43：化合物43的制备Example 43: Preparation of Compound 43
Figure PCTCN2022070423-appb-000070
Figure PCTCN2022070423-appb-000070
化合物43的合成参考实施例31中化合物31的合成步骤，其中第一步用乙胺盐酸盐代替二甲胺盐酸盐，合成得到化合物43。The synthesis of compound 43 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, ethylamine hydrochloride is used instead of dimethylamine hydrochloride to synthesize compound 43.
MS(ESI):515.2[M+1] +。 MS(ESI): 515.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.00(d,J＝7.3Hz,1H),7.70-7.57(m,2H),7.49(t,J＝6.8Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.83(s,1H),6.69(t,J＝5.2Hz,1H),5.80(q,J＝6.8Hz,1H),4.37(dd,J＝10.8,2.7Hz,1H),4.15(d,J＝12.7Hz,1H),4.02(dd,J＝21.7,12.0Hz,3H),3.09(tt,J＝11.1,5.6Hz,3H),2.98(dd,J＝12.3,10.1Hz,1H),2.76-2.65(m,1H),2.58-2.54(m,1H),2.26(s,3H),1.60(d,J＝7.1Hz,3H),1.04(t,J＝7.1Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.00(d,J=7.3Hz,1H),7.70-7.57(m,2H),7.49(t,J=6.8Hz,1H),7.29(t,J ＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.83(s,1H),6.69(t,J＝5.2Hz,1H),5.80(q,J＝6.8Hz,1H), 4.37(dd,J＝10.8,2.7Hz,1H),4.15(d,J＝12.7Hz,1H),4.02(dd,J＝21.7,12.0Hz,3H),3.09(tt,J＝11.1,5.6Hz ,3H),2.98(dd,J=12.3,10.1Hz,1H),2.76-2.65(m,1H),2.58-2.54(m,1H),2.26(s,3H),1.60(d,J=7.1 Hz,3H),1.04(t,J=7.1Hz,3H).
实施例44：化合物44的制备Example 44: Preparation of Compound 44
Figure PCTCN2022070423-appb-000071
Figure PCTCN2022070423-appb-000071
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000072
Figure PCTCN2022070423-appb-000072
制备方法：Preparation:
第一步：合成化合物44BStep 1: Synthesis of compound 44B
将化合物44A(10.0g，46.0mmol)，(3S)-3-(2-羟基乙基)-1-哌嗪羧酸叔丁酯(10.6g，46.0mmol)溶于DMF(100mL)中，再称取DIEA(7.13g，55.2mmol)加入反应瓶中，然后将反应液升温到80℃搅拌反应16h。TLC显示反应结束后(有15％左右的SM1原料反应不完)，向反应液中加入乙酸乙酯(100mL)和饱和食盐水(100mL)，分出有机层，水相用乙酸乙酯(20mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))得到化合物44B(11.0g，25.8mmol，淡黄色油状物，产率56.1％)。Compound 44A (10.0 g, 46.0 mmol), (3S)-tert-butyl 3-(2-hydroxyethyl)-1-piperazinecarboxylate (10.6 g, 46.0 mmol) was dissolved in DMF (100 mL), followed by DIEA (7.13 g, 55.2 mmol) was weighed into the reaction flask, and then the reaction solution was heated to 80° C. and stirred for 16 h. After TLC showed that the reaction was completed (about 15% of SM1 raw material was not fully reacted), ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, the organic layer was separated, and the aqueous phase was washed with ethyl acetate (20 mL). ×2) Extracted twice, combined the organic phases, dried, spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 44B (11.0 g) , 25.8 mmol, pale yellow oil, 56.1% yield).
MS(ESI):m/z 428.2[M+1] +。 MS(ESI): m/z 428.2[M+1] + .
第二步：合成化合物44CStep 2: Synthesis of compound 44C
将化合物44B(11.0g，25.8mmol)溶于DMF(110mL)中，反应液冷却到0℃，在0℃下分批加入60％的氢化钠(1.24g，31.0mmol)，然后升温到45℃搅拌反应1h。TLC显示反应结束后，将反应液冷却到0℃，向反应液中逐滴滴加甲醇(2mL)，搅拌至不再产生气泡，再向反应液中加入乙酸乙酯(100mL)和饱和食盐水(100mL)，分出有机 层，水相用乙酸乙酯(20mL×2)萃取两次，合并有机相，干燥，旋干，得到化合物44C(9.1g，22.4mmol，淡黄色油状，产率87.0％)。Compound 44B (11.0 g, 25.8 mmol) was dissolved in DMF (110 mL), the reaction solution was cooled to 0 °C, 60% sodium hydride (1.24 g, 31.0 mmol) was added in portions at 0 °C, and then the temperature was raised to 45 °C The reaction was stirred for 1 h. After TLC showed that the reaction was completed, the reaction solution was cooled to 0°C, methanol (2 mL) was added dropwise to the reaction solution, stirred until no bubbles were generated, and then ethyl acetate (100 mL) and saturated brine were added to the reaction solution (100 mL), the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), the organic phases were combined, dried, and spin-dried to give compound 44C (9.1 g, 22.4 mmol, pale yellow oil, yield 87.0 %).
MS(ESI):m/z 408.2[M+1] +。 MS(ESI): m/z 408.2[M+1] + .
第三步：合成化合物44DStep 3: Synthesis of Compound 44D
将化合物44C(9.1g，22.4mmol)溶于甲醇(90mL)中，再向反应液中加入10％湿Pb/C(0.91g，10％)，加完后，用氮气置换三次气体，再用氢气置换三次气体后，保持氢气压力50psi，25℃反应5h。TLC显示反应结束后，将反应液过滤，滤液旋干后，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1(体积比))得到化合物44D(7.55g，淡黄色固体，产率90.0％)。Compound 44C (9.1 g, 22.4 mmol) was dissolved in methanol (90 mL), and 10% wet Pb/C (0.91 g, 10%) was added to the reaction solution. After the hydrogen was replaced three times, the hydrogen pressure was kept at 50 psi, and the reaction was carried out at 25 °C for 5 h. After TLC showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 (volume ratio)) to obtain compound 44D (7.55 g) , pale yellow solid, yield 90.0%).
MS(ESI):m/z 378.2[M+1] +。 MS(ESI): m/z 378.2[M+1] + .
第四步：合成化合物44EStep 4: Synthesis of Compound 44E
将化合物44D(7.55g，20.2mmol)溶于乙酸乙酯(35mL)中，将反应液冷却到0℃，再向反应液中滴加8％HCl-EtOAc(105mL)，然后反应液加热至40℃下搅拌2h。TLC显示反应结束后，浓缩，再加入乙酸乙酯(30mL×2)置换两次(除去部分的盐酸，防止吸潮)，最后加入乙酸乙酯(35mL)打浆，过滤，滤饼干燥得到化合物44E(7.2g,类白色固体，产率100.0％)。Compound 44D (7.55 g, 20.2 mmol) was dissolved in ethyl acetate (35 mL), the reaction solution was cooled to 0 °C, 8% HCl-EtOAc (105 mL) was added dropwise to the reaction solution, and then the reaction solution was heated to 40 Stir at ℃ for 2h. After TLC showed that the reaction was over, concentrate, and then add ethyl acetate (30 mL×2) to replace twice (remove part of hydrochloric acid to prevent moisture absorption), finally add ethyl acetate (35 mL) to make slurry, filter, and dry the filter cake to obtain compound 44E (7.2 g, off-white solid, 100.0% yield).
MS(ESI):m/z 278.2[M+1] +。 MS(ESI): m/z 278.2[M+1] + .
第五步：合成化合物44FStep 5: Synthesis of compound 44F
将化合物44E(7.2g，20.2mmol)加入到乙腈(80mL)中，再加6N HCl-MeCN(10mL，60.6mmol)，将反应液放入闷罐中，然后加热到110℃搅拌16h。TLC显示反应结束后，浓缩，再加入乙腈(30mL×2)置换两次(除去部分的盐酸，防止吸潮)，最后加入乙腈(35mL)打浆，过滤，滤饼用少量乙腈洗涤，得到化合物44F(5.56g，类白色固体，产率：85.0％)。Compound 44E (7.2 g, 20.2 mmol) was added to acetonitrile (80 mL), followed by 6N HCl-MeCN (10 mL, 60.6 mmol), the reaction solution was placed in a stuffy tank, then heated to 110 °C and stirred for 16 h. After TLC showed that the reaction was over, concentrate, and then add acetonitrile (30 mL×2) for replacement twice (remove part of hydrochloric acid to prevent moisture absorption), finally add acetonitrile (35 mL) to make slurry, filter, and wash the filter cake with a small amount of acetonitrile to obtain compound 44F (5.56 g, off-white solid, yield: 85.0%).
MS(ESI):m/z 287.1[M+1] +。 MS(ESI): m/z 287.1[M+1] + .
第六步：合成化合物44GStep 6: Synthesis of compound 44G
将化合物44F(0.56g，1.72mmol)和环丙烷甲酸(0.16g，1.89mmol)加入到DMF(55mL)中，将反应液冷却到0℃，向反应液中逐滴滴加T 3P(1.42g，2.24mmol)，再逐滴滴加三乙胺(0.52g，5.16mmol)，滴加完毕，将反应液升温至25℃下反应1h。TLC显示反应结束后，再向反应液中加入乙酸乙酯(20mL)和饱和食盐水(20mL)，分出 有机层，水相用乙酸乙酯(4mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20：1(体积比))，得到化合物44G(0.5g，土黄色固体，产率81.9％)。 Compound 44F (0.56 g, 1.72 mmol) and cyclopropanecarboxylic acid (0.16 g, 1.89 mmol) were added to DMF (55 mL), the reaction solution was cooled to 0 °C, and T 3 P (1.42 mmol) was added dropwise to the reaction solution. g, 2.24 mmol), then triethylamine (0.52 g, 5.16 mmol) was added dropwise, the dropwise addition was completed, and the reaction solution was heated to 25° C. for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (4 mL×2), and the organic phases were combined, Dry, spin dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)) to obtain compound 44G (0.5 g, khaki solid, yield 81.9%).
MS(ESI):m/z 355.2[M+1] +。 MS(ESI): m/z 355.2[M+1] + .
第七步：合成化合物44HStep 7: Synthesis of compound 44H
向化合物44G(0.5g，1.41mmol)中加入1，2-二氯乙烷(5mL)中，再加四氯化碳(1.73g，11.3mmol)，然后加入三苯基膦(1.48g，5.64mmol)，加完后，用氮气置换三次气体，然后氮气保护下将反应液加热到80℃下搅拌2h。TLC显示反应结束后，旋干，得到粗品化合物44H(0.52g，1.41mmol，深棕色油状)，无需纯化直接用于下一步。To compound 44G (0.5 g, 1.41 mmol) was added 1,2-dichloroethane (5 mL), followed by carbon tetrachloride (1.73 g, 11.3 mmol), followed by triphenylphosphine (1.48 g, 5.64 g) mmol), after the addition, the gas was replaced three times with nitrogen, and then the reaction solution was heated to 80 °C under nitrogen protection and stirred for 2 h. After TLC showed that the reaction was complete, it was spin-dried to give crude compound 44H (0.52 g, 1.41 mmol, dark brown oil), which was used in the next step without purification.
MS(ESI):m/z 373.2[M+1] + MS(ESI): m/z 373.2[M+1] +
第八步：合成化合物44Step 8: Synthesis of Compound 44
向化合物44H(0.26g，0.7mmol)中加入NMP(2.5mL)，再加(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(0.14g，0.7mmol，1.0eq)和DIEA(0.18g，1.4mmol，2.0eq)，加完后，将反应液加热到100℃下搅拌3h。TLC显示反应结束后，向反应液中加入乙酸乙酯(20mL)和饱和食盐水(20mL)，分出有机层，水相用乙酸乙酯(4mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20：1(体积比))，层析纯化的产物再用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物44(0.1g，白色固体，产率27.1％)。To compound 44H (0.26 g, 0.7 mmol) was added NMP (2.5 mL) followed by (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (0.14 g, 0.7 mmol, 1.0 eq) and DIEA (0.18 g, 1.4 mmol, 2.0 eq), after the addition, the reaction solution was heated to 100 °C and stirred for 3 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (4 mL×2), the organic phases were combined and dried , spin-dried, the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)), and the chromatographically purified product was purified by HPLC preparation (Waters Sunfire OBD 100×30 mm, 5 μm, Mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile for 10 min, 95% acetonitrile for 14 min, 10% acetonitrile for 16 min), Compound 44 was obtained (0.1 g, white solid, 27.1% yield).
MS(ESI):m/z 526.2[M+1] +。 MS(ESI): m/z 526.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.14(d,J＝7.0Hz,1H),7.78(s,1H),7.67(t,J＝7.2Hz,1H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝52Hz,1H),6.90(s,1H),5.87–5.73(m,1H),4.61(m,1H),4.22(m,2H),4.07-3.97(m,2H),3.63-3.51(m,2H),3.15–2.99(m,2H),2.27(s,3H),2.16-2.05(m,2H),1.98–1.79(m,1H),1.60(d,J＝7.0Hz,3H),0.78(d,J＝3.4Hz,4H). 1 H NMR (400MHz, DMSO) δ (ppm) 8.14 (d, J=7.0Hz, 1H), 7.78 (s, 1H), 7.67 (t, J=7.2Hz, 1H), 7.49 (t, J=6.9 Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=52Hz, 1H), 6.90(s, 1H), 5.87–5.73(m, 1H), 4.61(m, 1H) ,4.22(m,2H),4.07-3.97(m,2H),3.63-3.51(m,2H),3.15-2.99(m,2H),2.27(s,3H),2.16-2.05(m,2H) ,1.98–1.79(m,1H),1.60(d,J=7.0Hz,3H),0.78(d,J=3.4Hz,4H).
实施例45：化合物45的制备Example 45: Preparation of Compound 45
Figure PCTCN2022070423-appb-000073
Figure PCTCN2022070423-appb-000073
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000074
Figure PCTCN2022070423-appb-000074
制备方法：Preparation:
第一步：合成化合物45BStep 1: Synthesis of compound 45B
将化合物45A(1g,5.79mmol)溶于DMF(15mL)中，冰浴下分批加入NBS(1.03g,5.79mmol)，反应升温至室温搅拌1h。TLC显示反应结束后，将反应液倒入水中，白色固体析出，过滤，滤饼收集旋干得到化合物45B(1.5g，白色固体，产率96％)。Compound 45A (1 g, 5.79 mmol) was dissolved in DMF (15 mL), NBS (1.03 g, 5.79 mmol) was added in portions under ice bath, and the reaction was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was completed, the reaction solution was poured into water, white solid was precipitated, filtered, and the filter cake was collected and spin-dried to obtain compound 45B (1.5 g, white solid, yield 96%).
MS(ESI):m/z 251.0[M+H] +。 MS (ESI): m/z 251.0 [M+H] + .
第二步：合成化合物45CStep 2: Synthesis of compound 45C
将化合物45B(1.4g,5.57mmol)加入到原乙酸三乙酯(8mL)中,加入甲酸铵(1.76g,27.8mmol)，然后升至100度搅拌18h。TLC显示反应结束后，将反应液慢慢加入水:乙酸乙酯(体积比1:1,40mL)中，有灰色固体析出，过滤，收集滤饼，旋干得到化合物45C(0.6g，灰色固体，产率39％)。Compound 45B (1.4 g, 5.57 mmol) was added to triethyl orthoacetate (8 mL), ammonium formate (1.76 g, 27.8 mmol) was added, and the mixture was heated to 100 degrees and stirred for 18 h. After TLC showed that the reaction was over, the reaction solution was slowly added to water: ethyl acetate (volume ratio 1:1, 40 mL), a gray solid was precipitated, filtered, the filter cake was collected, and spin-dried to obtain compound 45C (0.6 g, gray solid) , the yield is 39%).
MS(ESI):m/z 274.0[M+H] +。 MS (ESI): m/z 274.0 [M+H] + .
第三步：合成化合物45DStep 3: Synthesis of Compound 45D
将化合物45C(50mg,0.18mmol)加入到二氧六环dioxane(2mL)中，加入三苯基膦(95mg,0.36mmol)和四氯化碳(84mg,0.55mmol)，氮气保护下升至70度搅拌4h。TLC显示反应结束后，旋干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2:1(体积比))得到化合物45D(30mg，淡黄色油状物，产率56％)。Compound 45C (50 mg, 0.18 mmol) was added to dioxane dioxane (2 mL), triphenylphosphine (95 mg, 0.36 mmol) and carbon tetrachloride (84 mg, 0.55 mmol) were added, and it was raised to 70 under nitrogen protection Stir for 4h. After TLC showed that the reaction was over, spin to dryness, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2:1 (volume ratio)) to obtain compound 45D (30 mg, pale yellow oil, yield 56%).
MS(ESI):m/z 292.9[M+H] +。 MS(ESI): m/z 292.9 [M+H] + .
第四步：合成化合物45EStep 4: Synthesis of Compound 45E
将化合物45D(30mg,0.1mmol)加入到DMF(1mL)中，加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(23mg,0.12mmol)和DIEA(40mg,0.31mmol)，升至50度搅拌3h。TLC显示反应结束后，缓慢加入水中，白色固体析出，过滤，滤饼收集并旋干得到化合物45E(30mg，白色固体，产率65％)。Compound 45D (30 mg, 0.1 mmol) was added to DMF (1 mL), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (23 mg, 0.12 mmol) and DIEA (40 mg, 0.31 mmol), raised to 50 degrees and stirred for 3 h. After TLC showed that the reaction was completed, water was slowly added, white solid was precipitated, filtered, and the filter cake was collected and spin-dried to obtain compound 45E (30 mg, white solid, yield 65%).
MS(ESI):m/z 445.0[M+H] +。 MS (ESI): m/z 445.0 [M+H] + .
第五步：合成化合物45GStep 5: Synthesis of Compound 45G
将化合物45E(300mg,0.67mmol)加入到DMSO(10mL)中，加入化合物45F(230mg,0.81mmol)和氟化铯(410mg,2.69mmol)，升至90度搅拌3h。TLC显示反应结束后，乙酸乙酯稀释，加入水中，萃取，用无水硫酸钠干燥有机相，旋干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1:1(体积比))得到化合物45G(400mg，淡黄色固体，产率85％)。Compound 45E (300 mg, 0.67 mmol) was added to DMSO (10 mL), compound 45F (230 mg, 0.81 mmol) and cesium fluoride (410 mg, 2.69 mmol) were added, and the mixture was heated to 90 degrees and stirred for 3 h. After TLC showed that the reaction was complete, ethyl acetate was diluted, added to water, extracted, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1: 1 (volume ratio)) to obtain compound 45G (400 mg, pale yellow solid, 85% yield).
MS(ESI):m/z 693.2[M+H] +。 MS(ESI): m/z 693.2 [M+H] + .
第六步：合成化合物45HStep 6: Synthesis of compound 45H
将化合物45G(400mg,0.57mmol)加入到乙酸乙酯(4mL)中，滴加8％HCl/乙酸乙酯(5mL)，升至室温搅拌12h。TLC显示反应结束后，旋干，加入碳酸氢钠水溶液，乙酸乙酯萃取，用无水硫酸钠干燥有机相，旋干，残余物用硅胶柱层析纯化(洗脱剂：乙酸乙酯/甲醇＝15:1(体积比))得到化合物45H(300mg，淡黄色固体，产率87％)。Compound 45G (400 mg, 0.57 mmol) was added to ethyl acetate (4 mL), 8% HCl/ethyl acetate (5 mL) was added dropwise, and the mixture was warmed to room temperature and stirred for 12 h. After TLC showed that the reaction was over, spin to dryness, add aqueous sodium bicarbonate solution, extract with ethyl acetate, dry the organic phase with anhydrous sodium sulfate, spin dry, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol) = 15:1 (volume ratio)) to obtain compound 45H (300 mg, pale yellow solid, yield 87%).
