WO2023051635A1 - 一种稠环化合物、其制备方法及其应用 - Google Patents

一种稠环化合物、其制备方法及其应用 Download PDF

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WO2023051635A1
WO2023051635A1 PCT/CN2022/122241 CN2022122241W WO2023051635A1 WO 2023051635 A1 WO2023051635 A1 WO 2023051635A1 CN 2022122241 W CN2022122241 W CN 2022122241W WO 2023051635 A1 WO2023051635 A1 WO 2023051635A1
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alkyl
substituted
independently
membered heterocyclic
heterocyclic group
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PCT/CN2022/122241
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French (fr)
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罗会兵
周华勇
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上海艾力斯医药科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • 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
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention relates to a condensed ring compound, its preparation method and its application.
  • RAS protein is a guanine trinucleotide phosphate (GTP) binding protein with a molecular weight of 21 kDa located on the cell membrane, consisting of 188 or 189 amino acids.
  • GTP guanine trinucleotide phosphate
  • the activity of RAS protein is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When binding to GDP, it is in an "inactive" state, and when binding to GTP, it is in an “activating" state.
  • RAS protein itself has relatively weak GTPase hydrolysis function and slow nucleotide exchange rate, combined with GTPase activating proteins (GAP), can enhance the GTP hydrolysis function of RAS protein, and guanine nucleotide exchange The factor (GEF) can catalyze the exchange of nucleotides (GTP exchange GDP).
  • GAP GTPase activating proteins
  • GEF guanine nucleotide exchange GDP
  • SOS1 Non of Sevenless 1
  • SOS1 Non of Sevenless 1
  • the combination of SOS1 and RAS can promote RAS to release GDP and combine with GTP, thereby activating RAS.
  • RAS After RAS is activated, it can activate multiple downstream signaling pathways, including MAPK signaling pathway and PI3K signaling pathway. These signaling pathways play an important role in promoting cell differentiation, proliferation and survival.
  • RAS mutations are genetic drivers of many cancers and are present in 20%-30% of human tumors, such as lung, colorectal, and
  • the RAS gene family includes KRAS, NRAS and HRAS.
  • KRAS mutations exist in a variety of tumors, such as lung adenocarcinoma (32%), colorectal cancer (41%), and pancreatic cancer (86%), and the KRAS mutation is the most common G12 mutation at the 12th codon, for example, In lung adenocarcinoma, colorectal cancer and pancreatic cancer with KRAS mutation, G12 mutation accounts for 85%, 68% and 91% respectively; HRAS mutation and NRAS mutation frequency are relatively low, mainly occurring in melanoma, leukemia and thyroid cancer among other types of cancer.
  • RAS protein (such as gene mutation, amplification and overexpression, etc.) is also closely related to the resistance of some anti-tumor drugs, such as EGFR monoclonal antibody and EGFR small molecule inhibitors. Therefore, RAS-related signaling pathways have become important anti-tumor targets.
  • the guanine nucleotide exchange factor of the RAS family involved in cancer-related signaling pathways is mainly SOS1, and reducing the expression of SOS1 can significantly inhibit the proliferation and survival of KRAS-mutated cancer cells. Since SOS1 is a common node for multiple activation of RAS signaling pathways, and almost all growth factor receptors activate RAS signaling pathways through SOS1, SOS1 inhibitors have the potential to become broad-spectrum anticancer drugs. The signaling pathways that SOS1 is involved in activation also play important roles in other mutation types of cancer.
  • SOS1 can interact with the adapter protein Grb2 to form a SOS1/Grb2 complex, which binds to activated receptor tyrosine kinases (such as EGFR, HER2, Erbb4, TRKA, TRKB, TRKC, RET and AXL, etc.).
  • SOS1 can also be recruited to phosphorylated cell surface receptors such as T-cell receptor, B-cell receptor, and monocyte colony-stimulating factor receptor.
  • the location of SOS1 on the cell membrane enables SOS1 to better promote the activation of RAS family proteins and activate downstream signaling pathways.
  • SOS1 is also involved in the activation of other GTP hydrolases, such as RAC1, etc.
  • RAC1 is also involved in the pathogenesis of various human cancers and other diseases.
  • SOS1 mutations were found in lung adenocarcinoma, embryonal rhabdomyosarcoma, and cutaneous granulosa cell tumors, and overexpression of SOS1 was found in bladder and prostate cancers.
  • inherited SOS1 mutations are also associated with the pathogenesis of RAS lesions, including Noonan syndrome, heart-facial-skin syndrome, and type 1 hereditary gingival fibroma.
  • the technical problem to be solved by the present invention is the defects of existing SOS1 inhibitors such as single structure.
  • the present invention provides a condensed ring compound, its preparation method and its application. Such compounds have better inhibitory activity on SOS1.
  • the present invention provides a condensed ring compound as shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvates;
  • X and Y are each independently -O-, -S-, -NH- or -CH 2 -;
  • Z is -CR 10 or N
  • Ring A is a C 6-12 aryl group, a 5-10 membered heteroaryl group, a C 3-7 cycloalkyl group, a C 3-7 cycloalkenyl group or a 3-7 membered heterocyclic group;
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h and R 1i is independently deuterium, hydroxyl, halogen, -N(R 7 ) 2 , -SR 9 , Nitro, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 1 substituted by one or more R 1-a -6 alkyl, C 1-6 alkyl-O-substituted by one or more R 1-b , C 2-6 alkenyl substituted by one or more R 1-c , one or more R 1-d substituted C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-O-, 3-7 membered heterocyclyl , 3-7 membered heterocyclyl-O-, C 3-7 cycloalkyl or C 3-7 cycloalkyl
  • R 1-a , R 1-b , R 1-c , R 1-d , R 1 -e , R 1-f , R 1-g , R 1-h and R 1-i is independently Deuterium, hydroxyl, halogen, -N(R 7 ) 2 , -SR 9 , nitro, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2 -6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl or 3-7 membered heterocyclyl;
  • Ring D is C 6-12 aryl, 5-6 membered heteroaryl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl or 3-7 membered heterocyclic group;
  • R 2 is absent, hydrogen, deuterium, hydroxyl, halogen, amino, cyano, oxo, nitro, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl or 3-7 membered heterocyclic group;
  • R 3 is hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3a , C 2-6 alkenyl, C 2-6 substituted by one or more R 3b Alkenyl, C 2-6 alkynyl, C 2-6 alkynyl substituted by one or more R 3c , C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3d , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R 3e , C 6-12 aryl, C 6-12 aryl substituted by one or more R 3f , 5 -10-membered heteroaryl, 5-10- membered heteroaryl, C3-7 cycloalkenyl substituted by one or more R3g or C3-7 cycloalkenyl substituted by one or more R3h ;
  • R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g and R 3h is independently deuterium, hydroxyl, halogen, -N(R 7 ) 2 , cyano, nitro, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 3-a , C 1-6 alkyl-O-, C 1-6 alkane substituted by one or more R 3-b -O-, C 2-6 alkenyl, C 2-6 alkynyl, C 2-6 alkenyl substituted by one or more R 3-c , C 2 substituted by one or more R 3-d -6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3-e , 3-7 membered heterocyclyl, substituted by one or more R 3-f 3-7 membered heterocyclic group, C 6-12 aryl, C 6-12 aryl substituted by one or
  • Each R 4 is independently deuterium, hydroxyl, halogen, -N(R 7 ) 2 , cyano, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 1-4 alkylene-N(R 7 ) 2 , C 1-6 alkyl substituted by one or more R 4a , C 1-6 alkyl-O-, C substituted by one or more R 4b 1-6 alkyl-O-, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 4c , 3-7 membered heterocyclyl, substituted by one or more R 4d
  • the 3-7 membered heterocyclyl, C 3-7 cycloalkenyl or C 3-7 cycloalkenyl substituted by one or more R 4e , or two R 4 together with the connected atoms form C 3- 7 Cycloalkyl, C 3-7 cycloalkyl substituted by one or
  • R4 can be connected in the ring on any ring atom allowed by the valence of , e.g. attached to a ring X, Y or any methylene group);
  • R 4a , R 4b , R 4c and R 4d are independently deuterium, hydroxyl, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenes Base or C 2-6 alkynyl;
  • R 5 is absent, oxo, hydrogen, deuterium, hydroxyl, halogen, amino, cyano, nitro, C 1-6 alkyl, C 1-6 alkyl substituted by one or more R 5a , C 1 -6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 5b , 3-7 A membered heterocyclic group, a 3-7 membered heterocyclic group substituted by one or more R 5c , a C 3-7 cycloalkenyl group or a C 3-7 cycloalkenyl group substituted by one or more R 5d ;
  • each R 5a , R 5b and R 5c is independently deuterium, C 1-6 alkyl, hydroxyl, halogen, amino or cyano;
  • R 6 is hydrogen, deuterium, hydroxyl, halogen, amino, cyano, oxo, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl or does not exist;
  • Each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkenyl, or two R 7 form a 3-7 membered hetero Cyclic group or 3-7 membered heterocyclic group substituted by one or more R 7a ;
  • Each R 7a is independently deuterium, C 1-6 alkyl, halogen, hydroxyl, amino, cyano, C 1-6 alkyl-O-, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each R 8 and R 9 are independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl or 3-7 membered heterocyclic group;
  • R 10 is hydrogen, deuterium, hydroxyl, halogen, amino, cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 2-6 alkenyl, C 2-6 alkynyl, C 3- 7 cycloalkyl groups, C 3-7 cycloalkenyl groups or 3-7 membered heterocyclic groups;
  • R 11 is hydrogen, deuterium, cyano, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 11a ;
  • each R 11a is independently deuterium, halogen or hydroxy
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • p 1, 2, 3, 4, 5 or 6;
  • the 3-7 membered heterocyclic groups are each independently a heteroatom type independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 3-7 membered heterocyclic groups
  • the 3-7-membered heterocyclic group is a 3-7-membered heterocyclic group, a 3-7-membered heterocyclic group-O-, a 3-7-membered heterocyclic group substituted by a substituent, and a 3-7-membered heterocyclic group substituted by a substituent
  • the 5-10 membered heteroaryls are each independently a heteroatom type independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-10 membered heteroaryls
  • the 5 The -10-membered heteroaryl group is a 5-10-membered heteroaryl group in a 5-10-membered heteroaryl group and a 5-10-membered heteroaryl group substituted by a substituent; that is, the "ring A, R 1 , R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 1i , R 3 , R 3a , R 3b , R 3c , R 3d , R 3e , R 3f , R 3g , and R 3h "The 5-10 membered heteroaryl in the 5-10 membered heteroaryl group substituted by substituents, the 5-10 membered heteroaryl group);
  • the 5-6 membered heteroaryl is a heteroatom type independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 5-6 membered heteroaryl;
  • the condensed ring compound shown in formula I is or a mixture thereof.
  • Z is N.
  • L is a single bond.
  • ring A is C 6-12 aryl or 5-10 membered heteroaryl; for example, ring A is C 6-12 aryl.
  • each R 1 is independently hydroxyl, halogen, -N(R 7 ) 2 , cyano, C 1-6 alkyl, C 1-6 alkyl-O-, replaced by one or more C 1-6 alkyl substituted by R 1a , C 1-6 alkyl-O- substituted by one or more R 1b , or two R 1 and attached ring atoms together form a C 3-7 cycloalkyl , C 3-7 cycloalkyl substituted by one or more R 1e , 3-7 membered heterocyclyl, 3-7 membered heterocyclyl substituted by one or more R 1f , C 3-7 cycloalkenyl Or C 3-7 cycloalkenyl substituted by one or more R 1i ; for example, each R 1 is independently halogen, C 1-6 alkyl or C 1-6 alkyl substituted by one or more R 1a .
  • each of R 1a , R 1b , R 1e , R 1f and R 1i is independently hydroxyl, halogen, -N(R 7 ) 2 , C 1-6 alkyl or replaced by one or more R 1-a substituted C 1-6 alkyl; eg each R 1a is independently halogen.
  • each R 1-a is independently C 1-6 alkyl or halogen.
  • ring D is a 3-7 membered heterocyclic group; for example, ring D is a six-membered heterocyclic group whose heteroatom type is N and the number of heteroatoms is 1 or 2, and another example is 1,2 -Dihydropyridyl, and for example "c" indicates that the atom is located meta to the Z atom of the B ring.
  • R2 is hydrogen
  • R 3 is hydrogen, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3d , 3-7 membered heterocyclyl or substituted by one or more R 3-7 membered heterocyclyl, C 3-7 cycloalkenyl substituted by 3e, or C 3-7 cycloalkenyl substituted by one or more R 3h ; for example, R 3 is 3-7 membered heterocyclic group or substituted by one Or a 3-7 membered heterocyclic group substituted by multiple R 3e .
  • each R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f and R 3-i are independently hydroxyl, halogen, -N(R 7 ) 2 , nitro, cyano, C 1-6 alkyl or C 1-6 alkyl-O-; eg each R 3-b is independently hydroxyl or halogen.
  • each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N(R 7 ) 2 , C 1-6 alkane substituted by one or more R 4a Base, 3-7 membered heterocyclic group or 3-7 membered heterocyclic group substituted by one or more R 4d ; for example, each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene -N(R 7 ) 2 , 3-7 membered heterocyclic group or 3-7 membered heterocyclic group substituted by one or more R 4d .
  • each R 4a and R 4d is independently C 1-6 alkyl or halogen; eg, each R 4d is independently C 1-6 alkyl or halogen.
  • R 5 is hydrogen or C 1-6 alkyl.
  • R 6 is oxo
  • each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkenyl; or two R 7 together with the attached nitrogen atom Forming a 3-7 membered heterocyclyl or a 3-7 membered heterocyclyl substituted by one or more R 7a ; for example each R 7 is independently hydrogen or C 1-6 alkyl.
  • each R 7a is independently C 1-6 alkyl or halogen.
  • each R 8 and R 9 is independently hydrogen or C 1-6 alkyl; eg, each R 9 is independently hydrogen or C 1-6 alkyl.
  • R 11 is C 1-6 alkyl.
  • n 0, 1, 2 or 3; eg m is 1, 2 or 3.
  • n is 0, 1, 2 or 3; eg n is 0, 1 or 2.
  • p is 1, 2 or 3.
  • the 3-7 membered heterocyclic groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • Heterocyclic group (the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic group and a 3-7 membered heterocyclic group in a 3-7 membered heterocyclic group substituted by a substituent.
  • the 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group whose heteroatoms are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • X and Y are each independently -O-, -NH- or -CH 2 -;
  • L is a single bond
  • Ring A is C 6-12 aryl or 5-10 membered heteroaryl
  • Each R 1 is independently hydroxyl, halogen, -N(R 7 ) 2 , cyano, C 1-6 alkyl, C 1-6 alkyl-O-, C 1 substituted by one or more R 1a -6 alkyl, C 1-6 alkyl-O-substituted by one or more R 1b , or, two R 1 and the ring atoms connected together form a C 3-7 cycloalkyl, substituted by one or more C 3-7 cycloalkyl, 3-7 membered heterocyclyl, 3-7 membered heterocyclyl, C 3-7 cycloalkenyl substituted by one or more R 1f , or one or more A C 3-7 cycloalkenyl substituted by R 1i ;
  • R 1a , R 1b , R 1e , R 1f and R 1i is independently hydroxyl, halogen, -N(R 7 ) 2 , C 1-6 alkyl, or substituted by one or more R 1-a C 1-6 alkyl;
  • Each R 1-a is independently C 1-6 alkyl or halogen
  • Ring D is a 3-7 membered heterocyclic group
  • R is hydrogen
  • R 3 is hydrogen, C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by one or more R 3d , 3-7 membered heterocyclyl, 3-7 substituted by one or more R 3e Member heterocyclyl, C 3-7 cycloalkenyl or C 3-7 cycloalkenyl substituted by one or more R 3h ;
  • R 3-a , R 3-b , R 3-c , R 3-d , R 3-e , R 3-f and R 3-i is independently hydroxyl, halogen, -N(R 7 ) 2. Nitro, cyano, C 1-6 alkyl or C 1-6 alkyl-O- ;
  • Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N(R 7 ) 2 , C 1-6 alkyl substituted by one or more R 4a , 3-7 members Heterocyclyl or 3-7 membered heterocyclyl substituted by one or more R 4d ;
  • each R 4a and R 4d is independently C 1-6 alkyl or halogen
  • R 5 is hydrogen or C 1-6 alkyl
  • R 6 is oxo
  • Each R 7 is independently hydrogen, C 1-6 alkyl, C 3-7 cycloalkyl or C 3-7 cycloalkenyl; or two R 7 together form a 3-7 membered hetero Cyclic group or 3-7 membered heterocyclic group substituted by one or more R 7a ;
  • Each R 7a is independently C 1-6 alkyl or halogen
  • each R 8 and R 9 are independently hydrogen or C 1-6 alkyl
  • R 11 is C 1-6 alkyl
  • n 0, 1, 2 or 3;
  • n 0, 1, 2 or 3;
  • p 1, 2 or 3;
  • the 3-7 membered heterocyclic groups are each independently a heteroatom type independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3 3-7 membered heterocyclic groups (the The 3-7 membered heterocyclic group is the 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group and the 3-7 membered heterocyclic group substituted by a substituent.
  • the R 3 and R 4 are substituted The 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by the base, the 3-7 membered heterocyclic group; the 3-7 membered heterocyclic group in the ring D; the two R 1 and the ring atom connected 3-7 membered heterocyclyl, 3-7 membered heterocyclyl in the 3-7 membered heterocyclyl substituted by one or more R 1f formed together; two R 3d , two R 3e or two R The 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by one or more R 3-f formed together with the connected ring atoms, the 3-7 membered heterocyclic group; two R 7 The 3-7 membered heterocyclic group in the 3-7 membered heterocyclic group substituted by one or more R 7a formed together with the connected nitrogen atom, the 3-7 membered heterocyclic group);
  • the 5-10 membered heteroaryl group is a 5-10 membered heteroaryl group whose heteroatoms are independently selected from N, O and S, and the number of heteroatoms is 1, 2 or 3.
  • X and Y are each independently -O-;
  • each R 1 is independently halogen, C 1-6 alkyl, or C 1-6 alkyl substituted by one or more R 1a ;
  • each R 1a is independently halogen
  • Ring A is C 6-12 aryl
  • L is a single bond
  • R is hydrogen
  • R 3 is a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more R 3e ;
  • R 5 is hydrogen or C 1-6 alkyl
  • Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N(R 7 ) 2 , 3-7 membered heterocyclyl, or 3-7 substituted by one or more R 4d membered heterocyclyl;
  • each R 4d is independently C 1-6 alkyl or halogen
  • Each R 7 is independently hydrogen or C 1-6 alkyl
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 11 is C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • X and Y are each independently -O- or -CH 2 -;
  • each R 1 is independently halogen, C 1-6 alkyl, or C 1-6 alkyl substituted by one or more R 1a ;
  • each R 1a is independently halogen
  • Ring A is C 6-12 aryl
  • Ring D is a six-membered heterocyclic group whose heteroatom type is N and the number of heteroatoms is 1 or 2, such as 1,2-dihydropyridyl, and another example is "c" indicates that the atom is located in the meta position of the Z atom in the B ring; Z is N;
  • L is a single bond
  • R is hydrogen
  • R 3 is a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more R 3e ;
  • each R3 -b is independently hydroxyl or halogen
  • R 5 is hydrogen or C 1-6 alkyl
  • R 6 is oxo
  • Each R 4 is independently C 1-6 alkyl, -C 1-4 alkylene-N(R 7 ) 2 , 3-7 membered heterocyclyl, or 3-7 substituted by one or more R 4d membered heterocyclyl;
  • each R 4d is independently C 1-6 alkyl or halogen
  • Each R 7 is independently hydrogen or C 1-6 alkyl
  • Each R 9 is independently hydrogen or C 1-6 alkyl
  • R 11 is C 1-6 alkyl
  • n 1, 2 or 3;
  • n 0, 1 or 2.
  • L is a single bond
  • R 11 is methyl
  • L is a single bond
  • R 11 is methyl
  • ring A is a C 6-12 aryl group
  • the C 6-12 aryl group is phenyl or naphthyl, for example, phenyl.
  • the 5-10-membered heteroaryl group is a 5-10-membered heteroaryl group whose heteroatom type is N and the number of heteroatoms is 1 or 2 Heteroaryl, such as
  • R 1 is C 1-6 alkyl substituted by one or more R 1a
  • the C 1-6 alkyl substituted by one or more R 1a is -CHF 2 , - CF3 , -CF2CH3 , -CF2CH2OH , or -CF2C ( CH3 ) 2OH .
  • the C 3- 7 Cycloalkenyl is cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, for example cyclopentenyl.
  • the 3-7 membered heterocyclic group is a 3-7 membered heterocyclic group with heteroatoms independently selected from O, N and S, and the number of heteroatoms is 1 or 2, such as "a" indicates that this part is the position where ring A is connected in parallel.
  • the 3-7 membered heterocyclic group is a six-membered heterocyclic ring with the heteroatom type being N and the number of heteroatoms being 1 or 2 base, such as 1,2-dihydropyridyl, and another example is "c" indicates that the atom is located meta to the Z atom of the B ring.
  • R 3 is a 3-7 membered heterocyclic group or a 3-7 membered heterocyclic group substituted by one or more R 3e
  • the 3-7 membered heterocyclic group is independent of the type of heteroatom is selected from N and O, and the number of heteroatoms is 1 or 2 5-7 membered heterocyclic groups, such as
  • R 3 is C 3-7 cycloalkyl or C 3-7 cycloalkyl substituted by one or more R 3d , said C 3-7 cycloalkyl is cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
  • each of R 3d and R 3e is independently a C 2-6 alkynyl
  • the C 2-6 alkynyl is ethynyl or propynyl.
  • R 4 is -C 1-4 alkylene-N(R 7 ) 2
  • two R 7 and the connected nitrogen atoms together form a 3-7 membered heterocyclic group or are replaced by one or
  • a 3-7-membered heterocyclic group substituted by multiple R 7a for example, the -C 1-4 alkylene-N(R 7 ) 2 is
  • R 4 is -C 1-4 alkylene-N(R 7 ) 2
  • R 7 is independently a C 1-6 alkyl group; for example, said -C 1-4 Alkylene-N(R 7 ) 2 is
  • the 3-7 membered heterocyclic group is that the heteroatom type is N , a 5-7 membered heterocyclic group with 1 or 2 heteroatoms, such as
  • the 3-7 membered heterocyclic group is a 5-7 membered heterocyclic group whose heteroatom type is N and the number of heteroatoms is 1 or 2, for example
  • each of the C 1-6 alkyl groups is independently a C 1-4 alkyl group, such as methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and another example is methyl, ethyl or isobutyl.
  • the C 1-6 alkyl-O- are each independently a C 1-4 alkane Group -O-, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, another example is methoxy group, ethoxy group or isopropoxy group, and for example methoxy group or ethoxy group.
  • R 1 is F, Cl, -CN, -CHF 2 , -CF 3 , -CH 3 , -CF 2 CH 2 OH, -CF 2 CH 3 , -NH 2 or -CF 2 C( CH 3 ) 2 OH; or two R 1 together with the ring atoms to which they are attached "a" indicates that this part is the position where ring A is connected in parallel.
  • R3 is For example for
  • R3 is
  • R 4 is -CH 3 .
  • the b-terminal is connected to the Z atom.
  • R 11 is methyl
  • the condensed ring compound represented by the formula I is selected from any of the following compounds:
  • the present invention also provides a condensed ring compound represented by formula I as described above, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutical
  • the preparation method of the solvate of above acceptable salt it comprises the following steps:
  • the Buchwald-Hartwig coupling reaction is carried out in the presence of a catalyst and a base;
  • the catalyst is conventional in the art, such as RuPhos Pd G3 (methanesulfonate Acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium ( II)),
  • BrettPhos Pd G3 Metalhanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl )(2'-amino-1,1'-biphenyl-2-yl)palladium(II)
  • XPhos Pd G3 methanesulfonic acid (2-dicyclohexylphosphin
  • the scheme one further includes the following steps:
  • the compound I-1 undergoes a substitution reaction with R 5 -NH 2 to obtain compound Ia-1;
  • the compound Ia-1 is reacted with an iodo reagent (such as N-iodosuccinimide, I 2 ) to obtain the compound Ia-2 through iodination;
  • an iodo reagent such as N-iodosuccinimide, I 2
  • the compound Ia-3 is subjected to a ring-closing reaction under the action of a base to obtain compound Ia-4;
  • the compound Ia-4 is reacted with a brominating reagent to obtain compound Ia-5 through bromination;
  • the iodination reagent is conventional in the art, such as N-iodosuccinimide and/or I 2 .
  • the base is conventional in the art, such as one or more of sodium methyl mercaptide, sodium methoxide and sodium ethoxide;
  • the bromination reagent is conventional in the art, such as N-bromosuccinimide and/or Br 2 .
  • the second scheme also includes the following steps:
  • R 12 is methyl or ethyl
  • the compound I-1 undergoes an acylation reaction under the action of a strong base to obtain the compound Ib-1;
  • Compound Ib-1 reacts with malonate and decarboxylates to obtain Compound Ib-2;
  • the strong base is conventional in the art, such as lithium diisopropylamide
  • the malonate is conventional in the art, such as methyl malonate and ethyl malonate.
  • the invention provides a pharmaceutical composition; the pharmaceutical composition comprises:
  • Substance X said substance X is the aforementioned condensed ring compound shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or a solvate of a pharmaceutically acceptable salt thereof, and
  • the present invention provides the application of a substance X or the pharmaceutical composition as described above in the preparation of SOS1 inhibitors.
  • the substance X is the condensed ring compound shown in formula I as described above, and its tautomorphism isomers, stereoisomers thereof, pharmaceutically acceptable salts thereof, solvates thereof, or solvates of pharmaceutically acceptable salts thereof.
  • said SOS1 inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, for example: as a standard sample or control sample to provide comparison, or according to the art
  • the conventional method is made into a kit to provide rapid detection of the effect of the compound on inhibiting SOS1.
  • the present invention provides the application of a substance X or the pharmaceutical composition as described above in the preparation of medicine;
  • the substance X is the condensed ring compound represented by formula I as described above, and its tautomer , its stereoisomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt;
  • the drug can treat and/or prevent diseases related to SOS1 activity or expression Medicines for diseases.
  • said disease related to SOS1 activity or expression is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanin tumor, embryonal rhabdomyosarcoma, cutaneous granulosa cell tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, Renal cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer, urothelial cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia, splenomegaly Hypereosinophilic syndrome and multiple myeloid carcinoma, and disorders associated with inherited mutations in SOS1, including but not limited to
  • the present invention provides the application of a substance X or the pharmaceutical composition as described above in the preparation of medicine;
  • the substance X is the condensed ring compound represented by formula I as described above, and its tautomer , its stereoisomer, its pharmaceutically acceptable salt, its solvate or the solvate of its pharmaceutically acceptable salt;
  • the drug is a drug for treating and/or preventing the following diseases;
  • the The disease is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer, thyroid cancer, melanoma, embryonal rhabdomyosarcoma, granulosa cell tumor of the skin, liver cancer, rectal cancer, bladder cancer, Throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, kidney cancer, skin cancer, lymphoma, stomach cancer,
  • the present invention provides a method of inhibiting SOS1, which comprises administering a therapeutically effective amount of substance X or a pharmaceutical composition as described above to a patient (such as a human being);
  • the substance X is the aforementioned condensed ring compound represented by formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable Solvates of accepted salts.
  • the present invention provides a method for treating and/preventing diseases, which comprises administering a therapeutically effective amount of substance X or a pharmaceutical composition as described above to a patient (such as a human being);
  • the substance X is the aforementioned condensed ring compound represented by formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable Solvates of accepted salts;
  • the disease is a disease related to SOS1 activity or expression.
