WO2023165581A1 - Pyridine derivative and use thereof - Google Patents

Pyridine derivative and use thereof Download PDF

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Publication number
WO2023165581A1
WO2023165581A1 PCT/CN2023/079436 CN2023079436W WO2023165581A1 WO 2023165581 A1 WO2023165581 A1 WO 2023165581A1 CN 2023079436 W CN2023079436 W CN 2023079436W WO 2023165581 A1 WO2023165581 A1 WO 2023165581A1
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alkyl
cycloalkyl
halogen
cyano
independently selected
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PCT/CN2023/079436
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French (fr)
Chinese (zh)
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陈寿军
强晓明
熊勇
丁兆
王忠波
王海波
刘科
廖登明
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四川汇宇制药股份有限公司
四川汇宇海玥医药科技有限公司
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Publication of WO2023165581A1 publication Critical patent/WO2023165581A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of medical technology, in particular to a compound used as a KRAS G12C inhibitor and/or PI3K protein inhibitor and its application.
  • RAS protein is an important class of signaling molecules involved in various processes such as cell proliferation, differentiation, survival and motility.
  • the RAS family consists of KRAS, NRAS and HRAS, etc. They have two states in the cell: an inactive state bound to GDP and an activated state bound to GTP. When RAS is activated, it can activate multiple downstream signaling pathways, including MAPK signaling pathway, PI3K signaling pathway and Ral-GEFs signaling pathway, which play an important role in promoting cell survival, proliferation and cytokine release.
  • RAS The activation of RAS depends on the phosphorylation of the receptor after the binding of signal molecules by tyrosine kinase receptors, exposing the binding site, and the complex of guanine nucleotide exchange factors (GEF, such as SOS1) and growth factor receptor binding protein (Grb2) Binding to this site, the SH2 domain of Grb2 binds to it to form a RTK/Grb2/SOS complex, and SHP2 can further promote the binding of this complex to RAS, prompting it to release GDP and bind GTP, thereby activating RAS.
  • GEF guanine nucleotide exchange factors
  • Grb2 growth factor receptor binding protein
  • RAS Zika virus
  • the RAS protein consists of 6 ⁇ sheets and 5 ⁇ helices, of which the 166 amino acids at the N-terminal form the G domain, while the C-terminal is the membrane binding region.
  • the G domain (subdivided into G1-G5) is a functional domain that can directly bind to GDP/GTP, G2 (Switch I) binds to GTP, and G3 (Switch II) binds to GDP.
  • KRAS is widely expressed in body tissues, and its mRNA level can be detected in almost all tissues. KRAS plays a role in the cell by participating in the hydrolysis of GTP.
  • GTPase As a GTPase, it functions in catalyzing the conversion of guanine trinucleotide phosphate (GTP) and guanine dinucleotide phosphate (Guanosine diphosphate, GDP), promoting Cell survival, migration and proliferation.
  • GTP guanine trinucleotide phosphate
  • GDP guanine dinucleotide phosphate
  • GEF Guanine Nucleotide Exchange Factor
  • SOS1 Guanine Nucleotide Exchange Factor
  • GAP GTPase-activating protein
  • KRAS is the main mutation in RAS, KRAS mutations widely occur in cancer patients, including 5-30% of lung cancer patients, 36-40% of colon cancer patients and about 90% of pancreatic cancer patients, in addition to other tumors such as uterus KRAS mutations have also been found in patients with endometrial cancer, skin cancer, and multiple myeloma.
  • mutations at G12 are the main ones, accounting for 83%, followed by G13 at 14%, and Q61, etc.; G12 mutations are mainly G12V, G12D, and G12C. G12C mutations are present in 14% of patients with non-small cell lung cancer, 5% in colon cancer, and 2% in pancreatic ductal adenocarcinoma.
  • the mutation of KRAS can promote its combination with GTP, and it is always in an activated state, continuously activating the growth of cells, thus leading to the occurrence of tumors. All these indicate that KRAS mutation has important value in clinical treatment.
  • KRAS G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine 12 to cysteine.
  • KRAS G12C mutation is also the most common in lung cancer. According to the data reported in the literature (Cox, A.D.; et al. Nat. Rev. Drug Discov. 2014, 13, 828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients . For more than 30 years, there has been no breakthrough in the search for drugs that specifically target KRAS, so KRAS is generally considered an "undruggable target" (Undruggable Target).
  • KRAS G12C inhibitors have become one of the current hot areas of drug development.
  • the literature (Ostrem, JM; et al. Nature. 2013, 503, 548-551) reported a class of covalent binding inhibitors targeting the KRAS G12C mutation, but the enzymatic activity of these compounds is not high, and there is no activity at the cellular level.