MS(ESI):m/z 593.2[M+H] +。 MS (ESI): m/z 593.2 [M+H] + .
第七步：合成化合物45Step 7: Synthesis of Compound 45
将化合物45H(0.11g,0.19mmol)溶于甲苯(4mL)中,加入Xphos Pd G3(15mg,0.02mmol)和碳酸铯(0.12g,0.37mmol),氮气保护下，将反应液升温至100℃搅拌16h。TLC显示反应结束后，加入水，用乙酸乙酯萃取，用无水硫酸钠干燥有机相，旋干，残余物经过HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物45(30mg，白色固体，产率31％)Compound 45H (0.11g, 0.19mmol) was dissolved in toluene (4mL), Xphos Pd G3 (15mg, 0.02mmol) and cesium carbonate (0.12g, 0.37mmol) were added, and the reaction solution was heated to 100°C under nitrogen protection Stir for 16h. After TLC showed that the reaction was over, water was added, extracted with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, spin-dried, and the residue was purified by HPLC preparation (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA in water , mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile for 10 min, 95% acetonitrile for 14 min, 10% acetonitrile for 16 min) to obtain compound 45 (30 mg, white solid, Yield 31%)
MS(ESI):m/z 513.2[M+H] +。 MS(ESI): m/z 513.2 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.24-8.17(m,2H),7.64(t,J＝7.2Hz,1H),7.50(t,J＝6.8Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),5.83–5.70(m,1H),4.67–4.32(m,3H),4.25-4.15(m,1H),3.99-3.80(m,1H),3.20-2.95(m,2H),2.95-2.70(m,2H),2.29(s,3H),2.17-2.04(m,1H),1.59(d,J＝8.0Hz,3H),0.90-0.60(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm) 8.24-8.17(m, 2H), 7.64(t, J=7.2Hz, 1H), 7.50(t, J=6.8Hz, 1H), 7.29( t, J=7.7Hz, 1H), 7.23 (t, J=54.4Hz, 1H), 5.83-5.70 (m, 1H), 4.67-4.32 (m, 3H), 4.25-4.15 (m, 1H), 3.99 -3.80(m, 1H), 3.20-2.95(m, 2H), 2.95-2.70(m, 2H), 2.29(s, 3H), 2.17-2.04(m, 1H), 1.59(d, J=8.0Hz ,3H),0.90-0.60(m,4H).
实施例46：化合物46的制备Example 46: Preparation of Compound 46
Figure PCTCN2022070423-appb-000075
Figure PCTCN2022070423-appb-000075
化合物46的合成参考实施例27中化合物27的合成步骤，其中第四步用(1S,2R)-2-氟环丙烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物46。The synthesis of compound 46 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (1S,2R)-2-fluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 46.
MS(ESI):530.2[M+1] +。 MS(ESI): 530.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.02(t,J＝9.6Hz,1H),7.68-7.61(m,2H),7.49(t,J＝7.2Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.85(d,J＝4.5Hz,1H),5.80(q,J＝7.0Hz,1H),5.00-4.69(m,1H),4.58-4.40(m,3H),4.17-3.97(m,2H),3.08-2.71(m,5H),2.28(s,3H),1.60(d,J＝7.0Hz,3H),1.52-1.37(m,1H),1.28-1.12(m,1H). 1 H NMR(400MHz,DMSO)δ(ppm)8.02(t,J=9.6Hz,1H),7.68-7.61(m,2H),7.49(t,J=7.2Hz,1H),7.28(t,J =7.7Hz,1H),7.23(t,J=54.4Hz,1H),6.85(d,J=4.5Hz,1H),5.80(q,J=7.0Hz,1H),5.00-4.69(m,1H) ), 4.58-4.40(m, 3H), 4.17-3.97(m, 2H), 3.08-2.71(m, 5H), 2.28(s, 3H), 1.60(d, J=7.0Hz, 3H), 1.52- 1.37(m,1H),1.28-1.12(m,1H).
实施例47：化合物47的制备Example 47: Preparation of Compound 47
Figure PCTCN2022070423-appb-000076
Figure PCTCN2022070423-appb-000076
化合物47的合成参考实施例27中化合物27的合成步骤，其中第四步用(1S,2S)-2-氟环丙烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物47。The synthesis of compound 47 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, (1S,2S)-2-fluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 47.
MS(ESI):530.2[M+1] +。 MS(ESI): 530.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)9.65-9.50(m,1H),7.84(s,1H),7.72(t,J＝7.5Hz,1H),7.57(t,J＝7.2Hz,1H),7.41-7.35(m,1H),7.24(t,J＝54.4Hz,1H),6.97(s,1H),5.98-5.88(m,1H),5.09-4.81(m,1H),4.64–4.35(m,3H),4.21-3.98(m,2H),3.54-3.43(m,1H),3.17-2.75(m,3H),2.48(s,3H),2.30-2.11(m,1H),1.69(d,J＝7.0Hz,3H),1.64-1,48(m,1H),1.12-1.03(m,1H). 1 H NMR (400MHz, DMSO) δ (ppm) 9.65-9.50 (m, 1H), 7.84 (s, 1H), 7.72 (t, J=7.5Hz, 1H), 7.57 (t, J=7.2Hz, 1H) ),7.41-7.35(m,1H),7.24(t,J＝54.4Hz,1H),6.97(s,1H),5.98-5.88(m,1H),5.09-4.81(m,1H),4.64– 4.35(m, 3H), 4.21-3.98(m, 2H), 3.54-3.43(m, 1H), 3.17-2.75(m, 3H), 2.48(s, 3H), 2.30-2.11(m, 1H), 1.69(d, J＝7.0Hz, 3H), 1.64-1, 48(m, 1H), 1.12-1.03(m, 1H).
实施例48：化合物48的制备Example 48: Preparation of Compound 48
Figure PCTCN2022070423-appb-000077
Figure PCTCN2022070423-appb-000077
化合物48的合成参考实施例27中化合物27的合成步骤，其中第四步用2,2-二氟环丙羧酸代替3-氧杂环丁烷羧酸，合成得到化合物48。The synthesis of compound 48 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2,2-difluorocyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 48.
MS(ESI):548.2[M+1] +。 MS(ESI): 548.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.20(s,1H),8.14(s,1H),7.67(d,J＝10.7Hz,2H),7.49(d,J＝6.5Hz,1H),7.29(t,J＝7.5Hz,1H),7.16(d,J＝54.3Hz,1H),6.88(d,J＝4.9Hz,1H),5.87-5.74(m,1H),4.49(t,J＝16.8Hz,2H),4.13(ddd,J＝31.0,24.7,7.6Hz,3H),3.45(d,J＝13.9Hz,1H),3.32(d,J＝8.3Hz,1H),3.12(d,J＝12.9Hz,1H),3.01(d,J＝11.6Hz,1H),2.84-2.67(m,1H),2.29(s,3H),2.00-1.86(m,2H),1.61(d,J＝5.2Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.20(s,1H),8.14(s,1H),7.67(d,J=10.7Hz,2H),7.49(d,J=6.5Hz,1H), 7.29(t,J＝7.5Hz,1H),7.16(d,J＝54.3Hz,1H),6.88(d,J＝4.9Hz,1H),5.87-5.74(m,1H),4.49(t,J =16.8Hz,2H),4.13(ddd,J=31.0,24.7,7.6Hz,3H),3.45(d,J=13.9Hz,1H),3.32(d,J=8.3Hz,1H),3.12(d , J=12.9Hz, 1H), 3.01(d, J=11.6Hz, 1H), 2.84-2.67(m, 1H), 2.29(s, 3H), 2.00-1.86(m, 2H), 1.61(d, J=5.2Hz, 3H).
实施例49：化合物49的制备Example 49: Preparation of Compound 49
Figure PCTCN2022070423-appb-000078
Figure PCTCN2022070423-appb-000078
化合物49的合成参考实施例27中化合物27的合成步骤，其中第四步用1-甲基环丙烷-1-羧酸代替3-氧杂环丁烷羧酸，合成得到化合物49。The synthesis of compound 49 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylcyclopropane-1-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 49.
MS(ESI):526.2[M+1] +。 MS(ESI): 526.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.87(s,1H),7.81(s,1H),7.72(t,J＝7.1Hz,1H),7.52(t,J＝6.7Hz,1H),7.31(t,J＝7.6Hz,1H),7.23(t,J＝54.3Hz,1H),6.93(s,1H),5.93-5.80(m,1H),4.60-4.32(m,3H),4.20-4.00(m,2H),3.66-3.58(m,1H),3.15-3.11(m,2H),2.85-2.80(m,1H),2.37(s,3H),1.65(d,J＝6.9Hz,3H),1.28(s,3H),0.86(s,2H),0.59(s,2H). 1 H NMR(400MHz,DMSO)δ(ppm)8.87(s,1H),7.81(s,1H),7.72(t,J=7.1Hz,1H),7.52(t,J=6.7Hz,1H), 7.31(t,J＝7.6Hz,1H),7.23(t,J＝54.3Hz,1H),6.93(s,1H),5.93-5.80(m,1H),4.60-4.32(m,3H),4.20 -4.00(m, 2H), 3.66-3.58(m, 1H), 3.15-3.11(m, 2H), 2.85-2.80(m, 1H), 2.37(s, 3H), 1.65(d, J=6.9Hz ,3H),1.28(s,3H),0.86(s,2H),0.59(s,2H).
实施例50：化合物50的制备Example 50: Preparation of Compound 50
Figure PCTCN2022070423-appb-000079
Figure PCTCN2022070423-appb-000079
化合物50的合成参考实施例27中化合物27的合成步骤，其中第四步用2,2,3,3-四甲基环丙烷甲酸代替3-氧杂环丁烷羧酸，合成得到化合物50。The synthesis of compound 50 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2,2,3,3-tetramethylcyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 50.
MS(ESI):568.2[M+1] +。 MS(ESI): 568.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.79(s,1H),7.77(s,1H),7.73-7.68(m,1H),7.51(t,J＝7.0Hz,1H),7.30(t,J＝7.6Hz,1H),7.16(t,J＝54.3Hz,1H),6.97(s,1H),5.94-5.74(m,1H),4.69-4.38(m,2H),4.20-4.0(s,3H),3.26-3.17(m,2H),3.00-2.80(m,2H),2.73-2.67(m,1H),2.36(s,3H),1.64(d,J＝6.9Hz,3H),1.21-1.12(m,12H). 1 H NMR(400MHz,DMSO)δ(ppm)8.79(s,1H),7.77(s,1H),7.73-7.68(m,1H),7.51(t,J=7.0Hz,1H),7.30(t , J=7.6Hz, 1H), 7.16(t, J=54.3Hz, 1H), 6.97(s, 1H), 5.94-5.74(m, 1H), 4.69-4.38(m, 2H), 4.20-4.0( s,3H),3.26-3.17(m,2H),3.00-2.80(m,2H),2.73-2.67(m,1H),2.36(s,3H),1.64(d,J=6.9Hz,3H) ,1.21-1.12(m,12H).
实施例51：化合物51的制备Example 51: Preparation of Compound 51
Figure PCTCN2022070423-appb-000080
Figure PCTCN2022070423-appb-000080
化合物51的合成参考实施例8中化合物8的合成步骤，在三并环中间体的合成中，用(S)-1-Boc-3-羟甲基哌嗪代替(R)-1-Boc-3-羟甲基哌嗪合成得到化合物51。Synthesis of compound 51 Referring to the synthesis procedure of compound 8 in Example 8, in the synthesis of the tricyclic intermediate, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 51.
MS(ESI):512.2[M+1] +。 MS(ESI): 512.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ8.15(s,1H),8.11(d,J＝7.4Hz,1H),7.67-7.63(m,2H),7.49(t,J＝7.1Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.86(s,1H),5.85-5.76(m,1H),4.59-4.42(m,3H),4.13-3.98(m,2H),3.23-3.08(m,2H),2.99-2.91(m,1H),2.82-2.69(m,1H),2.27(s,3H),2.18-2.07(m,1H),1.61(d,J＝7.1Hz,3H),0.87-0.70(m,4H). 1 H NMR (400MHz, DMSO-d 6 )δ8.15(s, 1H), 8.11(d, J=7.4Hz, 1H), 7.67-7.63(m, 2H), 7.49(t, J=7.1Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.86(s, 1H), 5.85-5.76(m, 1H), 4.59-4.42(m, 3H) ),4.13-3.98(m,2H),3.23-3.08(m,2H),2.99-2.91(m,1H),2.82-2.69(m,1H),2.27(s,3H),2.18-2.07(m ,1H),1.61(d,J＝7.1Hz,3H),0.87-0.70(m,4H).
实施例52：化合物52的制备Example 52: Preparation of Compound 52
Figure PCTCN2022070423-appb-000081
Figure PCTCN2022070423-appb-000081
化合物52的合成参考实施例30中化合物30的合成步骤，在三并环中间体的合成中，用(S)-1-Boc-3-羟甲基哌嗪代替(R)-1-Boc-3-羟甲基哌嗪合成得到化合物52。Synthesis of compound 52 Referring to the synthetic procedure of compound 30 in Example 30, in the synthesis of the tricyclic intermediate, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 52.
MS(ESI):512.2[M+1] +。 MS(ESI): 512.2[M+1] + .
1H NMR(400MHz,Chloroform-d)δ(ppm)9.14(br.s,1H),8.77(s,1H),7.70-7.56(m,2H),7.46(t,J＝7.1Hz,1H),7.19(t,J＝7.7Hz,1H),6.92(t,J＝55.0Hz,1H),6.80(s,1H),5.76-5.67(m,1H),4.35-4.12(m,3H),4.07-4.01(m,2H),3.76(s,3H),3.25-3.18(m,1H),3.12-3.03(m,1H),2.94-2.85(m,1H),2.73-2.62(m,1H),2.44(s,3H),1.72(d,J＝7.0Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ(ppm) 9.14(br.s, 1H), 8.77(s, 1H), 7.70-7.56(m, 2H), 7.46(t, J=7.1Hz, 1H) ,7.19(t,J＝7.7Hz,1H),6.92(t,J＝55.0Hz,1H),6.80(s,1H),5.76-5.67(m,1H),4.35-4.12(m,3H), 4.07-4.01(m, 2H), 3.76(s, 3H), 3.25-3.18(m, 1H), 3.12-3.03(m, 1H), 2.94-2.85(m, 1H), 2.73-2.62(m, 1H) ), 2.44(s, 3H), 1.72(d, J=7.0Hz, 3H).
实施例53：化合物53的制备Example 53: Preparation of Compound 53
Figure PCTCN2022070423-appb-000082
Figure PCTCN2022070423-appb-000082
化合物53的合成参考实施例37中化合物37的合成步骤，在三并环中间体的合成中，用(S)-1-Boc-3-羟甲基哌嗪代替(R)-1-Boc-3-羟甲基哌嗪合成得到化合物53。Synthesis of compound 53 Referring to the synthetic procedure of compound 37 in Example 37, in the synthesis of the tricyclic intermediate, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 53.
MS(ESI):530.2[M+1] +。 MS(ESI): 530.2[M+1] + .
1H NMR(400MHz,Chloroform-d)δ(ppm)8.80(s,1H),7.75-7.50(m,2H),7.50-7.41(m,1H),7.24-7.16(m,1H),6.92(t,J＝55.0Hz,1H),6.89-6.80(m,1H),5.79-5.67(m,1H),4.81-4.64(m,1H),4.37-4.28(m,1H),4.14-3.88(m,3H),3.73(t,J＝6.3Hz,2H),3.37(s,3H),3.35-3.28(m,1H),3.24-3.12(m,1H),3.00-2.82(m,2H),2.76-2.55(m,2H),2.45(s,3H),1.73(d,J＝7.0Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ(ppm) 8.80(s, 1H), 7.75-7.50(m, 2H), 7.50-7.41(m, 1H), 7.24-7.16(m, 1H), 6.92( t, J＝55.0Hz, 1H), 6.89-6.80(m, 1H), 5.79-5.67(m, 1H), 4.81-4.64(m, 1H), 4.37-4.28(m, 1H), 4.14-3.88( m, 3H), 3.73(t, J=6.3Hz, 2H), 3.37(s, 3H), 3.35-3.28(m, 1H), 3.24-3.12(m, 1H), 3.00-2.82(m, 2H) ,2.76-2.55(m,2H),2.45(s,3H),1.73(d,J=7.0Hz,3H).
实施例54：化合物54的制备Example 54: Preparation of Compound 54
Figure PCTCN2022070423-appb-000083
Figure PCTCN2022070423-appb-000083
化合物54的合成参考实施例40中化合物40的合成步骤，在三并环中间体的合成中，用(S)-1-Boc-3-羟甲基哌嗪代替(R)-1-Boc-3-羟甲基哌嗪合成得到化合物54。Synthesis of compound 54 Referring to the synthetic procedure of compound 40 in Example 40, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 54.
MS(ESI):516.2[M+1] +。 MS(ESI): 516.2[M+1] + .
1H NMR(400MHz,Chloroform-d)δ(ppm)8.96(br.s,1H),8.79(s,1H),7.72-7.55(m,2H),7.47(d,J＝7.1Hz,1H),7.21(t,J＝7.2Hz,1H),6.92(t,J＝55.0Hz,1H),6.89-6.81(m,1H),5.77-5.68(m,1H),4.74-4.56(m,1H),4.37-4.29(m,1H),4.24-4.17(m,1H),4.15-4.03(m,3H),3.45(s,3H),3.37-3.15(m,2H),2.99-2.85(m,2H),2.54-2.47(m,1H),2.46(s,3H),1.73(d,J＝7.0Hz,3H). 1 H NMR (400MHz, Chloroform-d)δ(ppm) 8.96(br.s,1H),8.79(s,1H),7.72-7.55(m,2H),7.47(d,J=7.1Hz,1H) ,7.21(t,J＝7.2Hz,1H),6.92(t,J＝55.0Hz,1H),6.89-6.81(m,1H),5.77-5.68(m,1H),4.74-4.56(m,1H) ), 4.37-4.29(m, 1H), 4.24-4.17(m, 1H), 4.15-4.03(m, 3H), 3.45(s, 3H), 3.37-3.15(m, 2H), 2.99-2.85(m ,2H),2.54-2.47(m,1H),2.46(s,3H),1.73(d,J=7.0Hz,3H).
实施例55：化合物55的制备Example 55: Preparation of Compound 55
Figure PCTCN2022070423-appb-000084
Figure PCTCN2022070423-appb-000084
化合物55的合成参考实施例42中化合物42的合成步骤，在三并环中间体的合成中，用(S)-1-Boc-3-羟甲基哌嗪代替(R)-1-Boc-3-羟甲基哌嗪合成得到化合物55。Synthesis of compound 55 Referring to the synthetic procedure of compound 42 in Example 42, (S)-1-Boc-3-hydroxymethylpiperazine was used instead of (R)-1-Boc- 3-Hydroxymethylpiperazine was synthesized to give compound 55.
MS(ESI):501.2[M+1] +。 MS(ESI): 501.2[M+1] + .
1H NMR(400MHz,Chloroform-d)δ(ppm)9.21(br.s,1H),8.77(s,1H),7.66(t,J＝7.5Hz,1H),7.59(s,1H),7.47(t,J＝7.1Hz,1H),7.19(t,J＝7.7Hz,1H),6.91(t,J＝55.0Hz,1H),6.77(s,1H),5.87-5.77(m,1H),5.35(br.s,1H),4.25-4.11(m,2H),3.99-3.90(m,3H),3.19-3.07(m,2H),2.85(s,3H),2.82-2.79(m,1H),2.60-2.53(m,1H),2.51(s,3H),1.74(d,J＝7.1Hz,3H). 1 H NMR (400MHz, Chloroform-d) δ(ppm) 9.21(br.s, 1H), 8.77(s, 1H), 7.66(t, J=7.5Hz, 1H), 7.59(s, 1H), 7.47 (t, J=7.1Hz, 1H), 7.19 (t, J=7.7Hz, 1H), 6.91 (t, J=55.0Hz, 1H), 6.77 (s, 1H), 5.87-5.77 (m, 1H) ,5.35(br.s,1H),4.25-4.11(m,2H),3.99-3.90(m,3H),3.19-3.07(m,2H),2.85(s,3H),2.82-2.79(m, 1H), 2.60-2.53(m, 1H), 2.51(s, 3H), 1.74(d, J=7.1Hz, 3H).