  • the disease related to SOS1 activity or expression is selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, colon cancer , thyroid cancer, melanoma, embryonal rhabdomyosarcoma, cutaneous granulosa cell tumor, liver cancer, rectal cancer, bladder cancer, throat cancer, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer Carcinoma, esophageal cancer, kidney cancer, skin cancer, lymphoma, gastric cancer, bile duct cancer, uterine cancer, endometrial cancer, urothelial cancer, acute myeloid leukemia, myelofibrosis, B-cell lymphoma, monocytic leukemia , splenomegaly, polycythemia, eosinophilic syndrome, and multiple mye
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (eg, C 1-10 , preferably C 1-6 , more preferably C 1-4 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, or n-hexyl, and the like.
  • alkylene means a saturated divalent hydrocarbyl group obtained by removing two hydrogen atoms from a saturated straight or branched chain hydrocarbyl group; that is, an alkyl group in which one of the hydrogen atoms has been replaced, the definition of alkyl group is as above .
  • alkylene groups include methylene (-CH 2 -), ethylene ⁇ including -CH 2 CH 2 - or -CH(CH 3 )- ⁇ , isopropylidene ⁇ including -CH(CH 3 )CH 2 -or -C(CH 3 ) 2 - ⁇ etc.
  • alkenyl refers to a straight or branched hydrocarbon chain group having at least one double bond, consisting only of carbon atoms and hydrogen atoms, having specified carbon atoms (such as C 2-10 , preferably C 2-6 , more preferably C 2-4 ), and is attached to the rest of the molecule by a single bond, for example alkenyl including but not limited to ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert- Butenyl, n-pentenyl, 2-methylbutenyl, 2,2-dimethylpropenyl or n-hexenyl, etc.
  • alkynyl refers to a straight or branched hydrocarbon chain group having at least one triple bond, consisting only of carbon atoms and hydrogen atoms, having specified carbon atoms (such as C 2-10 , preferably C 2-6 , more preferably C 2-4 ), and is attached to the rest of the molecule by a single bond, for example alkynyl including but not limited to ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, sec-butynyl Alkynyl, tert-butynyl, n-pentynyl, 2-methylbutynyl, 2,2-dimethylpropynyl or n-hexynyl, etc.
  • C 1-6 alkyl-O- the definition of C 1-6 alkyl is as described above.
  • cycloalkyl means a saturated monocyclic or polycyclic (e.g., bicyclic, tricyclic, or multicyclic bridged, fused (fused) or spirocyclic ring system) carbocyclic substituent, which can be replaced by Any suitable carbon atom is attached to the remainder of the molecule by a single bond; for example having 3 to 15 ring carbon atoms, preferably 3 to 10 ring carbon atoms, more preferably 3 to 7 ring carbon atoms; said ring Alkyl groups may be further substituted with oxo substituents; for example C 3-7 cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or wait.
  • cycloalkenyl means a monocyclic or polycyclic (e.g. bicyclic, tricyclic or multicyclic bridged ring, amalgamated (fused ring) or spiro ring system having at least one double bond (such as a carbon-carbon double bond) ) and it may be attached to the rest of the molecule by a single bond via any suitable carbon atom; for example having 3 to 15 ring carbon atoms, preferably having 3 to 10 ring carbon atoms, more preferably having 3 to 7 ring carbon atoms; the cycloalkenyl can be further substituted by oxo substituents; for example C 3-7 cycloalkenyl includes but not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • aryl refers to an aromatic group of a conjugated hydrocarbon ring system composed of carbon atoms satisfying the 4n+2 rule, and each ring has aromaticity.
  • aryl refers to an aromatic group having 6 to 18 (preferably 6-12) carbon atoms. Examples of aryl groups include, but are not limited to, phenyl or naphthyl, and the like.
  • heteroaryl means 5 to 20 membered (preferably 5 to 12 membered, more preferably 5 to 10 membered) having 2 to 15 carbon atoms and 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur in the ring. Conjugated ring system groups. Unless specifically stated otherwise in this specification, heteroaryl may be a monocyclic, bicyclic, tricyclic or multicyclic ring system, and may be fused to a cycloalkyl or heterocyclyl as defined above, provided that hetero An aryl group is connected to the rest of the molecule by a single bond through an atom on the aromatic ring.
  • heteroaryl refers to an aromatic group containing heteroatoms, and each ring has aromaticity; preferably, the type of heteroatoms is independently selected from N, O and S, and the number of heteroatoms is 1 , 2 or 3 5-10-membered heteroaryl or 5-6-membered heteroaryl.
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, diazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, Pyridazinyl, benzimidazolyl (such as ), benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolyl, isoxazolyl, thiadiazolyl, isoindolyl, indazole Base, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl,
  • cycloalkyl-O- cycloalkyl is as defined above.
  • cycloalkenyl-O- the definition of cycloalkenyl is as described above.
  • heterocyclyl-O- the definition of heterocyclyl is as mentioned above.
  • a "-" at the end of a group means that the group is attached to other fragments in the molecule through this site.
  • one or more means ie 1, 2, 3, 4, 5, 6, 7, 8, 9 or more.
  • each step and condition can refer to the conventional operation steps and conditions in the art.
  • the present invention employs standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques were used for chemical synthesis, chemical analysis.
  • the fused ring compound represented by formula I of the present invention may contain one or more chiral centers and exist in different optically active forms.
  • the compound contains enantiomers.
  • the present invention includes both these isomers and mixtures of isomers, such as racemic mixtures. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • diastereoisomers may exist.
  • the present invention includes resolved optically pure specific isomers as well as mixtures of diastereomers. Diastereoisomers can be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • stereoisomer includes conformational isomers and configurational isomers, wherein configurational isomers mainly include cis-trans isomers and optical isomers.
  • the compounds of the present invention may exist in the form of stereoisomers, and thus encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, enantiomers, diastereomers, Atropisomers, etc., the compound of the present invention can also be in the form of any combination or any mixture of the aforementioned stereoisomers, such as mesoform, racemate, atropisomer equivalent mixture, etc. exist.
  • a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof For example a single enantiomer, a single diastereoisomer or a mixture thereof, or a single atropisomer or a mixture thereof.
  • the compounds described herein contain olefinic double bonds, unless otherwise specified, they include cis-isomers and trans-isomers, and any combination thereof.
  • Atropisomers of the present invention are stereoisomers based on axial or planar chirality resulting from restricted intramolecular rotation.
  • the present invention provides the compounds shown in the above various structures, or their cis-trans isomers, mesomers, racemates, enantiomers, diastereoisomers, atropisomers, Isomers, tautomers, or mixtures thereof, wherein "the mixture thereof” includes any of the aforementioned stereoisomers (such as cis-trans isomers, enantiomers, diastereoisomers, atropisomers), tautomers and/or mixtures (meso, racemate), e.g.
  • tautomer refers to isomers of functional groups resulting from the rapid movement of an atom in a molecule between two positions.
  • the fused ring compound shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt's solvate are intended to cover such as Any isotopic labeling of the fused ring compound represented by formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt solvate (or "radiolabeled") variants.
  • This variant can be a fused ring compound as shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable salt
  • the radionuclide used will depend on the particular application of the radiolabeled variant. For example, for in vitro receptor labeling and competition assays, 3H or14C are often useful. For radiographic applications, 11C or18F are often useful.
  • isotopic variants of the compounds of the invention may be useful, for example, to investigate the mechanism of action or the distribution of the active ingredient in vivo; due to the relative ease of preparation and Detectability, compounds labeled with 3 H or 14 C isotopes are particularly suitable for this purpose.
  • the incorporation of isotopes such as deuterium may confer particular therapeutic benefit due to better metabolic stability of the compound, e.g. increasing half-life in vivo or lowering the effective dose required; case constitutes a preferred embodiment of the invention.
  • Isotopic variants of the compounds of the present invention can be prepared by methods known to those skilled in the art, for example by the methods described below and in the working examples, by using corresponding isotopically modified specific reagents and/or starting compounds .
  • pharmaceutical composition refers to a formulation comprising a compound of the present invention and a vehicle generally accepted in the art for the delivery of a biologically active compound to a mammal (eg, a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, facilitate the absorption of the active ingredient and thus exert its biological activity.
  • pharmaceutically acceptable refers to substances (such as pharmaceutical excipients) that do not affect the biological activity or properties of the compounds of the present invention, and are relatively non-toxic, that is, the substances can be administered to individuals without causing adverse effects Biologically react or interact in an undesirable manner with any component contained in the composition.
  • pharmaceutical excipient or “pharmaceutically acceptable carrier” refers to the excipients and additives used in the production of drugs and formulation of prescriptions, and refers to all substances contained in pharmaceutical preparations except active ingredients.
  • the pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition.
  • Described pharmaceutical adjuvant can comprise one or more in the following adjuvant: binding agent, suspending agent, emulsifying agent, diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antiadhesive Glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.
  • compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, milling, encapsulating, entrapping or lyophilizing processes.
  • the condensed ring compound shown in formula I, its tautomer, its stereoisomer, its pharmaceutically acceptable salt, its solvate or its pharmaceutically acceptable may be administered in any form of pharmaceutical composition.
  • These compositions may be prepared according to methods well known in the art of pharmacy and may be administered by various routes depending upon the need for local or systemic treatment and the area to be treated.
  • Administration can be topical (including epidermal and transdermal, ocular and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (eg, by powder or aerosol inhalation or insufflation, including by nebulizer; intratracheal or intranasal) , oral (solid and liquid preparations) or parenteral administration forms.
  • solid oral formulations include, but are not limited to, powders, capsules, caplets, gelcaps, and tablets.
  • liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions.
  • topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations.
  • formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in pharmaceutically acceptable carriers, suspensions for injection, and emulsions for injection.
  • Pharmaceutical compositions and formulations for topical administration may include transdermal patches, salves, emulsions, ointments, gels, drops, suppositories, sprays, liquids and powders.
  • Oral administration may include dosage forms formulated for once-daily or twice-daily (BID) administration.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, eg, intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or it can be by a continuous infusion pump.
  • Conventional pharmaceutical carriers, water, powder or oil bases, thickeners and the like may be necessary or desirable.
  • Pharmaceutical compositions comprising the present invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres).
  • treatment refers to therapeutic therapy or palliative measures.
  • treatment means: (1) amelioration of one or more biological manifestations of the disease or condition, (2) interference with (a) one or more points in the biological cascade leading to or causing the condition or (b ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, Or (4) slowing the development of the disorder or one or more biological manifestations of the disorder.
  • Treatment can also refer to prolonging survival as compared to expected survival if not receiving treatment.
  • prevention refers to a reduction in the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by those skilled in the art.
  • patient refers to any animal that is about to or has received the administration of the compound or composition according to the embodiments of the present invention, preferably a mammal, and most preferably a human.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being most preferred.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids and organic acids.
  • solvate refers to a substance formed after crystallization of a compound with a solvent (including but not limited to: water, methanol, ethanol, etc.). Solvates are divided into stoichiometric solvates and non-stoichiometric solvates.
  • solvate of a pharmaceutically acceptable salt refers to a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for patient use) acid or base, solvent (including but not limited to: water, methanol, ethanol etc.), wherein the pharmaceutically acceptable salt has the same meaning as the term “pharmaceutically acceptable salt” above.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the fused ring compound represented by formula I of the present invention has better inhibitory activity on SOS1; it is expected to treat and/or prevent diseases related to SOS1 activity or expression.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm).
  • the determination of nuclear magnetic resonance is to use Bruker (Bruker) AVANCE-400 nuclear magnetic instrument, the measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ) or deuterated chloroform (CDCl 3 ), internal standard is tetramethylsilane (TMS ).
  • the determination of mass spectrometry was performed with an Agilent (Agilent) 1260-6125B single quadrupole liquid mass spectrometer, and an electrospray ionization source (ESI) was used.
  • Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used for thin-layer chromatography silica gel plates, and the specifications used are 0.15mm-0.20mm, and the specifications used for preparative thin-layer chromatography are 0.4mm-0.5mm.
  • Preparative high-performance liquid chromatography used an AutoPurification LC preparative system equipped with an ACQUITy QDa mass spectrometer detector produced by Waters (Waters).
  • the preparative chromatographic column used was SunFire C18 5 ⁇ m 19x250mm OBD preparative column.
  • the mobile phase used different gradients of water (with 0.1% formic acid)-acetonitrile to elute the compounds.
  • Step 3 4-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6-chloro-3-((4-methoxybenzyl)oxy) pyridine
  • Step 5 8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine
  • Step 7 6-Chloro-7-iodo-N-methyl-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-8-amine
  • Step 8 Ethyl 3-(6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxy[2,3-b]pyridin-7-yl)acrylate
  • 6-Chloro-7-iodo-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridin-8-amine (819mg, 2.5mmol) was dissolved in N, N-Dimethylformamide (15 mL), added ethyl acrylate (376 mg, 3.76 mmol), triethylamine (380 mg, 3.76 mmol), palladium acetate (56 mg, 0.25 mmol), tris(o-methylphenyl)phosphine (152 mg, 0.5 mmol). Under the protection of argon, the temperature was raised to 100° C. for 2 hours.
  • Step 9 6-Chloro-10-methyl-2,3-dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 10 8-Bromo-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6]naphthyridine-9(10H) -ketone
  • Step 11 8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3 -h][1,6]naphthyridin-9(10H)-one
  • Step 12 (R)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl )amino)-10-methyl-2,3-dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one (Compound 1)
  • Step 1 (S)-4-Bromo-6-chloro-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-((4 -methoxybenzyl)oxy)pyridine
  • Step 2 (R)-3-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-di alcohol
  • Step 3 (S)-3-((4-Bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-di alcohol dimesylate
  • Step 4 (S)-3-((4-Bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)propane-1,2-diol dimesylate
  • step 3 The crude product (14.4 g) obtained in step 3 was dissolved in dichloromethane (20 mL), added with trifluoroacetic acid (20 mL), and stirred at room temperature for 0.5 hours.
  • the reaction solution was spin-dried under reduced pressure, diluted with saturated aqueous sodium bicarbonate (300 mL), and extracted with ethyl acetate (500 mL).
  • Step 5 (R)-(8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-2-yl)methyl mesylate
  • Step 6 (S)-6-Chloro-N-methyl-2-((methylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine -8-amine
  • Step 7 tert-Butyl(S)-(6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-2-yl) Methyl)(methyl)carbamate
  • Step 8 tert-Butyl(S)-(6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine -2-yl)methyl)(methyl)carbamate
  • Step 9 (S)-3-(2-(tert-Butoxycarbonyl)(methyl)amino)methyl)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4 ]dioxane[2,3-b]pyridin-7-yl)ethyl acrylate
  • Step 10 tert-Butyl(S)-((6-Chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3- h][1,6]naphthyridin-2-yl)methyl)(methyl)carbamate
  • Step 11 tert-butyl(S)-((8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[ 2,3-h][1,6]naphthyridin-2-yl)methyl)(methyl)carbamate
  • Step 12 tert-Butyl(S)-((8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9 ,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthyridin-2-yl)methyl)(methyl)carbamate
  • Step 13 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((methylamino)methyl)-2,3- Dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 14 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-chloro-2-((dimethylamino)methyl)-10-methyl-2, 3-Dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 15 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorobenzene base)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1 ,6] Naphthyridin-9(10H)-one (compound 2)
  • step 3 The synthesis of compound 3 refers to step 1 to step 15 of Example 2, except that the raw material (S)-glycerol acetal in step 1 is replaced by (R)-glycerol acetonide.
  • Step 1 (S)-2-((1-azido-3-((4-methoxybenzyl)oxy)propan-2-yl)oxy)-4-bromo-6-chloro- 3-((4-methoxybenzyl)oxy)pyridine
  • Step 2 (S)-2-((1-Azido-3-hydroxypropan-2-yl)oxy)-4-bromo-6-chloropyridin-3-ol
  • Step 3 (S)-N-((8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-3-yl)methyl) -1,1,1-Triphenylphosphorimide
  • Step 4 (S)-3-(Aminomethyl)-6-chloro-N-methyl-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-8- amine
  • Step 5 tert-Butyl(S)-((6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-3-yl ) methyl) carbamate
  • Step 6 tert-Butyl(S)-((6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine -3-yl)methyl)carbamate
  • Step 7 (S)-3-(3-(((tert-butoxycarbonyl)amino)methyl)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4]di Oxane[2,3-b]pyridin-7-yl)ethyl acrylate
  • Step 8 tert-Butyl(S)-((6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[2,3- h][1,6]naphthyridin-3-yl)methyl)carbamate
  • Step 9 tert-butyl(S)-((8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane[ 2,3-h][1,6]naphthyridin-3-yl)methyl)carbamate
  • Step 10 tert-Butyl(S)-((8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-2,3,9 ,10-tetrahydro-[1,4]dioxane[2,3-h][1,6]naphthyridin-3-yl)methyl)carbamate
  • Step 11 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-3-(aminomethyl)-6-chloro-10-methyl-2,3-dihydro- [1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 12 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-chloro-3-((dimethylamino)methyl)-10-methyl-2, 3-Dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 13 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorobenzene Base)ethyl)amino)-3-((dimethylamino)methyl)-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1 ,6] Naphthyridin-9(10H)-one (Compound 4)
  • Step 1 tert-butyl (R)-2-((S)-2-((4-bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl) Oxy)-1-hydroxyethyl)pyrrolidine-1-carboxylate
  • Step 2 4-Bromo-6-chloro-2-((S)-2-hydroxy-2-((R)-pyrrolidin-2-yl)ethoxy)pyridin-3-ol
  • Step 3 tert-Butyl (R)-2-((S)-2-((4-bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)-1-hydroxyethyl)pyrrolidine -1-carboxylate
  • Step 4 tert-butyl(R)-2-((R)-8-bromo-6-chloro-2,3-dihydro-[1,4]dioxane[2,3-b]pyridine-2 -yl)pyrrolidine-1-carboxylate
  • Step 5 tert-butyl(R)-2-((R)-6-chloro-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2,3-b ]pyridin-2-yl)pyrrolidine-1-carboxylate
  • Step 6 tert-butyl (R)-2-((R)-6-chloro-7-iodo-8-(methylamino)-2,3-dihydro-[1,4]dioxane[2, 3-b]pyridin-2-yl)pyrrolidine-1-carboxylate
  • Step 7 tert-Butyl(R)-2-((R)-6-chloro-7-(3-ethoxy-3-oxopropan-1-en-1-yl)-8-(methylamino )-2,3-dihydro-[1,4]dioxy[2,3-b]pyridin-2-yl)pyrrolidine-1-carboxylate
  • Step 8 tert-butyl (R)-2-((R)-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4]dioxane [2,3-h][1,6]naphthyridin-2-yl)pyrrolidine-1-carboxylate
  • Step 9 tert-butyl (R)-2-((R)-8-bromo-6-chloro-10-methyl-9-oxo-2,3,9,10-tetrahydro-[1,4 ]dioxane[2,3-h][1,6]naphthyridin-2-yl)pyrrolidine-1-carboxylate
  • Step 10 tert-Butyl(R)-2-((R)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo- 2,3,9,10-tetrahydro-[1,4]dioxy[2,3-h][1,6]naphthyridin-2-yl)pyrrolidine-1-carboxylate
  • Step 11 (R)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((R)-pyrrolidin-2-yl)- 2,3-Dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 12 (R)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-2-((R)-1-methylpyrrolidin-2 -yl)-2,3-dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Step 13 (R)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorobenzene Base) ethyl) amino)-10-methyl-2-((R)-1-methylpyrrolidin-2-yl)-2,3-dihydro-[1,4]dioxane[2, 3-h][1,6]naphthyridin-9(10H)-one (Compound 5)
  • step 1
  • Step 1 The crude product obtained in Step 1 was dissolved in anhydrous methanol (10 mL), and a methanolic solution of sodium methoxide (238 mg, 1.32 mmol, 30% wtin MeOH) was added. The reaction was stirred at room temperature for 16 hours. Add water (40 mL) to dilute, add ethyl acetate (80 mL) to extract. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, cooled to room temperature, concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 11 as a yellow solid (6 mg, yield 15%). ESI-MS m/z: 618.4 [M+1] + .
  • step 1
  • Compound 21 was prepared according to the method in step 2 of Example 11. ESI-MS m/z: 614.3 [M+1] + .
  • step 1
  • Step 2 (R)-6-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-10-methyl-8-(1-methylcyclopropyl )-2,3-dihydro-[1,4]dioxan[2,3-h][1,6]naphthyridin-9(10H)-one
  • Example 37 Referring to the preparation method of Example 37, the intermediate 8-bromo-6-chloro-10-methyl-2,3-dihydro-[1,4]dioxane[2,3-h][1,6 ]naphthyridin-9(10H)-one and appropriate borate esters or amine derivatives were used as raw materials to prepare Examples 38-43 in Table 2, namely compounds 38-43.
  • Step 1 (R)-4-Bromo-6-chloro-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-((4 -methoxybenzyl)oxy)pyridine
  • Step 2 (S)-3-((4-Bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-di alcohol
  • Step 3 (R)-3-((4-Bromo-6-chloro-3-((4-methoxybenzyl)oxy)pyridin-2-yl)oxy)propane-1,2-di alcohol dimesylate
  • Step 4 (R)-3-((4-Bromo-6-chloro-3-hydroxypyridin-2-yl)oxy)propane-1,2-diol dimesylate
  • Step 5 (S)-(8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-2-yl)methyl mesylate
  • Step 6 (R)-1-(8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-2-yl)-N-( 2,4-Dimethoxybenzyl)methanamine
  • Step 7 (R)-(8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-2-yl)methanamine
  • Step 8 (R)-1-(8-Bromo-6-chloro-2,3-dihydro-[1,4]dioxan[2,3-b]pyridin-2-yl)-N,N -Dimethylmethylamine
  • reaction solution was concentrated under reduced pressure, water (80 mL) was added, the pH was adjusted to about 1 with concentrated hydrochloric acid, extracted with ethyl acetate (100 mL), the organic phase was discarded, the pH of the aqueous phase was adjusted to about 8 with solid potassium carbonate, and the pH was adjusted to about 8 with ethyl acetate. Ester (100 mL) was extracted, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product as a colorless liquid (4.3 g, yield 81%).
  • Step 9 (R)-8-Bromo-6-chloro-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-b] Pyridine-7-carbaldehyde
  • the inner temperature of the reaction solution was lowered to -70°C, and then anhydrous N,N-dimethylformamide (8.8 g, 0.120 mol) was slowly added dropwise thereto. After the dropwise addition, keep the internal temperature at -70°C and continue stirring for 2 hours.
  • the reaction solution was kept at an internal temperature of -70°C, and the reaction was quenched with acetic acid (6 mL), followed by the addition of water (5 mL).
  • the reaction solution was raised to room temperature, water (50 mL) was added, extracted with ethyl acetate (100 mL), the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Step 10 Ethyl (R)-2-(6-chloro-2-((dimethylamino)methyl)-7-formyl-2,3-dihydro-[1,4]dioxane[ 2,3-b]pyridin-8-yl) ethyl acetate
  • Ethanol (50 mL) was added to the residue, followed by concentrated sulfuric acid (3 mL) was added slowly, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was concentrated under reduced pressure to remove ethanol, added water (50 mL), adjusted the pH to 8 with solid potassium carbonate, extracted with ethyl acetate (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product as a colorless liquid ( 85mg, yield 25%).
  • Step 11 (R)-6-Chloro-8-(1-(difluoromethyl)cyclopropane)-2-((dimethylamino)methyl)-2,3-dihydro-[1,4 ]dioxan[2,3-c][2,7]naphthyridin-9(8H)-one
  • reaction solution was lowered to room temperature, and the solid was removed by filtration.
  • the filtrate was concentrated under reduced pressure and added to anhydrous dioxane (10 mL), zirconium tetrachloride (58 mg, 0.25 mmol), and heated overnight at 100°C in a sealed tube.
  • the reaction solution was lowered to room temperature, added saturated potassium carbonate aqueous solution (10mL), extracted with ethyl acetate (50mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography to obtain the product, an orange-yellow solid (22mg ,twenty three%).
  • ESI-MS m/z 386.1 [M+1] + .
  • Step 12 (R)-6-(((R)-1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-8-(1-(difluoromethyl) Cyclopropyl)-2-((dimethylamino)methyl)-2,3-dihydro-[1,4]dioxane[2,3-c][2,7]naphthyridine-9( 8H)-ketone (compound 44)
  • Example 44 Refer to the preparation method of Example 44 and use appropriate raw materials to prepare Examples 45-70 in Table 3, namely compounds 45-70.
  • Lithium diisopropylamide (106.5mL, 213mmol, 2.0M in THF) was added to tetrahydrofuran solution (150mL) at -70°C, and 6-chloro-3-methoxy was added dropwise at -70°C under nitrogen protection - 2-Methylpyridine (21 g, 133 mmol) in tetrahydrofuran (50 mL).
  • reaction was stirred at -70°C for 1 hour, then a solution of (R)-2-((4-methoxybenzyl)oxy)methyl)oxirane (26 g, 133 mmol) in THF was added dropwise at -70°C (50 mL), the reaction was warmed to room temperature and stirred for 16 hours.
  • the reaction solution was diluted with saturated ammonium chloride (600 mL) and water (600 mL), and extracted with ethyl acetate (500 mL X 2).
  • Step 4 (S)-8-Bromo-6-chloro-2-((4-methoxybenzyl)oxy)methyl)-3,4-dihydro-2H-pyrano[3,2- b] pyridine
  • Step 6 (S)-(8-Bromo-6-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-2-yl)methyl mesylate
  • Step 7 (S)-6-Chloro-N-methyl-2-((methylamino)methyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-amine
  • Step 8 tert-butyl (S)-(6-chloro-8-(methylamino)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-2-yl)methyl)( Methyl) carbamate
  • Step 9 tert-Butyl(S)-(6-chloro-7-iodo-8-(methylamino)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-2-yl) Methyl)(methyl)carbamate
  • Step 10 tert-Butyl(S,E)-(6-chloro-7-iodo-8-(methylamino)-3,4-dihydro-2H-pyrano[3,2-b]pyridine-2- base) methyl) (methyl) carbamate
  • Step 11 tert-butyl(S)-(6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1, 6] Naphthyridin-2-yl) methyl) (methyl) carbamate
  • Step 12 tert-Butyl(S)-(8-bromo-6-chloro-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyrano[3,2-h ][1,6]naphthyridin-2-yl)methyl)(methyl)carbamate
  • Step 13 tert-Butyl(S)-(8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-chloro-10-methyl-9-oxo-3,4,9, 10-tetrahydro-2H-pyrano[3,2-h][1,6]naphthyridin-2-yl)methyl)(methyl)carbamate
  • Step 14 tert-Butyl (((S)-8-(1-acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl) -2-fluorophenyl)ethyl)amino)-10-methyl-9-oxo-3,4,9,10-tetrahydro-2H-pyran[3,2-h][1,6] Naphthyridin-2-yl)methyl)(methyl)carbamate
  • Step 15 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorobenzene Base) ethyl) amino)-10-methyl-2-((methylamino)methyl)-3,4-dihydro-2H-pyran[3,2-h][1,6]naphthyridine- 9(10H)-keto
  • Step 16 (S)-8-(1-Acetyl-4-hydroxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorobenzene Base)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyrano[3,2-h][1,6]naphthalene Pyridin-9(10H)-one
  • Step 17 (S)-8-(1-Acetyl-4-fluoropiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2-fluorobenzene Base)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyrano[3,2-h][1,6]naphthalene Pyridin-9(10H)-one
  • Step 18 (S)-8-(1-Acetyl-4-methoxypiperidin-4-yl)-6-(((R)-1-(3-(difluoromethyl)-2- Fluorophenyl)ethyl)amino)-2-((dimethylamino)methyl)-10-methyl-3,4-dihydro-2H-pyran[3,2-h][1,6 ]naphthyridin-9(10H)-one
  • step 17 The crude product prepared in step 17 was dissolved in methanol (15 mL), and a methanolic solution of sodium methoxide (1.08 g, 5.81 mmol, 30% wtin MeOH) was added. The reaction solution was stirred at 40°C for 48 hours. After cooling to room temperature, it was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain the product as a yellow solid (55 mg, yield 15%). ESI-MS m/z: 616.4 [M+1] + .