实施例56：化合物56的制备Example 56: Preparation of Compound 56
Figure PCTCN2022070423-appb-000085
Figure PCTCN2022070423-appb-000085
化合物56的合成参考实施例27中化合物27的合成步骤，其中第四步用2-氧杂环丁烷羧代替3-氧杂环丁烷羧酸，合成得到化合物56。The synthesis of compound 56 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 2-oxetanecarboxylate is used instead of 3-oxetanecarboxylate to synthesize compound 56.
MS(ESI):528.2[M+1] +。 MS(ESI): 528.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.12-8.00(m,1H),7.66(dt,J＝12.5,5.2Hz,2H),7.49(t,J＝6.8Hz,1H),7.29(t,J＝7.6Hz,1H),7.23(t,J＝54.4Hz,1H),6.89-6.77(m,1H),5.80(q,J＝6.6Hz,1H),5.57-5.43(m,1H),4.64-4.26(m,4H),4.19-3.91(m,3H),3.88-3.68(m,1H),3.40-3.05(m,2H),3.01-2.65(m,3H),2.27(s,3H),1.60(d,J＝7.0Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.12-8.00(m,1H),7.66(dt,J=12.5,5.2Hz,2H),7.49(t,J=6.8Hz,1H),7.29(t ,J=7.6Hz,1H),7.23(t,J=54.4Hz,1H),6.89-6.77(m,1H),5.80(q,J=6.6Hz,1H),5.57-5.43(m,1H) ,4.64-4.26(m,4H),4.19-3.91(m,3H),3.88-3.68(m,1H),3.40-3.05(m,2H),3.01-2.65(m,3H),2.27(s, 3H),1.60(d,J=7.0Hz,3H).
实施例57：化合物57的制备Example 57: Preparation of Compound 57
Figure PCTCN2022070423-appb-000086
Figure PCTCN2022070423-appb-000086
化合物57的合成参考实施例31中化合物31的合成步骤，其中第一步用环丙胺代替二甲胺盐酸盐，合成得到化合物57。The synthesis of compound 57 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, cyclopropylamine is used instead of dimethylamine hydrochloride to synthesize compound 57.
MS(ESI):527.2[M+1] +。 MS(ESI): 527.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.44(s,1H),7.74-7.63(m,2H),7.51(t,J＝6.9Hz,1H),7.30(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.87(s,1H),6.81(s,1H),5.89-5.77(m,1H),4.39(dd,J＝10.8,2.7Hz,1H),4.13(d,J＝12.5Hz,1H),4.01(dd,J＝19.8,9.9Hz,3H),3.14-3.05(m,1H),3.01-2.92(m,1H),2.81-2.63(m,2H),2.54(s,1H),2.32(s,3H),1.62(d,J＝7.0Hz,3H),0.63-0.53(m,2H),0.45-0.36(m,2H). 1 H NMR (400MHz, DMSO) δ (ppm) 8.44 (s, 1H), 7.74-7.63 (m, 2H), 7.51 (t, J=6.9Hz, 1H), 7.30 (t, J=7.7Hz, 1H) ), 7.23(t, J＝54.4Hz, 1H), 6.87(s, 1H), 6.81(s, 1H), 5.89-5.77(m, 1H), 4.39(dd, J＝10.8, 2.7Hz, 1H) ,4.13(d,J＝12.5Hz,1H),4.01(dd,J＝19.8,9.9Hz,3H),3.14-3.05(m,1H),3.01-2.92(m,1H),2.81-2.63(m ,2H),2.54(s,1H),2.32(s,3H),1.62(d,J=7.0Hz,3H),0.63-0.53(m,2H),0.45-0.36(m,2H).
实施例58：化合物58的制备Example 58: Preparation of Compound 58
Figure PCTCN2022070423-appb-000087
Figure PCTCN2022070423-appb-000087
化合物58的合成参考实施例31中化合物31的合成步骤，其中第一步用环丙醇代替二甲胺盐酸盐，合成得到化合物58。The synthesis of compound 58 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, cyclopropanol is used instead of dimethylamine hydrochloride to synthesize compound 58.
MS(ESI):528.2[M+1] +。 MS(ESI): 528.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.40(s,1H),8.04(d,J＝7.3Hz,1H),7.68-7.62(m,2H),7.48(t,J＝6.8Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(d,J＝54.4Hz,1H),6.83(s,1H),5.87-5.73(m,1H),4.42(d,J＝9.0Hz,1H),4.19-3.90(m,5H),3.18-3.04(m,2H),2.80-2.62(m,2H),2.25(s,3H),1.59(d,J＝7.1Hz,3H),0.69-0.62(m,4H). 1 H NMR (400MHz, DMSO) δ (ppm) 8.40 (s, 1H), 8.04 (d, J=7.3Hz, 1H), 7.68-7.62 (m, 2H), 7.48 (t, J=6.8Hz, 1H) ), 7.28(t, J＝7.7Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.83(s, 1H), 5.87-5.73(m, 1H), 4.42(d, J＝9.0Hz ,1H),4.19-3.90(m,5H),3.18-3.04(m,2H),2.80-2.62(m,2H),2.25(s,3H),1.59(d,J=7.1Hz,3H), 0.69-0.62(m,4H).
实施例59：化合物59的制备Example 59: Preparation of Compound 59
Figure PCTCN2022070423-appb-000088
Figure PCTCN2022070423-appb-000088
化合物59的合成参考实施例31中化合物31的合成步骤，其中第一步用吗啡啉代替二甲胺盐酸盐，合成得到化合物59。The synthesis of compound 59 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, morpholine is used instead of dimethylamine hydrochloride to synthesize compound 59.
MS(ESI):557.2[M+1] +。 MS(ESI): 557.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.15(s,1H),8.03(d,J＝7.2Hz,1H),7.69-7.58(m,2H),7.49(t,J＝6.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.84(s,1H),5.80(q,J＝6.9Hz,1H),4.44(dd,J＝10.8,2.7Hz,1H),4.05-3.96(m,2H),3.76(d,J＝12.4Hz,1H),3.66(d,J＝12.4Hz,1H),3.60(t,J＝4.4Hz,4H),3.25-3.20(m,5H),3.11-3.04(m,1H),2.87-2.77(m,1H),2.65-2.57(m,1H),2.26(s,3H),1.60(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO) δ (ppm) 8.15 (s, 1H), 8.03 (d, J=7.2Hz, 1H), 7.69-7.58 (m, 2H), 7.49 (t, J=6.9Hz, 1H) ),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.84(s,1H),5.80(q,J＝6.9Hz,1H),4.44(dd,J ＝10.8,2.7Hz,1H),4.05-3.96(m,2H),3.76(d,J＝12.4Hz,1H),3.66(d,J＝12.4Hz,1H),3.60(t,J＝4.4Hz ,4H),3.25-3.20(m,5H),3.11-3.04(m,1H),2.87-2.77(m,1H),2.65-2.57(m,1H),2.26(s,3H),1.60(d ,J=7.1Hz,3H).
实施例60：化合物60的制备Example 60: Preparation of Compound 60
Figure PCTCN2022070423-appb-000089
Figure PCTCN2022070423-appb-000089
化合物60的合成参考实施例27中化合物27的合成步骤，其中第四步用四氢吡喃-4-甲酸代替3-氧杂环丁烷羧酸，合成得到化合物60。The synthesis of compound 60 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, tetrahydropyran-4-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 60.
MS(ESI):556.2[M+1] +。 MS(ESI): 556.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.07(d,J＝6.8Hz,1H),7.73-7.60(m,2H),7.49(t,J＝6.4Hz,1H),7.28(t,J＝7.6Hz,1H),7.23(d,J＝54.4Hz,1H),6.85(s,1H),5.89-5.75(m,1H),4.65-4.41(m,2H),4.29-4.15(m,1H),4.05(dd,J＝18.6,9.8Hz,3H),3.87(d,J＝9.7Hz,3H),3.21-3.10(m,1H),3.10-2.64(m,4H),2.27(s,3H),1.71-1.45(m,7H). 1 H NMR(400MHz,DMSO)δ(ppm)8.07(d,J=6.8Hz,1H),7.73-7.60(m,2H),7.49(t,J=6.4Hz,1H),7.28(t,J ＝7.6Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.85(s, 1H), 5.89-5.75(m, 1H), 4.65-4.41(m, 2H), 4.29-4.15(m, 1H), 4.05(dd, J=18.6, 9.8Hz, 3H), 3.87(d, J=9.7Hz, 3H), 3.21-3.10(m, 1H), 3.10-2.64(m, 4H), 2.27(s ,3H),1.71-1.45(m,7H).
实施例61：化合物61的制备Example 61: Preparation of Compound 61
Figure PCTCN2022070423-appb-000090
Figure PCTCN2022070423-appb-000090
化合物61的合成参考实施例27中化合物27的合成步骤，其中第四步用1-甲基哌啶-4-甲酸代替3-氧杂环丁烷羧酸，合成得到化合物61。The synthesis of compound 61 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylpiperidine-4-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 61.
MS(ESI):569.2[M+1] +。 MS(ESI): 569.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ(ppm)8.19(s,2H),8.03(d,J＝7.3Hz,1H),7.67-7.63(m,2H),7.49(t,J＝7.1Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.85-5.76(m,1H),5.79(d,J＝9.0Hz,1H),4.59(d,J＝13.0Hz,1H),4.51-4.43(m,2H),4.19-4.14(m,1H),4.10-4.00(m,3H),3.37(t,J＝12.6Hz,1H),3.21-3.13(m,1H),3.06-2.88(m,3H),2.82-2.69(m,2H),2.33(s,3H),2.26(s,3H),2.24-2.20(m,1H),1.73-1.66(m,3H),1.60(d,J＝7.1Hz,3H). 1 H NMR (400MHz, DMSO-d 6 )δ(ppm) 8.19(s, 2H), 8.03(d, J=7.3Hz, 1H), 7.67-7.63(m, 2H), 7.49(t, J=7.1 Hz, 1H), 7.28(t, J＝7.7Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 6.85-5.76(m, 1H), 5.79(d, J＝9.0Hz, 1H), 4.59(d,J=13.0Hz,1H),4.51-4.43(m,2H),4.19-4.14(m,1H),4.10-4.00(m,3H),3.37(t,J=12.6Hz,1H) ,3.21-3.13(m,1H),3.06-2.88(m,3H),2.82-2.69(m,2H),2.33(s,3H),2.26(s,3H),2.24-2.20(m,1H) ,1.73-1.66(m,3H),1.60(d,J=7.1Hz,3H).
实施例62：化合物62的制备Example 62: Preparation of Compound 62
Figure PCTCN2022070423-appb-000091
Figure PCTCN2022070423-appb-000091
化合物62的合成参考实施例31中化合物31的合成步骤，其中第一步用N-甲基哌嗪代替二甲胺盐酸盐，合成得到化合物62。The synthesis of compound 62 refers to the synthesis steps of compound 31 in Example 31, wherein in the first step, N-methylpiperazine is used instead of dimethylamine hydrochloride to synthesize compound 62.
MS(ESI):570.2[M+1] +。 MS(ESI): 570.2[M+1] + .
1H NMR(400MHz,DMSO)δ(ppm)8.26(s,1H),7.72–7.61(m,2H),7.50(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.86(s,1H),5.82(p,J＝6.9Hz,1H),4.45(dd,J＝10.7,2.6Hz,1H),4.05–4.00(m,2H),3.74(d,J＝12.6Hz,1H),3.64(d,J＝ 12.4Hz,1H),3.51–3.45(m,2H),3.26–3.13(m,3H),3.10–3.02(m,1H),2.86–2.81(m,1H),2.66–2.57(m,1H),2.50–2.46(m,4H),2.29(s,6H),1.61(d,J＝7.0Hz,3H). 1 H NMR(400MHz,DMSO)δ(ppm)8.26(s,1H),7.72-7.61(m,2H),7.50(t,J=7.0Hz,1H),7.29(t,J=7.7Hz,1H) ), 7.23(t, J＝52.0Hz, 1H), 6.86(s, 1H), 5.82(p, J＝6.9Hz, 1H), 4.45(dd, J＝10.7, 2.6Hz, 1H), 4.05–4.00 (m, 2H), 3.74 (d, J=12.6Hz, 1H), 3.64 (d, J= 12.4Hz, 1H), 3.51–3.45 (m, 2H), 3.26–3.13 (m, 3H), 3.10– 3.02(m,1H), 2.86-2.81(m,1H), 2.66-2.57(m,1H), 2.50-2.46(m,4H), 2.29(s,6H), 1.61(d,J=7.0Hz, 3H).
实施例63：化合物63的制备Example 63: Preparation of Compound 63
Figure PCTCN2022070423-appb-000092
Figure PCTCN2022070423-appb-000092
化合物63的合成参考实施例27中化合物27的合成步骤，其中第四步用1-甲基吡唑-5-甲酸代替3-氧杂环丁烷羧酸，合成得到化合物63。The synthesis of compound 63 refers to the synthesis steps of compound 27 in Example 27, wherein in the fourth step, 1-methylpyrazole-5-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 63.
MS(ESI):552.2[M+1] +。 MS(ESI): 552.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.15(s,1H),8.03(s,1H),7.80(s,1H),7.67-6.62(m,2H),7.49(t,J＝6.6Hz,1H),7.28(t,J＝7.7Hz,1H),7.17(t,J＝54.4Hz,1H),6.85(s,1H),6.64(s,1H),5.85-5.74(m,1H),5.26-5.24(m,1H),4.68-4.62(m,1H),4.49-4.41(m,1H),4.12-4.06(m,2H),3.92(s,3H),3.25-3.16(m,2H),2.89-2.85(m,2H),2.26(s,3H),1.60(d,J＝6.9Hz,3H). 1 H NMR (400MHz, DMSO) δ8.15(s, 1H), 8.03(s, 1H), 7.80(s, 1H), 7.67-6.62(m, 2H), 7.49(t, J=6.6Hz, 1H) ),7.28(t,J＝7.7Hz,1H),7.17(t,J＝54.4Hz,1H),6.85(s,1H),6.64(s,1H),5.85-5.74(m,1H),5.26 -5.24(m,1H),4.68-4.62(m,1H),4.49-4.41(m,1H),4.12-4.06(m,2H),3.92(s,3H),3.25-3.16(m,2H) ,2.89-2.85(m,2H),2.26(s,3H),1.60(d,J=6.9Hz,3H).
实施例64：化合物64的制备Example 64: Preparation of Compound 64
Figure PCTCN2022070423-appb-000093
Figure PCTCN2022070423-appb-000093
化合物64的合成参考实施例27中化合物27的合成步骤，其中第二步用(1R)-1-(3-(二氟(四氢呋喃-2-基)甲基)苯基)乙-1-胺代替(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺，第四步用环丙烷甲酸代替3-氧杂环丁烷羧酸，合成得到化合物64。The synthesis of compound 64 refers to the synthesis procedure of compound 27 in Example 27, wherein (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine is used in the second step Substitute (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, and in the fourth step, use cyclopropanecarboxylic acid instead of 3-oxetane carboxylic acid to synthesize Compound 64.
MS(ESI):552.2[M+1]+。MS(ESI): 552.2[M+1]+.
1H NMR(400MHz,DMSO)δ8.15(s,1H),8.03(s,1H),7.80(s,1H),7.67-6.62(m,2H),7.49(t,J＝6.6Hz,1H),7.28(t,J＝7.7Hz,1H),7.17(t,J＝54.4Hz,1H),6.85(s,1H),6.64(s, 1H),5.85-5.74(m,1H),5.26-5.24(m,1H),4.68-4.62(m,1H),4.49-4.41(m,1H),4.12-4.06(m,2H),3.92(s,3H),3.25-3.16(m,2H),2.89-2.85(m,2H),2.26(s,3H),1.60(d,J＝6.9Hz,3H). 1 H NMR (400MHz, DMSO) δ8.15(s, 1H), 8.03(s, 1H), 7.80(s, 1H), 7.67-6.62(m, 2H), 7.49(t, J=6.6Hz, 1H) ), 7.28(t, J＝7.7Hz, 1H), 7.17(t, J＝54.4Hz, 1H), 6.85(s, 1H), 6.64(s, 1H), 5.85-5.74(m, 1H), 5.26 -5.24(m,1H),4.68-4.62(m,1H),4.49-4.41(m,1H),4.12-4.06(m,2H),3.92(s,3H),3.25-3.16(m,2H) ,2.89-2.85(m,2H),2.26(s,3H),1.60(d,J=6.9Hz,3H).
实施例65：化合物65的制备Example 65: Preparation of Compound 65
Figure PCTCN2022070423-appb-000094
Figure PCTCN2022070423-appb-000094
化合物65的合成参考实施例44中化合物44的合成步骤，其中第八步用(1R)-1-(3-(二氟(四氢呋喃-2-基)甲基)苯基)乙-1-胺代替(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺，合成得到化合物65。The synthesis of compound 65 refers to the synthesis procedure of compound 44 in Example 44, wherein the eighth step uses (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methyl)phenyl)ethan-1-amine In place of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, compound 65 was synthesized.
MS(ESI):578.2[M+1] +。 MS(ESI): 578.2[M+1] + .
1H NMR(300MHz,dmso)δ8.21-8.06(m,2H),7.78-7.70(m,1H),7.64-7.51(m,2H),7.41-7.31(m,2H),6.87(s,1H),5.70-5.50(m,1H),4.60(t,J＝11.5Hz,1H),4.45-4.30(m,1H),4.28-4.10(m,2H),4.10-3.91(m,1H),3.73-3.55(m,3H),3.53-3.47(m,2H),3.08-2.95(m,2H),2.33-2.25(m,3H),2.15-2.01(m,2H),1.97-1.66(m,4H),1.64-1.46(m,4H),0.87-0.63(m,4H). 1 H NMR(300MHz,dmso)δ8.21-8.06(m,2H),7.78-7.70(m,1H),7.64-7.51(m,2H),7.41-7.31(m,2H),6.87(s, 1H), 5.70-5.50(m, 1H), 4.60(t, J=11.5Hz, 1H), 4.45-4.30(m, 1H), 4.28-4.10(m, 2H), 4.10-3.91(m, 1H) ,3.73-3.55(m,3H),3.53-3.47(m,2H),3.08-2.95(m,2H),2.33-2.25(m,3H),2.15-2.01(m,2H),1.97-1.66( m,4H),1.64-1.46(m,4H),0.87-0.63(m,4H).
实施例66：化合物66的制备Example 66: Preparation of Compound 66
Figure PCTCN2022070423-appb-000095
Figure PCTCN2022070423-appb-000095
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000096
Figure PCTCN2022070423-appb-000096
制备方法：Preparation:
第一步：合成化合物66AStep 1: Synthesis of compound 66A
将化合物44F(5.6g，17.2mmol)和乙酸(1.14g，18.9mmol)加入到DMF(55mL)中，将反应液冷却到0℃，向反应液中逐滴滴加T 3P(14.2g，22.4mmol)，再逐滴滴加三乙胺(5.2g，51.6mmol)，滴加完毕，将反应液升温至25℃下反应1h。TLC显示反应结束后，再向反应液中加入乙酸乙酯(200mL)和饱和食盐水(200mL)，分出有机层，水相用乙酸乙酯(40mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20：1(体积比))，得到化合物66A(5.1g，土黄色固体，产率82.2％)。 Compound 44F (5.6 g, 17.2 mmol) and acetic acid (1.14 g, 18.9 mmol) were added to DMF (55 mL), the reaction solution was cooled to 0°C, and T 3 P (14.2 g, 22.4 mmol), and then triethylamine (5.2 g, 51.6 mmol) was added dropwise, the dropwise addition was completed, and the reaction solution was heated to 25° C. and reacted for 1 h. After TLC showed that the reaction was over, ethyl acetate (200 mL) and saturated brine (200 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (40 mL×2), and the organic phases were combined, Dry, spin dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20:1 (volume ratio)) to obtain compound 66A (5.1 g, khaki solid, yield 82.2%).