  • Compound 73 was synthesized according to the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium ethoxide.
  • Compound 74 was synthesized according to the steps of Example 71, except that sodium methoxide in step 18 was replaced by sodium isopropoxide.
  • Compound 75 was synthesized according to the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium hydroxyethoxide.
  • Compound 76 was synthesized according to the steps of Example 71, except that sodium methoxide in step 18 was replaced with sodium trifluoroethoxide.
  • Test Example 1 Compounds inhibit cell growth of NCI-H358 and MIA PaCa-2 tumor cell lines under 3D culture conditions
  • NCI-H358 was purchased from Shanghai Dijin Biotechnology Co., Ltd.
  • MIA PaCa-2 was purchased from Shanghai Dior Biotechnology Co., Ltd.
  • the details are as follows: take the stock solution (10mM) of the compound dissolved in DMSO in advance, dilute it to 10 gradient concentrations by doubling ratio (4 times), and dilute it to 10 times of the target concentration in another 96-well plate with medium, and then in Add 20 ⁇ l/well of the compound solution to the 96-well plate inoculated with the cells to reach the target concentration (10000, 2500, 625, 156, 39, 10, 2.5, 0.6, 0.15, 0.04 nM). Three replicate wells were set up for each concentration, and a blank control was set up.
  • GraphPad Prism 8.3 software was used to analyze the data, and the nonlinear S-curve regression was used to fit the data to obtain the dose-effect curve, and the IC 50 value was calculated accordingly. The results are shown in Table 4.
  • BI-3406 is a SOS1 inhibitor reported in the literature (Cancer Discovery 2021(11) 142-157).
  • the compound of the present invention exhibits good cell growth inhibitory effect on NCI-H358 and MIA PaCa-2 tumor cell lines.

Abstract

本发明公开了一种稠环化合物、其制备方法及其应用。本发明提供了一种如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。本发明的如式I所示的稠环化合物对SOS1具有较好地抑制活性；有望治疗和/或预防与SOS1活性或表达量相关的疾病；(I).

Description

一种稠环化合物、其制备方法及其应用
本申请要求申请日为2021年9月28日的中国专利申请2021111465322的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种稠环化合物、其制备方法及其应用。
背景技术
RAS蛋白是一种位于细胞膜上的分子量为21kDa的鸟嘌呤三核苷酸磷酸(GTP)结合蛋白，由188或189个氨基酸构成。RAS蛋白的活性则是通过与GTP或鸟嘌呤二核苷酸磷酸(GDP)的结合进行调节，当与GDP结合时，处于“失活”状态，当与GTP结合时，处于“激活”状态。RAS蛋白本身有比较微弱的GTP酶水解功能和较慢的核苷酸交换速率，结合GTP酶激活蛋白(GTPase activating proteins，GAP)，可以增强RAS蛋白的GTP水解功能，而鸟嘌呤核苷酸交换因子(GEF)可以催化核苷酸的交换(GTP交换GDP)。SOS1(Son of Sevenless 1)是一种RAS特异的GEF，SOS1与RAS结合可以促进RAS释放GDP而与GTP结合，从而激活RAS。RAS被激活后，可以激活多条下游信号通路，包括MAPK信号通路、PI3K信号通路，这些信号通路在促进细胞分化、增殖、生存方面具有重要作用。RAS突变是许多癌症的基因驱动因素，20％-30％的人类肿瘤中都存在RAS突变，例如肺癌、结直肠癌和胰腺癌。
RAS基因家族包括KRAS、NRAS和HRAS。KRAS突变存在于多种肿瘤中，如肺腺癌(32％)、结直肠癌(41％)、胰腺癌(86％)，KRAS突变又以第12位密码子的G12突变最为常见，例如，在KRAS突变的肺腺癌、结直肠癌及胰腺癌中，G12突变又分别占85％、68％及91％；HRAS突变和NRAS突变频率相对较低，主要发生于黑色素瘤、白血病和甲状腺癌等癌症种类中。另外，RAS蛋白的异常激活(如基因突变、扩增和过表达等)和一些抗肿瘤药物的耐药性也紧密相关，如EGFR单抗和EGFR小分子抑制剂等。因此，RAS相关信号通路成为重要的抗肿瘤靶标。
参与癌症相关的信号通路的RAS家族的鸟嘌呤核苷酸交换因子主要为SOS1，降低SOS1的表达可以显著抑制KRAS突变的癌细胞的增殖和存活。由于SOS1是多条激活RAS信号通路的共有节点，几乎所有的生长因子受体是通过SOS1来启动RAS信号通路，因此SOS1抑制剂有潜力成为广谱抗癌药物。SOS1参与激活的信号通路在其他突变类型的癌症中也起着重要的作用。SOS1可以和接头蛋白Grb2相互作用，形成SOS1/Grb2复合体，结合到活化的受体酪氨酸激酶上(如EGFR、HER2、Erbb4、TRKA、TRKB、TRKC、RET和AXL等)。SOS1也可以被招募到磷酸化的细胞表面受体上，如T细胞受体、B细胞受体和单核细胞集落刺激因子受体等。SOS1在细胞膜上的定位使得SOS1可以更好地促进RAS家族蛋白活化，激活下游信号通路。SOS1还参与了其他GTP水解酶的活化，如RAC1等，RAC1也和多种人类癌症和其他疾病的发病机制有关。除此之外，SOS1突变被发现存在于肺腺 癌、胚胎性横纹肌肉瘤和皮肤颗粒细胞肿瘤中，SOS1的过表达被发现存在于膀胱癌和前列腺癌中。除癌症以外，遗传性的SOS1突变也和RAS病变的发病机制相关，包括努南氏综合征、心-面-皮肤综合征以及一型遗传性牙龈纤维瘤等。
目前尚无SOS1抑制剂批准上市，因此需要开发新的疗效好的SOS1抑制剂来满足临床需求。
发明内容
本发明要解决的技术问题是现有的SOS1抑制剂结构单一等缺陷，本发明提供了一种稠环化合物、其制备方法及其应用。该类化合物对SOS1具有较好地抑制活性。
本发明提供了一种如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
Figure PCTCN2022122241-appb-000001
其中：
X和Y各自独立地为-O-、-S-、-NH-或-CH 2-；
Z为-CR 10或N；
L为单键、-C(＝O)-、-C(＝O)O-、-C(＝O)NR 8-、-NR 8-、-S-、-O-、-S(O)-、-S(O) 2-或-(CH 2) p-；
环A为C 6-12芳基、5-10元杂芳基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
每个R 1独立地为氘、羟基、卤素、-N(R 7) 2、-SR 9、氰基、氧代(＝O)、硝基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 1a取代的C 1-6烷基、被一个或多个R 1b取代的C 1-6烷基-O-、被一个或多个R 1c取代的C 2-6烯基、被一个或多个R 1d取代的C 2-6炔基、C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 6-12芳基、被一个或多个R 1g取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 1h取代的5-10元杂芳基、C 3-7环烯基、被一个或多个R 1i取代的C 3-7环烯基、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-S(O)-N(R 7) 2、-S(O)-R 9、-NR 8-S(O)-R 9、-NR 8-S(O)-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9，或两个R 1与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基；
每个R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h和R 1i各自独立地为氘、羟基、卤素、-N(R 7) 2、-SR 9、硝基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 1-a取代的C 1-6烷基、被一 个或多个R 1-b取代的C 1-6烷基-O-、被一个或多个R 1-c取代的C 2-6烯基、被一个或多个R 1-d取代的C 2- 6炔基、C 3-7环烷基、C 3-7环烷基-O-、3-7元杂环基、3-7元杂环基-O-、被一个或多个R 1-e取代的C 3-7环烷基或C 3-7环烷基-O-、被一个或多个R 1-f取代的3-7元杂环基或3-7元杂环基-O-、C 6-12芳基、被一个或多个R 1-g取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 1-h取代的5-10元杂芳基、C 3-7环烯基、C 3-7环烯基-O-、被一个或多个R 1-i取代的C 3-7环烯基或C 3-7环烯基-O-、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-S(O)-N(R 7) 2、-S(O)-R 9、-NR 8-S(O)-R 9、-NR 8-S(O)-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9；
每个R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h和R 1-i各自独立地为氘、羟基、卤素、-N(R 7) 2、-SR 9、硝基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
环D为C 6-12芳基、5-6元杂芳基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
R 2为不存在、氢、氘、羟基、卤素、氨基、氰基、氧代、硝基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
R 3为氢、氘、C 1-6烷基、被一个或多个R 3a取代的C 1-6烷基、C 2-6烯基、被一个或多个R 3b取代的C 2-6烯基、C 2-6炔基、被一个或多个R 3c取代的C 2-6炔基、C 3-7环烷基、被一个或多个R 3d取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3e取代的3-7元杂环基、C 6-12芳基、被一个或多个R 3f取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 3g取代的5-10元杂芳基、C 3-7环烯基或被一个或多个R 3h取代的C 3-7环烯基；
每个R 3a、R 3b、R 3c、R 3d、R 3e、R 3f、R 3g和R 3h各自独立地为氘、羟基、卤素、-N(R 7) 2、氰基、硝基、C 1-6烷基、被一个或多个R 3-a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 3-c取代的C 2-6烯基、被一个或多个R 3-d取代的C 2-6炔基、C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3-f取代的3-7元杂环基、C 6-12芳基、被一个或多个R 3-g取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 3-h取代的5-10元杂芳基、C 3-7环烯基、被一个或多个R 3-i取代的C 3-7环烯基、-SR 9、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-S(O)-N(R 7) 2、-S(O)-R 9、-NR 8-S(O)-R 9、-NR 8-S(O)-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9，或两个R 3d、两个R 3e、两个R 3f、两个R 3g或两个R 3h与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3-f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3-i取代的C 3-7环烯基；
每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h和R 3-i各自独立地为氘、羟基、卤素、-N(R 7) 2、硝基、氰基、C 1-6烷基、C 1-6烷基-O-、C 3-7环烷基、C 3-7环烯基、3-7元杂环基、-SR 9、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9；
每个R 4独立地为氘、羟基、卤素、-N(R 7) 2、氰基、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 1-4 亚烷基-N(R 7) 2、被一个或多个R 4a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 4b取代的C 1-6烷基-O-、C 3-7环烷基、被一个或多个R 4c取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 4d取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 4e取代的C 3-7环烯基，或两个R 4与所相连的原子一起形成C 3- 7环烷基、被一个或多个R 4c取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 4d取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 4e取代的C 3-7环烯基；
(R 4可连接在环
Figure PCTCN2022122241-appb-000002
的任意化合价允许的环原子上，例如连接在环
Figure PCTCN2022122241-appb-000003
的X、Y或任意亚甲基上)；
每个R 4a、R 4b、R 4c和R 4d各自独立地为氘、羟基、卤素、氨基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基或C 2-6炔基；
R 5为不存在、氧代、氢、氘、羟基、卤素、氨基、氰基、硝基、C 1-6烷基、被一个或多个R 5a取代的C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、被一个或多个R 5b取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 5c取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 5d取代的C 3-7环烯基；
每个R 5a、R 5b和R 5c各自独立地为氘、C 1-6烷基、羟基、卤素、氨基或氰基；
R 6为氢、氘、羟基、卤素、氨基、氰基、氧代、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基或不存在；
每个R 7独立地为氢、C 1-6烷基、C 3-7环烷基或C 3-7环烯基，或两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基；
每个R 7a独立地为氘、C 1-6烷基、卤素、羟基、氨基、氰基、C 1-6烷基-O-、C 2-6烯基或C 2-6炔基；
每个R 8和R 9各自独立地为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
R 10为氢、氘、羟基、卤素、氨基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
R 11为氢、氘、氰基、C 1-6烷基或被一个或多个R 11a取代的C 1-6烷基；
每个R 11a独立地为氘、卤素或羟基；
m为0、1、2、3、4或5；
n为0、1、2、3、4、5或6；
p为1、2、3、4、5或6；
所述的3-7元杂环基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的3-7元杂环基(所述3-7元杂环基为3-7元杂环基、3-7元杂环基-O-、被取代基取代的3-7元杂环基和被取代基取代的3-7元杂环基-O-里的3-7元杂环基；即所述“环A、R 1、R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h、R 1i、R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h、R 1-i、环D、R 2、R 3、R 3a、R 3b、 R 3c、R 3d、R 3e、R 3f、R 3g、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h、R 3-i、R 4、R 5、R 8、R 9和R 10中被取代基取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 1与所相连的环原子一起形成的被一个或多个R 1f取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 3d、两个R 3e、两个R 3f、两个R 3g或两个R 3h与所相连的环原子一起形成的被一个或多个R 3-f取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 4与所相连的原子一起形成的被一个或多个R 4d取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 7与所相连的氮原子一起形成的被一个或多个R 7a取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h和R 1i中被一个或多个R 1-f取代的3-7元杂环基-O-里的3-7元杂环基，3-7元杂环基-O-里的3-7元杂环基”)；
所述5-10元杂芳基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基(所述5-10元杂芳基为5-10元杂芳基和被取代基取代的5-10元杂芳基里的5-10元杂芳基；即所述“环A、R 1、R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h、R 1i、R 3、R 3a、R 3b、R 3c、R 3d、R 3e、R 3f、R 3g和R 3h”中被取代基取代的5-10元杂芳基里的5-10元杂芳基，5-10元杂芳基)；
所述5-6元杂芳基为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-6元杂芳基；
当*的碳原子具有手性时，如式I所示的稠环化合物为
Figure PCTCN2022122241-appb-000004
Figure PCTCN2022122241-appb-000005
或其混合物。
在某一方案中，如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物中，某些基团具有如下定义，未提及的基团的定义如本发明中任一方案所述(本段内容以下简称为“在某一方案中”)：X和Y各自独立地为-O-、-NH-或-CH 2-；例如X和Y各自独立地为-O-或-CH 2-。
在某一方案中，Z为N。
在某一方案中，L为单键。
在某一方案中，环A为C 6-12芳基或5-10元杂芳基；例如环A为C 6-12芳基。
在某一方案中，每个R 1独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 1a取代的C 1-6烷基、被一个或多个R 1b取代的C 1-6烷基-O-，或两个R 1与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基；例如每个R 1独立地为卤素、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基。
在某一方案中，每个R 1a、R 1b、R 1e、R 1f和R 1i各自独立地为羟基、卤素、-N(R 7) 2、C 1-6烷基或被一个或多个R 1-a取代的C 1-6烷基；例如每个R 1a独立地为卤素。
在某一方案中，每个R 1-a独立地为C 1-6烷基或卤素。
在某一方案中，环D为3-7元杂环基；例如环D为杂原子种类为N，杂原子个数为1个或2个的六元杂环基，再例如为1,2-二氢吡啶基，又例如为
Figure PCTCN2022122241-appb-000006
“c”表示该原子位于B环Z原子的间位。
在某一方案中，R 2为氢。
在某一方案中，R 3为氢、C 3-7环烷基、被一个或多个R 3d取代的C 3-7环烷基、3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3h取代的C 3-7环烯基；例如R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基。
在某一方案中，每个R 3d、R 3e和R 3h各自独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、被一个或多个R 3-a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 3-c取代的C 2-6烯基、被一个或多个R 3-d取代的C 2-6炔基、-C(＝O)-R 9、-NR 8C(＝O)-R 9，或两个R 3d、两个R 3e或两个R 3h与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3-f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3- i取代的C 3-7环烯基；例如每个R 3e独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6炔基或-C(＝O)-R 9；再例如每个R 3e独立地为羟基、C 1-6烷基-O-或-C(＝O)-R 9。
在某一方案中，每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f和R 3-i各自独立地为羟基、卤素、-N(R 7) 2、硝基、氰基、C 1-6烷基或C 1-6烷基-O-；例如每个R 3-b独立地为羟基或卤素。
在某一方案中，每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、被一个或多个R 4a取代的C 1-6烷基、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；例如每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基。
在某一方案中，每个R 4a和R 4d各自独立地为C 1-6烷基或卤素；例如每个R 4d独立地为C 1-6烷基或卤素。
在某一方案中，R 5为氢或C 1-6烷基。
在某一方案中，R 6为氧代。
在某一方案中，每个R 7独立地为氢、C 1-6烷基、C 3-7环烷基或C 3-7环烯基；或两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基；例如每个R 7独立地氢或C 1-6烷基。
在某一方案中，每个R 7a独立地为C 1-6烷基或卤素。
在某一方案中，每个R 8和R 9各自独立地为氢或C 1-6烷基；例如每个R 9独立地为氢或C 1-6烷基。
在某一方案中，R 11为C 1-6烷基。
在某一方案中，m为0、1、2或3；例如m为1、2或3。
在某一方案中，n为0、1、2或3；例如n为0、1或2。
在某一方案中，p为1、2或3。
在某一方案中，所述的3-7元杂环基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的3-7元杂环基(所述3-7元杂环基为3-7元杂环基和被取代基取代的3-7元杂环基里的3-7元杂环基。即所述R 3和R 4中的被取代基取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；环D中的3-7元杂环基；两个R 1与所相连的环原子一起形成的被一个或多个R 1f取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 3d、两个R 3e或两个R 3h与所相连的环原子一起形成的被一个或多个R 3-f取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 7与所相连的氮原子一起形成的被一个或多个R 7a取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基)。
在某一方案中，所述5-10元杂芳基为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基。
在某一方案中，所述式I所示的稠环化合物中，
X和Y各自独立地为-O-、-NH-或-CH 2-；
Z为N；
L为单键；
环A为C 6-12芳基或5-10元杂芳基；
每个R 1独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 1a取代的C 1-6烷基、被一个或多个R 1b取代的C 1-6烷基-O-，或，两个R 1与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 3- 7环烯基或被一个或多个R 1i取代的C 3-7环烯基；
每个R 1a、R 1b、R 1e、R 1f和R 1i各自独立地为羟基、卤素、-N(R 7) 2、C 1-6烷基或被一个或多个R 1-a取代的C 1-6烷基；
每个R 1-a独立地为C 1-6烷基或卤素；
环D为3-7元杂环基；
R 2为氢；
R 3为氢、C 3-7环烷基、被一个或多个R 3d取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3e取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3h取代的C 3-7环烯基；
每个R 3d、R 3e和R 3h各自独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、被一个或多个R 3-a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 3-c取代的C 2-6烯基、被一个或多个R 3-d取代的C 2-6炔基、-C(＝O)-R 9、-NR 8C(＝O)-R 9，或两个R 3d、两个R 3e或两个R 3h与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基或被一个或多个R 3-f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3-i取代的C 3- 7环烯基；
每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f和R 3-i各自独立地为羟基、卤素、-N(R 7) 2、硝基、氰基、C 1- 6烷基或C 1-6烷基-O-；
每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、被一个或多个R 4a取代的C 1-6烷基、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
每个R 4a和R 4d各自独立地为C 1-6烷基或卤素；
R 5为氢或C 1-6烷基；
R 6为氧代；
每个R 7独立地为氢、C 1-6烷基、C 3-7环烷基或C 3-7环烯基；或两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基；
每个R 7a独立地C 1-6烷基或卤素；
每个R 8和R 9各自独立地为氢或C 1-6烷基；
R 11为C 1-6烷基；
m为0、1、2或3；
n为0、1、2或3；
p为1、2或3；
所述的3-7元杂环基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的3-7元杂环基(所述3-7元杂环基为3-7元杂环基和被取代基取代的3-7元杂环基里的3-7元杂环基。即所述R 3和R 4中的被取代基取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；环D中的3-7元杂环基；两个R 1与所相连的环原子一起形成的被一个或多个R 1f取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 3d、两个R 3e或两个R 3h与所相连的环原子一起形成的被一个或多个R 3-f取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基；两个R 7与所相连的氮原子一起形成的被一个或多个R 7a取代的3-7元杂环基里的3-7元杂环基，3-7元杂环基)；
所述5-10元杂芳基为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基。
在某一方案中，所述式I所示的稠环化合物中，
X和Y各自独立地为-O-；
每个R 1独立地为卤素、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基；
每个R 1a独立地为卤素；
环A为C 6-12芳基；
Figure PCTCN2022122241-appb-000007
为
Figure PCTCN2022122241-appb-000008
L为单键；
R 2为氢；
R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基；
每个R 3e独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6炔基或-C(＝O)-R 9；
R 5为氢或C 1-6烷基；
每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
每个R 4d独立地为C 1-6烷基或卤素；
每个R 7独立地氢或C 1-6烷基；
每个R 9独立地为氢或C 1-6烷基；
R 11为C 1-6烷基；
m为1、2或3；
n为0、1或2。
在某一方案中，所述式I所示的稠环化合物中，
X和Y各自独立地为-O-或-CH 2-；
每个R 1独立地为卤素、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基；
每个R 1a独立地为卤素；
环A为C 6-12芳基；
环D为杂原子种类为N，杂原子个数为1个或2个的六元杂环基，例如为1,2-二氢吡啶基，再例如为
Figure PCTCN2022122241-appb-000009
“c”表示该原子位于B环Z原子的间位；Z为N；
L为单键；
R 2为氢；
R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基；
每个R 3e独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6炔基或-C(＝O)-R 9；
每个R 3-b独立地为羟基或卤素；
R 5为氢或C 1-6烷基；
R 6为氧代；
每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
每个R 4d独立地为C 1-6烷基或卤素；
每个R 7独立地氢或C 1-6烷基；
每个R 9独立地为氢或C 1-6烷基；
R 11为C 1-6烷基；
m为1、2或3；
n为0、1或2。
在某一方案中，所述式I所示的稠环化合物中，
Figure PCTCN2022122241-appb-000010
为
Figure PCTCN2022122241-appb-000011
Figure PCTCN2022122241-appb-000012
为
Figure PCTCN2022122241-appb-000013
Figure PCTCN2022122241-appb-000014
L为单键；
R 3为
Figure PCTCN2022122241-appb-000015
R 11为甲基。
在某一方案中，所述式I所示的稠环化合物中，
Figure PCTCN2022122241-appb-000016
为
Figure PCTCN2022122241-appb-000017
Figure PCTCN2022122241-appb-000018
为
Figure PCTCN2022122241-appb-000019
Figure PCTCN2022122241-appb-000020
L为单键；
R 3为
Figure PCTCN2022122241-appb-000021
R 11为甲基。
在某一方案中，当环A为C 6-12芳基时，所述C 6-12芳基为苯基或萘基，例如为苯基。
在某一方案中，当环A为5-10元杂芳基时，所述5-10元杂芳基为杂原子种类为N，杂原子个数 为1个或2个的5-10元杂芳基，例如为
Figure PCTCN2022122241-appb-000022
在某一方案中，当R 1为被一个或多个R 1a取代的C 1-6烷基时，所述被一个或多个R 1a取代的C 1-6烷基为-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH或-CF 2C(CH 3) 2OH。
在某一方案中，当两个R 1与所相连的环原子一起形成C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基时，所述C 3-7环烯基为环丙烯基、环丁烯基、环戊烯基、环己烯基或环庚烯基，例如为环戊烯基。
在某一方案中，当两个R 1与所相连的环原子一起形成3-7元杂环基或被一个或多个R 1f取代的3-7元杂环基时，所述3-7元杂环基为杂原子独立地选自O、N和S，杂原子个数为1个或2个的3-7元杂环基，例如为
Figure PCTCN2022122241-appb-000023
“a”表示此部分为与环A并环连接的位置。
在某一方案中，当环D为3-7元杂环基时，所述3-7元杂环基为杂原子种类为N，杂原子个数为1个或2个的六元杂环基，例如为1,2-二氢吡啶基，再例如为
Figure PCTCN2022122241-appb-000024
“c”表示该原子位于B环Z原子的间位。
在某一方案中，当R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基时，所述3-7元杂环基为杂原子种类独立地选自N和O，杂原子个数为1个或2个的5-7元杂环基，例如为
Figure PCTCN2022122241-appb-000025
Figure PCTCN2022122241-appb-000026
在某一方案中，当R 3为C 3-7环烷基或被一个或多个R 3d取代的C 3-7环烷基时，所述的C 3-7环烷基为环丙基、环丁基、环戊基、环己基、环庚基或
Figure PCTCN2022122241-appb-000027
在某一方案中，当每个R 3d和R 3e各自独立地C 2-6炔基时，所述C 2-6炔基为乙炔基或丙炔基。
在某一方案中，当R 4为-C 1-4亚烷基-N(R 7) 2时，两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基时，例如所述-C 1-4亚烷基-N(R 7) 2为
Figure PCTCN2022122241-appb-000028
在某一方案中，当R 4为-C 1-4亚烷基-N(R 7) 2时，所述R 7独立地为C 1-6烷基时；例如所述-C 1-4亚烷 基-N(R 7) 2为
Figure PCTCN2022122241-appb-000029
在某一方案中，当R 4为3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基，所述3-7元杂环基为杂原子种类为N，杂原子个数为1个或2个的5-7元杂环基，例如为
Figure PCTCN2022122241-appb-000030
在某一方案中，两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基时，所述3-7元杂环基为杂原子种类为N，杂原子个数为1个或2个的5-7元杂环基，例如为
Figure PCTCN2022122241-appb-000031
在某一方案中，当R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3- e、R 3-f、R 3-i、R 4、R 4a、R 4d、R 5、R 7、R 7a、R 8、R 9或R 11为C 1-6烷基或被取代基取代的C 1-6烷基时，所述C 1-6烷基各自独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，再例如为甲基、乙基或异丁基。
在某一方案中，当R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3- e、R 3-f、R 3-i、R 4a、R 4d或R 7a为卤素时，所述卤素各自独立地为F、Cl、Br或I，例如为F或Cl。
在某一方案中，当R 1、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f或R 3-i为C 1-6烷基-O-或被取代基取代的C 1-6烷基-O-时，所述C 1-6烷基-O-各自独立地为C 1-4烷基-O-，例如为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，再例如为甲氧基、乙氧基或异丙氧基，又例如为甲氧基或乙氧基。
在某一方案中，环A为
Figure PCTCN2022122241-appb-000032
在某一方案中，R 1为F、Cl、-CN、-CHF 2、-CF 3、-CH 3、-CF 2CH 2OH、-CF 2CH 3、-NH 2或-CF 2C(CH 3) 2OH；或两个R 1与所相连的环原子一起形成
Figure PCTCN2022122241-appb-000033
“a”表示此部分为与环A并环连接的位置。
在某一方案中，
Figure PCTCN2022122241-appb-000034
为
Figure PCTCN2022122241-appb-000035
Figure PCTCN2022122241-appb-000036
Figure PCTCN2022122241-appb-000037
例如为
Figure PCTCN2022122241-appb-000038
在某一方案中，R 3为
Figure PCTCN2022122241-appb-000039
Figure PCTCN2022122241-appb-000040
Figure PCTCN2022122241-appb-000041
例如为
Figure PCTCN2022122241-appb-000042
在某一方案中，R 3为
Figure PCTCN2022122241-appb-000043
Figure PCTCN2022122241-appb-000044
在某一方案中，
Figure PCTCN2022122241-appb-000045
为
Figure PCTCN2022122241-appb-000046
Figure PCTCN2022122241-appb-000047
例如为
Figure PCTCN2022122241-appb-000048
Figure PCTCN2022122241-appb-000049
在某一方案中，R 4为-CH 3、
Figure PCTCN2022122241-appb-000050
在某一方案中，
Figure PCTCN2022122241-appb-000051
为
Figure PCTCN2022122241-appb-000052
例如为
Figure PCTCN2022122241-appb-000053
Figure PCTCN2022122241-appb-000054
其中，所述b端与Z原子相连。
在某一方案中，
Figure PCTCN2022122241-appb-000055
为
Figure PCTCN2022122241-appb-000056
Figure PCTCN2022122241-appb-000057
Figure PCTCN2022122241-appb-000058
例如为
Figure PCTCN2022122241-appb-000059
Figure PCTCN2022122241-appb-000060
在某一方案中，
Figure PCTCN2022122241-appb-000061
为
Figure PCTCN2022122241-appb-000062
Figure PCTCN2022122241-appb-000063
Figure PCTCN2022122241-appb-000064
例如为
Figure PCTCN2022122241-appb-000065
Figure PCTCN2022122241-appb-000066
在某一方案中，
Figure PCTCN2022122241-appb-000067
为
Figure PCTCN2022122241-appb-000068
Figure PCTCN2022122241-appb-000069
Figure PCTCN2022122241-appb-000070
例如为
Figure PCTCN2022122241-appb-000071
Figure PCTCN2022122241-appb-000072
在某一方案中，
Figure PCTCN2022122241-appb-000073
为
Figure PCTCN2022122241-appb-000074
Figure PCTCN2022122241-appb-000075
Figure PCTCN2022122241-appb-000076
Figure PCTCN2022122241-appb-000077
例如为
Figure PCTCN2022122241-appb-000078
Figure PCTCN2022122241-appb-000079
Figure PCTCN2022122241-appb-000080
在某一方案中，所述如式I所示的稠环化合物为
Figure PCTCN2022122241-appb-000081
Figure PCTCN2022122241-appb-000082
在某一方案中，R 11为甲基。
在某一方案中，所述式I所示的稠环化合物选自以下任一化合物：
Figure PCTCN2022122241-appb-000083
Figure PCTCN2022122241-appb-000084
Figure PCTCN2022122241-appb-000085
Figure PCTCN2022122241-appb-000086
Figure PCTCN2022122241-appb-000087
Figure PCTCN2022122241-appb-000088
Figure PCTCN2022122241-appb-000089
Figure PCTCN2022122241-appb-000090
Figure PCTCN2022122241-appb-000091
Figure PCTCN2022122241-appb-000092
Figure PCTCN2022122241-appb-000093
Figure PCTCN2022122241-appb-000094
Figure PCTCN2022122241-appb-000095
Figure PCTCN2022122241-appb-000096
Figure PCTCN2022122241-appb-000097
Figure PCTCN2022122241-appb-000098
Figure PCTCN2022122241-appb-000099
Figure PCTCN2022122241-appb-000100
Figure PCTCN2022122241-appb-000101
Figure PCTCN2022122241-appb-000102
Figure PCTCN2022122241-appb-000103
Figure PCTCN2022122241-appb-000104
Figure PCTCN2022122241-appb-000105
本发明还提供了一种如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的制备方法，其包括以下步骤：
方案一：当所述如式I所示的稠环化合物为化合物Ia时，化合物Ia-6与
Figure PCTCN2022122241-appb-000106
经Buchwald–Hartwig偶联反应得到化合物Ia；
Figure PCTCN2022122241-appb-000107
方案二：当所述如式I所示的稠环化合物为化合物Ib时，化合物Ib-3与
Figure PCTCN2022122241-appb-000108
经Buchwald– Hartwig偶联反应得到化合物Ib；
Figure PCTCN2022122241-appb-000109
较佳地，所述制备方法中，方案一或方案二中，所述Buchwald–Hartwig偶联反应是在催化剂、碱存在下进行；所述催化剂为本领域常规，例如为RuPhos Pd G3(甲磺酸(2-二环己基膦基-2',6'-二异丙氧基-1,1'-联苯基)(2-氨基-1,1'-联苯-2-基)钯(II))、BrettPhos Pd G3(甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II))、XPhos Pd G3(甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II))、XantPhos Pd G3(甲烷磺酸(9,9-二甲基-4,5-双二苯基膦氧杂蒽)(2'-氨基-1,1'-联苯-2-基)钯(II))、RuPhos Pd G4(甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II))和BrettPhos Pd G4(甲烷磺酸(2-二环己基膦-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-甲胺基-1,1'-联苯-2-基)钯(II))中的一种或多种；所述碱为本领域常规，例如为碳酸铯、碳酸钠、磷酸钾、碳酸钠、叔丁醇钾和叔丁醇钠中的一种或多种。
所述制备方法中，较佳地，所述方案一中还包括以下步骤：
Figure PCTCN2022122241-appb-000110
所述化合物I-1与R 5-NH 2发生取代反应，得到化合物Ia-1；
所述化合物Ia-1与碘代试剂(如N-碘代丁二酰亚胺、I 2)经碘代反应得到化合物Ia-2；
所述化合物Ia-2与
Figure PCTCN2022122241-appb-000111
经Heck偶联反应得到化合物Ia-3；
所述化合物Ia-3在碱作用下经关环反应得到化合物Ia-4；
所述化合物Ia-4与溴化试剂经溴代反应得到化合物Ia-5；
所述化合物Ia-5与相应取代的酮、胺、硼酸酯衍生物发生反应得到化合物Ia-6；
较佳地，所述碘代反应中，所述碘代试剂为本领域常规，例如为N-碘代丁二酰亚胺和/或I 2。
较佳地，所述关环反应中，所述碱为本领域常规，例如为甲硫醇钠、甲醇钠和乙醇钠中的一种或多种；
较佳地，所述溴代反应中，所述溴化试剂为本领域常规，例如为N-溴代丁二酰亚胺和/或Br 2。
所述制备方法中，较佳地，所述方案二中还包括以下步骤：
Figure PCTCN2022122241-appb-000112
其中R 12为甲基或乙基；
所述化合物I-1在强碱作用下发生酰基化反应得到化合物Ib-1；
化合物Ib-1与丙二酸酯反应并脱羧得到化合物Ib-2；
化合物Ib-2与H 2N-L-R 3发生关环反应得到化合物Ib-3；
较佳地，所述酰基化反应中，所述强碱为本领域常规，例如为二异丙基氨基锂；
较佳地，所述丙二酸酯为本领域常规，例如为丙二酸甲酯、丙二酸乙酯。
本发明提供了一种药物组合物；所述药物组合物包含：
(1)物质X，所述物质X为如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，及
(2)药学可接受的辅料。
本发明提供了一种物质X或如前所述的药物组合物在制备SOS1抑制剂中的应用，所述物质X为如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
所述的应用中，较佳地，所述的SOS1抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒，为化合物抑制SOS1的效果提供快速检测。
本发明提供了一种物质X或如前所述的药物组合物在制备药物中的应用；所述物质X为如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物可为治疗和/或预防与SOS1活性或表达量相关的疾病的药物。
所述的应用中，较佳地，所述与SOS1活性或表达量相关的疾病选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、黑色素瘤、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈 癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、胆管癌、子宫癌、子宫内膜癌、尿路上皮癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征和多发性骨髓癌，以及和SOS1遗传性突变相关的疾病，包括但不限于一型神经纤维瘤、努南氏综合征、多发雀斑样恁型努南氏综合征、毛细血管畸形—动静脉畸形综合征、心-面-皮肤综合征、克斯提洛氏综合征、雷吉士综合征和一型遗传性牙龈纤维瘤。
本发明提供了一种物质X或如前所述的药物组合物在制备药物中的应用；所述物质X为如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物为治疗和/或预防以下各类疾病的药物；所述疾病选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、黑色素瘤、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、胆管癌、子宫癌、子宫内膜癌、尿路上皮癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征和多发性骨髓癌，以及一型神经纤维瘤、努南氏综合征、多发雀斑样恁型努南氏综合征、毛细血管畸形—动静脉畸形综合征、心-面-皮肤综合征、克斯提洛氏综合征、雷吉士综合征和一型遗传性牙龈纤维瘤。
本发明提供了一种抑制SOS1的方法，其包括向患者(例如人类)施用治疗有效量的物质X或如前所述的药物组合物；
所述物质X为如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
本发明提供了一种治疗和/预防疾病的方法，其包括向患者(例如人类)施用治疗有效量的物质X或如前所述的药物组合物；
所述物质X为如前所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
所述疾病为与SOS1活性或表达量相关的疾病。
所述治疗和/预防疾病的方法中，较佳地，所述与SOS1活性或表达量相关的疾病选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、黑色素瘤、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、胆管癌、子宫癌、子宫内膜癌、尿路上皮癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征和多发性骨髓癌，以及和SOS1遗传性突变相关的疾病，包括但不限于一型神经纤维瘤、努南氏综合征、多发雀斑样恁型努南氏综合征、毛细血管畸形—动静脉畸形综合征、心-面-皮肤综合征、克斯提洛氏综合征、雷吉士综合征和一型遗传性牙龈纤维瘤。
如无特别说明，本发明所用术语具有如下含义：
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数(例如C 1-10，优选C 1-6，更优选C 1-4)的直链或支链烷基。烷基包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基或正己基等。
术语“亚烷基”表示从饱和的直链或支链烃基中去掉两个氢原子所得到的饱和的二价烃基基团；即烷基中的一个氢被取代，烷基的定义如上所述。亚烷基基团的实例包括亚甲基(-CH 2-)，亚乙基{包括-CH 2CH 2-或-CH(CH 3)-}，亚异丙基{包括-CH(CH 3)CH 2-或-C(CH 3) 2-}等。
术语“烯基”是指具有至少一个双键的直链或支链的烃链基，仅由碳原子和氢原子组成、具有指定碳原子(例如C 2-10，优选C 2-6，更优选C 2-4)，且通过单键与分子的其余部分连接，例如烯基包括但不限于乙烯基、正丙烯基、异丙烯基、正丁烯基、异丁烯基、仲丁烯基、叔丁烯基、正戊烯基、2-甲基丁烯基、2,2-二甲基丙烯基或正己烯基等。
术语“炔基”是指具有至少一个三键的直链或支链的烃链基，仅由碳原子和氢原子组成、具有指定碳原子(例如C 2-10，优选C 2-6，更优选C 2-4)，且通过单键与分子的其余部分连接，例如炔基包括但不限于乙炔基、正丙炔基、异丙炔基、正丁炔基、异丁炔基、仲丁炔基、叔丁炔基、正戊炔基、2-甲基丁炔基、2,2-二甲基丙炔基或正己炔基等。
术语“C 1-6烷基-O-”中，C 1-6烷基的定义如前所述。
术语“环烷基”意指饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的碳环取代基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；例如具有3至15个环碳原子，优选具有3至10个环碳原子，更优选具有3至7个环碳原子；所述的环烷基可以进一步被氧代取代基取代；例如C 3-7环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基或
Figure PCTCN2022122241-appb-000113
等。
术语“环烯基”意指具有至少一个双键(如碳碳双键)的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)的环烃基，且其可经由任何适宜的碳原子通过单键与分子的其余部分连接；例如具有3至15个环碳原子，优选具有3至10个环碳原子，更优选具有3至7个环碳原子；所述的环烯基可以进一步被氧代取代基取代；例如C 3-7环烯基包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基或环庚烯基。
术语“杂环基”是指由2至14个(优选2至6个)碳原子以及1至6个选自N、O、S、S(＝O)和S(＝O) 2的杂原子或杂原子基团组成的稳定的3至20元(优选3-10元，更优选3-7元，最优选5-7元，再优选6元)的饱和或部分不饱和的单环或多环(例如双环、三环或更多环的桥环、并环(稠环)或螺环体系)杂环烃基，所述的杂环基可以进一步被氧代取代基取代；优选含有1至3个选自N、O和S的杂原子的3-7元杂环基，例如为氮杂环丙基、环氧乙烷基、环氧丙烷基、硫杂环丁烷基、四氢噻吩基、噻唑烷基、异噻唑烷基、噁唑烷基、异噁唑烷基、吡唑烷基、哌啶基、四氢吡喃基、哌嗪基、四氢吡啶基、氮杂环丁基、吡咯烷基、吗啉基、2-氧杂-5-氮杂双环[2.2.1]庚基、2H-吡喃基、氧氮杂卓基、二 氮杂卓基、硫氮杂卓基、氮杂双环庚基、噻恶烷基、二氢呋喃基、咪唑啉基、咪唑烷基、硫杂环己基、三嗪烷基、二硫杂环己基、二硫杂环戊基、二氧杂环己基、2,6-二氮杂螺[3.3]庚基、1,2-二氢吡啶基、高哌嗪基、硫代吗啉基、噻喃基、四氢呋喃基、4H-吡喃基或二氢吡咯基，再例如为
Figure PCTCN2022122241-appb-000114
Figure PCTCN2022122241-appb-000115
术语“芳基”是指由碳原子组成的满足4n+2规则的共轭烃环体系的芳香基团，每个环均具有芳香性。在某一方案中，“芳基”是指具有6至18个(优选6-12个)碳原子的芳香基团。芳基的实例包括但不限于苯基或萘基等。
术语“杂芳基”意指环内具有2至15个碳原子和1至5个选自氮、氧和硫的杂原子的5至20元(优选5至12元，更优选5至10元)共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。在某一方案中，术语“杂芳基”是指含有杂原子的芳香基团，每个环均具有芳香性；优选杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基或5-6元杂芳基。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、二唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基(例如为
Figure PCTCN2022122241-appb-000116
)、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异唑基、噻二唑基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并异噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、苯并恶唑基或苯并异唑基。
术语“环烷基-O-”中，环烷基的定义如前所述。
术语“环烯基-O-”中，环烯基的定义如前所述。
术语“杂环基-O-”中，杂环基的定义如前所述。
基团末端的“-”是指该基团通过该位点与分子中的其他片段连接。
应该理解，在本发明中使用的单数形式，如“一种”，包括复数指代，除非另有规定。
术语“一个或多个”是指即1、2、3、4、5、6、7、8、9或更多。
除非另有说明，本发明采用质谱、元素分析的传统方法，各步骤和条件可参照本领域常规的操作步骤和条件。
除非另有指明，本发明采用分析化学、有机合成化学和光学的标准命名及标准实验室步骤和技术。在某些情况下，标准技术被用于化学合成、化学分析。
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“…独立地为”应做广义理解，是指所描述的各个个体之间是相互独立的，可以独立地为相同或不同的具体基团。更详细地，描述方式“…独立地为”既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响；也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响。
本领域技术人员可以理解，根据本领域中使用的惯例，本申请描述基团的结构式中所使用的
Figure PCTCN2022122241-appb-000117
是指，相应的基团R通过该位点与化合物中的其它片段、基团进行连接。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的标准含义。倘若对于某术语存在多个定义，则以本文定义为准。
如本文中所使用的，本发明式I所示的稠环化合物可以含有一个或多个手性中心，并以不同的光学活性形式存在。当化合物含有一个手性中心时，化合物包含对映异构体。本发明包括这两种异构体和异构体的混合物，如外消旋混合物。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式I所示的稠环化合物含有多于一个手性中心时，可以存在非对映异构体。本发明包括拆分过的光学纯的特定异构体以及非对映异构体的混合物。非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。术语“立体异构体”包括构象异构体和构型异构体，其中构型异构体主要包括顺反异构体和旋光异构体。本发明所述化合物可以以立体异构体的形式存在，并因此涵盖所有可能的立体异构体形式，包括但不限于顺反异构体、对映异构体、非对映异构体、阻转异构体等，本发明所述化合物也可以以前述的立体异构体的任何组合或任何混合物，例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体，单一非对映异构体或以上的混合物，或单一阻转异构体或其混合物。当本发明所述的化合物含有烯烃双键时，除非特别说明，否则其包括顺式异构体和反式异构体，以及其任何组合。本发明的阻转异构体为基于分子内旋转受限制而产生的轴向或平面手性的立体异构体。
如前所述，本发明提供了上述各类结构所示化合物，或其顺反异构体、内消旋体、外消旋体、对映异构体、非对映异构体、阻转异构体、互变异构体或其混合物形式，其中“其混合物形式”包括前述的任一立体异构体(例如顺反异构体、对映异构体、非对映异构体、阻转异构体)、互变异构体和/或混合物(内消旋体、外消旋体)之间的任意形式的混合，例如顺反异构体的混合物，对映异构体和非对映异构体的混合物，非对映异构体的混合物，阻转异构体的混合物，或顺反异构体和外消旋体的混合， 对映异构体和非对映异构体混合物的混合、顺反异构体和互变异构体的混合物、阻转异构体与非对映异构体混合物的混合等。
术语“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。
如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物意图涵盖如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的任何同位素标记的(或“放射性标记的”)变体。这种变体可以是如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物中一个或多个原子被原子质量或质量数不同于通常在自然界中所发现的原子质量或质量数的原子置换而得到。所使用的放射性核素将取决于该放射性标记的变体的具体应用。举例来说，对于体外受体标记和竞争测定， 3H或 14C常常是有用的。对于放射成像应用， 11C或 18F常常是有用的。
本发明化合物的特定同位素变体，特别是其中已经结合一种或多种放射性同位素的同位素变体，可有益于例如考察作用机制或在体内的活性组份分布；由于相对容易的可制备性和可检测性，标记有 3H或 14C同位素的化合物特别适用于此目的。另外，纳入同位素如氘，由于该化合物具有更好的代谢稳定性，例如延长体内的半衰期或降低所需的有效剂量，可产生特别的治疗益处；因此本发明化合物的这种修饰还可在一些情况下构成本发明的优选实施方案。本发明化合物的同位素变体可通过本领域技术人员已知的方法，例如通过以下描述的方法及操作实施例中描述的方法，通过使用相应的同位素修饰的特定试剂和/或起始化合物来制备。
在本申请中，“药物组合物”是指包含本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。
在本申请中，“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如药用辅料)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
术语“药用辅料”或“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009Sixth Edition)。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、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、矫味剂和甜味剂。
本发明的药物组合物可根据公开的内容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、包埋或冻干工艺。
当用作药物时，所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物可以以药物组合物的任何形式给药。这些组合物可根据药学领域熟知的方法制备，可以各种途径施用，视需要局部或系统性治疗和要治疗的区域而定。给予可以是局部(包括表皮和透皮，眼部和粘膜，包括鼻内，阴道和直肠递送)，肺(例如，通过粉末或气溶胶吸入或吹入，包括通过喷雾器；气管内或鼻内)，口服(固体和液体制剂)或胃肠外给予形式。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的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。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干制剂、注射用悬浮液和注射用乳剂。外用给药的药物组合物和制剂可包括透皮贴片、油膏剂、乳液、软膏剂、凝胶、滴剂、栓剂、喷剂、液体和粉末。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂；气雾剂：如鼻腔喷雾剂或吸入剂。口服给药可以包括配制为每日一次或每日两次(BID)给药的剂型。胃肠外给药包括静脉内、动脉内、皮下、腹膜内肌肉内或注射或输液；或颅内如鞘内或心室内给药。胃肠外给药可以单次推注剂量形式，或可以是通过连续灌注泵。常规药学载体、水、粉末或油状基底、增稠剂等可能是必须或需要的。包括本发明的药物组合物还可以是控释或延迟释放剂型(例如脂质体或微球)。
术语“治疗”指治疗性疗法或缓解性措施。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。“治疗”也可以指与不接受治疗的期望存活相比延长生存期。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物或组合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
除非另外说明，应当应用本文所使用的下列定义。出于本发明的目的，化学元素与元素周期表CAS版，和《化学和物理手册》，第75版，1994一致。此外，有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,John Wiley&Sons,New York:2007中的描述，其全部内容通过引用并入本文。
术语“药学上可接受的盐”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸 或碱反应得到的盐。当化合物中含有相对酸性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的碱与化合物的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包括但不限于钠盐、钾盐、钙盐、铝盐、镁盐、铋盐、铵盐等。当化合物中含有相对碱性的官能团时，可以通过在合适的惰性溶剂中用足量的药学上可接受的酸与化合物的游离形式接触的方式获得酸加成盐。所述药学上可接受的酸包括无机酸和有机酸。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指化合物与溶剂(包括但不限于：水、甲醇、乙醇等)结晶后形成的物质。溶剂合物分为化学计量类溶剂合物和非化学计量类溶剂合物。
术语“药学上可接受的盐的溶剂合物”是指化合物与药学上可接受的(相对无毒、安全、适合于患者使用)酸或碱、溶剂(包括但不限于：水、甲醇、乙醇等)结合形成的物质，其中，药学上可接受的盐与上文术语“药学上可接受的盐”的含义相同。
在符合本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的如式I所示的稠环化合物对SOS1具有较好地抑制活性；有望治疗和/或预防与SOS1活性或表达量相关的疾病。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的反应步骤，均可以按照本领域内的常规方法和条件，或按照商品说明书进行。
以下实施例对本发明进行更详细的说明，但对本发明不具有任何限定作用。
本发明的化合物结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。核磁共振化学位移(δ)以百万分之一(ppm)的单位给出。核磁共振的测定是用布鲁克(Bruker)AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)或氘代氯仿(CDCl 3)，内标为四甲基硅烷(TMS)。质谱的测定是用安捷伦(Agilent)1260-6125B单四极杆液质联用仪，采用的是电喷雾离子源(ESI)。
对于硅胶柱层析，使用的是拜泰齐(Biotage)Selekt快速制备色谱仪以及适当规格的拜泰齐生产的BK-SIL硅胶预填充柱或艾杰尔(Agela)生产的Claricep Flash硅胶预填充柱。
薄层层析色谱硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，采用的规格是0.15mm～0.20mm，制备薄层层析色谱采用的规格是0.4mm～0.5mm。
制备高效液相色谱(制备HPLC)使用的是沃特世(Waters)公司生产的配备ACQUITy QDa质谱检测器的AutoPurification LC制备系统。制备色谱柱用的是SunFire C18 5μm 19x250mm OBD制备柱。流动相使用不同梯度的水(含0.1％甲酸)-乙腈来洗脱化合物。
I.本发明化合物制备实施例
实施例1(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物1)
Figure PCTCN2022122241-appb-000118
步骤1：4-溴-6-氯-2-氟吡啶-3-醇
Figure PCTCN2022122241-appb-000119
6-氯-2-氟吡啶-3-醇(80.0g，542mmol)溶于乙腈(800mL)中，加入N-溴代丁二酰亚胺(106.4g，596mmol)，室温搅拌反应1.5小时。反应液浓缩，加入水(600mL)稀释，乙酸乙酯(2L)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，黄色油状物(128g，粗品)。ESI-MS m/z：225.9，227.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ11.34(s,1H),7.73(s,1H).
步骤2：4-溴-6-氯-2-氟-3-((4-甲氧基苄基)氧基)吡啶
Figure PCTCN2022122241-appb-000120
4-溴-6-氯-2-氟吡啶-3-醇(20g，88.3mmol)溶于N,N-二甲基甲酰胺(200mL)，加入碳酸钾(36.6g，265mmol)和4-甲氧基苄基氯(18.0g，115mmol)，室温搅拌反应1小时。将反应液缓慢倒入水(400mL)中，过滤。滤饼用无水乙醇(100mL)打浆处理，得到产物，淡黄色固体(25.0g，收率83％)。ESI-MS m/z：346.0，348.0[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ7.90(s,1H),7.39(d,J＝8.6Hz,2H),6.94(d,J＝8.7Hz,2H),5.16-5.07(m,2H),3.76(s,3H).
步骤3：4-溴-2-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)-6-氯-3-((4-甲氧基苄基)氧基)吡啶
Figure PCTCN2022122241-appb-000121
4-溴-6-氯-2-氟-3-((4-甲氧基苄基)氧基)吡啶(3.48g，10mmol)溶于四氢呋喃(40mL)，0℃下加 入氢化钠(600mg，13mmol)，搅拌10分钟后加入2-((叔丁基二甲基硅烷基)氧基)乙醇(3.52g，20mmol)，0℃下反应0.5小时后再于室温搅拌反应1小时。加入饱和氯化铵淬灭反应，加水稀释，再以乙酸乙酯萃取，有机相用饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，得到产物粗品，直接用于下一步反应。ESI-MS m/z：502.1，504.1[M+H] +。
步骤4：4-溴-6-氯-2-(2-羟基乙氧基)吡啶-3-醇
Figure PCTCN2022122241-appb-000122
将步骤3得到的4-溴-2-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)-6-氯-3-((4-甲氧基苄基)氧基)吡啶粗品溶于4.0M盐酸甲醇溶液(45mL)，室温下搅拌反应30分钟，减压浓缩，残留物加入饱和碳酸氢钠溶液中和至中性，乙酸乙酯萃取，有机相以饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，得到产物，白色固体(5.1g，粗品)。ESI-MS m/z：268.0，270.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ＝10.07(s,1H),7.27(s,1H),4.29(t,J＝4.0Hz,2H),3.74(t,J＝4.0Hz,2H).
步骤5：8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶
Figure PCTCN2022122241-appb-000123
4-溴-6-氯-2-(2-羟基乙氧基)吡啶-3-醇(5.1g，19mmol)溶于四氢呋喃(60mL)，加入三苯基膦(6.0g，28mmol)，0℃下缓慢加入偶氮二甲酸二异丙酯(5.68g，28mmol)，反应物在室温搅拌反应1小时。加入乙酸乙酯稀释，依次以水、饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析纯化(石油醚/乙酸乙酯＝10:1，体积比)，得到产物，白色固体(3.68g)。ESI-MS m/z：249.9，251.9[M+H] +。 1H NMR(400MHz,CDCl 3)δ7.14(s,1H),4.47–4.45(m,2H),4.36–4.34(m,2H).
步骤6：6-氯-N-甲基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺
Figure PCTCN2022122241-appb-000124
8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶(1.75g，7mmol)溶于乙二醇二甲醚(20mL)，加入甲胺水溶液(25mL)，加热至100℃搅拌反应4小时。冷却至室温后，加入乙酸乙酯，再依次以水、饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，得到产物粗品，直接用于下一步反应。ESI-MS m/z：201.0[M+H] +。
步骤7：6-氯-7-碘-N-甲基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺
Figure PCTCN2022122241-appb-000125
将步骤6得到的6-氯-N-甲基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺产物粗品(1.1g)溶于N,N-二甲基甲酰胺(15mL)，加入N-碘代丁二酰亚胺(1.48g，6.6mmol)，氩气保护下加热至85℃反应2小时。冷却至室温后，反应物加入乙酸乙酯稀释，再依次以水、饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析纯化(石油醚/乙酸乙酯＝2:1，体积比)，得到产物，白色固体(819mg)。ESI-MS m/z：326.9，328.9[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ4.36–4.34(m,2H),4.19–4.17(m,2H),3.30(s,1H),3.11(s,3H).
步骤8：3-(6-氯-8-(甲氨基)-2,3-二氢-[1,4]二氧基[2,3-b]吡啶-7-基)丙烯酸乙酯
Figure PCTCN2022122241-appb-000126
6-氯-7-碘-N-甲基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺(819mg，2.5mmol)溶于N,N-二甲基甲酰胺(15mL)，加入丙烯酸乙酯(376mg，3.76mmol)，三乙胺(380mg，3.76mmol)，醋酸钯(56mg，0.25mmol)，三(邻甲基苯基)膦(152mg，0.5mmol)。氩气保护下，升温至100℃反应2小时。冷却至室温后，反应物加入乙酸乙酯稀释，再依次以水、饱和氯化钠洗涤，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析纯化(石油醚/乙酸乙酯＝2:1，体积比)，得到产物，白色固体(406mg)。ESI-MS m/z：299.1[M+H] +。
步骤9：6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000127
3-(6-氯-8-(甲氨基)-2,3-二氢-[1,4]二氧基[2,3-b]吡啶-7-基)丙烯酸乙酯(406mg，1.36mmol)溶于乙醇(8mL)，加入甲硫醇钠(105mg，1.5mmol)，室温反应15分钟。减压浓缩，残留物加入水(100mL)稀释，加乙酸乙酯(100mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，白色固体(200mg)。ESI-MS m/z：253.0[M+H] +。
步骤10：8-溴-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000128
6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(1.29g，5.1mmol)溶于N,N-二甲基甲酰胺(20mL)，加入N-溴代丁二酰亚胺(2.27g，12.7mmol)，升温至70℃反应2小时。加入饱和亚硫酸钠水溶液(100mL)稀释，用乙酸乙酯(200mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，白色固体(2.03g)。ESI-MS m/z：330.9，332.9[M+H] +。 1H NMR(400MHz,CDCl 3)δ＝8.33(s,1H),4.53–4.51(m,2H),4.37–4.35(m,2H),3.86(s,3H).