MS(ESI):m/z 329.2[M+1] +。 MS(ESI): m/z 329.2[M+1] + .
第二步：合成化合物66BThe second step: synthesis of compound 66B
向化合物66A(4.64g，14.1mmol)中加入1，2-二氯乙烷(50mL)中，再加四氯化碳(1.73g，11.3mmol)，然后加入三苯基膦(1.48g，5.64mmol，4.0eq)，加完后，用氮气置换三次气体，然后氮气保护下将反应液加热到80℃下搅拌2h。TLC显示反应结束后，旋干，得到粗品化合物66B(5.0g，深棕色油状)，无需进一步纯化，直接用于下一步。To compound 66A (4.64 g, 14.1 mmol) was added 1,2-dichloroethane (50 mL), followed by carbon tetrachloride (1.73 g, 11.3 mmol), followed by triphenylphosphine (1.48 g, 5.64 g) mmol, 4.0 eq), after the addition, the gas was replaced three times with nitrogen, and then the reaction solution was heated to 80° C. and stirred for 2 h under nitrogen protection. After TLC showed that the reaction was complete, it was spin-dried to obtain the crude compound 66B (5.0 g, dark brown oil), which was directly used in the next step without further purification.
MS(ESI):m/z 347.1[M+1] +。 MS(ESI): m/z 347.1[M+1] + .
第三步：合成化合物66CThe third step: synthesis of compound 66C
向上一步得到的粗品化合物66B(5.0g)中加入NMP(50mL)，再加(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(2.84g，15.0mmol，1.0eq)和DIEA(3.8g，30.0mmol)，加完后，将反应液加热到100℃下搅拌3h。TLC显示反应结束后，向反应液中加入乙酸乙酯(100mL)和饱和食盐水(100mL)，分出有机层，水相用乙酸乙酯(100mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂为二氯甲烷：甲醇＝20：1(体积比))，得到化合物66C(6.0g，淡黄色固体，两步产率85.2％)。To the crude compound 66B (5.0 g) obtained in the previous step was added NMP (50 mL), followed by (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine (2.84 g) g, 15.0 mmol, 1.0 eq) and DIEA (3.8 g, 30.0 mmol), after the addition, the reaction solution was heated to 100 °C and stirred for 3 h. After TLC showed that the reaction was over, ethyl acetate (100 mL) and saturated brine (100 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (100 mL×2), the organic phases were combined and dried , spin to dry, and the residue was purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1 (volume ratio)) to obtain compound 66C (6.0 g, pale yellow solid, two-step yield 85.2%) .
MS(ESI):m/z 500.2[M+1] +。 MS(ESI): m/z 500.2[M+1] + .
第四步：合成化合物66DStep 4: Synthesis of Compound 66D
将化合物66C(6.0g,12mmol)加入到乙醇(60mL)中，再加入浓盐酸(12mL)，然后升温到90℃，反应12小时，TLC显示反应结束，旋干得到化合物66D的盐酸盐粗品(5.8g,白色固体)，无需进一步纯化，直接用于下一步。Compound 66C (6.0 g, 12 mmol) was added to ethanol (60 mL), then concentrated hydrochloric acid (12 mL) was added, then the temperature was raised to 90° C., and the reaction was performed for 12 hours. TLC showed that the reaction was over, and spin-dried to obtain the crude hydrochloride of compound 66D. (5.8 g, white solid) was used in the next step without further purification.
第五步：合成化合物66Step 5: Synthesis of Compound 66
将化合物66D的粗品盐酸盐(0.24g，0.5mmol)加入到DCM(2mL)中，然后向反应液中加入三乙胺(100mg，1.0mmol)，将反应液冷却到0℃，分批加入三光气(296mg，1.0mmol)，加完后，0℃反应30min。TLC显示反应结束后，再加入二甲胺盐酸盐(81.5mg，1.0mmol)，并补加三乙胺(100mg，1.0mmol)，加完后，将反应液升温到室温搅拌反应1h。TLC显示反应结束后，向反应液中加入水(50mL)，分出有机层，水相用乙酸乙酯(5mL×2)萃取两次，合并有机相，干燥，旋干，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物66(87mg,白色固体，产率33.0％)。The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) was added to DCM (2 mL), then triethylamine (100 mg, 1.0 mmol) was added to the reaction solution, the reaction solution was cooled to 0 °C, and added in batches Triphosgene (296 mg, 1.0 mmol) was added and reacted at 0°C for 30 min. After TLC showed that the reaction was completed, dimethylamine hydrochloride (81.5 mg, 1.0 mmol) was added, and triethylamine (100 mg, 1.0 mmol) was added. After the addition, the reaction solution was warmed to room temperature and stirred for 1 h. After TLC showed that the reaction was over, water (50 mL) was added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 mL×2), the organic phases were combined, dried, and spun to dry, and the residue was prepared by HPLC Purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile was run to the end of 16 min) to give compound 66 (87 mg, white solid, 33.0% yield).
MS(ESI):529.2[M+1] +。 MS(ESI): 529.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.18(s,2H),7.80(s,1H),7.67(t,J＝7.2Hz,1H),7.49(t,J＝6.8Hz,1H),7.29(t,J＝7.6Hz,1H),7.23(t,J＝56Hz,1H),6.88(s,1H),5.87–5.68(m,1H),4.67(t,J＝10.8Hz,1H),4.19(d,J＝10.8Hz,1H),3.62(d,J＝11.6Hz,1H),3.36(t,J＝11.2Hz,2H),3.15-3.08(m,2H),3.05–2.92(m,2H),2.80(s,6H),2.27(s,3H),2.15-2.05(m,1H),1.87(d,J＝15.2Hz,1H),1.60(d,J＝7.2Hz,3H). 1 H NMR (400MHz, DMSO) δ8.18(s, 2H), 7.80(s, 1H), 7.67(t, J=7.2Hz, 1H), 7.49(t, J=6.8Hz, 1H), 7.29( t, J＝7.6Hz, 1H), 7.23(t, J＝56Hz, 1H), 6.88(s, 1H), 5.87–5.68(m, 1H), 4.67(t, J＝10.8Hz, 1H), 4.19 (d, J＝10.8Hz, 1H), 3.62(d, J＝11.6Hz, 1H), 3.36(t, J＝11.2Hz, 2H), 3.15-3.08(m, 2H), 3.05-2.92(m, 2H), 2.80(s, 6H), 2.27(s, 3H), 2.15-2.05(m, 1H), 1.87(d, J=15.2Hz, 1H), 1.60(d, J=7.2Hz, 3H).
实施例67：化合物67的制备Example 67: Preparation of Compound 67
Figure PCTCN2022070423-appb-000097
Figure PCTCN2022070423-appb-000097
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000098
Figure PCTCN2022070423-appb-000098
制备方法：Preparation:
第一步：合成化合物67Step 1: Synthesis of compound 67
将化合物66D的粗品盐酸盐(0.24g，0.5mmol)和化合物3-氧杂环丁烷羧酸(175mg，1.72mmol)加入到DMF(5.5mL)中，将反应液冷却到0℃，向反应液中逐滴滴加T3P(712mg，2.24mmol)，再逐滴滴加三乙胺(0.52g，5.16mmol)，滴加完毕，将反应液升温至25℃下反应1h。TLC显示反应结束后，再向反应液中加入乙酸乙酯(20mL)和饱和食盐水(20mL)，分出有机层，水相用乙酸乙酯(20mL×2)萃取两次，合并有机相，干燥，旋干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20：1(体积比))，柱层析纯化的产物再用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物67(60mg，灰白色固体，两步产率22.1％)。The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) and compound 3-oxetane carboxylic acid (175 mg, 1.72 mmol) were added to DMF (5.5 mL), the reaction solution was cooled to 0 °C, and the mixture was added to DMF (5.5 mL). T3P (712 mg, 2.24 mmol) was added dropwise to the reaction solution, and then triethylamine (0.52 g, 5.16 mmol) was added dropwise. After the addition was completed, the reaction solution was heated to 25° C. and reacted for 1 h. After TLC showed that the reaction was over, ethyl acetate (20 mL) and saturated brine (20 mL) were added to the reaction solution, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (20 mL×2), and the organic phases were combined, Dry, spin dry, the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol = 20:1 (volume ratio)), and the product purified by column chromatography is purified by HPLC preparative purification (Waters Sunfire OBD 100x30mm, 5μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile to 14 min, 10% acetonitrile to 16 min to end ) to give compound 67 (60 mg, off-white solid, 22.1% yield for two steps).
MS(ESI):m/z 542.2[M+1] +。 MS(ESI): m/z 542.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.17(d,J＝7.3Hz,1H),7.77(d,J＝5.3Hz,1H),7.66(t,J＝7.3Hz,1H),7.49(t,J＝7.0Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.90(d,J＝4.5Hz,1H),5.82-5.77(m,1H),4.84-4.64(m,4H),4.61-4.49(m,1H),4.30-4.10 (m,3H),3.25-3.17(m,3H),3.06-3.02(m,2H),2.28(s,3H),2.11–2.07(m,1H),1.92–1.85(m,1H),1.60(d,J＝7.1Hz,3H). 1 H NMR(400MHz, DMSO)δ8.17(d,J=7.3Hz,1H),7.77(d,J=5.3Hz,1H),7.66(t,J=7.3Hz,1H),7.49(t, J＝7.0Hz, 1H), 7.29(t, J＝7.7Hz, 1H), 7.23(t, J＝52.0Hz, 1H), 6.90(d, J＝4.5Hz, 1H), 5.82-5.77(m, 1H), 4.84-4.64(m, 4H), 4.61-4.49(m, 1H), 4.30-4.10 (m, 3H), 3.25-3.17(m, 3H), 3.06-3.02(m, 2H), 2.28( s, 3H), 2.11–2.07 (m, 1H), 1.92–1.85 (m, 1H), 1.60 (d, J=7.1Hz, 3H).
实施例68：化合物68的制备Example 68: Preparation of Compound 68
Figure PCTCN2022070423-appb-000099
Figure PCTCN2022070423-appb-000099
化合物68的合成参考实施例67中化合物67的合成步骤，其中第一步用(R)-四氢-3-呋喃甲酸代替3-氧杂环丁烷羧酸，合成得到化合物68。The synthesis of compound 68 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, (R)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 68.
MS(ESI):556.2[M+1] +。 MS(ESI): 556.2[M+1] + .
1H NMR(400MHz,DMSO)δ9.83-9.69(m,1H),7.98(s,1H),7.79-7.70(m,1H),7.59(t,J＝6.7Hz,1H),7.39(t,J＝7.7Hz,1H),7.24(t,J＝54.2Hz,1H),7.01(d,J＝2.9Hz,1H),6.02-5.78(m,1H),4.80-4.59(m,1H),4.38(dd,J＝6.7,4.0Hz,1H),4.21(d,J＝12.0Hz,1H),4.06-3.85(m,3H),3.81-3.64(m,3H),3.60-3.44(m,2H),3.28-3.19(m,3H),2.51(s,3H),2.27-2.16(s,1H),2.12-1.96(m,3H),1.10(d,J＝7.0Hz,3H). 1 H NMR(400MHz,DMSO)δ9.83-9.69(m,1H),7.98(s,1H),7.79-7.70(m,1H),7.59(t,J=6.7Hz,1H),7.39(t , J=7.7Hz, 1H), 7.24(t, J=54.2Hz, 1H), 7.01(d, J=2.9Hz, 1H), 6.02-5.78(m, 1H), 4.80-4.59(m, 1H) ,4.38(dd,J＝6.7,4.0Hz,1H),4.21(d,J＝12.0Hz,1H),4.06-3.85(m,3H),3.81-3.64(m,3H),3.60-3.44(m ,2H),3.28-3.19(m,3H),2.51(s,3H),2.27-2.16(s,1H),2.12-1.96(m,3H),1.10(d,J=7.0Hz,3H).
实施例69：化合物69的制备Example 69: Preparation of Compound 69
Figure PCTCN2022070423-appb-000100
Figure PCTCN2022070423-appb-000100
化合物69的合成参考实施例67中化合物67的合成步骤，其中第一步用(S)-四氢-3-呋喃甲酸代替3-氧杂环丁烷羧酸，合成得到化合物69。The synthesis of compound 69 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, (S)-tetrahydro-3-furancarboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 69.
MS(ESI):556.2[M+1] +。 MS(ESI): 556.2[M+1] + .
1H NMR(400MHz,DMSO)δ9.88-9.70(m,1H),7.95(s,1H),7.78-7.69(m,1H),7.58(t,J＝6.7Hz,1H),7.38(t,J＝7.7Hz,1H),7.25(t,J＝54.2Hz,1H),7.00(d,J＝2.9Hz,1H), 6.01-5.78(m,1H),4.79-4.59(m,1H),4.36(dd,J＝6.7,4.0Hz,1H),4.20(d,J＝12.0Hz,1H),4.05-3.83(m,3H),3.80-3.64(m,3H),3.59-3.44(m,2H),3.28-3.18(m,3H),2.52(s,3H),2.25-2.14(s,1H),2.12-1.96(m,3H),1.69(d,J＝7.0Hz,3H). 1 H NMR(400MHz, DMSO)δ9.88-9.70(m,1H),7.95(s,1H),7.78-7.69(m,1H),7.58(t,J=6.7Hz,1H),7.38(t , J=7.7Hz, 1H), 7.25(t, J=54.2Hz, 1H), 7.00(d, J=2.9Hz, 1H), 6.01-5.78(m, 1H), 4.79-4.59(m, 1H) ,4.36(dd,J＝6.7,4.0Hz,1H),4.20(d,J＝12.0Hz,1H),4.05-3.83(m,3H),3.80-3.64(m,3H),3.59-3.44(m ,2H),3.28-3.18(m,3H),2.52(s,3H),2.25-2.14(s,1H),2.12-1.96(m,3H),1.69(d,J=7.0Hz,3H).
实施例70：化合物70的制备Example 70: Preparation of Compound 70
Figure PCTCN2022070423-appb-000101
Figure PCTCN2022070423-appb-000101
化合物70的合成参考实施例67中化合物67的合成步骤，其中第一步用1-氰基-1-环丙烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物70。The synthesis of compound 70 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-cyano-1-cyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 70.
MS(ESI):551.2[M+1] +。 MS(ESI): 551.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.25-8.14(m,1H),7.80(s,1H),7.67(t,J＝7.1Hz,1H),7.49(t,J＝7.1Hz,1H),7.29(t,J＝7.2Hz,1H),7.23(d,J＝54.4Hz,1H),6.91(s,1H),5.87-5.74(m,1H),4.62(t,J＝11.2Hz,1H),4.30-4.14(m,2H),4.10-3.95(m,1H),3.72-3.53(m,2H),3.20-3.08(m,3H),2.28(s,3H),2.20-2.06(m,1H),2.00-1.85(m,1H),1.75-1.40(m,7H). 1 H NMR(400MHz, DMSO)δ8.25-8.14(m,1H),7.80(s,1H),7.67(t,J=7.1Hz,1H),7.49(t,J=7.1Hz,1H), 7.29(t, J＝7.2Hz, 1H), 7.23(d, J＝54.4Hz, 1H), 6.91(s, 1H), 5.87-5.74(m, 1H), 4.62(t, J＝11.2Hz, 1H) ), 4.30-4.14(m, 2H), 4.10-3.95(m, 1H), 3.72-3.53(m, 2H), 3.20-3.08(m, 3H), 2.28(s, 3H), 2.20-2.06(m ,1H),2.00-1.85(m,1H),1.75-1.40(m,7H).
实施例71：化合物71的制备Example 71: Preparation of Compound 71
Figure PCTCN2022070423-appb-000102
Figure PCTCN2022070423-appb-000102
化合物71的合成参考实施例67中化合物67的合成步骤，其中第一步用1-甲氧基环丙烷羧酸代替3-氧杂环丁烷羧酸，合成得到化合物71。The synthesis of compound 71 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-methoxycyclopropanecarboxylic acid is used instead of 3-oxetanecarboxylic acid to synthesize compound 71.
MS(ESI):556.2[M+1] +。 MS(ESI): 556.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.20(d,J＝6.8Hz,1H),7.79(s,1H),7.67(t,J＝7.2Hz,1H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.2Hz,1H),7.23(t,J＝56Hz,1H),6.91(s,1H), 5.86–5.74(m,1H),4.64(t,J＝10.8Hz,1H),4.21(d,J＝11.2Hz,1H),4.08(br.s,1H),3.32-3.25(m,7H),3.12-3.01(m,2H),2.28(s,3H),2.18-2.02(m,1H),1.90(d,J＝14.0Hz,1H),1.60(d,J＝7.2Hz,3H),1.02-0.87(m,4H). 1 H NMR(400MHz,DMSO)δ8.20(d,J=6.8Hz,1H),7.79(s,1H),7.67(t,J=7.2Hz,1H),7.49(t,J=6.9Hz, 1H), 7.29(t, J=7.2Hz, 1H), 7.23(t, J=56Hz, 1H), 6.91(s, 1H), 5.86–5.74(m, 1H), 4.64(t, J=10.8Hz) ,1H),4.21(d,J＝11.2Hz,1H),4.08(br.s,1H),3.32-3.25(m,7H),3.12-3.01(m,2H),2.28(s,3H), 2.18-2.02(m, 1H), 1.90(d, J=14.0Hz, 1H), 1.60(d, J=7.2Hz, 3H), 1.02-0.87(m, 4H).
实施例72：化合物72的制备Example 72: Preparation of Compound 72
Figure PCTCN2022070423-appb-000103
Figure PCTCN2022070423-appb-000103
化合物72的合成参考实施例66中化合物66的合成步骤，其中第五步用氯甲酸甲酯代替二甲胺盐酸盐，合成得到化合物72。The synthesis of compound 72 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, methyl chloroformate is used instead of dimethylamine hydrochloride to synthesize compound 72.
MS(ESI):516.2[M+1] +。 MS(ESI): 516.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.15(s,1H),7.79(s,1H),7.67(t,J＝7.2Hz,1H),7.49(t,J＝6.8Hz,1H),7.29(t,J＝7.2Hz,1H),7.23(t,J＝56Hz,1H),6.89(s,1H),5.86–5.73(m,1H),4.58(t,J＝10.6Hz,1H),4.20(d,J＝11.2Hz,1H),3.93(d,J＝7.2Hz,1H),3.74(d,J＝12.0Hz,1H),3.65(s,3H),3.25-3.17(m,4H),3.05(s,1H),2.27(s,3H),2.15-2.05(m,1H),1.88(d,J＝14Hz,1H),1.60(d,J＝7.2Hz,3H). 1 H NMR(400MHz, DMSO)δ8.15(s,1H),7.79(s,1H),7.67(t,J=7.2Hz,1H),7.49(t,J=6.8Hz,1H),7.29( t, J＝7.2Hz, 1H), 7.23(t, J＝56Hz, 1H), 6.89(s, 1H), 5.86–5.73(m, 1H), 4.58(t, J＝10.6Hz, 1H), 4.20 (d, J=11.2Hz, 1H), 3.93 (d, J=7.2Hz, 1H), 3.74 (d, J=12.0Hz, 1H), 3.65 (s, 3H), 3.25-3.17 (m, 4H) ,3.05(s,1H),2.27(s,3H),2.15-2.05(m,1H),1.88(d,J=14Hz,1H),1.60(d,J=7.2Hz,3H).