步骤11：8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000129
8-溴-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(390mg，1.18mmol)溶于四氢呋喃(20mL)，加入1-乙酰基哌啶-4-酮(664mg，4.71mmol)，反应液降温至-40℃，缓慢加入碘化钐(82mL，8.2mmol，0.1M in THF)，继续于-40℃搅拌反应2小时。加入饱和氯化铵水溶液(60mL)稀释，再用乙酸乙酯(200mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝20:1，体积比)得到产物，棕色固体(239mg)。ESI-MS m/z：394.1[M+H] +。
步骤12：(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物1)
Figure PCTCN2022122241-appb-000130
8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(239mg，0.61mmol)溶于甲苯(8mL)，加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(270mg，1.21mmol，根据专利WO2019122129A1中描述的方法制备)、甲烷磺酸(2-二环己基膦)-3,6-二甲 氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(Brettphos Pd G3，55mg，0.06mmol)和叔丁醇钠(175mg，1.82mmol)。氮气保护，100℃搅拌反应16小时。冷却至室温后，减压浓缩，残留物通过硅胶柱层析(二氯甲烷/甲醇＝20:1，体积比)得到化合物1，白色固体(209mg)。ESI-MS m/z：547.2[M+H] +。 1H NMR(400MHz,DMSO-d 6)δ8.34(s,1H),7.64–7.61(m,1H),7.47(t,J＝4.0Hz,1H),7.26(t,J＝4.0Hz,1H),7.23(s,1H),5.48–5.44(m,1H),4.32-4.30(m,2H),4.12–4.11(m,2H),3.75(s,3H),3.72-3.69(m,1H),3.51–3.43(m,1H),2.95–2.91(m,1H),2.45–2.36(m,2H),2.03(s,3H),1.64–1.61(m,1H),1.56–1.52(m,1H),1.50(d,J＝4.8Hz,3H),1.40–1.37(m,1H),1.34(s,1H),1.30–1.25(m,1H). 13C NMR(400MHz,DMSO-d 6)δ168.30,162.83,150.47,148.30,148.24,137.76,129.82,124.97,118.35,99.14,65.41,63.74,42.40,37.36,35.41,34.64,32.01,31.75,22.12,21.78.
实施例2(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物2)
Figure PCTCN2022122241-appb-000131
步骤1：(S)-4-溴-6-氯-2-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)-3-((4-甲氧基苄基)氧基)吡啶
Figure PCTCN2022122241-appb-000132
向500mL三口瓶中加入氢化钠(2.3g,57.8mmol)以及无水N,N-二甲基甲酰胺(100mL)，冷却至0℃，缓慢滴加(S)-甘油醇缩丙酮(5.7g,43.4mmol)溶于50mL无水N,N-二甲基甲酰胺的溶液。滴加完毕后继续于0℃搅拌1小时。再缓慢滴加4-溴-6-氯-2-氟-3-((4-甲氧基苄基)氧基)吡啶(10.0g，28.9mmol)溶于50mL无水N,N-二甲基甲酰胺的溶液。滴加完毕后反应液继续于0℃搅拌1小时。向反应液中加入饱和氯化铵水溶液(50mL)淬灭反应。反应液加入到乙酸乙酯(300mL)和水(100mL)中，萃取分层，有机相用水洗(200mL)，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石 油醚/乙酸乙酯＝10:1，体积比)得到产物，白色固体(12.8g，收率97％)。ESI-MS m/z：458.0，460.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ7.39(d,J＝8.4Hz,2H),7.39(s,1H),6.91(d,J＝8.4Hz,2H),5.03(s,2H),4.46-4.52(m,1H),4.39(dd,J＝4.4Hz,J＝11.2Hz,1H),4.33(dd,J＝5.6Hz,J＝11.2Hz,1H),4.10(dd,J＝6.8Hz,J＝8.4Hz,1H),3.85(dd,J＝6.0Hz,J＝8.4Hz,1H),3.75(s,3H),1.36(s,3H),1.32(s,3H).
步骤2：(R)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇
Figure PCTCN2022122241-appb-000133
(S)-4-溴-6-氯-2-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)-3-((4-甲氧基苄基)氧基)吡啶(12.8g，27.9mmol)溶于甲醇(30mL)，0℃下加入4.0M盐酸甲醇溶液(30mL)，反应升至室温搅拌1小时。0℃下加入三乙胺调节pH至中性，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，黄色固体(10.5g，收率90％)。ESI-MS m/z：418.0，420.0[M+1] +。
步骤3：(S)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇二甲磺酸酯
Figure PCTCN2022122241-appb-000134
(R)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇(10.5g，25.1mmol)溶于二氯甲烷(20mL)，0℃下加入三乙胺(6.3g，62.6mmol)和甲基磺酰氯(7.2g，62.6mmol)，0℃下搅拌反应0.5小时。加入水(100mL)稀释，加乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物(14.4g)，粗品直接用于下一步反应。ESI-MS m/z：574.0，576.0[M+1] +。
步骤4：(S)-3-((4-溴-6-氯-3-羟基吡啶-2-基)氧基)丙烷-1,2-二醇二甲磺酸酯
Figure PCTCN2022122241-appb-000135
将步骤3得到的产物粗品(14.4g)溶于二氯甲烷(20mL)，加入三氟乙酸(20mL)，室温下搅拌0.5小时。反应液减压旋干，加入饱和碳酸氢钠水溶液(300mL)稀释，加乙酸乙酯(500mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/乙酸乙酯＝8:1，体积比)得到产物，黄色油状物(8.2g，两步收率72％)。ESI-MS m/z：453.9，455.9[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),7.36(s,1H),5.21(dd,J＝6.4,3.6Hz,1H),4.71(dd,J＝11.5,6.3Hz,1H),4.65-4.46(m,3H),3.30(s,3H),3.26(s,3H).
步骤5：(R)-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基甲磺酸酯
Figure PCTCN2022122241-appb-000136
(S)-3-((4-溴-6-氯-3-羟基吡啶-2-基)氧)丙烷-1,2-二醇二甲磺酸酯(8.2g，18.0mmol)，溶于N,N-二甲基甲酰胺(50mL)，加入碳酸钾(7.5g，54.1mmol)，60℃搅拌1小时。加入水(300mL)稀释，乙酸乙酯(600mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝10:1，体积比)得到产物，黄色油状物(6.4g，收率98％)。ESI-MS m/z：357.9，359.9[M+1] +。
步骤6：(S)-6-氯-N-甲基-2-((甲氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺
Figure PCTCN2022122241-appb-000137
(R)-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基甲磺酸酯(6.4g，17.8mmol)溶于1,4-二氧六环(50mL)，加入甲胺水溶液(40mL)，100℃封管搅拌反应16小时。冷却至室温后，减压浓缩，得到产物粗品，直接用于下一步反应。ESI-MS m/z：244.1[M+1] +。
步骤7：叔丁基(S)-(6-氯-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000138
将步骤6得到的产物粗品溶于四氢呋喃(60mL)，加入三乙胺(1.8g，17.8mmol)和二碳酸二叔丁酯(5.8g，26.7mmol)，室温下搅拌6小时。加入水(150mL)稀释，加乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，黄色油状物(3.0g，两步收率49％)。ESI-MS m/z：344.2[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ6.23(s,1H),6.16(d,J＝20.9Hz,1H),4.40(d,J＝39.2Hz,1H),4.27(d,J＝11.2Hz,1H),4.21-4.03(m,1H),3.59(dd,J＝14.8,8.0Hz,1H),3.44(s,1H),2.91-2.85(m,3H),2.72(d,J＝4.8Hz,3H),1.35(d,J＝43.9Hz,9H).
步骤8：叔丁基(S)-(6-氯-7-碘-8-(甲胺基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000139
叔丁基(S)-(6-氯-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯(3.0g，8.73mmol)溶于乙酸(30mL)，加入N-碘代丁二酰亚胺(2.1g，9.60mmol)，室温搅拌1小时。加入饱和亚硫酸钠水溶液(100mL)稀释，加入饱和碳酸氢钠水溶液(150mL)中和，加乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，黄色油状物(3.1g，收率76％)。ESI-MS m/z：470.1[M+1] +。
步骤9：(S)-3-(2-(叔丁氧羰基)(甲基)氨基)甲基)-6-氯-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-7-基)丙烯酸乙酯
Figure PCTCN2022122241-appb-000140
叔丁基(S)-(6-氯-7-碘-8-(甲胺基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯(3.1g，6.60mmol)，醋酸钯(148mg，0.660mmol)，三(邻甲基苯基)膦(400mg，1.32mmol)，三乙胺(1.4g，13.2mmol)和丙烯酸乙酯(2.0g，19.9mmol)，溶于N,N-二甲基甲酰胺(40mL)。氮气保护，100℃搅拌反应3小时。冷却至室温后，加入水(300mL)稀释，加乙酸乙酯(500mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝2:1，体积比)得到产物，黄色油状物(2.3g，收率79％)。ESI-MS m/z：442.2[M+1] +。
步骤10：叔丁基(S)-((6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基) 甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000141
(S)-3-(2-(叔丁氧羰基)(甲基)氨基)甲基)-6-氯-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-7-基)丙烯酸乙酯(2.3g，5.20mmol)溶于乙醇(20mL)，加入甲硫醇钠(400mg，5.72mmol)，室温搅拌0.5小时。减压浓缩，残留物加入水(100mL)稀释，加乙酸乙酯(150mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，黄色固体(1.9g，收率93％)。ESI-MS m/z：396.2[M+1] +。
步骤11：叔丁基(S)-((8-溴-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000142
叔丁基(S)-((6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(1.9g，4.80mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N-溴代丁二酰亚胺(2.5g，14.4mmol)，反应70℃下搅拌2小时。加入饱和亚硫酸钠水溶液(100mL)稀释，加乙酸乙酯(250mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝2:1，体积比)得到产物，黄色固体(1.2g，收率53％)。ESI-MS m/z：474.1，476.1[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ8.52-8.25(m,1H),4.76-4.51(m,2H),4.43-4.22(m,1H),3.85(s,3H),3.84-3.74(m,1H),3.40-3.25(m,1H),2.96-2.80(m,3H),1.29(m,9H).
步骤12：叔丁基(S)-((8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000143
叔丁基(S)-((8-溴-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(400mg，0.842mmol)和1-乙酰基哌啶-4-酮(475mg，3.37mmol)溶于四氢呋喃(20mL)，氮气保护，于-30℃下滴加碘化钐(33.7mL，3.37mmol，0.1M in THF)。反应-30℃下搅拌0.5小时。-30℃下加入饱和氯化铵水溶液(100mL)稀释，加乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝20:1，体积比)得到产物，白色固体(230mg，收率51％)。ESI-MS m/z：481.2[M-t-Bu] +。
步骤13：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-2-((甲氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000144
叔丁基(S)-((8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(230mg，0.428mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)，室温搅拌1小时。减压浓缩，得到产物粗品，直接用于下一步反应。ESI-MS m/z：437.2[M+1] +。
步骤14：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000145
将步骤13得到的产物粗品溶于四氢呋喃(15mL)，加入30％甲醛水溶液(3mL)，加入三乙酰氧基硼氢化钠(227mg，1.07mmol)，室温下搅拌0.5小时。减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝12:1，体积比)得到产物，白色固体(130mg，两步收率67％)。ESI-MS m/z：451.2[M+1] +。
步骤15：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物2)
Figure PCTCN2022122241-appb-000146
(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(130mg，0.288mmol)，甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(Brettphos Pd G3，39mg，0.029mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(196mg，0.865mmol，根据专利WO2019122129A1中描述的方法制备)和叔丁醇钠(166mg，1.73mmol)溶于甲苯(6mL)。氮气保护，100℃搅拌反应16小时。冷却至室温后，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝20:1，体积比)得到化合物2，黄色固体(120mg，收率69％)。ESI-MS m/z：604.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.76(d,J＝1.6Hz,1H),7.50(dq,J＝22.0,7.2Hz,2H),7.17(td,J＝7.6,2.4Hz,1H),6.92(t,J＝55.1Hz,1H),5.97(brs,1H),5.89(dd,J＝10.8,7.2Hz,1H),5.64-5.65(m,1H),4.54(d,J＝12.6Hz,1H),4.49(dt,J＝11.2,2.0Hz,1H),4.25-4.18(m,1H),4.14(dd,J＝11.2,7.6Hz,1H),3.92(s,3H),3.66(d,J＝9.6,2H),3.12(td,J＝12.8,2.8Hz,1H),2.68-2.57(m,2H),2.33(s,6H),2.18(td,J＝13.6,2.8Hz,1H),2.07(d,J＝12.8Hz,3H),2.03-1.96(m,1H),1.93-1.77(m,2H),1.58(dd,J＝7.2,3.2Hz,3H).
实施例3(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物3)
Figure PCTCN2022122241-appb-000147
化合物3的合成参照实施例2的步骤1～步骤15，只是将步骤1中原料(S)-甘油醇缩丙酮替换为 (R)-甘油醇缩丙酮。ESI-MS m/z：604.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.65(s,1H),7.42(dt,J＝13.0,7.0Hz,2H),7.09(t,J＝7.1Hz,1H),6.86(dd,J＝74.1,36.0Hz,1H),5.70(s,1H),5.52(d,J＝4.3Hz,1H),4.44(dd,J＝33.3,11.4Hz,2H),4.26(s,1H),4.17–4.06(m,1H),3.84(s,3H),3.60(s,2H),3.06(t,J＝12.7Hz,1H),2.66(s,2H),2.34(d,J＝2.6Hz,6H),2.11(d,J＝12.2Hz,1H),2.00(t,J＝11.6Hz,3H),1.94(d,J＝15.1Hz,1H),1.89–1.71(m,2H),1.58–1.45(m,3H). 13C NMR(101MHz,CDCl 3)δ167.83(s),163.15(s),149.25(s),147.22(s),136.70(s),131.40(d,J＝12.6Hz),129.52(s),126.45(s),124.28(s),123.30(s),116.52(s),109.70(s),98.69(s),69.73(d,J＝14.5Hz),66.68(s),58.12(s),45.02(s),44.76(s),41.47(s),36.49(s),35.67(d,J＝14.5Hz),34.31(d,J＝7.4Hz),33.83(s),28.68(s),25.92(s),20.57(dd,J＝21.5,6.8Hz).
实施例4(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物4)
Figure PCTCN2022122241-appb-000148
步骤1：(S)-2-((1-叠氮基-3-((4-甲氧基苄基)氧基)丙烷-2-基)氧基)-4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶
Figure PCTCN2022122241-appb-000149
参照实施例2的步骤1制备，只是将(S)-甘油醇缩丙酮替换为(S)-1-叠氮基-3-((4-甲氧基苄基)氧基)丙基-2-醇。ESI-MS m/z：563.1，565.1[M+1] +。
步骤2：(S)-2-((1-叠氮基-3-羟基丙烷-2-基)氧基)-4-溴-6-氯吡啶-3-醇
Figure PCTCN2022122241-appb-000150
(S)-2-((1-叠氮基-3-((4-甲氧基苄基)氧基)丙烷-2-基)氧基)-4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶(24.4g，43.4mmol)，溶于二氯甲烷(100mL)，加入三氟乙酸(50mL)，室温搅拌1小时。减压浓缩，残留物重新溶于乙酸乙酯(600mL)，加入饱和碳酸氢钠溶液调节pH值到8-9，加入水(400mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝2:1，体积比)得到产物，白色固体(12g，收率85.7％)。ESI-MS m/z：323.0，325.0[M+1] +。
步骤3：(S)-N-((8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-3-基)甲基)-1,1,1-三苯基磷亚胺
Figure PCTCN2022122241-appb-000151
(S)-2-((1-叠氮基-3-羟基丙烷-2-基)氧基)-4-溴-6-氯吡啶-3-醇(960mg，3mmol)溶于四氢呋喃(20mL)，氮气保护0℃下加入三苯基膦(1.57g，6mmol)和偶氮二甲酸二异丙酯(667mg，3.3mmol)。反应升至室温搅拌1小时。减压浓缩得到产物粗品，直接用于下一步反应。ESI-MS m/z：539.0，541.0[M+1] +。
步骤4：(S)-3-(氨甲基)-6-氯-N-甲基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺
Figure PCTCN2022122241-appb-000152
将步骤3得到的(S)-N-((8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-3-基)甲基)-1,1,1-三苯基磷亚胺粗品(3.5g)溶于甲胺水溶液(40mL)，100℃封管搅拌24小时。减压浓缩，残留物溶于乙酸乙酯(100mL)，加入4M盐酸甲醇溶液(10mL)，室温搅拌5分钟，加入水(100mL)萃取，水相再用浓氨水碱化至pH至10，加入乙酸乙酯(50mL，3次)，萃取，有机相用无水硫酸钠干燥，减压浓缩，得到产物粗品，黄色油状物(960mg)，直接用于下一步反应。ESI-MS m/z：230.1[M+1] +。
步骤5：叔丁基(S)-((6-氯-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-3-基)甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000153
将步骤4得到的(S)-3-(氨甲基)-6-氯-N-甲基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-胺粗品溶于四氢呋喃(30mL)，加入三乙胺(1mL)，加入二碳酸二叔丁酯(972mg，1.5mmol)，室温下搅拌1小时。加入水(30mL)稀释，加乙酸乙酯(30mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝1:1，体积比)得到产物，白色固体(960mg，3步总收率46％)。ESI-MS m/z：330.1[M+1] +。
步骤6：叔丁基(S)-((6-氯-7-碘-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-3-基)甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000154
参照实施例2的步骤8制备。ESI-MS m/z：456.1[M+1] +。 1H NMR(400MHz,CDCl 3)δ5.09(s,1H),4.39(dd,J＝7.0,4.9Hz,1H),4.30(dd,J＝11.5,2.1Hz,1H),3.83(dd,J＝11.2,8.3Hz,1H),3.55(d,J＝14.3Hz,1H),3.41(d,J＝15.2Hz,1H),3.22(s,3H),1.44(s,9H).
步骤7：(S)-3-(3-(((叔丁氧羰基)氨基)甲基)-6-氯-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-7-基)丙烯酸乙酯
Figure PCTCN2022122241-appb-000155
参照实施例2的步骤9制备。ESI-MS m/z：428.2[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝16.3Hz,1H),6.20(t,J＝9.9Hz,1H),4.37(ddd,J＝13.7,7.9,2.2Hz,2H),4.27(q,J＝7.1Hz,2H),3.96–3.83(m,1H),3.54(t,J＝14.9Hz,1H),3.43(dd,J＝13.0,6.9Hz,1H),2.95(d,J＝11.4Hz,3H),1.44(s,11H),1.34(t,J＝7.1Hz,3H).
步骤8：叔丁基(S)-((6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-3-基)甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000156
参照实施例2的步骤10制备。ESI-MS m/z：382.1[M+1] +。1H NMR(400MHz,CDCl 3)δ7.92(t,J＝9.4Hz,1H),6.62(d,J＝9.8Hz,1H),5.16(s,1H),4.58–4.39(m,2H),4.00–3.86(m,4H),3.66–3.44(m,2H),1.47(d,J＝21.6Hz,9H).
步骤9：叔丁基(S)-((8-溴-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-3-基)甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000157
参照实施例2的步骤11制备。ESI-MS m/z：460.0，462.0[M+1] +。
步骤10：叔丁基(S)-((8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-3-基)甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000158
参照实施例2的步骤12制备。ESI-MS m/z：523.2[M+1] +。
步骤11：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-3-(氨甲基)-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000159
参照实施例2的步骤13制备。ESI-MS m/z：423.1[M+1] +。
步骤12：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-3-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁 烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000160
参照实施例2的步骤14制备。ESI-MS m/z：451.2[M+1] +。
步骤13：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物4)
Figure PCTCN2022122241-appb-000161
化合物4参照实施例2的步骤15制备。ESI-MS m/z：604.3[M+1] +。 1H NMR(400MHz,MeOD)δ8.19(s,1H),7.60–7.50(m,1H),7.45(t,J＝7.0Hz,1H),7.20(t,J＝7.7Hz,1H),7.00(t,J＝54.9Hz,1H),5.62–5.47(m,1H),4.62(s,1H),4.50(d,J＝12.9Hz,1H),4.22(dt,J＝15.9,8.0Hz,1H),3.95–3.78(m,5H),3.65(td,J＝13.1,2.5Hz,1H),3.10(ddd,J＝21.0,13.5,9.1Hz,2H),2.80(dd,J＝13.4,3.5Hz,1H),2.55(d,J＝7.6Hz,6H),2.37–2.22(m,2H),2.17(s,3H),2.00–1.75(m,2H),1.60(d,J＝7.0Hz,3H). 13C NMR(101MHz,MeOD)δ171.42(s),164.98(s),151.29(s),150.11(s),138.92(s),134.91(d,J＝13.6Hz),132.00(s),130.98(s),130.30(s),126.14(s),125.44(s),119.29(s),100.98(s),73.04(s),72.53(s),66.47(s),59.94(s),46.27(s),45.74(s),43.76(s),38.87(s),36.68(s),35.85(d,J＝6.8Hz),35.20(s),21.85(s),21.22(s).
实施例5(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物5)
Figure PCTCN2022122241-appb-000162
步骤1：叔丁基(R)-2-((S)-2-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)-1-羟乙基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000163
(R)-2-((S)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯(30.0g，130mmol)，4-溴-6-氯-2-氟-3-((4-甲氧基苄基)氧基)吡啶(36.0g，104mmol)和碳酸铯(50.7g，156mmol)溶于二甲基亚砜(300mL)，室温搅拌4小时。反应液加入水(1.5L)稀释，加乙酸乙酯(1L)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝12:1，体积比)得到产物，黄色油状物(11.5g，收率24％)。ESI-MS m/z：579.1，581.1[M+Na] +。 1H NMR(400MHz,CDCl 3)δ7.47(s,2H),7.10-7.03(m,1H),6.94-6.82(m,2H),5.20-5.09(m,1H),5.05(d,J＝10.0Hz,1H),4.49(dd,J＝11.4,2.9Hz,1H),4.36(dd,J＝11.4,4.7Hz,1H),4.13(brs,1H),3.89(brs,1H),3.84-3.77(m,3H),3.51(s,1H),3.42-3.25(m,1H),2.03-1.59(m,4H),1.49(d,J＝3.7Hz,9H).
步骤2：4-溴-6-氯-2-((S)-2-羟基-2-((R)-吡咯烷-2-基)乙氧基)吡啶-3-醇
Figure PCTCN2022122241-appb-000164
叔丁基(R)-2-((S)-2-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)-1-羟乙基)吡咯烷-1-羧酸酯(11.5g，20.6mmol)，溶于二氯甲烷(20mL)，加入三氟乙酸(20mL)，室温搅拌 1小时。减压旋干溶剂，得到产物粗品，直接用于下一步反应。ESI-MS m/z：337.0，339.0[M+1] +。
步骤3：叔丁基(R)-2-((S)-2-((4-溴-6-氯-3-羟基吡啶-2-基)氧基)-1-羟乙基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000165
将步骤2得到的产物粗品溶于四氢呋喃(60mL)和水(20mL)，加入三乙胺调节pH值到8-9，再加入二碳酸二叔丁酯(8.9g，41.2mmol)，室温下搅拌16小时。加入水(300mL)稀释，乙酸乙酯(600mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝9:1，体积比)得到产物，白色固体(5.3g，收率59％)。ESI-MS m/z：459.0，461.0[M+Na] +。 1H NMR(400MHz,DMSO-d 6)δ9.92(s,1H),7.27(s,1H),5.03-4.97(m,1H),4.30(d,J＝8.0Hz,1H),4.04(brs,1H),3.95(brs,1H),3.72-3.60(m,1H),3.40(brs,1H),3.20(brs,1H),1.93(s,3H),1.73(s,1H),1.42(s,9H).
步骤4：叔丁基(R)-2-((R)-8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000166
叔丁基(R)-2-((S)-2-((4-溴-6-氯-3-羟基吡啶-2-基)氧基)-1-羟乙基)吡咯烷-1-羧酸酯(5.3g，12.1mmol)溶于四氢呋喃(50mL)，氮气保护，0℃下加入三苯基膦(3.8g，14.6mmol)和偶氮二甲酸二异丙酯(2.9g，14.6mmol)。反应升至室温搅拌1小时。加入水(200mL)稀释，乙酸乙酯(400mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝12:1，体积比)得到产物，白色固体(4.0g，收率79％)。ESI-MS m/z：363.0[M-t-Bu] +。 1H NMR(400MHz,CDCl 3)δ7.13(s,1H),4.54(d,J＝10.8Hz,1H),4.27-4.09(m,2H),4.02(s,1H),3.61-3.30(m,2H),2.21(s,1H),2.08-2.03(m,1H),2.00-1.90(m,2H),1.48(s,9H).
步骤5：叔丁基(R)-2-((R)-6-氯-8-(甲胺基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000167
叔丁基(R)-2-((R)-8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯(4.0g，9.55mmol)溶于二甲基亚砜(40mL)，加入甲胺水溶液(30mL)，100℃封管搅拌24小时。冷却至室温后，加入水(150mL)稀释，乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩得到产物，黄色油状物(3.5g，粗品收率100％)。ESI-MS m/z：370.2[M+1] +。
步骤6：叔丁基(R)-2-((R)-6-氯-7-碘-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000168
叔丁基(R)-2-((R)-6-氯-8-(甲胺基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯(3.5g，9.55mmol)溶于乙酸(20mL)，加入N-碘代丁二酰亚胺(2.3g，10.5mmol)，室温搅拌1小时。加入饱和亚硫酸钠水溶液(100mL)稀释，加入饱和碳酸氢钠水溶液(150mL)中和，乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝4:1，体积比)得到产物，白色固体(3.5g，收率74％)。ESI-MS m/z：496.1[M+1] +。
步骤7：叔丁基(R)-2-((R)-6-氯-7-(3-乙氧基-3-氧代丙烷-1-烯-1-基)-8-(甲氨基)-2,3-二氢-[1,4]二氧基[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000169
叔丁基(R)-2-((R)-6-氯-7-碘-8-(甲氨基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯(3.5g，7.06mmol)，醋酸钯(159mg，0.706mmol)，三(邻甲基苯基)膦(430mg，1.41mmol)，三乙胺(1.4g，14.1mmol)和丙烯酸乙酯(1.8g，1.16mmol)，溶于N,N-二甲基甲酰胺(40mL)。氮气保护，100℃搅拌反应3小时。冷却至室温后，加入水(300mL)稀释，加乙酸乙酯(500mL) 萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝4:1，体积比)得到产物，黄色油状物(2.3g，收率70％)。ESI-MS m/z：468.2[M+1] +。 1H NMR(400MHz,CDCl3)δ7.71(d,J＝16.4Hz,1H),6.20(d,J＝16.4Hz,1H),4.46(d,J＝10.4Hz,1H),4.27(q,J＝7.2Hz,2H),4.17-4.07(m,2H),4.00(brs,1H),3.57-3.43(m,1H),3.40-3.28(m,1H),3.00(s,3H),2.12-1.93(m,4H),1.48(s,9H),1.34(t,J＝7.2Hz,3H).
步骤8：叔丁基(R)-2-((R)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000170
叔丁基(R)-2-((R)-6-氯-7-(3-乙氧基-3-氧代丙烷-1-烯-1-基)-8-(甲氨基)-2,3-二氢-[1,4]二氧基[2,3-b]吡啶-2-基)吡咯烷-1-羧酸酯(2.3g，4.91mmol)溶于乙醇(30mL)，加入甲硫醇钠(378mg，5.41mmol)，室温搅拌0.5小时。减压蒸干溶剂，加入水(100mL)稀释，乙酸乙酯(150mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，黄色固体(2.2g，收率100％)。ESI-MS m/z：422.2[[M+1] +。
步骤9：叔丁基(R)-2-((R)-8-溴-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000171
叔丁基(R)-2-((R)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)吡咯烷-1-羧酸酯(2.2g，4.91mmol)溶于N,N-二甲基甲酰胺(30mL)，加入N-溴代丁二酰亚胺(2.6g，14.7mmol)，70℃下搅拌反应2小时。加入饱和亚硫酸钠水溶液(100mL)稀释，乙酸乙酯(150mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，白色固体(535mg，收率90％)。ESI-MS m/z：500.1，502.1[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ8.36(s,1H),4.56(d,J＝11.6Hz,1H),4.37-4.26(m,1H),4.24(dd,J＝11.6,8.8Hz,1H),4.00(s,1H),3.86(s,3H),3.40(s,1H),3.23(brs,1H),2.03-1.90(m,3H),1.85-1.78(m,1H),1.41(s,9H).