实施例73：化合物73的制备Example 73: Preparation of Compound 73
Figure PCTCN2022070423-appb-000104
Figure PCTCN2022070423-appb-000104
化合物73的合成参考实施例67中化合物67的合成步骤，其中第一步用氮杂环丁烷-1-乙酸盐酸盐代替3-氧杂环丁烷羧酸，合成得到化合物73。The synthesis of compound 73 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, azetidine-1-acetic acid hydrochloride is used instead of 3-oxetane carboxylic acid to synthesize compound 73.
MS(ESI):555.2[M+1] +。 MS(ESI): 555.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.20(s,1H),7.78(s,1H),7.71-7.61(m,1H),7.50(t,J＝4.0Hz,1H),7.29(t,J＝4.0Hz,1H),7.24(t,J＝56Hz,1H),6.90(s,1H),5.85-5.73(m,1H), 4.66-4.49(m,1H),4.25-4.10(m,2H),3.97-3.85(m,1H),3.75-3.70(m,1H),3.47-3.40(m,2H),3.34-3.29(m,4H),3.27-3.22(m,1H),3.19-3.08(m,3H),2.62-2.53(m,1H),2.28(s,3H),2.15-2.0(m,2H),1.93-1.78(s,1H),1.60(d,J＝6.4Hz,3H). 1 H NMR (400MHz, DMSO) δ8.20(s, 1H), 7.78(s, 1H), 7.71-7.61(m, 1H), 7.50(t, J=4.0Hz, 1H), 7.29(t, J ＝4.0Hz, 1H), 7.24(t, J＝56Hz, 1H), 6.90(s, 1H), 5.85-5.73(m, 1H), 4.66-4.49(m, 1H), 4.25-4.10(m, 2H) ),3.97-3.85(m,1H),3.75-3.70(m,1H),3.47-3.40(m,2H),3.34-3.29(m,4H),3.27-3.22(m,1H),3.19-3.08 (m,3H),2.62-2.53(m,1H),2.28(s,3H),2.15-2.0(m,2H),1.93-1.78(s,1H),1.60(d,J=6.4Hz,3H ).
实施例74：化合物74的制备Example 74: Preparation of Compound 74
Figure PCTCN2022070423-appb-000105
Figure PCTCN2022070423-appb-000105
化合物74的合成参考实施例67中化合物67的合成步骤，其中第一步用甲氧基乙酸代替3-氧杂环丁烷羧酸，合成得到化合物74。The synthesis of compound 74 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, methoxyacetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 74.
MS(ESI):530.2[M+1] +。 MS(ESI): 530.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ8.18(s,1H),7.78(s,1H),7.67(t,J＝7.5Hz,1H),7.49(t,J＝7.1Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.90(s,1H),5.85-5.75(m,1H),4.66-4.55(m,1H),4.25-4.10(m,3H),3.97-3.85(m,1H),3.69-3.65(m,1H),3.34(s,2H),3.31(s,3H),3.26-3.14(m,3H),3.09-3.04(m,1H),2.27(s,3H),2.15-2.06(m,1H),1.93-1.84(m,1H),1.60(d,J＝7.0Hz,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.78 (s, 1H), 7.67 (t, J=7.5Hz, 1H), 7.49 (t, J=7.1Hz, 1H) ,7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.90(s,1H),5.85-5.75(m,1H),4.66-4.55(m,1H), 4.25-4.10(m, 3H), 3.97-3.85(m, 1H), 3.69-3.65(m, 1H), 3.34(s, 2H), 3.31(s, 3H), 3.26-3.14(m, 3H), 3.09-3.04(m, 1H), 2.27(s, 3H), 2.15-2.06(m, 1H), 1.93-1.84(m, 1H), 1.60(d, J=7.0Hz, 3H).
实施例75：化合物75的制备Example 75: Preparation of Compound 75
Figure PCTCN2022070423-appb-000106
Figure PCTCN2022070423-appb-000106
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000107
Figure PCTCN2022070423-appb-000107
制备方法：Preparation:
第一步：合成化合物75Step 1: Synthesis of Compound 75
将化合物66D的粗品盐酸盐(0.24g，0.5mmol)加入到无水乙腈(5ml)中，然后依次加入碳酸钾(138mg,1.0mmol)和甲磺酸四氢呋喃-3-基酯(166mg,1.0mmol),然后将反应液升温回流条件下反应12小时。TLC显示反应结束后，旋干后，加入水(20mL)和乙酸乙酯(20mL)，分出有机层，水相用乙酸乙酯(5mL×2)萃取两次，合并有机相，干燥，旋干，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物75(61mg,白色固体，产率23.0％)。The crude hydrochloride salt of compound 66D (0.24 g, 0.5 mmol) was added to anhydrous acetonitrile (5 ml), then potassium carbonate (138 mg, 1.0 mmol) and tetrahydrofuran-3-yl methanesulfonate (166 mg, 1.0 mmol) were added sequentially mmol), and then the reaction solution was heated and reacted under reflux conditions for 12 hours. After TLC showed that the reaction was over, after rotating to dryness, water (20 mL) and ethyl acetate (20 mL) were added, the organic layer was separated, the aqueous phase was extracted twice with ethyl acetate (5 mL×2), the organic phases were combined, dried, and rotated. Dry, the residue was purified by preparative HPLC (Waters Sunfire OBD 100x30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to give compound 75 (61 mg, white solid, 23.0% yield).
MS(ESI):528[M+1] +。 MS(ESI): 528[M+1] + .
1H NMR(300MHz,dmso)δ8.14(d,J＝7.3Hz,1H),7.79(s,1H),7.65(t,J＝7.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.28(t,J＝7.5Hz,1H),7.23(t,J＝53.8Hz,1H),6.84(s,1H),5.85-5.71(m,1H),4.65(t,J＝11.1Hz,1H),4.16(d,J＝8.4Hz,1H),3.85-3.74(m,2H),3.72-3.60(m,1H),3.53(t,J＝7.6Hz,1H),3.15-2.87(m,4H),2.80-2.66(m,1H),2.60-2.52(m,1H),2.37-2.17(m,5H),2.15-1.93(m,2H),1.86-1.69(m,2H),1.58(d,J＝6.7Hz,3H). 1 H NMR(300MHz,dmso)δ8.14(d,J=7.3Hz,1H),7.79(s,1H),7.65(t,J=7.4Hz,1H),7.47(d,J=7.2Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.23(t, J=53.8Hz, 1H), 6.84(s, 1H), 5.85-5.71(m, 1H), 4.65(t, J=11.1 Hz,1H),4.16(d,J＝8.4Hz,1H),3.85-3.74(m,2H),3.72-3.60(m,1H),3.53(t,J＝7.6Hz,1H),3.15-2.87 (m,4H),2.80-2.66(m,1H),2.60-2.52(m,1H),2.37-2.17(m,5H),2.15-1.93(m,2H),1.86-1.69(m,2H) ,1.58(d,J=6.7Hz,3H).
实施例76：化合物76的制备Example 76: Preparation of Compound 76
Figure PCTCN2022070423-appb-000108
Figure PCTCN2022070423-appb-000108
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000109
Figure PCTCN2022070423-appb-000109
制备方法：Preparation:
第一步：合成化合物76Step 1: Synthesis of Compound 76
将化合物66D的粗品盐酸盐(0.24g，0.5mmol)加入到无水THF(5ml)中，然后加入多聚甲醛(225mg,2.5mmol),室温下搅拌4小时，然后加入氰基硼氢化钠(157mg,2.5mmol)。在搅拌下将混合物加热至50℃过夜。冷却后加入25mL水，水相用二氯甲烷(10mL×2)萃取两次，合并有机相，干燥，旋干，残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物76(61mg,白色固体，产率26.0％)。The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) was added to anhydrous THF (5 ml), then paraformaldehyde (225 mg, 2.5 mmol) was added, stirred at room temperature for 4 hours, and then sodium cyanoborohydride was added (157 mg, 2.5 mmol). The mixture was heated to 50°C overnight with stirring. After cooling, 25 mL of water was added, the aqueous phase was extracted twice with dichloromethane (10 mL×2), the organic phases were combined, dried, and spun to dry, and the residue was purified by HPLC preparation (Waters Sunfire OBD 100×30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile for 10 min, 95% acetonitrile for 14 min, 10% acetonitrile for 16 min) to obtain compound 76 (61 mg, white solid, 26.0% yield).
MS(ESI):472.2[M+1] +。 MS(ESI): 472.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.23-8.12(m,2H),7.80(s,1H),7.67(t,J＝7.2Hz,1H),7.49(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.87(s,1H),5.79(q,J＝6.9Hz,1H),4.62(t,J＝10.8Hz,1H),4.18(dd,J＝7.6,3.4Hz,1H),3.37(t,J＝10.8Hz,2H),3.11(d,J＝11.6Hz,1H),3.04-2.96(m,1H),2.84(d,J＝10.8Hz,1H),2.63(d,J＝9.8Hz,1H),2.28(s,3H),2.27(s,3H),2.23-2.01(m,2H),1.83(d,J＝15.5Hz,1H),1.60(d,J＝7.0Hz,3H). 1 H NMR(400MHz, DMSO)δ8.23-8.12(m,2H),7.80(s,1H),7.67(t,J=7.2Hz,1H),7.49(t,J=6.9Hz,1H), 7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.87(s,1H),5.79(q,J＝6.9Hz,1H),4.62(t,J＝10.8 Hz,1H),4.18(dd,J=7.6,3.4Hz,1H),3.37(t,J=10.8Hz,2H),3.11(d,J=11.6Hz,1H),3.04-2.96(m,1H) ),2.84(d,J＝10.8Hz,1H),2.63(d,J＝9.8Hz,1H),2.28(s,3H),2.27(s,3H),2.23-2.01(m,2H),1.83 (d, J=15.5Hz, 1H), 1.60 (d, J=7.0Hz, 3H).
实施例77：化合物77的制备Example 77: Preparation of Compound 77
Figure PCTCN2022070423-appb-000110
Figure PCTCN2022070423-appb-000110
化合物77的合成参考实施例75中化合物75的合成步骤，其中第一步用1-溴-2-甲氧基乙烷代替甲磺酸四氢呋喃-3-基酯，合成得到化合物77。The synthesis of compound 77 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 1-bromo-2-methoxyethane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 77.
MS(ESI):516.2[M+1] +。 MS(ESI): 516.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.12(t,J＝7.1Hz,1H),7.80(d,J＝8.1Hz,1H),7.67(d,J＝7.1Hz,1H),7.49(d,J＝6.7Hz,1H),7.29(dd,J＝15.5,7.8Hz,1H),7.25(td,J＝54.4,15.5Hz,1H),6.87(d,J＝8.8Hz,,1H),5.85-5.71(m,1H),4.70-4.57(m,1H),4.17(s,1H),3.52-3.45(m,2H),3.40-3.35(m,1H),3.28(d,J＝8.8Hz,3H),3.13-3.04(m,1H),3.02-2.88(s,2H),2.75-2.65(m,1H),2.60-2.53(m,2H),2.36-2.28(m,1H),2.28(d,J＝7.1Hz,3H),2.25-2.18(m,1H),2.15-2.02(m,1H),1.86-1.77(m,1H),1.60(t,J＝7.1Hz,3H). 1 H NMR(400MHz, DMSO)δ8.12(t,J=7.1Hz,1H),7.80(d,J=8.1Hz,1H),7.67(d,J=7.1Hz,1H),7.49(d, J＝6.7Hz,1H),7.29(dd,J＝15.5,7.8Hz,1H),7.25(td,J＝54.4,15.5Hz,1H),6.87(d,J＝8.8Hz,,1H),5.85 -5.71(m, 1H), 4.70-4.57(m, 1H), 4.17(s, 1H), 3.52-3.45(m, 2H), 3.40-3.35(m, 1H), 3.28(d, J=8.8Hz ,3H),3.13-3.04(m,1H),3.02-2.88(s,2H),2.75-2.65(m,1H),2.60-2.53(m,2H),2.36-2.28(m,1H),2.28 (d, J=7.1Hz, 3H), 2.25-2.18 (m, 1H), 2.15-2.02 (m, 1H), 1.86-1.77 (m, 1H), 1.60 (t, J=7.1Hz, 3H).
实施例78：化合物78的制备Example 78: Preparation of Compound 78
Figure PCTCN2022070423-appb-000111
Figure PCTCN2022070423-appb-000111
化合物78的合成参考实施例66中化合物66的合成步骤，其中第五步用氮杂环丁烷代替二甲胺盐酸盐，合成得到化合物78。The synthesis of compound 78 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, azetidine is used instead of dimethylamine hydrochloride to synthesize compound 78.
MS(ESI):541.2[M+1] +。 MS(ESI): 541.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.18(d,J＝7.1Hz,2H),7.77(s,1H),7.67(t,J＝7.3Hz,1H),7.49(t,J＝6.7Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.88(s,1H),5.86-5.72(m,1H),4.62(t,J＝10.7Hz,1H),4.23-4.17(m,1H),4.01-3.89(m,4H),3.75(d,J＝12.6Hz,1H),3.29-3.23(m,2H),3.22-3.05(m,4H),3.03-2.94(m,1H),2.27(s,3H),2.22-2.04(m,3H),1.89(d,J＝15.0Hz,1H),1.60(d,J＝7.0Hz,3H). 1 H NMR(400MHz, DMSO)δ8.18(d,J=7.1Hz,2H),7.77(s,1H),7.67(t,J=7.3Hz,1H),7.49(t,J=6.7Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.88(s, 1H), 5.86-5.72(m, 1H), 4.62(t, J=10.7 Hz, 1H), 4.23-4.17(m, 1H), 4.01-3.89(m, 4H), 3.75(d, J=12.6Hz, 1H), 3.29-3.23(m, 2H), 3.22-3.05(m, 4H), 3.03-2.94(m, 1H), 2.27(s, 3H), 2.22-2.04(m, 3H), 1.89(d, J=15.0Hz, 1H), 1.60(d, J=7.0Hz, 3H ).
实施例79：化合物79的制备Example 79: Preparation of Compound 79
Figure PCTCN2022070423-appb-000112
Figure PCTCN2022070423-appb-000112
化合物79的合成参考实施例67中化合物67的合成步骤，其中第一步用烟酸代替3-氧杂环丁烷羧酸，合成得到化合物79。The synthesis of compound 79 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, nicotinic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 79.
MS(ESI):563.2[M+1] +。 MS(ESI): 563.2[M+1] + .
1H NMR(400MHz,DMSO)δ8.76-8.60(m,2H),8.20(br.s,1H),8.01-7.74(m,2H),7.68(t,J＝4.0,1H),7.58-7.46(m,2H),7.30(t,J＝8.0Hz,1H),7.24(t,J＝56Hz,1H),6.90(s,1H),5.87-5.74(m,1H),4.73-4.52(m,1H),4.42-4.09(m,2H),3.72-3.58(m,1H),3.47-3.36(m,2H),3.25-3.18(m,1H),3.15-3.09(m,2H),2.28(s,3H),2.21-1.75(m,2H),1.60(d,J＝7.2Hz,3H). 1 H NMR(400MHz,DMSO)δ8.76-8.60(m,2H),8.20(br.s,1H),8.01-7.74(m,2H),7.68(t,J=4.0,1H),7.58- 7.46(m, 2H), 7.30(t, J=8.0Hz, 1H), 7.24(t, J=56Hz, 1H), 6.90(s, 1H), 5.87-5.74(m, 1H), 4.73-4.52( m,1H),4.42-4.09(m,2H),3.72-3.58(m,1H),3.47-3.36(m,2H),3.25-3.18(m,1H),3.15-3.09(m,2H), 2.28(s, 3H), 2.21-1.75(m, 2H), 1.60(d, J=7.2Hz, 3H).
实施例80：化合物80的制备Example 80: Preparation of Compound 80
Figure PCTCN2022070423-appb-000113
Figure PCTCN2022070423-appb-000113
化合物80的合成参考实施例67中化合物67的合成步骤，其中第一步用乙酸代替3-氧杂环丁烷羧酸，合成得到化合物80。The synthesis of compound 80 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, acetic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 80.
MS(ESI):500.2[M+1] +。 MS(ESI): 500.2[M+1] + .
1H NMR(300MHz,dmso)δ8.14(d,J＝3.7Hz,1H),7.77(d,J＝2.3Hz,1H),7.65(t,J＝7.5Hz,1H),7.48(t,J＝7.2Hz,1H),7.27(t,J＝7.7Hz,1H),7.22(t,J＝57.0Hz,1H),6.88(s,1H),5.86-5.70(m,1H),4.63-4.52(m,1H),4.21-4.17(m,2H),3.95-3.84(m,2H),3.47-3.37(m,2H),3.14-2.98(m,2H),2.26(s,3H),2.08-2.02(m,4H),1.89-1.80(m,1H),1.57(d,J＝7.1Hz,3H). 1 H NMR(300MHz,dmso)δ8.14(d,J=3.7Hz,1H),7.77(d,J=2.3Hz,1H),7.65(t,J=7.5Hz,1H),7.48(t, J=7.2Hz, 1H), 7.27(t, J=7.7Hz, 1H), 7.22(t, J=57.0Hz, 1H), 6.88(s, 1H), 5.86-5.70(m, 1H), 4.63- 4.52(m, 1H), 4.21-4.17(m, 2H), 3.95-3.84(m, 2H), 3.47-3.37(m, 2H), 3.14-2.98(m, 2H), 2.26(s, 3H), 2.08-2.02(m, 4H), 1.89-1.80(m, 1H), 1.57(d, J=7.1Hz, 3H).
实施例81：化合物81的制备Example 81: Preparation of Compound 81
Figure PCTCN2022070423-appb-000114
Figure PCTCN2022070423-appb-000114
化合物81的合成参考实施例66中化合物66的合成步骤，其中第五步用3-氮杂环丁醇代替二甲胺盐酸盐，合成得到化合物81。The synthesis of compound 81 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, 3-azetidinol is used instead of dimethylamine hydrochloride to synthesize compound 81.
MS(ESI):558.2[M+1] +。 MS(ESI): 558.2[M+1] + .
1H NMR(300MHz,dmso)δ8.15(d,J＝7.5Hz,1H),7.79(s,1H),7.65(t,J＝7.4Hz,1H),7.48(t,J＝7.2Hz,1H),7.28(t,J＝7.5Hz,1H),7.23(t,J＝54.3Hz,1H),6.88(s,1H),5.86-5.71(m,1H),5.39-5.27(m,1H),4.78(t,J＝6.7Hz,2H),4.64-4.45(m,3H),4.25-4.14(m,1H),4.07-3.67(m,1H),3.26-3.14(m,4H),3.10-3.04(m,2H),2.26(s,3H),2.18-2.01(m,1H),1.94-1.82(m,1H),1.58(d,J＝7.0Hz,3H). 1 H NMR(300MHz,dmso)δ8.15(d,J=7.5Hz,1H),7.79(s,1H),7.65(t,J=7.4Hz,1H),7.48(t,J=7.2Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.23(t, J=54.3Hz, 1H), 6.88(s, 1H), 5.86-5.71(m, 1H), 5.39-5.27(m, 1H) ), 4.78(t, J＝6.7Hz, 2H), 4.64-4.45(m, 3H), 4.25-4.14(m, 1H), 4.07-3.67(m, 1H), 3.26-3.14(m, 4H), 3.10-3.04(m, 2H), 2.26(s, 3H), 2.18-2.01(m, 1H), 1.94-1.82(m, 1H), 1.58(d, J=7.0Hz, 3H).