步骤10：叔丁基(R)-2-((R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二氧基[2,3-h][1,6]萘啶-2-基)吡咯烷-1-羧酸酯
Figure PCTCN2022122241-appb-000172
叔丁基(R)-2-((R)-8-溴-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二噁烷[2,3-h][1,6]萘啶-2-基)吡咯烷-1-羧酸酯(500mg，1.00mmol)和1-乙酰基哌啶-4-酮(564mg，4.00mmol)溶于四氢呋喃(25mL)，氮气保护，于-30℃下滴加碘化钐(40.0mL，4.00mmol，0.1M in THF)。反应-30℃下搅拌0.5小时。-30℃下加入饱和氯化铵水溶液(100mL)稀释，加乙酸乙酯(300mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝30:1，体积比)得到产物，黄色固体(380mg，收率68％)。ESI-MS m/z：507.2[M-t-Bu] +。
步骤11：(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-2-((R)-吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000173
叔丁基(R)-2-((R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-2,3,9,10-四氢-[1,4]二氧基[2,3-h][1,6]萘啶-2-基)吡咯烷-1-羧酸酯(380mg，0.676mmol)溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)，室温搅拌1小时。减压蒸干溶剂，得到产物粗品，直接用于下一步反应。ESI-MS m/z：463.2[[M+1] +。
步骤12：(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000174
将步骤11得到的产物粗品溶于四氢呋喃(20mL)，加入甲醛水溶液(3mL)和三乙酰氧基硼氢化钠(358mg，1.69mmol)，室温下搅拌反应0.5小时。减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝8:1，体积比)得到产物，白色固体(280mg，收率88％)。ESI-MS m/z：477.2[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ8.27(s,1H),4.77(s,1H),4.68(d,J＝11.3Hz,1H),4.35-4.22(m,2H),3.83-3.80(m,1H),3.81(s,3H),3.70(d,J＝12.0Hz,1H),3.59(brs,2H),3.22-3.14(m,1H),2.95(s,3H),2.91-2.85(m,2H),2.64-2.54(m,1H),2.46-2.40(m,1H),2.26-2.05(m,3H),2.03(s,3H),2.00-1.86(m,2H),1.42-1.22(m,2H).
步骤13：(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物5)
Figure PCTCN2022122241-appb-000175
(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(200mg，0.42mmol)，甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(Brettphos Pd G3，39mg，0.042mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(285mg，1.26mmol，根据专利WO2019122129A1中描述的方法制备)和叔丁醇钠(242mg，2.56mmol)溶于1,4-二氧六环(15mL)，氮气保护，100℃搅拌反应16小时。冷却至室温后，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝20:1，体积比)得到粗产品，再通过制备HPLC纯化得到化合物5，黄色固体(43mg，收率16.3％)。ESI-MS m/z：630.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ8.09(s,1H),7.49(d,J＝9.2Hz,3H),7.18(t,J＝7.6Hz,1H),6.91(m,1H),5.75(brs,1H),5.57(s,1H),5.26(s,1H),4.60(d,J＝13.2Hz,1H),4.50(d,J＝11.8Hz,1H),4.36(t,J＝9.3Hz,1H),4.19(s,1H),3.92(s,3H),3.76-3.63(m,2H),3.29(s,1H),3.16(t,J＝12.8Hz,1H),2.89(s,1H),2.57(d,J＝5.2Hz,2H),2.51(s,1H),2.21(d,J＝10.8Hz,2H),2.12(d,J＝6.1Hz,3H),2.05-2.00(m,2H),1.97-1.84(m,4H),1.83-1.69(m,2H),1.62(d,J＝7.2Hz,3H).
实施例6(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物6)
Figure PCTCN2022122241-appb-000176
化合物6的合成参照实施例5的步骤1～步骤13，只是将步骤1中原料(R)-2-((S)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯替换为(R)-2-((R)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯。ESI-MS m/z：630.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.55-7.47(m,3H),7.20(td,J＝7.6,2.0Hz,1H),6.92(t,J＝55.0Hz,1H),5.75(s,1H),5.58(p,J＝6.8Hz,1H),5.45-5.27(m,1H),4.58(d,J＝13.6Hz,1H),4.50-4.37(m,2H),4.21(dd,J＝11.6,6.8Hz,1H),3.93(s,3H),3.73-3.63(m,2H),3.34(s,1H),3.15(td,J＝12.8,3.2Hz,1H),2.90(s,1H),2.64-2.42(m,3H),2.28-2.16(m,2H),2.11(d,J＝4.4Hz,3H),2.07-1.97(m,2H),1.96-1.85(m,4H),1.83-1.72(m,2H),1.61(d,J＝6.8Hz,3H).
实施例7(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((S)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物7)
Figure PCTCN2022122241-appb-000177
化合物7的合成参照实施例5的步骤1～步骤13，只是将步骤1中原料(R)-2-((S)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯替换为(S)-2-((S)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯。ESI-MS m/z：630.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.49(dt,J＝15.2,7.3Hz,2H),7.16(td,J＝7.6,2.1Hz,1H),7.07–6.74(m,1H),5.95(dd,J＝18.8,10.0Hz,1H),5.61(dd,J＝12.0,6.9Hz,1H),4.62–4.51(m,1H),4.47(d,J＝9.7Hz,1H),4.23–4.09(m,2H),3.93(s,3H),3.67(t,J＝6.5Hz,2H),3.22–3.06(m, 2H),2.78(s,1H),2.41(t,J＝10.6Hz,3H),2.38–2.13(m,3H),2.07(d,J＝18.4Hz,3H),2.02–1.88(m,3H),1.58(dd,J＝6.8,3.0Hz,3H). 13C NMR(101MHz,CDCl 3)δ168.77(d,J＝4.1Hz),164.25(s),157.11(s),150.60(s),148.17(s),137.58(s),132.51(d,J＝12.8Hz),130.43(s),130.18(s),127.78(d,J＝4.5Hz),125.20(s),124.22(s),118.14(s),110.77(s),99.62(d,J＝6.0Hz),74.71(s),70.81(d,J＝3.2Hz),66.23(s),65.07(d,J＝6.5Hz),57.64(s),45.78(s),42.42(d,J＝10.7Hz),37.51(s),36.79(s),36.56(s),35.37(d,J＝16.2Hz),34.92(d,J＝5.4Hz),29.69(s),27.00(s),23.38(s),21.57(dd,J＝14.1,8.4Hz).
实施例8(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((S)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物8)
Figure PCTCN2022122241-appb-000178
化合物8的合成参照实施例5的步骤1～步骤13，只是将步骤1中原料(R)-2-((S)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯替换为(S)-2-((R)-1,2-二羟乙基)吡咯烷-1-羧酸叔丁酯。ESI-MS m/z：630.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.71(d,J＝2.5Hz,1H),7.57–7.42(m,2H),7.16(t,J＝7.3Hz,1H),6.90(t,J＝55.1Hz,1H),5.77(dd,J＝13.7,6.5Hz,1H),5.58(d,J＝2.9Hz,1H),4.54(d,J＝12.5Hz,1H),4.47(d,J＝11.4Hz,1H),4.30–4.20(m,1H),3.98(s,1H),3.91(s,3H),3.66(d,J＝8.4Hz,2H),3.13(dd,J＝20.6,9.4Hz,2H),2.68(s,1H),2.43(s,3H),2.35(d,J＝5.8Hz,1H),2.24–2.12(m,2H),2.07(d,J＝10.7Hz,3H),1.99(d,J＝9.3Hz,2H),1.82(d,J＝18.4Hz,4H),1.57(d,J＝5.2Hz,3H).
实施例9(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-(吡咯烷-1-基甲基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物9)
Figure PCTCN2022122241-appb-000179
化合物9的合成参照实施例2。ESI-MS m/z：630.3[M+1] +。
实施例10(R)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-4,10-二甲基-3,4-二氢-[1,4]噁嗪[3,2-h][1,6]萘啶-9(10H)-酮(化合物10)
Figure PCTCN2022122241-appb-000180
化合物10的合成参照实施例1，只是将步骤3中的原料2-((叔丁基二甲基硅烷基)氧基)乙醇替换为N-[2-(叔丁基二甲基硅氧基)乙基]甲胺。ESI-MS m/z：560.2[M+1] +。
实施例11(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物11)
Figure PCTCN2022122241-appb-000181
步骤1：
Figure PCTCN2022122241-appb-000182
(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物2，80mg，0.132mmol)溶于二氯甲烷(3mL)，氮气保护，0℃下加入二乙氨基三氟化硫(DAST，42mg，0.265mmol)。然后反应物在室温下搅拌反应2小时。加入水(20mL)稀释，加乙酸乙酯(50mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物直接用于下一步反应。ESI-MS m/z：606.3[M+1] +。
步骤2：
Figure PCTCN2022122241-appb-000183
将步骤1得到的产物粗品溶于无水甲醇(10mL)，再加入甲醇钠的甲醇溶液(238mg，1.32mmol，30％w.t.in MeOH)。反应物于室温下搅拌16小时。加入水(40mL)稀释，加乙酸乙酯(80mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，冷却至室温后，减压浓缩，残留物制备HPLC纯化得到化合物11，黄色固体(6mg，收率15％)。ESI-MS m/z：618.4[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.66(s,1H),7.60-7.39(m,3H),7.19(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),5.58(s,1H),5.30(s,1H),4.52(dd,J＝23.6,12.0Hz,2H),4.34-4.11(m,3H),3.99-3.75(m,5H),3.69-3.62(m,1H),3.56-3.39(m,1H),3.24(s,3H),3.00-2.85(m,1H),2.82-2.59(m,3H),2.57-2.42(m,2H),2.39(s,6H),2.21-1.98(m,4H),1.95-1.82(m,1H),1.62(d,J＝6.8Hz,3H).
实施例12(R)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物12)
Figure PCTCN2022122241-appb-000184
化合物12以化合物1为原料，参照实施例11制备。ESI-MS m/z：561.2[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ＝7.64–7.61(m,1H),7.42-7.34(m,2H),7.24(t,J＝4.0Hz,1H),6.90(t,J＝4.0Hz,1H),5.26–5.34(m,1H),4.32-4.23(m,2H),3.55(s,2H),3.51-3.43(m,2H),3.35(s,3H),3.17–3.15(m,1H),3.09–3.08(m,2H),2.20–2.09(m,1H),2.03–2.01(m,1H),1.99(s,3H),1.55–1.46(m,1H),1.42–1.34(m,2H),1.30–1.26(m,2H),1.24(s,3H).
实施例13(R)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物13)
Figure PCTCN2022122241-appb-000185
化合物13以化合物3为原料，参照实施例11制备。ESI-MS m/z：618.3[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.58(s,1H),7.41(dd,J＝17.2,9.8Hz,2H),7.11(t,J＝7.5Hz,1H),6.99–6.66(m,1H),5.49(dd,J＝14.1,7.0Hz,1H),5.12(d,J＝7.6Hz,1H),4.49(d,J＝12.7Hz,1H),4.41(d,J＝10.7Hz,1H),4.20–4.01(m,2H),3.92–3.72(m,3H),3.66–3.55(m,1H),3.40(dd,J＝25.6,13.1Hz,1H),3.14(d,J＝26.1Hz,3H),3.06(s,1H),2.85(dd,J＝25.4,12.8Hz,1H),2.70(s,1H),2.38(t,J＝8.0Hz,3H),2.27–2.14(m,2H),2.05(s,3H),1.81(t,J＝12.1Hz,2H),1.70(s,3H),1.55(d,J＝6.9Hz,3H).
实施例14(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-3-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物14)
Figure PCTCN2022122241-appb-000186
化合物14以化合物4为原料，参照实施例11制备。ESI-MS m/z：618.4[M+1] +。 1H NMR(400MHz,CDCl3)δ7.56(s,1H),7.42(dt,J＝14.1,6.7Hz,2H),7.11(t,J＝7.6Hz,1H),6.99–6.66(m,1H),5.50(dd,J＝14.2,7.0Hz,1H),5.10(d,J＝7.7Hz,1H),4.48(d,J＝11.1Hz,1H),4.39(d,J＝5.9Hz,1H),4.26–4.13(m,1H),3.83(t,J＝5.3Hz,1H),3.79(d,J＝8.7Hz,3H),3.66–3.58(m,1H),3.39(dd,J＝23.3,10.5Hz,1H),3.17(d,J＝1.8Hz,3H),2.85(dd,J＝22.7,10.2Hz,1H),2.61(ddd,J＝20.0,13.0,6.5Hz,2H),2.51–2.38(m,2H),2.29(s,6H),2.03(d,J＝14.5Hz,3H),2.01–1.91(m,1H),1.81(t,J＝12.9Hz,1H), 1.54(d,J＝6.9Hz,3H). 13C NMR(101MHz,CDCl 3)δ167.92(s),161.12(s),149.19(s),146.86(s),137.23(s),131.28(d,J＝11.9Hz),129.87(s),128.15(s),126.61(s),124.41(s),123.42(s),117.38(s),109.70(s),98.09(s),71.60(s),64.84(s),58.24(s),49.23(s),45.85(s),45.08(s),41.34(s),36.33(s),33.52(s),31.90(s),31.14(s),30.78(s),29.94(s),28.67(s),20.92(s),20.42(s)。
实施例15(R)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物15)
Figure PCTCN2022122241-appb-000187
化合物15以化合物5为原料，参照实施例11制备。ESI-MS m/z：644.4[M+1] +。 1H NMR(400MHz,CDCl3)δ8.14(brs,1H),7.63(s,1H),7.55-7.43(m,2H),7.19(t,J＝7.6Hz,1H),6.89(t,J＝55.2Hz,1H),5.56(s,1H),5.15(s,1H),4.57(d,J＝13.6Hz,1H),4.50(d,J＝11.6Hz,1H),4.36-4.30(m,1H),4.16(s,1H),3.86(s,3H),3.69(d,J＝12.4Hz,1H),3.47(dt,J＝13.6,3.0Hz,1H),3.29(s,1H),3.25(s,2H),3.00-2.84(m,2H),2.58(d,J＝6.4Hz,3H),2.53-2.43(m,3H),2.13(s,3H),2.07-2.02(m,2H),1.96-1.84(m,4H),1.63(d,J＝7.2Hz,3H).
实施例16(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((R)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物16)
Figure PCTCN2022122241-appb-000188
化合物16以化合物6为原料，参照实施例11制备。ESI-MS m/z：644.4[M+1] +。
实施例17(R)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((S)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物17)
Figure PCTCN2022122241-appb-000189
化合物17以化合物7为原料，参照实施例11制备。ESI-MS m/z：644.4[M+1] +。 1H NMR(400MHz,CDCl 3)δ7.56(s,1H),7.41(dd,J＝14.0,6.6Hz,2H),7.11(t,J＝7.6Hz,1H),6.85(dd,J＝76.5,33.6Hz,1H),5.59–5.38(m,1H),5.07(d,J＝7.7Hz,1H),4.44(dt,J＝14.9,8.6Hz,2H),4.09(dd,J＝6.6,3.3Hz,2H),3.79(s,3H),3.62(d,J＝12.7Hz,1H),3.40(dd,J＝26.7,13.4Hz,1H),3.18(d,J＝1.7Hz,3H),2.85(dd,J＝26.6,13.1Hz,1H),2.66–2.33(m,4H),2.25(s,3H),2.05(s,3H),2.00–1.78(m,6H),1.55(d,J＝6.9Hz,3H). 13C NMR(101MHz,CDCl 3)δ167.94(s),161.16(s),149.30(s),146.65(s),137.43(s),128.14(s),126.68(s),124.47(s),123.44(s),116.93(s),98.20(s),70.07(s),66.92(s),58.41(s),49.24(s),45.98(s),45.14(s),41.35(s),36.36(s),33.63(s),32.09(s),30.93(s),29.79(s),28.68(s),20.95(s),20.41(s).
实施例18(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((S)-1-甲基吡咯烷-2-基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物18)
Figure PCTCN2022122241-appb-000190
化合物18以化合物8为原料，参照实施例11制备。ESI-MS m/z：644.4[M+1] +。
实施例19(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-(吡咯烷-1-基甲基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物19)
Figure PCTCN2022122241-appb-000191
化合物19以化合物9为原料，参照实施例11制备。ESI-MS m/z：644.3[M+1] +。
实施例20(R)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-4,10-二甲基-3,4-二氢-[1,4]噁嗪[3,2-h][1,6]萘啶-9(10H)-酮(化合物20)
Figure PCTCN2022122241-appb-000192
化合物20以化合物10为原料，参照实施例11制备。ESI-MS m/z：574.3[M+1] +。
实施例21(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物21)
Figure PCTCN2022122241-appb-000193
步骤1：
Figure PCTCN2022122241-appb-000194
参照实施例2步骤15的方法，由中间体(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-2-((二甲基氨基)甲基)-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮和原料(R)-1-(3-(二氟甲基)-2-甲基苯基)乙烷-1-胺盐酸盐(根据专利WO2019122129A1中描述的方法制备)反应制备。ESI-MS m/z：600.3[M+1] +。
步骤2：
Figure PCTCN2022122241-appb-000195
参照实施例11步骤1的方法制备。ESI-MS m/z：602.3[M+1] +。
步骤3：
Figure PCTCN2022122241-appb-000196
参照实施例11步骤2的方法制备得到化合物21。ESI-MS m/z：614.3[M+1] +。
参考实施例21的制备方法，使用适当的中间体和胺衍生物为原料，制备得到表1中实施例22～36，即化合物22～36。
表1实施例22～36
Figure PCTCN2022122241-appb-000197
Figure PCTCN2022122241-appb-000198
Figure PCTCN2022122241-appb-000199
Figure PCTCN2022122241-appb-000200
Figure PCTCN2022122241-appb-000201
实施例37(R)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-8-(1-甲基环丙基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(化合物37)
Figure PCTCN2022122241-appb-000202
步骤1：
Figure PCTCN2022122241-appb-000203
将8-溴-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(100mg，0.3mmol)，4,4,5,5-四甲基-2-(1-甲基环丙基)-1,3-二氧戊环(109mg，0.6mmol)，1,1-双(二苯基膦)二茂铁二氯化钯(24mg，0.03mmol)，碳酸钾(83mg，0.6mmol)溶于二氧六环(4mL)和水(1mL)，氮气保护，90℃搅拌反应16小时。冷却到室温后，旋干溶剂，残留物加水稀释，再用二氯甲烷萃取，有机相无水硫酸钠干燥，减压浓缩，制备薄层层析色谱(石油醚/乙酸乙酯＝1:1，体积比)，得到产物6-氯-10-甲基-8-(1-甲基环丙基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮，黄色固体(25mg，27％)。ESI-MS m/z：307.2[M+1] +。
步骤2：(R)-6-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-8-(1-甲基环丙基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000204
6-氯-10-甲基-8-(1-甲基环丙基)-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮(25mg，0.0847mmol)，甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(Brettphos Pd G3，7.7mg，0.00847mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(38mg，0.17mmol，根据专利WO2019122129A1中描述的方法制备)和叔丁醇钠(25mg，0.254mmol)溶于甲苯(3mL)，氮气保护，100℃搅拌反应14小时。冷却至室温后，减压浓缩，制备薄层层析色谱(二氯甲烷/甲醇＝20:1，体积比)得化合物37(5mg，收率12.8％)。ESI-MS m/z：460.1[M+1] +。
参考实施例37的制备方法，使用中间体8-溴-6-氯-10-甲基-2,3-二氢-[1,4]二噁烷[2,3-h][1,6]萘啶-9(10H)-酮和适当的硼酸酯或胺衍生物为原料，制备得到表2中实施例38～43，即化合物38～43。
表2实施例38～43
Figure PCTCN2022122241-appb-000205
Figure PCTCN2022122241-appb-000206
实施例44(R)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-8-(1-(二氟甲基)环丙基)-2-((二甲基氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-c][2,7]萘啶-9(8H)-酮(化合物44)
Figure PCTCN2022122241-appb-000207
步骤1：(R)-4-溴-6-氯-2-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)-3-((4-甲氧基苄基)氧基)吡啶
Figure PCTCN2022122241-appb-000208
在一1L三口瓶中装好低温温度计，机械搅拌以及恒压滴液漏斗。向其中加入氢化钠(60％，5.3g，0.1328mol)以及200mL无水N,N-二甲基甲酰胺。将反应物降至0℃，氩气保护下，向其中缓慢滴加(R)-甘油醇缩丙酮(13.2g,0.0996mol)溶于50mL无水N,N-二甲基甲酰胺的溶液。滴加完毕后， 反应液于0℃继续搅拌1小时。接着向其中缓慢滴加4-溴-6-氯-2-氟-3-((4-甲氧基苄基)氧基)吡啶(23g,0.0664mol)溶于100mL无水N,N-二甲基甲酰胺的溶液。滴加完毕后，反应液于0℃继续搅拌1小时。0℃下，反应液用100mL饱和氯化铵水溶液淬灭。反应液加入到乙酸乙酯(500mL)和水(300mL)中，萃取分层，有机层用水洗(200mL*3)，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝10:1，体积比)得到产物，白色固体(27.8g，收率91％)。ESI-MS m/z：458.0，460.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ7.39(d,J＝8.4Hz,2H),7.39(s,1H),6.91(d,J＝8.4Hz,2H),5.03(s,2H),4.46-4.52(m,1H),4.39(dd,J＝4.4Hz,J＝11.2Hz,1H),4.33(dd,J＝5.6Hz,J＝11.2Hz,1H),4.10(dd,J＝6.8Hz,J＝8.4Hz,1H),3.85(dd,J＝6.0Hz,J＝8.4Hz,1H),3.75(s,3H),1.36(s,3H),1.32(s,3H).
步骤2：(S)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇
Figure PCTCN2022122241-appb-000209
(R)-4-溴-6-氯-2-((2,2-二甲基-1,3-二氧戊环-4-基)甲氧基)-3-((4-甲氧基苄基)氧基)吡啶(27.8g,0.0606mol)溶于四氢呋喃(100mL)，再加入水(20mL)，向其中加入盐酸二氧六环溶液(4M,20mL,0.080mol)。反应液于室温下搅拌2小时。向反应液中加入水(100mL)，加入固体碳酸钾将pH调至8左右，旋干有机溶剂，用乙酸乙酯(200mL)萃取，有机相用饱和食盐水(50mL)洗完后用无水硫酸钠干燥，减压浓缩得到产物，白色固体(22.4g，收率88％)。ESI-MS m/z：418.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ7.40(d,J＝8.8Hz,2H),7.39(s,1H),6.92(d,J＝8.8Hz,2H),5.05(s,2H),4.37(dd,J＝4.0Hz,J＝11.2Hz,1H),4.25(dd,J＝6.0Hz,J＝10.8Hz,1H),3.88-3.93(m,1H),3.75(s,3H),3.73(t,J＝4.4Hz,1H),3.51(d,J＝5.6Hz,2H).
步骤3：(R)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇二甲磺酸酯
Figure PCTCN2022122241-appb-000210
(S)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇(22.4g，0.0535mol)和三乙胺(32.5g，0.321mol)加入到二氯甲烷(150mL)中，降温至0℃。向反应液中缓慢滴加甲磺酰氯(18.4g,0.1605mol)。加完后，反应液于0℃继续搅拌1小时。将反应液减压浓缩，加入水(100mL)，用乙酸乙酯(200mL)萃取，有机相用无水硫酸钠干燥，减压浓缩，得到产物，棕色液体(27.9g，收率90％)。ESI-MS m/z：574.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ7.48(s,1H),7.41(d,J＝8.4Hz,2H),6.93(d,J＝8.8Hz,2H),5.33-5.37(m,1H),5.03(s,2H),4.63(dd,J＝3.2Hz,J＝11.6Hz,2H),4.57(dd,J＝6.0Hz,J＝15.2Hz,1H),4.54(dd,J＝6.0Hz,J＝14.8Hz,1H),3.76(s,3H),3.28(s,3H),3.28(s,3H).
步骤4：(R)-3-((4-溴-6-氯-3-羟基吡啶-2-基)氧基)丙烷-1,2-二醇二甲磺酸酯
Figure PCTCN2022122241-appb-000211
(R)-3-((4-溴-6-氯-3-((4-甲氧基苄基)氧基)吡啶-2-基)氧基)丙烷-1,2-二醇二磺酸酯(27.9g,0.0485mol)溶于二氯甲烷(50mL)，向其中加入三氟乙酸(44.7g,0.392mol)。反应液于室温下搅拌2小时。将反应液减压浓缩，用饱和碳酸氢钠水溶液调至中性，乙酸乙酯(150mL)萃取，有机相用无水硫酸钠干燥，残留物硅胶柱层析(石油醚/乙酸乙酯＝1:1，体积比)，得到产物，白色固体(11.5g，收率52％)。ESI-MS m/z：453.9[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ10.28(s,1H),7.36(s,1H),5.18-5.23(m,1H),6.70(dd,J＝6.4Hz,J＝11.6Hz,1H),4.61(dd,J＝3.2Hz,J＝11.6Hz,1H),4.57(dd,J＝4.4Hz,J＝12.4Hz,1H),4.51(dd,J＝4.8Hz,J＝12.0Hz,1H),3.30(s,3H),3.26(s,3H).
步骤5：(S)-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基甲磺酸酯
Figure PCTCN2022122241-appb-000212
(R)-3-((4-溴-6-氯-3-羟基吡啶-2-基)氧基)丙烷-1,2-二醇二甲磺酸酯(11.5g，0.0253mol)溶于N,N-二甲基甲酰胺(150mL)，加入碳酸钾(7.0g,0.0506mol)，加热至60℃搅拌2小时。反应液倒入水(300mL)中，乙酸乙酯(300mL)萃取，有机相用100mL*3水洗，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝1:1，体积比)，得到产物，白色固体(7.5g，收率83％)。ESI-MS m/z：357.9[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ7.48(s,1H),4.72-4.76(m,1H),4.61(dd,J＝2.8Hz,J＝12.0Hz,1H),4.58(dd,J＝2.0Hz,J＝10.4Hz,1H),4.48(dd,J＝6.0Hz,J＝11.6Hz,1H),4.34(dd,J＝6.8Hz,J＝11.6Hz,1H),3.26(s,3H).
步骤6：(R)-1-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)-N-(2,4-二甲氧基苄基)甲胺
Figure PCTCN2022122241-appb-000213
(S)-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲基甲磺酸酯(8.9g,0.0248mol)，2，4-二甲基苄胺(10g,0.0744mol)以及三乙胺(19.4g,0.192mol)溶于N,N-二甲基乙酰胺(150mL)，加热至100℃搅拌过夜。将反应液倒入水中(300mL)，乙酸乙酯(300mL)萃取，有机相用水洗，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝1:1，体积比)，得到产物，无色液体(7.4g，收率69.4％)。ESI-MS m/z：451.1[M+Na] +。 1H NMR(400MHz,DMSO-d 6)δ7.42(s,1H),7.17(d,J＝8.0Hz,1H),6.53(d,J＝2.4Hz,1H),6.47(dd,J＝2.4Hz,J＝8.0Hz,1H),4.55(dd,J＝2.4Hz,J＝11.6Hz,1H),4.28-4.43(m,1H),4.27(dd,J＝7.2Hz,J＝11.6Hz,1H),3.77(s,3H),3.74(s,3H),3.64(dd,J＝13.6 Hz,J＝20.8Hz,2H),2.72-2.80(m,2H),2.14(s,1H).
步骤7：(R)-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲胺
Figure PCTCN2022122241-appb-000214
(R)-1-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)-N-(2,4-二甲氧基苄基)甲胺(7.4g,0.0172mol)与三氟乙酸(148.9g,1.306mol)混合，加热至回流过夜。将反应液减压浓缩，得到产物，蓝紫色液体(6.8g，收率100％)，直接用于下一步反应。ESI-MS m/z：278.9[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ8.16(s,3H),7.51(s,1H),4.64-4.69(m,1H),4.57(dd,J＝2.8Hz,J＝12.0Hz,1H),4.35(dd,J＝6.0Hz,J＝12.0Hz,1H),3.25-3.31(m,1H),3.13-3.19(m,1H).