实施例82：化合物82的制备Example 82: Preparation of Compound 82
Figure PCTCN2022070423-appb-000115
Figure PCTCN2022070423-appb-000115
化合物82的合成参考实施例75中化合物75的合成步骤，其中第一步用3-碘氧杂环丁烷代替甲磺酸四氢呋喃-3-基酯，合成得到化合物82。The synthesis of compound 82 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 3-iodooxetane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 82.
MS(ESI):514.2[M+1] +。 MS(ESI): 514.2[M+1] + .
1H NMR(300MHz,dmso)δ8.15(d,J＝7.2Hz,1H),7.81(s,1H),7.66(t,J＝7.3Hz,1H),7.48(t,J＝6.9Hz,1H),7.29(t,J＝7.7Hz,1H),7.23(t,J＝54.4Hz,1H),6.85(s,1H),5.87-5.70(m,1H),4.72-4.53(m,3H),4.47(t,J＝5.3Hz,2H),4.21-4.09(m,1H),3.56-3.45(m,1H),3.29-3.22(m,1H),3.17-3.08(m,1H),3.05-2.95(m,1H),2.82-2.69(m,1H),2.62-2.51(m,1H), 2.25(s,3H),2.25-2.20(m,3H),1.83(d,J＝15.8Hz,1H),1.58(d,J＝6.9Hz,3H). 1 H NMR(300MHz,dmso)δ8.15(d,J=7.2Hz,1H),7.81(s,1H),7.66(t,J=7.3Hz,1H),7.48(t,J=6.9Hz, 1H), 7.29(t, J=7.7Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.85(s, 1H), 5.87-5.70(m, 1H), 4.72-4.53(m, 3H) ), 4.47(t, J＝5.3Hz, 2H), 4.21-4.09(m, 1H), 3.56-3.45(m, 1H), 3.29-3.22(m, 1H), 3.17-3.08(m, 1H), 3.05-2.95(m, 1H), 2.82-2.69(m, 1H), 2.62-2.51(m, 1H), 2.25(s, 3H), 2.25-2.20(m, 3H), 1.83(d, J=15.8 Hz,1H),1.58(d,J＝6.9Hz,3H).
实施例83：化合物83的制备Example 83: Preparation of Compound 83
Figure PCTCN2022070423-appb-000116
Figure PCTCN2022070423-appb-000116
合成路线：synthetic route:
Figure PCTCN2022070423-appb-000117
Figure PCTCN2022070423-appb-000117
制备方法：Preparation:
第一步：合成化合物83Step 1: Synthesis of compound 83
将化合物66D的粗品盐酸盐(0.24g，0.5mmol)加入到异丙醇(5mL)中，然后分别加入5-碘-1-甲基-吡唑(208mg，1.0mmol)，乙二醇(0.33g,1.0mmol)，Cul(50mg,0.25mmol mmol)和无水磷酸钾(633mg,3.0mmol)。将反应混合物在氮气保护下，于密封管中加热到100℃反应16小时。TLC显示完成后，将反应混合物通过硅藻土过滤，用EtOAc(100mL)洗涤并将滤液真空浓缩。得到的残余物用HPLC制备纯化(Waters Sunfire OBD 100x30mm,5μm，流动相A∶0.1％TFA in water，流动相B∶乙腈，梯度∶10％乙腈运行1min，52％-52％乙腈运行至10min，95％乙腈运行至14min，10％乙腈运行至16min结束)，得到化合物83(56mg,白色固体，产率21.0％)。The crude hydrochloride of compound 66D (0.24 g, 0.5 mmol) was added to isopropanol (5 mL), then 5-iodo-1-methyl-pyrazole (208 mg, 1.0 mmol), ethylene glycol ( 0.33 g, 1.0 mmol), Cul (50 mg, 0.25 mmol mmol) and anhydrous potassium phosphate (633 mg, 3.0 mmol). The reaction mixture was heated to 100°C in a sealed tube under nitrogen protection for 16 hours. After TLC showed completion, the reaction mixture was filtered through celite, washed with EtOAc (100 mL) and the filtrate was concentrated in vacuo. The resulting residue was preparatively purified by HPLC (Waters Sunfire OBD 100x30 mm, 5 μm, mobile phase A: 0.1% TFA in water, mobile phase B: acetonitrile, gradient: 10% acetonitrile for 1 min, 52%-52% acetonitrile to 10 min, 95% acetonitrile run to 14 min, 10% acetonitrile run to 16 min end) to give compound 83 (56 mg, white solid, 21.0% yield).
MS(ESI):538.2[M+1] +。 MS(ESI): 538.2[M+1] + .
1H NMR(300MHz,dmso)δ8.18(d,J＝7.2Hz,1H),7.87(s,1H),7.67(t,J＝7.2Hz,1H),7.47(d,J＝6.6Hz,1H),7.34–7.25(m,2H),7.23(t,J＝54Hz,1H),6.88(s,1H),5.94(d,J＝1.8Hz,1H),5.83–5.73(m,1H),4.68(t,J＝11.1Hz,1H),4.24–4.16(m,1H),3.68(s,3H), 3.59–3.48(m,1H),3.27–3.13(m,3H),3.04–2.78(m,3H),2.26(s,3H),2.22–2.06(m,1H),1.99–1.88(m,1H),1.59(d,J＝7.2Hz,3H). 1 H NMR(300MHz,dmso)δ8.18(d,J=7.2Hz,1H),7.87(s,1H),7.67(t,J=7.2Hz,1H),7.47(d,J=6.6Hz, 1H), 7.34–7.25 (m, 2H), 7.23 (t, J=54Hz, 1H), 6.88 (s, 1H), 5.94 (d, J=1.8Hz, 1H), 5.83–5.73 (m, 1H) ,4.68(t,J＝11.1Hz,1H),4.24-4.16(m,1H),3.68(s,3H), 3.59-3.48(m,1H),3.27-3.13(m,3H),3.04-2.78 (m, 3H), 2.26 (s, 3H), 2.22–2.06 (m, 1H), 1.99–1.88 (m, 1H), 1.59 (d, J=7.2Hz, 3H).
实施例84：化合物84的制备Example 84: Preparation of Compound 84
Figure PCTCN2022070423-appb-000118
Figure PCTCN2022070423-appb-000118
化合物84的合成参考实施例66中化合物66的合成步骤，其中第五步用氨气代替二甲胺盐酸盐，合成得到化合物84。The synthesis of compound 84 refers to the synthesis steps of compound 66 in Example 66, wherein in the fifth step, ammonia gas is used instead of dimethylamine hydrochloride to synthesize compound 84.
MS(ESI):501.2[M+1] +。 MS(ESI): 501.2[M+1] + .
1H NMR(300MHz,dmso)δ8.16(d,J＝7.2Hz,1H),7.77(s,1H),7.65(t,J＝7.2Hz,1H),7.48(t,J＝6.9Hz,1H),7.28(t,J＝7.7Hz,1H),7.23(t,J＝52.0Hz,1H),6.86(s,1H),6.09(s,2H),5.80-5.75(m,1H),4.60(t,J＝10.5Hz,1H),4.19(d,J＝10.9Hz,1H),3.90(d,J＝12.9Hz,1H),3.66(s,1H),3.28-3.05(m,4H),3.02-2.91(m,1H),2.25(s,3H),2.09(s,1H),1.80(d,J＝15.5Hz,1H),1.58(d,J＝7.0Hz,3H). 1 H NMR(300MHz,dmso)δ8.16(d,J=7.2Hz,1H),7.77(s,1H),7.65(t,J=7.2Hz,1H),7.48(t,J=6.9Hz, 1H), 7.28(t, J=7.7Hz, 1H), 7.23(t, J=52.0Hz, 1H), 6.86(s, 1H), 6.09(s, 2H), 5.80-5.75(m, 1H), 4.60(t,J＝10.5Hz,1H),4.19(d,J＝10.9Hz,1H),3.90(d,J＝12.9Hz,1H),3.66(s,1H),3.28-3.05(m,4H) ), 3.02-2.91(m, 1H), 2.25(s, 3H), 2.09(s, 1H), 1.80(d, J=15.5Hz, 1H), 1.58(d, J=7.0Hz, 3H).
实施例85：化合物85的制备Example 85: Preparation of Compound 85
Figure PCTCN2022070423-appb-000119
Figure PCTCN2022070423-appb-000119
化合物85的合成参考实施例67中化合物67的合成步骤，其中第一步用1-甲基吡唑-5-甲酸代替3-氧杂环丁烷羧酸，合成得到化合物85。The synthesis of compound 85 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, 1-methylpyrazole-5-carboxylic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 85.
MS(ESI):566.2[M+1] +。 MS(ESI): 566.2[M+1] + .
1H NMR(300MHz,dmso)δ8.17(s,1H),7.79(s,1H),7.65(t,J＝7.2Hz,1H),7.55-7.44(m,2H),7.28(t,J＝8.0Hz,1H),7.22(t,J＝52Hz,2H),6.88(s,1H),6.59-6.44(m,1H),5.85- 5.71(m,1H),4.60(t,J＝10.8Hz,1H),4.41-4.05(m,2H),3.87(s,3H),3.83-3.68(m,1H),3.50-3.40(m,1H),3.31-3.23(m,2H),3.18-3.09(m,2H),2.26(s,3H),2.10-1.93(m,1H),1.88-1.72(m,1H),1.58(d,J＝7.2Hz,3H). 1 H NMR(300MHz,dmso)δ8.17(s,1H),7.79(s,1H),7.65(t,J=7.2Hz,1H),7.55-7.44(m,2H),7.28(t,J =8.0Hz,1H),7.22(t,J=52Hz,2H),6.88(s,1H),6.59-6.44(m,1H),5.85- 5.71(m,1H),4.60(t,J=10.8 Hz,1H),4.41-4.05(m,2H),3.87(s,3H),3.83-3.68(m,1H),3.50-3.40(m,1H),3.31-3.23(m,2H),3.18- 3.09(m, 2H), 2.26(s, 3H), 2.10-1.93(m, 1H), 1.88-1.72(m, 1H), 1.58(d, J=7.2Hz, 3H).
实施例86：化合物86的制备Example 86: Preparation of Compound 86
Figure PCTCN2022070423-appb-000120
Figure PCTCN2022070423-appb-000120
化合物86的合成参考实施例75中化合物75的合成步骤，其中第一步用1-溴丙烷代替甲磺酸四氢呋喃-3-基酯，合成得到化合物86。The synthesis of compound 86 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 1-bromopropane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 86.
MS(ESI):500.2[M+1] +。 MS(ESI): 500.2[M+1] + .
1H NMR(300MHz,dmso)δ8.12(d,J＝6.8Hz,1H),7.80(s,1H),7.66(t,J＝7.6Hz,1H),7.55-7.43(m,1H),7.34-7.25(m,1H),7.23(t,J＝54.5Hz,1H),6.84(s,1H),5.89-5.68(m,1H),4.65(t,J＝10.3Hz,1H),4.16(d,J＝10.0Hz,1H),3.31-3.24(m,1H),3.14-3.01(m,1H),2.96-2.80(m,2H),2.78-2.56(m,2H),2.44-2.30(m,2H),2.25(s,3H),2.16-1.97(m,1H),1.83(d,J＝15.1Hz,1H),1.58(d,J＝6.8Hz,3H),1.02(s,6H). 1 H NMR(300MHz,dmso)δ8.12(d,J=6.8Hz,1H),7.80(s,1H),7.66(t,J=7.6Hz,1H),7.55-7.43(m,1H), 7.34-7.25(m, 1H), 7.23(t, J=54.5Hz, 1H), 6.84(s, 1H), 5.89-5.68(m, 1H), 4.65(t, J=10.3Hz, 1H), 4.16 (d, J＝10.0Hz, 1H), 3.31-3.24(m, 1H), 3.14-3.01(m, 1H), 2.96-2.80(m, 2H), 2.78-2.56(m, 2H), 2.44-2.30 (m, 2H), 2.25(s, 3H), 2.16-1.97(m, 1H), 1.83(d, J=15.1Hz, 1H), 1.58(d, J=6.8Hz, 3H), 1.02(s, 6H).
实施例87：化合物87的制备Example 87: Preparation of Compound 87
Figure PCTCN2022070423-appb-000121
Figure PCTCN2022070423-appb-000121
化合物87的合成参考实施例75中化合物75的合成步骤，其中第一步用3-(溴甲基)氧杂环丁烷代替甲磺酸四氢呋喃-3-基酯，合成得到化合物87。The synthesis of compound 87 refers to the synthesis procedure of compound 75 in Example 75, wherein in the first step, 3-(bromomethyl)oxetane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 87.
MS(ESI):528.2[M+1] +。 MS(ESI): 528.2[M+1] + .
1H NMR(300MHz,dmso)δ8.11(d,J＝7.5Hz,1H),7.80(s,1H),7.65(t,J＝7.5Hz,1H),7.48(t,J＝6.8Hz,1H),7.27(t,J＝7.7Hz,1H),7.23(t,J＝54.0Hz,1H),6.83(s,1H),5.81- 5.72(m,1H),4.67-4.59(m,3H),4.31-4.26(m,2H),4.18-4.11(m,1H),3.31-3.17(m,2H),3.03(d,J＝11.4Hz,1H),2.96-2.89(m,1H),2.81(d,J＝11.1Hz,1H),2.69(d,J＝7.5Hz,2H),2.59(d,J＝9.6Hz,1H),2.28-2.23(m,4H),2.22-2.01(m,2H),1.79(d,J＝16.0Hz,1H),1.57(d,J＝7.0Hz,3H). 1 H NMR(300MHz,dmso)δ8.11(d,J=7.5Hz,1H),7.80(s,1H),7.65(t,J=7.5Hz,1H),7.48(t,J=6.8Hz, 1H), 7.27(t, J=7.7Hz, 1H), 7.23(t, J=54.0Hz, 1H), 6.83(s, 1H), 5.81- 5.72(m, 1H), 4.67-4.59(m, 3H) ), 4.31-4.26(m, 2H), 4.18-4.11(m, 1H), 3.31-3.17(m, 2H), 3.03(d, J=11.4Hz, 1H), 2.96-2.89(m, 1H), 2.81(d,J＝11.1Hz,1H),2.69(d,J＝7.5Hz,2H),2.59(d,J＝9.6Hz,1H),2.28-2.23(m,4H),2.22-2.01(m ,2H),1.79(d,J＝16.0Hz,1H),1.57(d,J＝7.0Hz,3H).
实施例88：化合物88的制备Example 88: Preparation of Compound 88
Figure PCTCN2022070423-appb-000122
Figure PCTCN2022070423-appb-000122
化合物88的合成参考实施例67中化合物67的合成步骤，其中第一步用特戊酸代替3-氧杂环丁烷羧酸，合成得到化合物88。The synthesis of compound 88 refers to the synthesis steps of compound 67 in Example 67, wherein in the first step, pivalic acid is used instead of 3-oxetane carboxylic acid to synthesize compound 88.
MS(ESI):542.2[M+1] +。 MS(ESI): 542.2[M+1] + .
1H NMR(300MHz,dmso)δ8.17(d,J＝7.6Hz,1H),7.76(s,1H),7.64(t,J＝7.6Hz,1H),7.48(t,J＝6.8Hz,1H),7.27(t,J＝8.8Hz,1H),7.22(t,J＝56Hz,2H),6.87(s,1H),5.82-5.70(m,1H),4.63(t,J＝10.4Hz,1H),4.28-4.14(m,2H),4.00(d,J＝12.4Hz,1H),3.34-3.25(m,3H),3.03-2.95(m,2H),2.25(s,3H),2.18-2.05(m,1H),1.92(d,J＝14.8Hz,1H),1.58(d,J＝7.2Hz,3H),1.23(s,9H). 1 H NMR(300MHz,dmso)δ8.17(d,J=7.6Hz,1H),7.76(s,1H),7.64(t,J=7.6Hz,1H),7.48(t,J=6.8Hz, 1H), 7.27(t, J=8.8Hz, 1H), 7.22(t, J=56Hz, 2H), 6.87(s, 1H), 5.82-5.70(m, 1H), 4.63(t, J=10.4Hz) ,1H),4.28-4.14(m,2H),4.00(d,J=12.4Hz,1H),3.34-3.25(m,3H),3.03-2.95(m,2H),2.25(s,3H), 2.18-2.05(m, 1H), 1.92(d, J=14.8Hz, 1H), 1.58(d, J=7.2Hz, 3H), 1.23(s, 9H).
实施例89：化合物89的制备Example 89: Preparation of Compound 89
Figure PCTCN2022070423-appb-000123
Figure PCTCN2022070423-appb-000123
化合物89的合成参考实施例75中化合物75的合成步骤，其中第一步用2-溴-1,1,1-三氟乙烷代替甲磺酸四氢呋喃-3-基酯，合成得到化合物89。The synthesis of compound 89 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, 2-bromo-1,1,1-trifluoroethane is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 89.
MS(ESI):540.2[M+1] +。 MS(ESI): 540.2[M+1] + .
1H NMR(300MHz,dmso)δ8.12(d,J＝7.2Hz,1H),7.83(s,1H),7.65(t,J＝7.2Hz,1H),7.48(t,J＝6.6Hz,1H),7.28(t,J＝7.5Hz,1H),7.23(t,J＝54Hz,1H),6.85(s,1H),5.84–5.72(m,1H),4.62(t,J＝10.8Hz,1H),4.17(d,J＝10.5Hz,1H),3.48-3.35(m,1H),3.30–3.20(m,2H),3.13–2.92(m,3H),2.78(d,J＝11.1Hz,1H),2.65(t,J＝10.2Hz,1H),2.57(d,J＝10.5Hz,1H),2.25(s,3H),2.16–1.99(m,1H),1.81(d,J＝15.6Hz,1H),1.58(d,J＝6.9Hz,3H). 1 H NMR(300MHz,dmso)δ8.12(d,J=7.2Hz,1H),7.83(s,1H),7.65(t,J=7.2Hz,1H),7.48(t,J=6.6Hz, 1H), 7.28(t, J=7.5Hz, 1H), 7.23(t, J=54Hz, 1H), 6.85(s, 1H), 5.84–5.72(m, 1H), 4.62(t, J=10.8Hz) ,1H),4.17(d,J=10.5Hz,1H),3.48-3.35(m,1H),3.30-3.20(m,2H),3.13-2.92(m,3H),2.78(d,J=11.1 Hz, 1H), 2.65(t, J=10.2Hz, 1H), 2.57(d, J=10.5Hz, 1H), 2.25(s, 3H), 2.16–1.99(m, 1H), 1.81(d, J =15.6Hz,1H),1.58(d,J=6.9Hz,3H).
实施例90：化合物90的制备Example 90: Preparation of Compound 90
Figure PCTCN2022070423-appb-000124
Figure PCTCN2022070423-appb-000124
化合物90的合成参考实施例75中化合物75的合成步骤，其中第一步用溴乙腈代替甲磺酸四氢呋喃-3-基酯，合成得到化合物90。The synthesis of compound 90 refers to the synthesis steps of compound 75 in Example 75, wherein in the first step, bromoacetonitrile is used instead of tetrahydrofuran-3-yl methanesulfonate to synthesize compound 90.
MS(ESI):497.2[M+1] +。 MS(ESI): 497.2[M+1] + .