步骤8：(R)-1-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)-N,N-二甲基甲胺
Figure PCTCN2022122241-appb-000215
将步骤7得到的(R)-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)甲胺粗品(6.8g，0.0172mol)溶于甲醇(80mL)中，加入甲醛(40％水溶液,12.8g,0.170mol)以及醋酸(0.1g,0.0017mol)。室温下搅拌10分钟，然后缓慢加入三乙酰基硼氢化钠(36.0g，0.17mol)。反应液于室温下继续搅拌1小时。反应液减压浓缩，加入水(80mL),用浓盐酸将pH调至1左右，乙酸乙酯(100mL)萃取，弃去有机相，水相用固体碳酸钾将pH调至8左右，乙酸乙酯(100mL)萃取，有机相用无水硫酸钠干燥后减压浓缩，得到产物，无色液体(4.3g，收率81％)。ESI-MS m/z：307.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ7.43(s,1H),4.64-4.69(m,1H),4.50(dd,J＝4.8Hz,J＝10.4Hz,1H),4.23(dd,J＝7.6Hz,J＝12.0Hz,1H),2.63(dd,J＝5.2Hz,J＝13.2Hz,1H),2.56(dd,J＝7.2Hz,J＝13.2Hz,1H),2.27(s,6H).
步骤9：(R)-8-溴-6-氯-2-((二甲基氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-7-甲醛
Figure PCTCN2022122241-appb-000216
(R)-1-(8-溴-6-氯-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-2-基)-N,N-二甲基甲胺(4.5g,0.0146mol)溶于无水四氢呋喃(63mL)中，氩气保护，将内温降至-40℃。向其中缓慢滴加二异丙基氨基锂(2M四氢呋喃溶液,23mL,0.046mol)。滴加完毕后，将反应液保持在内温-40℃至-50℃，继续搅拌2小时。将反应液内温降至-70℃，然后向其中缓慢滴加无水N,N-二甲基甲酰胺(8.8g，0.120mol)。滴加完毕后保持内温在-70℃，继续搅拌2小时。反应液保持在内温-70℃，用乙酸(6mL)淬灭反应，接着加入水(5mL)。将反应液升至室温，加入水(50mL)，用乙酸乙酯(100mL)萃取，有机相用无水硫 酸钠干燥，减压浓缩。残留物硅胶柱层析(石油醚/乙酸乙酯＝1:8，体积比)，得到产物，浅黄色固体(1.51g，收率31％)。ESI-MS m/z：335.0[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ10.15(s,1H),4.61(dd,J＝2.8Hz,J＝12.0Hz,1H),4.55-4.60(m,1H),4.34(dd,J＝7.2Hz,J＝11.6Hz,1H),2.64(dd,J＝5.2Hz,J＝13.6Hz,1H),2.56(dd,J＝7.2Hz,J＝13.2Hz,1H),2.27(s,6H).
步骤10：乙基(R)-2-(6-氯-2-((二甲基氨基)甲基)-7-甲酰基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-基)乙酸乙酯
Figure PCTCN2022122241-appb-000217
(R)-8-溴-6-氯-2-((二甲基氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-7-甲醛(330mg,0.98mmol)，丙二酸二甲酯(259mg,1.96mmol)，2-吡啶甲酸(24mg,0.196mmol)，碘化亚铜(19mg,0.098mmol)和碳酸钾(406mg,2.94mmol)加入到无水DMSO(15mL)中，氩气保护，反应液于90℃加热1小时。将反应液倒入水(30mL)中，用乙酸乙酯(30mL)萃取，有机层弃去，水相用稀盐酸调至pH＝1左右，减压浓缩。残留物中加入乙醇(50mL)，接着缓慢加入浓硫酸(3mL)，室温下搅拌1小时。反应液减压浓缩蒸去乙醇，加入水(50mL)，用固体碳酸钾将pH调至8，乙酸乙酯(50mL)萃取，无水硫酸钠干燥，减压浓缩，得到产物，无色液体(85mg，收率25％)。ESI-MS m/z：343.1[M+1] +。
步骤11：(R)-6-氯-8-(1-(二氟甲基)环丙烷)-2-((二甲基氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-c][2,7]萘啶-9(8H)-酮
Figure PCTCN2022122241-appb-000218
将(R)-2-(6-氯-2-((二甲基氨基)甲基)-7-甲酰基-2,3-二氢-[1,4]二噁烷[2,3-b]吡啶-8-基)乙酸乙酯(85mg,0.25mmol)，1-(二氟甲基)环丙基-1-胺盐酸盐(72mg,0.50mmol)，磷酸钾(53mg,0.25mmol)，2,2,2-三氟乙醇(50mg,0.50mmol)加入到无水四氢呋喃(10mL)中，反应液于封管中100℃加热2小时。将反应液降至室温，过滤除去固体，滤液减压浓缩后加入无水二氧六环(10mL)中，加入四氯化锆(58mg,0.25mmol)，于封管中100℃加热过夜。反应液降至室温，加入饱和碳酸钾水溶液(10mL)，乙酸乙酯(50mL)萃取，无水硫酸钠干燥，减压浓缩后残留物通过制备薄层色谱纯化，得到产物，橙黄色固体(22mg，23％)。ESI-MS m/z：386.1[M+1] +。 1H NMR(400MHz,DMSO-d 6)δ8.68(s,1H),6.50(s,1H),6.29(t,J＝56.4Hz,1H),4.53-4.70(m,1H),4.52(dd,J＝4.0Hz,J＝11.6Hz,1H),4.22(dd,J＝6.4Hz,J＝11.6Hz,1H),3.08(dd,J＝8.0Hz,J＝16.0Hz,1H),2.74(dd,J＝4.0Hz,J＝12.0Hz,1H),2.50 (s,6H),1.24(m,4H).
步骤12：(R)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-8-(1-(二氟甲基)环丙基)-2-((二甲基氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-c][2,7]萘啶-9(8H)-酮(化合物44)
Figure PCTCN2022122241-appb-000219
(R)-6-氯-8-(1-(二氟甲基)环丙烷)-2-((二甲基氨基)甲基)-2,3-二氢-[1,4]二噁烷[2,3-c][2,7]萘啶-9(8H)-酮(13mg,0.0337mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙基-1-胺(13mg,0.0674mmol)，甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(Brettphos Pd G3,3mg,0.00337mmol)，叔丁醇钠(13mg,0.135mmol)加入到无水二氧六环(3mL)中，氩气保护，90℃加热2小时。反应液用饱和氯化铵水溶液(10mL)淬灭，乙酸乙酯(20mL)萃取，无水硫酸钠干燥，减压浓缩，残留物通过制备HPLC纯化得到产品，黄色固体(3mg)。ESI-MS m/z：539.2[M+1] +。
参考实施例44的制备方法，使用适当的原料，制备得到表3中实施例45～70，即化合物45～70。
表3实施例45～70
Figure PCTCN2022122241-appb-000220
Figure PCTCN2022122241-appb-000221
Figure PCTCN2022122241-appb-000222
Figure PCTCN2022122241-appb-000223
Figure PCTCN2022122241-appb-000224
Figure PCTCN2022122241-appb-000225
Figure PCTCN2022122241-appb-000226
Figure PCTCN2022122241-appb-000227
Figure PCTCN2022122241-appb-000228
实施例71(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(化合物71)
Figure PCTCN2022122241-appb-000229
步骤1：(R)-4-(6-氯-3-甲氧基吡啶-2-基)-1-((4-甲氧苄基)氧基)丁醇
Figure PCTCN2022122241-appb-000230
将二异丙基氨基锂(106.5mL，213mmol，2.0M in THF)于-70℃下加入到四氢呋喃溶液(150mL)中，氮气保护下于-70℃滴加6-氯-3-甲氧基-2-甲基吡啶(21g，133mmol)的四氢呋喃溶液(50mL)。反应-70℃下搅拌1小时，随后-70℃下滴加(R)-2-((4-甲氧基苄基)氧基)甲基)环氧乙烷(26g，133mmol)的四氢呋喃溶液(50mL)，反应升至室温搅拌16小时。反应液加入饱和氯化铵(600mL)和水(600mL)稀释，乙酸乙酯(500mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝2:1，体积比)得到产物，黄色液体(34.5g，收率74％)。ESI-MS m/z：352.1[M+H] +。 1H NMR(400MHz,Chloroform-d)δ7.31-7.22(m,2H),7.12(d,J＝8.6Hz,1H),7.08(d,J＝8.6Hz,1H),4.48(s,2H),3.82(s,3H),3.81(s,3H),3.49(dd,J＝9.5,3.7Hz,1H),3.39(dd,J＝9.5,7.3Hz,1H),3.07-2.81(m,2H),2.53(brs,1H),1.97-1.73(m,2H).
步骤2：(R)-6-氯-2-(3-羟基-4-((4-甲氧基苄基)氧基)丁基)吡啶-3-醇
Figure PCTCN2022122241-appb-000231
将(R)-4-(6-氯-3-甲氧基吡啶-2-基)-1-((4-甲氧苄基)氧基)丁醇(34.5g，98.0mmol)溶于N,N-二甲基甲酰胺(350mL)，加入氢氧化钠(23.5g，588mmol)和十二硫醇(59g，294mmol)， 反应升至80℃搅拌6小时。反应液加入饱和氯化铵(600mL)和水(600mL)稀释，乙酸乙酯(500mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:2，体积比)得到产物，无色液体(28g，收率85％)。ESI-MS m/z：352.1[M+H] +。 1H NMR(400MHz,Chloroform-d)δ7.25-7.19(m,2H),7.17(d,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),6.93-6.83(m,2H),4.45(d,J＝1.7Hz,2H),3.81(s,3H),3.74-3.63(m,1H),3.47(dd,J＝9.5,3.0Hz,1H),3.30(dd,J＝9.5,8.2Hz,1H),3.14-3.03(m,1H),2.90-2.81(m,1H),1.96-1.84(m,1H),1.84-1.74(m,1H).
步骤3：(R)-4-溴-6-氯-2-(3-羟基-4-((4-甲氧基苄基)氧基)丁基)吡啶-3-醇
Figure PCTCN2022122241-appb-000232
将(R)-6-氯-2-(3-羟基-4-((4-甲氧基苄基)氧基)丁基)吡啶-3-醇(12.8g，27.9mmol)溶于二氯甲烷(300mL)，加入醋酸钠(15.2g，186mmol)和三溴化吡啶(29.7g，92.7mmol)，反应室温搅拌1小时。加入饱和亚硫酸钠水溶液(600mL)稀释，乙酸乙酯(500mL X 2)萃取。有机相用稀盐酸(300mL，1M in H 2O)洗涤，碳酸氢钠水溶液(300mL)洗涤，无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，黄色液体(31g，收率89％)。ESI-MS m/z：337.1[M+1] +。 1H NMR(400MHz,Chloroform-d)δ7.36(s,1H),7.25-7.19(m,2H),6.98-6.84(m,2H),4.54-4.40(m,2H),3.81(s,3H),3.76-3.68(m,1H),3.48(dd,J＝9.5,3.0Hz,1H),3.30(dd,J＝9.5,8.1Hz,1H),3.15-3.03(m,1H),2.96-2.85(m,1H),1.98-1.85(m,1H),1.85-1.74(m,1H).
步骤4：(S)-8-溴-6-氯-2-((4-甲氧基苄基)氧基)甲基)-3,4-二氢-2H-吡喃[3,2-b]吡啶
Figure PCTCN2022122241-appb-000233
将(R)-4-溴-6-氯-2-(3-羟基-4-((4-甲氧基苄基)氧基)丁基)吡啶-3-醇(31g，74.3mmol)溶于四氢呋喃(300mL)，氮气保护0℃下加入三苯基膦(29g，111mmol)和偶氮二甲酸二异丙酯(30g，149mmol)。反应升至室温搅拌2小时。加入水(500mL)稀释，加乙酸乙酯(500mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝5:1，体积比)得到产物，黄色液体(25.5g，收率86％)。ESI-MS m/z：397.1[M+1] +。
步骤5：(S)-(8-溴-6-氯-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲醇
Figure PCTCN2022122241-appb-000234
将(S)-8-溴-6-氯-2-((4-甲氧基苄基)氧基)甲基)-3,4-二氢-2H-吡喃[3,2-b]吡啶溶(25.5g，63.9mmol)于二氯甲烷(70mL)，加入三氟乙酸(70mL)，室温下搅拌1小时。反应液旋干，加入饱和碳酸氢钠水溶液(300mL)稀释，加乙酸乙酯(500mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/乙酸乙酯＝3:1，体积比)得到产物，黄色液体(14.5g，收率82％)。ESI-MS m/z：278.0[M+1] +。
步骤6：(S)-(8-溴-6-氯-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基甲磺酸酯
Figure PCTCN2022122241-appb-000235
将(S)-(8-溴-6-氯-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲醇(14.5g，52.0mmol)，溶于二氯甲烷(150mL)，0℃下加入三乙胺(7.9g，78.0mmol)和甲基磺酰氯(7.1g，62.4mmol)，0℃下搅拌0.5小时。0℃下加入水(200mL)稀释，加乙酸乙酯(500mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，黄色固体(17g，收率92％，粗品)。ESI-MS m/z：356.0[M+1] +。
步骤7：(S)-6-氯-N-甲基-2-((甲氨基)甲基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-8-胺
Figure PCTCN2022122241-appb-000236
将(S)-(8-溴-6-氯-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基甲磺酸酯(17g，47.6mmol)溶于1，4-二氧六环(100mL)，加入甲胺水溶液(200mL，23％in H 2O)，120℃封管搅拌20小时。冷却至室温后，减压浓缩，残留物直接用于下一步反应。ESI-MS m/z：242.2[M+1] +。
步骤8：叔丁基(S)-(6-氯-8-(甲氨基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000237
将步骤7得到产物粗品溶于四氢呋喃(300mL)，加入三乙胺(9.6g，95.2mmol)和二碳酸二叔丁酯(21g，95.2mmol)，室温下搅拌2小时。加入水(300mL)稀释，加乙酸乙酯(500mL)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，无色液体(15g，收率92％)。ESI-MS m/z：342.2[M+1] +。
步骤9：叔丁基(S)-(6-氯-7-碘-8-(甲氨基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000238
将叔丁基(S)-(6-氯-8-(甲氨基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯(15.0g，43.9mmol)溶于乙酸(50mL)，加入N-碘代丁二酰亚胺(10.8g，18.2mmol)，室温搅拌16小时。加入饱和亚硫酸钠水溶液(200mL)稀释，加入饱和碳酸氢钠水溶液(300mL)中和，加乙酸乙酯(500mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝4:1，体积比)得到产物，无色液体(18g，收率88％)。ESI-MS m/z：468.1[M+1] +。 1H NMR(400MHz,Chloroform-d)δ4.70(brs,1H),4.26-4.14(m,1H),3.76-3.58(m,1H),3.38(dd,J＝14.6,4.5Hz,1H),3.22(s,3H),2.96(s,3H),2.93-2.85(m,2H),2.06(d,J＝10.6Hz,1H),1.88-1.75(m,1H),1.45(d,J＝8.3Hz,9H).
步骤10：叔丁基(S，E)-(6-氯-7-碘-8-(甲氨基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000239
将叔丁基(S)-(6-氯-7-碘-8-(甲氨基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基)(甲基)氨 基甲酸酯(18g，38.5mmol)，醋酸钯(860mg，3.85mmol)，三(邻甲基苯基)磷(2.3mg，7.69mmol)，三乙胺(7.7g，76.9mmol)和丙烯酸乙酯(11.5g，115mmol)，溶于N,N-二甲基甲酰胺(150mL)。氮气保护，95℃搅拌反应6小时。冷却至室温后，加入水(500mL)稀释，加乙酸乙酯(500mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，黄色液体(15g，收率89％)。ESI-MS m/z：440.2[M+1] +。
步骤11：叔丁基(S)-(6-氯-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000240
将叔丁基(S，E)-(6-氯-7-碘-8-(甲氨基)-3,4-二氢-2H-吡喃[3,2-b]吡啶-2-基)甲基)(甲基)氨基甲酸酯(15g，34.1mmol)溶于乙醇(25mL)，加入甲硫醇钠(2.6g，37.5mmol)，室温搅拌0.5小时。减压旋干溶剂，残留物加入水(300mL)稀释，加乙酸乙酯(400mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，得到产物，残留物硅胶柱层析(石油醚/乙酸乙酯＝3:1，体积比)得到产物，黄色液体(10g，收率75％)。ESI-MS m/z：394.2[M+1] +。 1H NMR(400MHz,Chloroform-d)δ8.01(d,J＝9.6Hz,1H),6.74(d,J＝9.6Hz,1H),4.30(d,J＝10.8Hz,1H),3.94(s,3H),3.86-3.68(m,1H),3.41(d,J＝13.6Hz,1H),3.12-3.01(m,2H),2.97(s,3H),2.18(d,J＝13.8Hz,1H),1.98-1.83(m,1H),1.46(s,9H).
步骤12：叔丁基(S)-(8-溴-6-氯-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000241
将叔丁基(S)-(6-氯-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(10g，25.4mmol)溶于N,N-二甲基甲酰胺(100mL)，加入N-溴代丁二酰亚胺(13.5g，76.1mmol)，反应70℃下搅拌2小时。加入饱和亚硫酸钠水溶液(200mL)稀释，加乙酸乙酯(300mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(石油醚/乙酸乙酯＝2:1，体积比)得到产物，白色固体(5.0g，收率42％)。ESI-MS m/z：472.1[M+1] +。 1H NMR(400MHz,Chloroform-d)δ8.45(s,1H),4.31(brs,1H),4.01(s,3H),3.88-3.62(m,1H),3.49-3.30(m,1H),3.13-3.00(m,2H),2.97(s,3H),2.19(d,J＝14.3Hz,1H),1.99-1.85(m,1H),1.46(s,9H).
步骤13：叔丁基(S)-(8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000242
将叔丁基(S)-(8-溴-6-氯-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(500mg，1.05mmol)和1-乙酰哌啶-4-酮(596mg，4.23mmol)溶于四氢呋喃(20mL)，氮气保护，于-30℃下滴加碘化钐(42mL，4.23mmol，0.1M in THF)。反应-30℃下搅拌0.5小时。-30℃下加入饱和氯化铵水溶液(100mL)稀释，加乙酸乙酯(200mL X 2)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝20:1，体积比)得到产物，黄色固体(800mg，收率71％)。ESI-MS m/z：479.3[M-56] +。 1H NMR(400MHz,Chloroform-d)δ7.92(s,1H),4.61(s,1H),4.30(s,1H),3.97(s,3H),3.92-3.81(m,2H),3.77(t,J＝6.4Hz,1H),3.49-3.32(m,2H),3.09(dd,J＝10.0,6.0Hz,2H),2.97(s,3H),2.49(q,J＝6.8Hz,2H),2.20-2.15(m,7H),1.99-1.79(m,3H),1.45(d,J＝14.7Hz,9H).
步骤14：叔丁基(((S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯
Figure PCTCN2022122241-appb-000243
将叔丁基(S)-(8-(1-乙酰基-4-羟基哌啶-4-基)-6-氯-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(260mg，0.486mmol)，甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(44mg，0.049mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺(277mg，1.46mmol)和叔丁醇钠(140mg，1.46mmol)溶于甲苯(8mL)，氮气保护，100℃搅拌反应2小时。冷却至室温后，减压浓缩，残留物硅胶柱层析(二氯甲烷/ 甲醇＝20:1，体积比)得到产品，黄色固体(267mg，收率80％)。ESI-MS m/z：688.3[M+1] +。
步骤15：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-2-((甲氨基)甲基)-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000244
将叔丁基(((S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-10-甲基-9-氧代-3,4,9,10-四氢-2H-吡喃[3,2-h][1,6]萘啶-2-基)甲基)(甲基)氨基甲酸酯(400mg，0.580mmol)，溶于二氯甲烷(3mL)，加入三氟乙酸(1mL)，室温搅拌1小时。减压浓缩，残留物直接用于下一步反应。ESI-MS m/z：588.3[M+1] +。
步骤16：(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000245
将步骤15得到的产物粗品溶于四氢呋喃(15mL)，加入甲醛水溶液(3mL，30％in H 2O)，加入三乙酰氧基硼氢化钠(246mg，1.16mmol)，室温下搅拌0.5小时。加入饱和氯化钠钠水溶液(100mL)稀释，加二氯甲烷(150mL X 3)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物硅胶柱层析(二氯甲烷/甲醇＝15:1，体积比)得到产物，黄色固体(300mg，收率86％)。ESI-MS m/z：602.3[M+1] +。 1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.55(s,1H),7.53-7.46(m,1H),7.43(t,J＝7.2Hz,1H),7.15(t,J＝7.6Hz,1H),6.91(t,J＝55.2Hz,1H),5.82(s,1H),5.51(p,J＝6.8Hz,1H),5.08(d,J＝6.4Hz,1H),4.58(d,J＝12.8Hz,1H),4.13(brs,1H),3.91(s,3H),3.69(brs,2H),3.15(t,J＝11.4Hz,1H),3.05(dd,J＝12.8,7.2Hz,1H),2.91(dd,J＝12.8,3.6Hz,1H),2.86-2.67(m,2H),2.50(d,J＝3.7Hz,6H), 2.30-2.16(m,2H),2.13(d,J＝2.9Hz,3H),2.10-1.99(m,2H),1.99-1.84(m,2H),1.82-1.69(m,1H),1.62(d,J＝6.8Hz,3H).
步骤17：(S)-8-(1-乙酰基-4-氟哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000246
将(S)-8-(1-乙酰基-4-羟基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(350mg，0.581mmol)溶于二氯甲烷(15mL)，氮气保护，0℃下加入二乙氨基三氟化硫(187mg，1.16mmol)。反应0℃搅拌2小时。加入水(50mL)稀释，加二氯甲烷(50mL X 3)萃取。有机相用无水硫酸钠干燥，减压浓缩，残留物直接用于下一步反应。ESI-MS m/z：604.3[M+1] +。
步骤18：(S)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮
Figure PCTCN2022122241-appb-000247
将步骤17制备得到的产物粗品溶于甲醇(15mL)，加入甲醇钠的甲醇溶液(1.08g，5.81mmol，30％w.t.in MeOH)。反应液在40℃下搅拌48小时。冷却至室温后，减压浓缩，残留物通过制备HPLC纯化得到产品，黄色固体(55mg，收率15％)。ESI-MS m/z：616.4[M+1] +。 1H NMR(400MHz,Chloroform-d)δ8.21(s,1H),7.68(d,J＝2.0Hz,1H),7.56-7.39(m,2H),7.15(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),5.50(s,1H),4.93(s,1H),4.58(d,J＝13.0Hz,1H),4.18(s,1H),3.85(d,J＝1.7Hz,2H),3.70(d,J＝13.5Hz,1H),3.58-3.39(m,1H),3.27(s,3H),2.95(q,J＝14.2Hz,1H),2.87-2.72(m,3H),2.73-2.58(m,1H),2.48(d,J＝3.9Hz,6H),2.19-2.13(m,1H),2.13(s,3H),2.02(t,J＝11.6Hz,1H),1.97-1.80(m,2H), 1.63(d,J＝7.0Hz,3H).
实施例72(R)-8-(1-乙酰基-4-甲氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(化合物72)
Figure PCTCN2022122241-appb-000248
化合物72的合成参照实施例71的步骤制备，只是将步骤1中原料(R)-2-((4-甲氧基苄基)氧基)甲基)环氧乙烷替换为(S)-2-((4-甲氧基苄基)氧基)甲基)环氧乙烷。ESI-MS m/z：616.4[M+1] +。 1H NMR(400MHz,Chloroform-d)δ7.68(s,1H),7.50(q,J＝6.8Hz,1H),7.43(t,J＝7.2Hz,1H),7.15(t,J＝7.6Hz,1H),6.90(t,J＝55.2Hz,1H),5.50(d,J＝7.2Hz,1H),4.93(brs,1H),4.58(d,J＝13.2Hz,1H),4.10(brs,1H),3.87(s,3H),3.70(d,J＝11.2Hz,1H),3.49(t,J＝13.2Hz,1H),3.26(s,3H),2.98-2.82(m,2H),2.74(dd,J＝13.2,6.0Hz,1H),2.70-2.61(m,2H),2.61-2.44(m,5H),2.40(s,6H),2.13(s,4H),2.03(d,J＝13.2Hz,1H),1.88(d,J＝14.0Hz,1H),1.85-1.76(m,1H),1.62(d,J＝7.2Hz,3H).