1H NMR(300MHz,dmso)δ8.15(d,J＝7.5Hz,1H),7.81(s,1H),7.66(t,J＝7.2Hz,1H),7.48(t,J＝6.9Hz,1H),7.28(t,J＝7.8Hz,1H),7.23(t,J＝54Hz,1H),6.87(s,1H),5.83-5.71(m,1H),4.57(t,J＝11.1Hz,1H),4.19(d,J＝11.1Hz,1H),3.92–3.76(m,2H),3.38(d,J＝9.6Hz,1H),3.19(d,J＝11.1Hz,1H),3.09-3.01(m,1H),2.90(d,J＝10.8Hz,1H),2.68(d,J＝9.9Hz,1H),2.56-2.50(m,1H),2.40(t,J＝9.9Hz,1H),2.25(s,3H),2.15-2.02(m,1H),1.87(d,J＝14.7Hz,1H),1.58(d,J＝7.2Hz,3H). 1 H NMR(300MHz,dmso)δ8.15(d,J=7.5Hz,1H),7.81(s,1H),7.66(t,J=7.2Hz,1H),7.48(t,J=6.9Hz, 1H), 7.28(t, J=7.8Hz, 1H), 7.23(t, J=54Hz, 1H), 6.87(s, 1H), 5.83-5.71(m, 1H), 4.57(t, J=11.1Hz) ,1H),4.19(d,J＝11.1Hz,1H),3.92–3.76(m,2H),3.38(d,J＝9.6Hz,1H),3.19(d,J＝11.1Hz,1H),3.09 -3.01(m, 1H), 2.90(d, J=10.8Hz, 1H), 2.68(d, J=9.9Hz, 1H), 2.56-2.50(m, 1H), 2.40(t, J=9.9Hz, 1H), 2.25(s, 3H), 2.15-2.02(m, 1H), 1.87(d, J=14.7Hz, 1H), 1.58(d, J=7.2Hz, 3H).
实施例91：化合物91的制备Example 91: Preparation of Compound 91
Figure PCTCN2022070423-appb-000125
Figure PCTCN2022070423-appb-000125
化合物91的合成参考实施例44中化合物44的合成步骤，其中第六步用乙酸代替环丙烷甲酸，第八步用(1R)-1-(3-(二氟(四氢呋喃-2-基)甲基)苯基)乙-1-胺代替(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺，合成得到化合物91。The synthesis of compound 91 refers to the synthesis steps of compound 44 in Example 44, wherein acetic acid is used instead of cyclopropanecarboxylic acid in the sixth step, and (1R)-1-(3-(difluoro(tetrahydrofuran-2-yl)methane is used in the eighth step) (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine was synthesized to give compound 91.
MS(ESI):552.2[M+1] +。 MS(ESI): 552.2[M+1] + .
1H NMR(300MHz,dmso)δ8.14-8.06(m,1H),7.76-7.70(m,1H),7.63-7.52(m,2H),7.42(t,J＝7.6Hz,1H),7.34(d,J＝7.9Hz,1H),6.87(s,1H),5.67-5.52(m,1H),4.64-4.49(m,1H),4.44-4.27(m,1H),4.25-4.11(m,2H),3.98-3.79(m,1H),3.75-3.55(m,4H),3.21-3.11(m,3H),3.07-2.94(m,2H),2.29(d,J＝4.6Hz,3H),2.14-2.00(m,4H),1.95-1.67(m,4H),1.63-1.44(m,4H). 1 H NMR(300MHz,dmso)δ8.14-8.06(m,1H),7.76-7.70(m,1H),7.63-7.52(m,2H),7.42(t,J=7.6Hz,1H),7.34 (d, J=7.9Hz, 1H), 6.87(s, 1H), 5.67-5.52(m, 1H), 4.64-4.49(m, 1H), 4.44-4.27(m, 1H), 4.25-4.11(m ,2H),3.98-3.79(m,1H),3.75-3.55(m,4H),3.21-3.11(m,3H),3.07-2.94(m,2H),2.29(d,J=4.6Hz,3H ),2.14-2.00(m,4H),1.95-1.67(m,4H),1.63-1.44(m,4H).
实施例92：化合物92的制备Example 92: Preparation of Compound 92
Figure PCTCN2022070423-appb-000126
Figure PCTCN2022070423-appb-000126
化合物92的合成参考实施例44中化合物44的合成步骤，其中第八步用(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1，1-二氟-2-甲基丙-2-醇代替(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺，合成得到化合物92。The synthesis of compound 92 refers to the synthesis procedure of compound 44 in Example 44, wherein the eighth step uses (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro -2-Methylpropan-2-ol was substituted for (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine, and compound 92 was synthesized.
MS(ESI):584.2[M+1] +。 MS(ESI): 584.2[M+1] + .
1H NMR(400MHz,dmso)δ8.12(d,J＝7.3Hz,1H),7.78(s,1H),7.57(t,J＝6.6Hz,1H),7.28(t,J＝6.6Hz,1H),7.19(t,J＝7.7Hz,1H),6.87(s,1H),5.82–5.71(m,1H),5.30(s,1H), 4.60(t,J＝10.2Hz,1H),4.26–4.14(m,2H),4.06–3.96(m,1H),3.66–3.47(m,1H),3.27–2.99(m,4H),2.24(s,3H),2.16–1.99(m,2H),1.97–1.82(m,1H),1.55(d,J＝7.0Hz,3H),1.20(d,J＝12.3Hz,6H),0.81–0.68(m,4H). 1 H NMR(400MHz,dmso)δ8.12(d,J=7.3Hz,1H),7.78(s,1H),7.57(t,J=6.6Hz,1H),7.28(t,J=6.6Hz, 1H), 7.19(t, J＝7.7Hz, 1H), 6.87(s, 1H), 5.82–5.71(m, 1H), 5.30(s, 1H), 4.60(t, J＝10.2Hz, 1H), 4.26–4.14 (m, 2H), 4.06–3.96 (m, 1H), 3.66–3.47 (m, 1H), 3.27–2.99 (m, 4H), 2.24 (s, 3H), 2.16–1.99 (m, 2H) ), 1.97–1.82 (m, 1H), 1.55 (d, J=7.0Hz, 3H), 1.20 (d, J=12.3Hz, 6H), 0.81–0.68 (m, 4H).
实施例93：化合物93的制备Example 93: Preparation of Compound 93
Figure PCTCN2022070423-appb-000127
Figure PCTCN2022070423-appb-000127
化合物93的合成参考实施例70中化合物70的合成步骤，用(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1，1-二氟-2-甲基丙-2-醇代替(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺，合成得到化合物93。Synthesis of compound 93 Refer to the synthetic procedure of compound 70 in Example 70, using (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methyl Substituting (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine with ylpropan-2-ol, compound 93 was synthesized.
MS(ESI):609.2[M+1] +。 MS(ESI): 609.2[M+1] + .
1H NMR(400MHz,dmso)δ8.15(d,J＝5.5Hz,1H),7.79(s,1H),7.57(t,J＝6.6Hz,1H),7.28(t,J＝6.6Hz,1H),7.19(t,J＝7.7Hz,1H),6.89(s,1H),5.82–5.74(m,1H),5.30(s,1H),4.60(t,J＝10.6Hz,1H),4.26–4.14(m,2H),4.06–3.96(m,1H),3.73–3.33(m,4H),3.19–3.06(m,1H),2.24(s,3H),2.17–2.06(m,1H),1.99–1.89(m,1H),1.67–1.49(m,7H),1.20(d,J＝12.1Hz,6H). 1 H NMR(400MHz,dmso)δ8.15(d,J=5.5Hz,1H),7.79(s,1H),7.57(t,J=6.6Hz,1H),7.28(t,J=6.6Hz, 1H), 7.19(t, J=7.7Hz, 1H), 6.89(s, 1H), 5.82–5.74(m, 1H), 5.30(s, 1H), 4.60(t, J=10.6Hz, 1H), 4.26–4.14 (m, 2H), 4.06–3.96 (m, 1H), 3.73–3.33 (m, 4H), 3.19–3.06 (m, 1H), 2.24 (s, 3H), 2.17–2.06 (m, 1H) ), 1.99–1.89 (m, 1H), 1.67–1.49 (m, 7H), 1.20 (d, J=12.1Hz, 6H).
实施例94：化合物94的制备Example 94: Preparation of Compound 94
Figure PCTCN2022070423-appb-000128
Figure PCTCN2022070423-appb-000128
化合物94的合成参考实施例89中化合物89的合成步骤，用(R)-1-(3-(1-氨基乙基)-2-氟苯基)-1，1-二氟-2-甲基丙-2-醇代替(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺，合成得到化合物94。Synthesis of compound 94 Refer to the synthetic procedure of compound 89 in Example 89, using (R)-1-(3-(1-aminoethyl)-2-fluorophenyl)-1,1-difluoro-2-methyl Substituting (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine with ylpropan-2-ol, compound 94 was synthesized.
MS(ESI):598.2[M+1] +。 MS(ESI): 598.2[M+1] + .
1H NMR(400MHz,dmso)δ8.09(d,J＝7.0Hz,1H),7.82(s,1H),7.57(t,J＝6.5Hz,1H),7.29(t,J＝6.6Hz,1H),7.20(t,J＝7.7Hz,1H),6.84(s,1H),5.80–5.73(m,1H),5.30(s,1H),4.61(t,J＝10.6Hz,1H),4.18–4.15(m,1H),3.42–3.37(m,1H),3.29–3.22(m,2H),3.10–3.07(m,1H),3.02–2.99(m,2H),2.79–2.77(m,1H),2.68–2.64(m,1H),2.55(t,J＝10.3Hz,1H),2.24(s,3H),2.12–2.03(m,1H),1.84–1.80(m,1H),1.55(d,J＝7.1Hz,3H),1.21(d,J＝12.6Hz,6H). 1 H NMR(400MHz,dmso)δ8.09(d,J=7.0Hz,1H),7.82(s,1H),7.57(t,J=6.5Hz,1H),7.29(t,J=6.6Hz, 1H), 7.20(t, J＝7.7Hz, 1H), 6.84(s, 1H), 5.80–5.73(m, 1H), 5.30(s, 1H), 4.61(t, J＝10.6Hz, 1H), 4.18–4.15 (m, 1H), 3.42–3.37 (m, 1H), 3.29–3.22 (m, 2H), 3.10–3.07 (m, 1H), 3.02–2.99 (m, 2H), 2.79–2.77 (m ,1H),2.68–2.64(m,1H),2.55(t,J=10.3Hz,1H),2.24(s,3H),2.12–2.03(m,1H),1.84–1.80(m,1H), 1.55(d,J=7.1Hz,3H),1.21(d,J=12.6Hz,6H).
实验例1：KRAS(G12C)和SOS1结合实验Experimental Example 1: Binding Experiment of KRAS(G12C) and SOS1
此测定法可用于检查化合物抑制SOS1与KRAS G12C之间的蛋白-蛋白相互作用的效力。较低的IC 50值表示作为SOS1抑制剂的化合物在以下测定设置中的高效力。 This assay can be used to examine the potency of compounds to inhibit the protein-protein interaction between SOS1 and KRAS G12C. Lower IC50 values indicate high potency of compounds as SOS1 inhibitors in the following assay setup.
1.实验材料：1. Experimental materials:
KRAS(G12C)蛋白由普健生物科技有限公司合成；KRAS(G12C) protein was synthesized by Pujian Biotechnology Co., Ltd.;
SOS1蛋白交换人源重组域蛋白(564-1049)购自Cytoskeleton；SOS1 protein exchange human recombinant domain protein (564-1049) was purchased from Cytoskeleton;
抗带6组氨酸标签标记的XL665单抗(Mab Anti 6HIS-XL665)、抗带谷胱甘肽巯基转移酶标签标记铕穴状化合物单抗(Mab Anti GST-Eu cryptate)购自Cisbio。Anti-6-histidine-tagged monoclonal antibody XL665 (Mab Anti 6HIS-XL665) and anti-glutathione thioltransferase-tagged europium cryptate monoclonal antibody (Mab Anti GST-Eu cryptate) were purchased from Cisbio.
2.实验方法：2. Experimental method:
1X缓冲液配制(现配现用)：Hepes:5mM；NaCl:150mM；EDTA:10mM；Igepal:0.0025％；KF:100mM；DTT:1mM；BSA:005％。1X buffer preparation (as is): Hepes: 5 mM; NaCl: 150 mM; EDTA: 10 mM; Igepal: 0.0025%; KF: 100 mM; DTT: 1 mM; BSA: 005%.
将待测化合物用排枪进行3倍稀释至第8个浓度，即从100μM稀释至45.7nM。The compounds to be tested were diluted 3-fold to the 8th concentration, ie, from 100 μM to 45.7 nM, using a row gun.
用1X缓冲液将待测化合物各梯度稀释成DMSO为2％的工作液，5μL/孔加到对应孔中，设置双复孔实验。1000rpm条件下，离心1min。Dilute each compound to be tested with 1X buffer into a working solution of 2% DMSO, add 5 μL/well to the corresponding well, and set up a double-well experiment. Centrifuge for 1 min at 1000 rpm.
用1X缓冲液配制KRAS(G12C)(200nM)和Mab Anti GST-Eu cryptate(1ng/μL)的混合工作液，将该混合工作液放置25℃中孵育5min，2.5μL/孔加入到对应孔。A mixed working solution of KRAS(G12C) (200nM) and Mab Anti GST-Eu cryptate (1ng/μL) was prepared with 1X buffer, and the mixed working solution was placed at 25℃ for 5min, and 2.5μL/well was added to the corresponding well.
用1X缓冲液配制SOS1(80nM)和Mab Anti 6HIS-XL665(8g/μL)的混合工作液，2.5μL/孔加入到对应孔中，Blank孔中加入2.5μL Mab Anti 6HIS-XL665(8g/μL)稀释液，此时化合物终浓度梯度为1μM稀释至0.457nM，KRAS(G12C)(500nM)，MAb Anti GST- Eu cryptate(0.25ng/μL)，SOS1(20nM)，Mab Anti 6HIS-XL665(2g/μL)，反应体系置于25℃反应60min。反应结束后，采用多标记分析仪读取HTRF。Prepare a mixed working solution of SOS1 (80nM) and Mab Anti 6HIS-XL665 (8g/μL) with 1X buffer, add 2.5μL/well to the corresponding well, and add 2.5μL Mab Anti 6HIS-XL665 (8g/μL) to the Blank well ) dilution solution, at this time, the final concentration of the compound was diluted from 1 μM to 0.457nM, KRAS(G12C)(500nM), MAb Anti GST-Eucryptate(0.25ng/μL), SOS1(20nM), Mab Anti 6HIS-XL665(2g /μL), the reaction system was placed at 25 °C for 60 min. After the reaction, the HTRF was read using a multi-label analyzer.
Max孔:1％DMSO，KRAS(G12C)(500nM)，MAb Anti GST-Eu cryptate(0.25ng/μL)，SOS1(20nM)，Mab Anti 6HIS-XL665(2g/μL)Max well: 1% DMSO, KRAS(G12C) (500nM), MAb Anti GST-Eu cryptate (0.25ng/μL), SOS1 (20nM), Mab Anti 6HIS-XL665 (2g/μL)
Min孔：1％DMSO，KRAS(G12C)(500nM)，MAb Anti GST-Eu cryptate(0.25ng/μL)，Mab Anti 6HIS-XL665(2g/μL)Min well: 1% DMSO, KRAS(G12C)(500nM), MAb Anti GST-Eu cryptate(0.25ng/μL), Mab Anti 6HIS-XL665(2g/μL)
3.数据分析：3. Data analysis:
利用方程式(样品-Min)/(Max-Min)×100％，将原始数据换算成抑制率，IC 50值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。 Using the equation (sample-Min)/(Max-Min)×100%, the raw data is converted into inhibition rate, and the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
其中本发明制备得到的化合物1以及本领域常用的KRAS-SOS1抑制剂BI-3406对于KRAS(G12C)与SOS1结合的抑制活性如表1所示，其中+代表>1uM,++代表100nM-1uM,+++代表10nM-100nM,++++代表<10nM,ND代表未测试。The inhibitory activity of compound 1 prepared by the present invention and KRAS-SOS1 inhibitor BI-3406 commonly used in the art on the binding of KRAS (G12C) to SOS1 is shown in Table 1, wherein + represents >1uM, ++ represents 100nM-1uM , +++ stands for 10nM-100nM, ++++ stands for <10nM, ND stands for not tested.
表1.本发明的化合物对KRAS(G12C)和SOS1结合抑制的IC 50数据 Table 1. IC50 data for inhibition of KRAS(G12C) and SOS1 binding by compounds of the invention
化合物编号Compound number IC 50(nM) IC50 (nM)
对照化合物BI-3406Control compound BI-3406 8.38.3
化合物1Compound 1 7.677.67
化合物2Compound 2 7.977.97
化合物3Compound 3 14.0314.03
化合物4Compound 4 3.953.95
化合物5Compound 5 27.2227.22
化合物6Compound 6 2.572.57
化合物7Compound 7 20.820.8
化合物10Compound 10 8.688.68
化合物11Compound 11 13.113.1
化合物12Compound 12 20.1420.14
化合物13Compound 13 39.639.6
化合物14Compound 14 24.124.1
化合物15Compound 15 48.948.9
化合物16Compound 16 20.7920.79
化合物44Compound 44 3.43.4
化合物70Compound 70 10.110.1
化合物89Compound 89 9.19.1
由表1可知，本发明的化合物，对SOS1具有较好的抑制作用，针对KRAS(G12C)和SOS1的结合具有明显抑制效果，部分化合物的抑制作用小于10nM,具有很好的临床应用前景。It can be seen from Table 1 that the compounds of the present invention have a good inhibitory effect on SOS1, and have a significant inhibitory effect on the combination of KRAS(G12C) and SOS1, and the inhibitory effect of some compounds is less than 10nM, which has a good clinical application prospect.
实验例2：p-ERK实验Experimental example 2: p-ERK experiment
实验材料：Experimental Materials:
DLD-1细胞购自武汉普诺赛生命科技有限公司；1640培养基购自Biological Industries；胎牛血清购自Biosera；Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio。DLD-1 cells were purchased from Wuhan Prosser Life Technology Co., Ltd.; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.
实验方法：experimental method:
DLD-1细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个DLD-1细胞，细胞板放入二氧化碳培养箱，37度过夜孵育；DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80 μL of cell suspension per well, each well containing 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated at 37 degrees overnight;
将待测化合物用100％DMSO稀释到2mM作为第一个浓度，然后再用移液器进行5倍稀释至第8个浓度，即从2mM稀释至0.026μM。取2μL化合物加入78μL细胞饥饿培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时，此时化合物浓度为10μM至0.128nM，DMSO浓度为0.5％；Compounds to be tested were diluted with 100% DMSO to 2 mM as the first concentration, and then 5-fold diluted with a pipette to the eighth concentration, ie, from 2 mM to 0.026 [mu]M. Add 2 μL of compound to 78 μL of cell starvation medium, and after mixing, add 20 μL of compound solution to the corresponding cell plate wells, put the cell plate back into the carbon dioxide incubator and continue to incubate for 1 hour. is 0.5%;
结束孵育后，弃掉细胞上清加入50μL细胞裂解液每孔，室温摇晃孵育30分钟；After the incubation, discard the cell supernatant and add 50 μL of cell lysate to each well, and incubate with shaking at room temperature for 30 minutes;
使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody were diluted 20-fold with Detection buffer;
取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育4小时；Take 16μL of cell lysate supernatant per well into a new 384 white microplate, add 2μL of Phospho-ERK1/2 Eu Cryptate antibody dilution and 2μL of Phospho-ERK1/2 d2 antibody dilution, and incubate at room temperature for 4 hours;
孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm。After the incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。其中本发明制备得到的化合物1以及本领域常用的KRAS-SOS1抑制剂BI-3406对DLD-1细胞磷酸化的抑制活性如表2所示。Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived). Table 2 shows the inhibitory activity of compound 1 prepared by the present invention and KRAS-SOS1 inhibitor BI-3406 commonly used in the art on DLD-1 cell phosphorylation.