实施例73(S)-8-(1-乙酰基-4-乙氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(化合物73)
Figure PCTCN2022122241-appb-000249
化合物73的合成参照实施例71的步骤制备，只是将步骤18中的甲醇钠替换为乙醇钠。ESI-MS m/z：630.3[M+1] +。
实施例74(S)-8-(1-乙酰基-4-异丙氧基哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(化合物74)
Figure PCTCN2022122241-appb-000250
化合物74的合成参照实施例71的步骤制备，只是将步骤18中的甲醇钠替换为异丙醇钠。ESI-MS m/z：644.3[M+1] +。
实施例75(S)-8-(1-乙酰基-4-(2-羟基乙氧基)哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(化合物75)
Figure PCTCN2022122241-appb-000251
化合物75的合成参照实施例71的步骤制备，只是将步骤18中的甲醇钠替换为羟基乙醇钠。ESI-MS m/z：646.3[M+1] +。
实施例76(S)-8-(1-乙酰基-4-(2,2,2,-三氟乙氧基)哌啶-4-基)-6-(((R)-1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-((二甲基氨基)甲基)-10-甲基-3,4-二氢-2H-吡喃[3,2-h][1,6]萘啶-9(10H)-酮(化合物76)
Figure PCTCN2022122241-appb-000252
化合物76的合成参照实施例71的步骤制备，只是将步骤18中的甲醇钠替换为三氟乙醇钠。ESI-MS m/z：684.3[M+1] +。
II.本发明化合物活性测试实施例
测试实施例1：化合物对NCI-H358和MIA PaCa-2肿瘤细胞株在3D培养条件下的细胞生长抑制作用
细胞来源：NCI-H358购自上海迪津生物科技有限公司；MIA PaCa-2购自上海迪奥生物科技有限公司。
取处于对数生长期的细胞接种在超低吸附96孔板中(NCI-H358,MIA PaCa-2细胞分别为4000,2000个/孔,180μl/孔)，于37℃、5％CO 2培养，使细胞聚集形成微球，1天后加入梯度稀释的待测化合物。具体如下：取事先溶解在DMSO中的化合物储存液(10mM)，倍比(4倍)稀释为10个梯度浓度，并用培养基在另一96孔板中稀释到目的浓度的10倍，然后在接种细胞的96孔板中加入化合物溶液20μl/孔，即到达目的浓度(10000,2500,625,156,39,10,2.5,0.6,0.15,0.04nM)。每个浓度设3个复孔，并设空白对照。放入37℃、5％CO 2中继续培养6天后，每孔加入50μl
Figure PCTCN2022122241-appb-000253
3D试剂(用于检测3D细胞微球的荧光素酶ATP生物发光检测试剂，购自Promega,货号G9683)，震荡10min，室温孵育20min后，检测荧光发光强度(收光时间为100ms)。计算各浓度化合物对3D细胞微球的活性抑制率，细胞活性抑制率(％)＝[(发光强度 6天含细胞培养基对照组-发光强度 6天化合物组)/(发光强度 6天含 细胞培养基对照组–发光强度 6天无细胞培养基对照组)]×100％。使用GraphPad Prism 8.3软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC 50值。结果见表4。
表4
Figure PCTCN2022122241-appb-000254
“--”表示未测试；
其中，BI-3406为文献报道的SOS1抑制剂(Cancer Discovery 2021(11)142-157)。
本发明的化合物对NCI-H358和MIA PaCa-2肿瘤细胞株表现出良好的细胞生长抑制作用。

Claims (16)

  1. 一种如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，
    Figure PCTCN2022122241-appb-100001
    其中：
    X和Y各自独立地为-O-、-S-、-NH-或-CH 2-；
    Z为-CR 10或N；
    L为单键、-C(＝O)-、-C(＝O)O-、-C(＝O)NR 8-、-NR 8-、-S-、-O-、-S(O)-、-S(O) 2-或-(CH 2) p-；
    环A为C 6-12芳基、5-10元杂芳基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
    每个R 1独立地为氘、羟基、卤素、-N(R 7) 2、-SR 9、氰基、氧代(＝O)、硝基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 1a取代的C 1-6烷基、被一个或多个R 1b取代的C 1-6烷基-O-、被一个或多个R 1c取代的C 2-6烯基、被一个或多个R 1d取代的C 2-6炔基、C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 6-12芳基、被一个或多个R 1g取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 1h取代的5-10元杂芳基、C 3-7环烯基、被一个或多个R 1i取代的C 3-7环烯基、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-S(O)-N(R 7) 2、-S(O)-R 9、-NR 8-S(O)-R 9、-NR 8-S(O)-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9，或两个R 1与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基；
    每个R 1a、R 1b、R 1c、R 1d、R 1e、R 1f、R 1g、R 1h和R 1i各自独立地为氘、羟基、卤素、-N(R 7) 2、-SR 9、硝基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 1-a取代的C 1-6烷基、被一个或多个R 1-b取代的C 1-6烷基-O-、被一个或多个R 1-c取代的C 2-6烯基、被一个或多个R 1-d取代的C 2- 6炔基、C 3-7环烷基、C 3-7环烷基-O-、3-7元杂环基、3-7元杂环基-O-、被一个或多个R 1-e取代的C 3-7环烷基或C 3-7环烷基-O-、被一个或多个R 1-f取代的3-7元杂环基或3-7元杂环基-O-、C 6-12芳基、被一个或多个R 1-g取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 1-h取代的5-10元杂芳基、C 3-7环烯基、C 3-7环烯基-O-、被一个或多个R 1-i取代的C 3-7环烯基或C 3-7环烯基-O-、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-S(O)-N(R 7) 2、-S(O)- R 9、-NR 8-S(O)-R 9、-NR 8-S(O)-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9；
    每个R 1-a、R 1-b、R 1-c、R 1-d、R 1-e、R 1-f、R 1-g、R 1-h和R 1-i各自独立地为氘、羟基、卤素、-N(R 7) 2、-SR 9、硝基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
    环D为C 6-12芳基、5-6元杂芳基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
    R 2为不存在、氢、氘、羟基、卤素、氨基、氰基、氧代、硝基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
    R 3为氢、氘、C 1-6烷基、被一个或多个R 3a取代的C 1-6烷基、C 2-6烯基、被一个或多个R 3b取代的C 2-6烯基、C 2-6炔基、被一个或多个R 3c取代的C 2-6炔基、C 3-7环烷基、被一个或多个R 3d取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3e取代的3-7元杂环基、C 6-12芳基、被一个或多个R 3f取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 3g取代的5-10元杂芳基、C 3-7环烯基或被一个或多个R 3h取代的C 3-7环烯基；
    每个R 3a、R 3b、R 3c、R 3d、R 3e、R 3f、R 3g和R 3h各自独立地为氘、羟基、卤素、-N(R 7) 2、氰基、硝基、C 1-6烷基、被一个或多个R 3-a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 3-c取代的C 2-6烯基、被一个或多个R 3-d取代的C 2-6炔基、C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3-f取代的3-7元杂环基、C 6-12芳基、被一个或多个R 3-g取代的C 6-12芳基、5-10元杂芳基、被一个或多个R 3-h取代的5-10元杂芳基、C 3-7环烯基、被一个或多个R 3-i取代的C 3-7环烯基、-SR 9、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-S(O)-N(R 7) 2、-S(O)-R 9、-NR 8-S(O)-R 9、-NR 8-S(O)-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9，或两个R 3d、两个R 3e、两个R 3f、两个R 3g或两个R 3h与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3-f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3-i取代的C 3-7环烯基；
    每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-g、R 3-h和R 3-i各自独立地为氘、羟基、卤素、-N(R 7) 2、硝基、氰基、C 1-6烷基、C 1-6烷基-O-、C 3-7环烷基、C 3-7环烯基、3-7元杂环基、-SR 9、-C(＝O)-O-R 9、-O-C(＝O)-R 9、-C(＝O)-N(R 7) 2、-S(O) 2-R 9、-NR 8-S(O) 2-R 9、-NR 8-S(O) 2-N(R 7) 2、-S(O) 2-N(R 7) 2、-C(＝O)-R 9、-NR 8C(＝O)-R 9或-NR 8C(＝O)-O-R 9；
    每个R 4独立地为氘、羟基、卤素、-N(R 7) 2、氰基、氧代、C 1-6烷基、C 2-6烯基、C 2-6炔基、-C 1-4亚烷基-N(R 7) 2、被一个或多个R 4a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 4b取代的C 1-6烷基-O-、C 3-7环烷基、被一个或多个R 4c取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 4d取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 4e取代的C 3-7环烯基，或两个R 4与所相连的原子一起形成C 3- 7环烷基、被一个或多个R 4c取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 4d取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 4e取代的C 3-7环烯基；
    每个R 4a、R 4b、R 4c和R 4d各自独立地为氘、羟基、卤素、氨基、氰基、C 1-6烷基、C 1-6烷基-O-、 C 2-6烯基或C 2-6炔基；
    R 5为不存在、氧代、氢、氘、羟基、卤素、氨基、氰基、硝基、C 1-6烷基、被一个或多个R 5a取代的C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、被一个或多个R 5b取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 5c取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 5d取代的C 3-7环烯基；
    每个R 5a、R 5b和R 5c各自独立地为氘、C 1-6烷基、羟基、卤素、氨基或氰基；
    R 6为氢、氘、羟基、卤素、氨基、氰基、氧代、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基或不存在；
    每个R 7独立地为氢、C 1-6烷基、C 3-7环烷基或C 3-7环烯基，或两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基；
    每个R 7a独立地为氘、C 1-6烷基、卤素、羟基、氨基、氰基、C 1-6烷基-O-、C 2-6烯基或C 2-6炔基；
    每个R 8和R 9各自独立地为氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
    R 10为氢、氘、羟基、卤素、氨基、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、C 3-7环烷基、C 3-7环烯基或3-7元杂环基；
    R 11为氢、氘、氰基、C 1-6烷基或被一个或多个R 11a取代的C 1-6烷基；
    每个R 11a独立地为氘、卤素或羟基；
    m为0、1、2、3、4或5；
    n为0、1、2、3、4、5或6；
    p为1、2、3、4、5或6；
    所述的3-7元杂环基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的3-7元杂环基；
    所述5-10元杂芳基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基；
    所述5-6元杂芳基为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-6元杂芳基；
    当*的碳原子具有手性时，如式I所示的稠环化合物为
    Figure PCTCN2022122241-appb-100002
    Figure PCTCN2022122241-appb-100003
    或其混合物。
  2. 如权利要求1所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物满足以下条件中的一种或多种：
    (1)X和Y各自独立地为-O-、-NH-或-CH 2-；
    (2)Z为N；
    (3)L为单键；
    (4)环A为C 6-12芳基或5-10元杂芳基；
    (5)每个R 1独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 1a取代的C 1-6烷基、被一个或多个R 1b取代的C 1-6烷基-O-，或两个R 1与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基；
    (6)每个R 1a、R 1b、R 1e、R 1f和R 1i各自独立地为羟基、卤素、-N(R 7) 2、C 1-6烷基或被一个或多个R 1-a取代的C 1-6烷基；
    (7)每个R 1-a独立地为C 1-6烷基或卤素；
    (8)环D为3-7元杂环基；
    (9)R 2为氢；
    (10)R 3为氢、C 3-7环烷基、被一个或多个R 3d取代的C 3-7环烷基、3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3h取代的C 3-7环烯基；
    (11)每个R 3d、R 3e和R 3h各自独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、被一个或多个R 3-a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 3-c取代的C 2-6烯基、被一个或多个R 3-d取代的C 2-6炔基、-C(＝O)-R 9、-NR 8C(＝O)-R 9，或两个R 3d、两个R 3e或两个R 3h与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3-f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3-i取代的C 3-7环烯基；
    (12)每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f和R 3-i各自独立地为羟基、卤素、-N(R 7) 2、硝基、氰基、C 1-6烷基或C 1-6烷基-O-；
    (13)每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、被一个或多个R 4a取代的C 1-6烷基、3-7 元杂环基或被一个或多个R 4d取代的3-7元杂环基；
    (14)每个R 4a和R 4d各自独立地为C 1-6烷基或卤素；
    (15)R 5为氢或C 1-6烷基；
    (16)R 6为氧代；
    (17)每个R 7独立地为氢、C 1-6烷基、C 3-7环烷基或C 3-7环烯基；或两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基；
    (18)每个R 7a独立地为C 1-6烷基或卤素；
    (19)每个R 8和R 9各自独立地为氢或C 1-6烷基；
    (20)R 11为C 1-6烷基；
    (21)m为0、1、2或3；
    (22)n为0、1、2或3；
    (23)p为1、2或3；
    (24)所述的3-7元杂环基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的3-7元杂环基；
    (25)所述5-10元杂芳基为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基。
  3. 如权利要求1或2所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物中：
    X和Y各自独立地为-O-、-NH-或-CH 2-；
    Z为N；
    L为单键；
    环A为C 6-12芳基或5-10元杂芳基；
    每个R 1独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 1a取代的C 1-6烷基、被一个或多个R 1b取代的C 1-6烷基-O-，或两个R 1与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 1e取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 1f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基；
    每个R 1a、R 1b、R 1e、R 1f和R 1i各自独立地为羟基、卤素、-N(R 7) 2、C 1-6烷基或被一个或多个R 1-a取代的C 1-6烷基；
    每个R 1-a独立地为C 1-6烷基或卤素；
    环D为3-7元杂环基；
    R 2为氢；
    R 3为氢、C 3-7环烷基、被一个或多个R 3d取代的C 3-7环烷基、3-7元杂环基、被一个或多个R 3e取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3h取代的C 3-7环烯基；
    每个R 3d、R 3e和R 3h各自独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、被一个或多个R 3-a取代的C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6烯基、C 2-6炔基、被一个或多个R 3-c取代的C 2-6烯基、被一个或多个R 3-d取代的C 2-6炔基、-C(＝O)-R 9、-NR 8C(＝O)-R 9，或两个R 3d、两个R 3e或两个R 3h与所相连的环原子一起形成C 3-7环烷基、被一个或多个R 3-e取代的C 3-7环烷基、3-7元杂环基或被一个或多个R 3-f取代的3-7元杂环基、C 3-7环烯基或被一个或多个R 3-i取代的C 3- 7环烯基；
    每个R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f和R 3-i各自独立地为羟基、卤素、-N(R 7) 2、硝基、氰基、C 1- 6烷基或C 1-6烷基-O-；
    每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、被一个或多个R 4a取代的C 1-6烷基、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
    每个R 4a和R 4d各自独立地为C 1-6烷基或卤素；
    R 5为氢或C 1-6烷基；
    R 6为氧代；
    每个R 7独立地为氢、C 1-6烷基、C 3-7环烷基或C 3-7环烯基；或两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基；
    每个R 7a独立地C 1-6烷基或卤素；
    每个R 8和R 9各自独立地为氢或C 1-6烷基；
    R 11为C 1-6烷基；
    m为0、1、2或3；
    n为0、1、2或3；
    p为1、2或3；
    所述的3-7元杂环基各自独立地为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的3-7元杂环基；
    所述5-10元杂芳基为杂原子种类独立选自N、O和S，杂原子个数为1个、2个或3个的5-10元杂芳基。
  4. 如权利要求1或2所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物满足以下条件中的一种或多种：
    (1)X和Y各自独立地为-O-或-CH 2-；
    (2)环A为C 6-12芳基；
    (3)每个R 1独立地为卤素、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基；
    (4)每个R 1a独立地为卤素；
    (5)环D为杂原子种类为N，杂原子个数为1个或2个的六元杂环基，例如为1,2-二氢吡啶基， 再例如为
    Figure PCTCN2022122241-appb-100004
    “c”表示该原子位于B环Z原子的间位；
    (6)R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基；
    (7)每个R 3e独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6炔基或-C(＝O)-R 9；例如每个R 3e独立地为羟基、C 1-6烷基-O-或-C(＝O)-R 9；
    (8)每个R 3-b独立地为羟基或卤素；
    (9)每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
    (10)每个R 4d独立地为C 1-6烷基或卤素；
    (11)每个R 7独立地氢或C 1-6烷基；
    (12)每个R 9独立地为氢或C 1-6烷基；
    (13)m为1、2或3；
    (14)n为0、1或2。
  5. 如权利要求1-3任意一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物中：
    X和Y各自独立地为-O-；
    每个R 1独立地为卤素、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基；
    每个R 1a独立地为卤素；
    环A为C 6-12芳基；
    Figure PCTCN2022122241-appb-100005
    为
    Figure PCTCN2022122241-appb-100006
    L为单键；
    R 2为氢；
    R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基；
    每个R 3e独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、C 2-6炔基或-C(＝O)-R 9；
    R 5为氢或C 1-6烷基；
    每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
    每个R 4d独立地为C 1-6烷基或卤素；
    每个R 7独立地氢或C 1-6烷基；
    每个R 9独立地为氢或C 1-6烷基；
    R 11为C 1-6烷基；
    m为1、2或3；
    n为0、1或2。
  6. 如权利要求1-4任意一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物中：
    X和Y各自独立地为-O-或-CH 2-；
    每个R 1独立地为卤素、C 1-6烷基或被一个或多个R 1a取代的C 1-6烷基；
    每个R 1a独立地为卤素；
    环A为C 6-12芳基；
    环D为杂原子种类为N，杂原子个数为1个或2个的六元杂环基，例如为1,2-二氢吡啶基，再例如为
    Figure PCTCN2022122241-appb-100007
    “c”表示该原子位于B环Z原子的间位；
    Z为N；
    L为单键；
    R 2为氢；
    R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基；
    每个R 3e独立地为羟基、卤素、-N(R 7) 2、氰基、C 1-6烷基、C 1-6烷基-O-、被一个或多个R 3-b取代的C 1-6烷基-O-、C 2-6炔基或-C(＝O)-R 9；
    每个R 3-b独立地为羟基或卤素；
    R 5为氢或C 1-6烷基；
    R 6为氧代；
    每个R 4独立地为C 1-6烷基、-C 1-4亚烷基-N(R 7) 2、3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基；
    每个R 4d独立地为C 1-6烷基或卤素；
    每个R 7独立地氢或C 1-6烷基；
    每个R 9独立地为氢或C 1-6烷基；
    R 11为C 1-6烷基；
    m为1、2或3；
    n为0、1或2。
  7. 根据权利要求1-3、5任意一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物中：
    Figure PCTCN2022122241-appb-100008
    为
    Figure PCTCN2022122241-appb-100009
    Figure PCTCN2022122241-appb-100010
    为
    Figure PCTCN2022122241-appb-100011
    Figure PCTCN2022122241-appb-100012
    L为单键；
    R 3为
    Figure PCTCN2022122241-appb-100013
    R 11为甲基。
  8. 根据权利要求1-4、6任意一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物中：
    Figure PCTCN2022122241-appb-100014
    为
    Figure PCTCN2022122241-appb-100015
    Figure PCTCN2022122241-appb-100016
    为
    Figure PCTCN2022122241-appb-100017
    Figure PCTCN2022122241-appb-100018
    L为单键；
    R 3为
    Figure PCTCN2022122241-appb-100019
    R 11为甲基。
  9. 如权利要求1-3任意一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物满足以下条件中的一种或多种：
    (1)当环A为C 6-12芳基时，所述C 6-12芳基为苯基或萘基，例如为苯基；
    (2)当环A为5-10元杂芳基时，所述5-10元杂芳基为杂原子种类为N，杂原子个数为1个或2个的5-10元杂芳基，例如为
    Figure PCTCN2022122241-appb-100020
    (3)当R 1为被一个或多个R 1a取代的C 1-6烷基时，所述被一个或多个R 1a取代的C 1-6烷基为-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH或-CF 2C(CH 3) 2OH；
    (4)当两个R 1与所相连的环原子一起形成C 3-7环烯基或被一个或多个R 1i取代的C 3-7环烯基时， 所述C 3-7环烯基为环丙烯基、环丁烯基、环戊烯基、环己烯基或环庚烯基，例如为环戊烯基；
    (5)当两个R 1与所相连的环原子一起形成3-7元杂环基或被一个或多个R 1f取代的3-7元杂环基时，所述3-7元杂环基为杂原子独立地选自O、N和S，杂原子个数为1个或2个的3-7元杂环基，例如为
    Figure PCTCN2022122241-appb-100021
    “a”表示此部分为与环A并环连接的位置；
    (6)当环D为3-7元杂环基时，所述3-7元杂环基为杂原子种类为N，杂原子个数为1个或2个的六元杂环基，例如为1,2-二氢吡啶基，再例如为
    Figure PCTCN2022122241-appb-100022
    “c”表示该原子位于B环Z原子的间位；
    (7)当R 3为3-7元杂环基或被一个或多个R 3e取代的3-7元杂环基时，所述3-7元杂环基为杂原子种类独立地选自N和O，杂原子个数为1个或2个的5-7元杂环基，例如为
    Figure PCTCN2022122241-appb-100023
    Figure PCTCN2022122241-appb-100024
    (8)当R 3为C 3-7环烷基或被一个或多个R 3d取代的C 3-7环烷基时，所述的C 3-7环烷基为环丙基、环丁基、环戊基、环己基、环庚基或
    Figure PCTCN2022122241-appb-100025
    (9)当每个R 3d和R 3e各自独立地C 2-6炔基时，所述C 2-6炔基为乙炔基或丙炔基；
    (10)当R 4为-C 1-4亚烷基-N(R 7) 2时，两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基时，例如所述-C 1-4亚烷基-N(R 7) 2为
    Figure PCTCN2022122241-appb-100026
    (11)当R 4为-C 1-4亚烷基-N(R 7) 2时，所述R 7独立地为C 1-6烷基时；例如所述-C 1-4亚烷基-N(R 7) 2为
    Figure PCTCN2022122241-appb-100027
    (12)当R 4为3-7元杂环基或被一个或多个R 4d取代的3-7元杂环基，所述3-7元杂环基为杂原子种类为N，杂原子个数为1个或2个的5-7元杂环基，例如为
    Figure PCTCN2022122241-appb-100028
    (13)两个R 7与所相连的氮原子一起形成3-7元杂环基或被一个或多个R 7a取代的3-7元杂环基 时，所述3-7元杂环基为杂原子种类为N，杂原子个数为1个或2个的5-7元杂环基，例如为
    Figure PCTCN2022122241-appb-100029
    (14)当R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-i、R 4、R 4a、R 4d、R 5、R 7、R 7a、R 8、R 9或R 11为C 1-6烷基或被取代基取代的C 1-6烷基时，所述C 1-6烷基各自独立地为C 1-4烷基，例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，再例如为甲基、乙基或异丁基；
    (15)当R 1、R 1a、R 1b、R 1e、R 1f、R 1i、R 1-a、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f、R 3-i、R 4a、R 4d或R 7a为卤素时，所述卤素各自独立地为F、Cl、Br或I，例如为F或Cl；
    (16)当R 1、R 3d、R 3e、R 3h、R 3-a、R 3-b、R 3-c、R 3-d、R 3-e、R 3-f或R 3-i为C 1-6烷基-O-或被取代基取代的C 1-6烷基-O-时，所述C 1-6烷基-O-各自独立地为C 1-4烷基-O-，例如为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，再例如为甲氧基、乙氧基或异丙氧基；又例如为甲氧基或乙氧基。
  10. 如权利要求1-3任意一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物满足以下条件中的一种或多种：
    (1)环A为
    Figure PCTCN2022122241-appb-100030
    (2)R 1为F、Cl、-CN、-CHF 2、-CF 3、-CH 3、-CF 2CH 2OH、-CF 2CH 3、-NH 2或-CF 2C(CH 3) 2OH；或两个R 1与所相连的环原子一起形成
    Figure PCTCN2022122241-appb-100031
    “a”表示此部分为与环A并环连接的位置；
    (3)R 3为
    Figure PCTCN2022122241-appb-100032
    Figure PCTCN2022122241-appb-100033
    Figure PCTCN2022122241-appb-100034
    Figure PCTCN2022122241-appb-100035
    例如为
    Figure PCTCN2022122241-appb-100036
    (4)
    Figure PCTCN2022122241-appb-100037
    为
    Figure PCTCN2022122241-appb-100038
    Figure PCTCN2022122241-appb-100039
    例如为
    Figure PCTCN2022122241-appb-100040
    Figure PCTCN2022122241-appb-100041
    (5)R 4为-CH 3、
    Figure PCTCN2022122241-appb-100042
    (6)
    Figure PCTCN2022122241-appb-100043
    例如为
    Figure PCTCN2022122241-appb-100044
    其中，所述b端与Z原子相连；
    (7)R 11为甲基；
    较佳地，所述的如式I所示的稠环化合物满足以下条件中的一种或多种：
    (1A)
    Figure PCTCN2022122241-appb-100045
    为
    Figure PCTCN2022122241-appb-100046
    Figure PCTCN2022122241-appb-100047
    Figure PCTCN2022122241-appb-100048
    例如为
    Figure PCTCN2022122241-appb-100049
    (1B)
    Figure PCTCN2022122241-appb-100050
    为
    Figure PCTCN2022122241-appb-100051
    Figure PCTCN2022122241-appb-100052
    Figure PCTCN2022122241-appb-100053
    例如为
    Figure PCTCN2022122241-appb-100054
    Figure PCTCN2022122241-appb-100055
    更佳地，所述的如式I所示的稠环化合物满足以下条件中的一种或多种：
    (2A)
    Figure PCTCN2022122241-appb-100056
    为
    Figure PCTCN2022122241-appb-100057
    Figure PCTCN2022122241-appb-100058
    Figure PCTCN2022122241-appb-100059
    Figure PCTCN2022122241-appb-100060
    例如为
    Figure PCTCN2022122241-appb-100061
    Figure PCTCN2022122241-appb-100062
    Figure PCTCN2022122241-appb-100063
    (2B)所述如式I所示的稠环化合物为
    Figure PCTCN2022122241-appb-100064
  11. 如权利要求1所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；其特征在于，所述的如式I所示的稠环化合物选自以下任一化合物：
    Figure PCTCN2022122241-appb-100065
    Figure PCTCN2022122241-appb-100066
    Figure PCTCN2022122241-appb-100067
    Figure PCTCN2022122241-appb-100068
    Figure PCTCN2022122241-appb-100069
    Figure PCTCN2022122241-appb-100070
    Figure PCTCN2022122241-appb-100071
    Figure PCTCN2022122241-appb-100072
    Figure PCTCN2022122241-appb-100073
  12. 一种如权利要求1-11任一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物的制备方法，其包括以下步骤：
    方案一：当所述如式I所示的稠环化合物为化合物Ia时，化合物Ia-6与
    Figure PCTCN2022122241-appb-100074
    经Buchwald–Hartwig偶联反应得到化合物Ia；
    Figure PCTCN2022122241-appb-100075
    方案二：当所述如式I所示的稠环化合物为化合物Ib时，化合物Ib-3与
    Figure PCTCN2022122241-appb-100076
    经Buchwald– Hartwig偶联反应得到化合物Ib；
    Figure PCTCN2022122241-appb-100077
    较佳地，所述制备方法中，方案一或方案二中，所述Buchwald–Hartwig偶联反应是在催化剂、碱存在下进行；所述催化剂为RuPhos Pd G3、BrettPhos Pd G3、XPhos Pd G3、XantPhos Pd G3、RuPhos Pd G4和BrettPhos Pd G4中的一种或多种；所述碱为碳酸铯、碳酸钠、磷酸钾、碳酸钠、叔丁醇钾和叔丁醇钠中的一种或多种；
    所述制备方法中，较佳地，所述方案一中还包括以下步骤：
    Figure PCTCN2022122241-appb-100078
    所述化合物I-1与R 5-NH 2发生取代反应，得到化合物Ia-1；
    所述化合物Ia-1与碘代试剂(如N-碘代丁二酰亚胺、I 2)经碘代反应得到化合物Ia-2；
    所述化合物Ia-2与
    Figure PCTCN2022122241-appb-100079
    经Heck偶联反应得到化合物Ia-3；
    所述化合物Ia-3在碱作用下经关环反应得到化合物Ia-4；
    所述化合物Ia-4与溴化试剂经溴代反应得到化合物Ia-5；
    所述化合物Ia-5与相应取代的酮、胺、硼酸酯衍生物发生反应得到化合物Ia-6；
    更佳地，所述碘代反应中，所述碘代试剂为N-碘代丁二酰亚胺和/或I 2；
    更佳地，所述关环反应中，所述碱为甲硫醇钠、甲醇钠和乙醇钠中的一种或多种；
    更佳地，所述溴代反应中，所述溴化试剂为N-溴代丁二酰亚胺和/或Br 2；
    所述制备方法中，较佳地，所述方案二中还包括以下步骤：
    Figure PCTCN2022122241-appb-100080
    其中R 12为甲基或乙基；
    所述化合物I-1在强碱作用下发生酰基化反应得到化合物Ib-1；
    化合物Ib-1与丙二酸酯反应并脱羧得到化合物Ib-2；
    化合物Ib-2与H 2N-L-R 3发生关环反应得到化合物Ib-3；
    更佳地，所述酰基化反应中，所述强碱为二异丙基氨基锂；
    更佳地，所述丙二酸酯为丙二酸甲酯、丙二酸乙酯。
  13. 一种药物组合物；其特征在于，所述药物组合物包含：
    (1)物质X，所述物质X为如权利要求1-11任一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物，及
    (2)药学可接受的辅料。
  14. 一种物质X或如权利要求13所述的药物组合物在制备SOS1抑制剂中的应用，其特征在于，所述物质X为如权利要求1-11任一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。
  15. 一种物质X或如权利要求13所述的药物组合物在制备药物中的应用；其特征在于，所述物质X为如权利要求1-11任一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物可为治疗和/或预防与SOS1活性或表达量相关的疾病的药物；
    较佳地，所述与SOS1活性或表达量相关的疾病选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状腺癌、黑色素瘤、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、胆管癌、子宫癌、子宫内膜癌、尿路上皮癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征和多发性骨髓癌，以及和SOS1遗传性突变相关的疾病，如一型神经纤维瘤、努南氏综合征、多发雀斑样恁型努南氏综合征、毛细血管畸形—动静脉畸形综合征、心-面-皮肤综合征、克斯提洛氏综合征、雷吉士综合征和一型遗传性牙龈纤维瘤。
  16. 一种物质X或如权利要求13所述的药物组合物在制备药物中的应用；其特征在于，所述物质X为如权利要求1-11任一项所述的如式I所示的稠环化合物、其互变异构体、其立体异构体、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物为治疗和/或预防以下各类疾病的药物；所述疾病选自非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、结肠癌、甲状 腺癌、黑色素瘤、胚胎性横纹肌肉瘤、皮肤颗粒细胞肿瘤、肝癌、直肠癌、膀胱癌、咽喉癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、皮肤癌、淋巴瘤、胃癌、胆管癌、子宫癌、子宫内膜癌、尿路上皮癌、急性髓系白血病、骨髓纤维化、B细胞淋巴瘤、单核细胞白血病、脾大性红细胞增多、嗜酸性白细胞增多综合征和多发性骨髓癌，以及一型神经纤维瘤、努南氏综合征、多发雀斑样恁型努南氏综合征、毛细血管畸形—动静脉畸形综合征、心-面-皮肤综合征、克斯提洛氏综合征、雷吉士综合征和一型遗传性牙龈纤维瘤。
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