表2.本发明的化合物对DLD-1细胞磷酸化抑制活性测试结果IC 50数据 Table 2. Test results IC 50 data of the compounds of the present invention on DLD-1 cell phosphorylation inhibitory activity
化合物编号Compound number IC50(nM)IC50(nM) 化合物编号Compound number IC50(nM)IC50(nM)
对照化合物BI-3406Control compound BI-3406 20.0720.07 化合物47Compound 47 7.337.33
化合物1Compound 1 97.5797.57 化合物48Compound 48 23.1223.12
化合物2Compound 2 23.1123.11 化合物49Compound 49 73.9773.97
化合物3Compound 3 48.048.0 化合物50Compound 50 367.10367.10
化合物4Compound 4 5.905.90 化合物51Compound 51 30.6330.63
化合物5Compound 5 20.1120.11 化合物52Compound 52 103.70103.70
化合物6Compound 6 2.572.57 化合物53Compound 53 79.6779.67
化合物7Compound 7 82.9282.92 化合物54Compound 54 31.2931.29
化合物8Compound 8 13.8113.81 化合物55Compound 55 19.6719.67
化合物9Compound 9 513.3513.3 化合物56Compound 56 6.026.02
化合物10Compound 10 25.1225.12 化合物57Compound 57 177.50177.50
化合物11Compound 11 63.0763.07 化合物58Compound 58 99.2899.28
化合物12Compound 12 31.2531.25 化合物59Compound 59 5.395.39
化合物13Compound 13 39.5939.59 化合物60Compound 60 18.0718.07
化合物14Compound 14 24.1524.15 化合物61Compound 61 918.4918.4
化合物15Compound 15 48.9248.92 化合物62Compound 62 99.9899.98
化合物16Compound 16 20.7920.79 化合物63Compound 63 69.1069.10
化合物17Compound 17 387.2387.2 化合物64Compound 64 16.5216.52
化合物18Compound 18 344.4344.4 化合物65Compound 65 78.278.2
化合物19Compound 19 97.3497.34 化合物66Compound 66 47.1047.10
化合物20Compound 20 94.2394.23 化合物67Compound 67 13.2113.21
化合物21Compound 21 467.8467.8 化合物68Compound 68 10.2810.28
化合物22Compound 22 92.8192.81 化合物69Compound 69 18.2918.29
化合物23Compound 23 76.4376.43 化合物70Compound 70 19.1719.17
化合物24Compound 24 89.9389.93 化合物71Compound 71 49.1549.15
化合物25Compound 25 46.2546.25 化合物72Compound 72 78.1478.14
化合物26Compound 26 20.1120.11 化合物73Compound 73 389.9389.9
化合物27Compound 27 1.791.79 化合物74Compound 74 28.4628.46
化合物28Compound 28 22.2322.23 化合物75Compound 75 31.9531.95
化合物29Compound 29 21.1521.15 化合物76Compound 76 30.3030.30
化合物30Compound 30 12.612.6 化合物77Compound 77 11.4811.48
化合物31Compound 31 2.932.93 化合物78Compound 78 43.5043.50
化合物32Compound 32 806.8806.8 化合物79Compound 79 40.6540.65
化合物33Compound 33 295.9295.9 化合物80Compound 80 12.2112.21
化合物34Compound 34 15.9315.93 化合物81Compound 81 78.1978.19
化合物35Compound 35 267.1267.1 化合物82Compound 82 35.7835.78
化合物36Compound 36 76.6776.67 化合物83Compound 83 24.1424.14
化合物37Compound 37 20.8920.89 化合物84Compound 84 88.1788.17
化合物38Compound 38 20.3920.39 化合物85Compound 85 51.5451.54
化合物39Compound 39 4.614.61 化合物86Compound 86 75.3475.34
化合物40Compound 40 3.713.71 化合物87Compound 87 27.3927.39
化合物41Compound 41 25.7825.78 化合物88Compound 88 49.1549.15
化合物42Compound 42 20.8420.84 化合物89Compound 89 16.7116.71
化合物43Compound 43 48.6548.65 化合物90Compound 90 70.8070.80
化合物44Compound 44 11.1011.10 化合物92Compound 92 2.402.40
化合物45Compound 45 186.1186.1 化合物93Compound 93 2.402.40
化合物46Compound 46 25.9825.98 化合物94Compound 94 10.9010.90
由表2可知，本发明的化合物，多个化合物大幅度优于阳性对照BI-3406，对DLD-1细胞的磷酸化具有极其优秀的抑制作用，具有很好的临床应用前景。It can be seen from Table 2 that the compounds of the present invention, many of which are significantly better than the positive control BI-3406, have extremely excellent inhibitory effect on the phosphorylation of DLD-1 cells, and have good clinical application prospects.
实验例3：体内药效学实验二Experimental example 3: In vivo pharmacodynamic experiment 2
1.实验目的1. Experimental purpose
评价受试化合物在人胰腺癌MIA-PaCa2细胞皮下异体移植肿瘤模型上的体内药效。To evaluate the in vivo efficacy of test compounds in human pancreatic cancer MIA-PaCa2 cell subcutaneous xenograft tumor model.
2.实验动物2. Experimental animals
BALB/裸小鼠，雌性，6-8周龄，体重18-22克，由北京维通利华科技股份有限公司提供。BALB/nude mice, female, 6-8 weeks old, weighing 18-22 g, were provided by Beijing Weitong Lihua Technology Co., Ltd.
3.实验方法3. Experimental method
将MIA-PaCa2肿瘤细胞重悬于PBS中，制备成密度为1×10 7个/mL的细胞悬液，皮下接种0.2mL细胞悬液于每只小鼠的右后背(加入基质胶，体积比为1：1)，等待肿瘤生长。在肿瘤平均体积达到约150mm 3时，开始进行随机分组给药。给药后，每周两次用游标卡尺测量肿瘤直径，肿瘤体积的计算公式如下： The MIA-PaCa2 tumor cells were resuspended in PBS to prepare a cell suspension with a density of 1×10 7 cells/mL, and 0.2 mL of the cell suspension was subcutaneously inoculated on the right back of each mouse (Add Matrigel, volume ratio of 1:1), waiting for tumor growth. Randomization was initiated when the mean tumor volume reached approximately 150 mm3 . After administration, tumor diameters were measured with a vernier caliper twice a week, and the tumor volume was calculated as follows:
V＝0.5a×b 2，其中a和b分别表示肿瘤的长径和短径。 V=0.5a×b 2 , where a and b represent the long and short diameters of the tumor, respectively.
化合物的抑瘤疗效用TGI(％)评价，TGI(％)反映了肿瘤生长抑制率，其计算如下：The tumor-inhibitory efficacy of a compound was evaluated by TGI (%), which reflects the tumor growth inhibition rate and was calculated as follows:
TGI(％)＝[(1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。TGI(%)=[(1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-at the beginning of treatment in the solvent control group Mean tumor volume)] × 100%.
4.实验结果4. Experimental results
相关结果如表9所示。The related results are shown in Table 9.
表9.体内药效实验结果Table 9. In vivo efficacy test results
Figure PCTCN2022070423-appb-000129
Figure PCTCN2022070423-appb-000129
5.实验结论5. Experimental conclusion
开始给药22天后，在同等剂量下，本发明中的化合物与阳性对照物BI-3406相比，具有更加显著的肿瘤抑制效果，TGI最高能达到80％，表明本发明中的化合物在人胰腺癌MIA-PaCa2皮下异体移植肿瘤模型上展示出良好的体内药效。22 days after the start of administration, under the same dose, the compound of the present invention has a more significant tumor inhibitory effect compared with the positive control BI-3406, and the TGI can reach 80% at the highest, indicating that the compound of the present invention is effective in human pancreas. The cancer MIA-PaCa2 subcutaneous xenograft tumor model showed good in vivo efficacy.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制。在不脱离本发明的原理和宗旨的情况下，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型，这些变化、修改、替换和变型均涵盖在本发明的范围之中。Although the embodiments of the present invention have been shown and described above, it is to be understood that the above-described embodiments are exemplary and should not be construed to limit the present invention. Without departing from the principles and spirit of the present invention, those of ordinary skill in the art can make changes, modifications, substitutions and alterations to the above-mentioned embodiments within the scope of the present invention, and these changes, modifications, substitutions and modifications are all included in the within the scope of the present invention.

Claims (10)

  1. 四并环化合物，其特征在于，所述化合物为如式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、代谢产物或前药，A tetracyclic compound, characterized in that the compound is a compound represented by formula I or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, metabolite or pro- medicine,
    Figure PCTCN2022070423-appb-100001
    Figure PCTCN2022070423-appb-100001
    其中，in,
    A选自C 6-C 10芳基、5至6元单环杂芳基或9至10元二环杂芳基，且其中所述芳基、单环杂芳基和二环杂芳基各自任选地被m个独立的R 4取代，其中m独立地为0至5中的任一整数； A is selected from C 6 -C 10 aryl, 5- to 6-membered monocyclic heteroaryl, or 9- to 10-membered bicyclic heteroaryl, and wherein each of the aryl, monocyclic and bicyclic heteroaryl groups optionally substituted with m independent R 4 , wherein m is independently any integer from 0 to 5;
    X和Y各自独立地选自CR 7或N； X and Y are each independently selected from CR or N;
    Z 1和Z 2各自独立地选自-O-、-CR 7-或-NR 7-； Z 1 and Z 2 are each independently selected from -O-, -CR 7 - or -NR 7 -;
    L 1、L 2和L 3各自独立地独立选自-(CH 2) n-或-(CH 2) n-O-(CH 2) p-O-(CH 2) o-或-O-(CH 2) q-，其中每一个n、o、p和q各自独立地为0至3中的任一整数； L 1 , L 2 and L 3 are each independently independently selected from -(CH 2 ) n - or -(CH 2 ) n -O-(CH 2 ) p -O-(CH 2 ) o - or -O-( CH 2 ) q -, wherein each of n, o, p and q is independently any integer from 0 to 3;
    R 1和R 2各自独立地选自氢和C 1-C 8烷基，或者R 1和R 2与其所连接的碳原子共同形成C 3-C 6环烷基，所述烷基和环烷基各自任选地被至少1个R 8取代，R 1或R 2与A环形成4-8元饱和碳环或杂环； R 1 and R 2 are each independently selected from hydrogen and C 1 -C 8 alkyl, or R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl, said alkyl and cycloalkane Each group is optionally substituted by at least 1 R 8 , and R 1 or R 2 and A ring form a 4-8 membered saturated carbocyclic or heterocyclic ring;
    R 3选自氢、卤素、氰基、羟基、氨基、-NH(R 7)、-C(＝O)-NH(R 7)、C 1-C 6烷基、C 2-C 4烯基、C 2-C 4炔基、C 3-C 6环烷基、3至8元杂环烷基、C 1-C 3烷氧基和C 1-C 6卤代烷基，且其中所述烷基、烯基、炔基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 3 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R 7 ), -C(=O)-NH(R 7 ), C 1 -C 6 alkyl, C 2 -C 4 alkenyl , C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, 3 to 8 membered heterocycloalkyl, C 1 -C 3 alkoxy and C 1 -C 6 haloalkyl, and wherein said alkyl , alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl are each optionally substituted with at least 1 R 8 ;
    R 4选自氢、卤素、氰基、羟基、氨基、-NH(R 7)、-C(＝O)-NH(R 7)、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环烷基、C 1-C 3烷氧基和C 1-C 6卤代烷基，且其中所述烷基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 4 is selected from hydrogen, halogen, cyano, hydroxyl, amino, -NH(R 7 ), -C(=O)-NH(R 7 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkane alkyl, 3- to 8-membered heterocycloalkyl, C 1 -C 3 alkoxy and C 1 -C 6 haloalkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl each is optionally substituted with at least 1 R;
    R 5和R 6各自独立地选自氢、卤素、氰基、羟基、氨基、-N(R 7)(R 8)、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环烷基、C 1-C 3烷氧基和C 1-C 6卤代烷基，或者R 7和R 8与其所连接的氮原子共同形成5至6元杂环烷基，且其中所述烷基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 10取代； R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, -N(R 7 )(R 8 ), C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3 to 8-membered heterocycloalkyl, C1 - C3alkoxy, and C1 - C6 haloalkyl, or R7 and R8 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocycloalkyl, and wherein The alkyl, cycloalkyl, heterocycloalkyl, alkoxy and haloalkyl groups are each optionally substituted with at least 1 R 10 ;
    R 7各自独立地选自氢、卤素、氰基、羟基、氨基、-N(R 8)(R 9)、-C(＝O)-N(R 8)(R 9)、-C(＝O)-R 8、-C(＝O)-OR 8、-S(＝O) 2-R 8、C 1-C 6烷基、C 3-C 6环烷基、3至8元杂环烷基、5-10元芳基或杂芳基、C 1-C 3烷氧基或C 1-C 6卤代烷基，或者R 8和R 9与其所连接的氮原子共同形成5至6元杂环烷基，且其中所述烷基、环烷基、杂环烷基、烷氧基和卤代烷基各自任选地被至少1个R 8取代； R 7 is each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, -N(R 8 )(R 9 ), -C(=O)-N(R 8 )(R 9 ), -C(= O)-R 8 , -C(=O)-OR 8 , -S(=O) 2 -R 8 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3- to 8-membered heterocycle Alkyl, 5-10-membered aryl or heteroaryl, C1 - C3 alkoxy or C1 - C6 haloalkyl, or R8 and R9 together with the nitrogen atom to which they are attached form a 5- to 6-membered heteroalkyl group cycloalkyl, and wherein said alkyl, cycloalkyl, heterocycloalkyl, alkoxy, and haloalkyl are each optionally substituted with at least 1 R;
    每一个R 8和R 9各自独立地选自氢、卤素、氰基、羟基、氨基、氨基甲酰基、C 1-C 6烷基、C 1-C 6杂烷基、C 3-C 8环烷基、3至14元杂环烷基、C 1-C 3烷氧基、C 1-C 3卤代烷氧基、C 6-C 10芳基、5至6元单环杂芳基或9至10元二环杂芳基，且其中所述烷基、杂烷基、环烷基、杂环烷基、烷氧基、卤代烷氧基、芳基、单环杂芳基和二环杂芳基各自任选地被至少1个R 10取代； Each of R 8 and R 9 is independently selected from hydrogen, halogen, cyano, hydroxy, amino, carbamoyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 ring Alkyl, 3- to 14-membered heterocycloalkyl, C1 - C3alkoxy, C1 - C3haloalkoxy , C6 -C10aryl, 5- to 6-membered monocyclic heteroaryl or 9- to 10 membered bicyclic heteroaryl, and wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkoxy, haloalkoxy, aryl, monocyclic heteroaryl and bicyclic heteroaryl each is optionally substituted with at least 1 R 10 ;
    R 1至R 9中所述杂烷基、杂环烷基、杂环烷氧基、杂芳基中所含的杂原子或杂原子团分别独立地选自-C(＝O)N(R 10)-、-N(R 10)-、-NH-、-N＝、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-和-N(R 10)C(＝O)N(R 10)-，所述杂原子或杂原子团的数目分别独立地选自1、2和3； The heteroatom or heteroatom group contained in the heteroalkyl group, heterocycloalkyl group, heterocycloalkoxy group, heteroaryl group described in R 1 to R 9 are independently selected from -C(=O)N(R 10 )-, -N(R 10 )-, -NH-, -N=, -O-, -S-, -C(=O)O-, -C(=O)-, -C(=S) -, -S(=O)-, -S(=O) 2 - and -N(R 10 )C(=O)N(R 10 )-, the number of said heteroatoms or heteroatoms is independently selected from 1, 2 and 3;
    每一个R 10各自独立地选自氢、氯、氟、氰基、羟基、氨基、异丙基、环丙基、甲基、二氟甲基、三氟甲基、甲氧基、三氟甲氧基、乙氧基、2,2-二氟乙氧基、2,2,2-三氟乙氧基和苯基。 Each R 10 is independently selected from hydrogen, chlorine, fluorine, cyano, hydroxy, amino, isopropyl, cyclopropyl, methyl, difluoromethyl, trifluoromethyl, methoxy, trifluoromethyl oxy, ethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy and phenyl.
  2. 根据权利要求1所述的化合物，其特征在于，其为如式I-1、I-2、I-3、I-4、I-5或I-6任一所示的化合物，The compound according to claim 1, characterized in that it is a compound represented by any one of formula I-1, I-2, I-3, I-4, I-5 or I-6,
    Figure PCTCN2022070423-appb-100002
    Figure PCTCN2022070423-appb-100002
    Figure PCTCN2022070423-appb-100003
    Figure PCTCN2022070423-appb-100003
  3. 根据权利要求2所述的化合物，其特征在于，其为如式I-1-1、I-2-1、I-3-1、I-4-1、I-5-1或I-6-1任一所示的化合物，The compound according to claim 2, wherein it is of formula I-1-1, I-2-1, I-3-1, I-4-1, I-5-1 or I-6 -1 any of the compounds shown,
    Figure PCTCN2022070423-appb-100004
    Figure PCTCN2022070423-appb-100004
  4. 根据权利要求3所述的化合物，其特征在于，其为如式1至式94任一所示的化合物，The compound according to claim 3, characterized in that it is a compound represented by any one of Formula 1 to Formula 94,
    Figure PCTCN2022070423-appb-100005
    Figure PCTCN2022070423-appb-100005
    Figure PCTCN2022070423-appb-100006
    Figure PCTCN2022070423-appb-100006
    Figure PCTCN2022070423-appb-100007
    Figure PCTCN2022070423-appb-100007
    Figure PCTCN2022070423-appb-100008
    Figure PCTCN2022070423-appb-100008
    Figure PCTCN2022070423-appb-100009
    Figure PCTCN2022070423-appb-100009
    Figure PCTCN2022070423-appb-100010
    Figure PCTCN2022070423-appb-100010
    Figure PCTCN2022070423-appb-100011
    Figure PCTCN2022070423-appb-100011
    Figure PCTCN2022070423-appb-100012
    Figure PCTCN2022070423-appb-100012
  5. 一种药物组合物，其特征在于，其含有有效剂量的如权利要求1～4中任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其互变异构体、或其水合物、或其溶剂化物、或其代谢产物、或其前药的一种或多种。A pharmaceutical composition, characterized in that it contains an effective dose of the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or its interconversion One or more of the isomers, or their hydrates, or their solvates, or their metabolites, or their prodrugs.
  6. 根据权利要求5所述的药物组合物，其特征在于，所述药物组合物中还包含至少一种药学上可接受的辅料。The pharmaceutical composition according to claim 5, characterized in that, the pharmaceutical composition further comprises at least one pharmaceutically acceptable adjuvant.
  7. 一种如权利要求1～4中任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其互变异构体、或其水合物、或其溶剂化物、或其代谢产物、或其前药、或其药物组合物在制备预防和/或治疗由SOS1过度表达引起的疾病的药物中的用途。A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer, or a hydrate thereof, or a solvate thereof , or a metabolite thereof, or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing and/or treating diseases caused by overexpression of SOS1.
  8. 一种如权利要求1～4中任一项所述的式I所示化合物、或其药学上可接受的盐、或其立体异构体、或其互变异构体、或其水合物、或其溶剂化物、或其代谢产物、或其前药、或其药物组合物在制备SOS1抑制剂药物中的用途。A compound shown in formula I as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, Use of its solvate, or its metabolite, or its prodrug, or its pharmaceutical composition in the preparation of a SOS1 inhibitor medicine.
  9. 一种如权利要求1～4中任一项所述的化合物、或其药学上可接受的盐、或其立体异构体、或其互变异构体、或其水合物、或其溶剂化物、或其代谢产物、或其前药、或其药物组合物在制备治疗和/或预防癌症药物中的用途。A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a tautomer, or a hydrate thereof, or a solvate thereof , or a metabolite thereof, or a prodrug thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating and/or preventing cancer.
  10. 根据权利要求9所述的用途，其特征在于，所述癌症为胰腺癌、结直肠癌和肺癌中的任一种或多种。The use according to claim 9, wherein the cancer is any one or more of pancreatic cancer, colorectal cancer and lung cancer.
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