  • Another class of compounds reported in the literature (Lito, P.; et al. Science, 2016, 351, 604-608; Patricelli, MP; et al. Cancer Discov. 2016, 6, 316-329) exhibited ⁇ M-level anti-inflammatory activity at the cellular level.
  • WO2016164675 and WO2016168540 respectively reported a class of quinazoline derivatives and fused tricyclic quinazoline derivatives with high enzyme binding activity. and exhibits anti-proliferation activity at the ⁇ M level, with a stable structure and certain selectivity.
  • Amgen (WO2018119183) and AstraZeneca (WO2018206539) respectively had The patent disclosure on KRAS G12C inhibitors, and Amgen's KRAS G12C inhibitor AMG-510 launched a phase 1 clinical study in July 2018.
  • KRAS G12C inhibitors under development that are progressing rapidly mainly include ARS-1620 from Araxes, AMG-510 from Amgen, and MRTX-849 from Mirati (WO2020216190).
  • AMG-510 has the fastest progress and will be approved for marketing in 2021. It started phase I clinical trials in 2018 and is the earliest KRAS G12C inhibitor to enter clinical trials.
  • the technical problem mainly solved by the present invention is to provide a pyridine derivative, which has a strong inhibitory effect on PI3K.
  • the present invention provides a compound having the structure shown in formula I or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
  • a 1 is selected from CR 10 , CR 11 R 12 or N
  • a 2 is selected from CR 13 , CR 14 R 15 or N
  • a 3 is selected from CR 16 , CR 17 R 18 or N
  • a 4 is selected from CR 19 , CR 20 R 21 or N
  • a 5 is selected from C, CR 41 , N or S
  • a 6 is selected from CR 9 , CR 42 R 43 , N or A 6 is absent
  • a 7 is selected from CR 8 , CR 44 R 45 , N, NR 8 or S
  • a 8 is selected from C, CR 46 or N, wherein, when A 1 and A 3 are N at the same time, A 6 does not exist;
  • B for The rings of B 1 and B 2 are 5-10 membered azacycloalkyl groups, 5-10 membered azacycloalkenyl groups, and the rings of B 1 and B 2 are monocyclic, spiro or bridged rings, B 1 selected from C, CR 22 or N, B 2 selected from C, CR 23 or N, and at least one of B 1 and B 2 is N;
  • R 7 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR n , -NR o R p , -C(O)R 24.
  • alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more halogen, Cyano, Alkyl, Cycloalkyl, Heteroalicyclic, -OR n , -NR o R p , -C(O)R 24 , -C(O)NR o R p , -C(O)OR n replace;
  • n 1 is selected from 0, 1, 2, 3, 4;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, alkyl, aliphatic heterocyclic group, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 25 , - S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C(O)OR a , and R 5 and R 6 not be hydrogen at the same time; optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 on the B ring to form a 4-12-membered aliphatic heterocyclic group; wherein, the Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 28 ;
  • R 28 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, -OR a , -NR b R c , -C(O)R 25 , -C(O)NR b R c , -C(O)OR a ;
  • R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aliphatic heterocyclic group, and -C(O)R 29 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally replaced by One or more of the following substituents are substituted: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic ring; when "-----" in ring E is a bond, R2 is none ;
  • R 3 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g , -NR h R i , -C(O)R 30 , -C (O)R h R i , -C(O)ORg, when the "-----" in ring E is none, R3 can also be the carbon atom connected to it to form a carbonyl group, wherein, alkyl, ring Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R;
  • R 31 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR g , -NR h R i , -C(O)R 32 , -C(O)NR h R i , -C(O)OR g ;
  • R is selected from alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl, wherein, alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally replaced by one or more R 33 replacement;
  • Each occurrence of R 33 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR j , -NR k R m , -C(O)R 34 , -C(O)NR k R m , -C(O)OR j , wherein, the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, heteroaryl group are optionally replaced by one or more R 35 replaced;
  • R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR j , -NR k R m , -C(O)R 36 , -C(O)NR k R m , -C(O)OR j ;
  • R 8 , R 9 , R 10 , R 16 , R 19 , R 11 , R 12 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 are independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR q , -NR r R s , -C(O )R 37 , -C(O)NR r R s , -C(O)OR q or none, wherein the alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or Multiple R 38 substitutions;
  • R 38 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR q , -NR r R s , -C(O)R 39 , -C(O)NR r R s , -C(O)OR q ;
  • R 13 , R 14 , and R 15 are independently selected from hydrogen and methyl
  • R a , R b , R c , R g , R h , R i , R j , R k , R m , R n , R o , R p , R q , R r , R s are selected independently for each occurrence. from H, alkyl, cycloalkyl, aliphatic heterocyclic group, -C(O)R 40 , wherein the alkyl, cycloalkyl, aliphatic heterocyclic group is optionally substituted by one or more of the following substituents : Halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic heterocyclic;
  • R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , R 40 are each independently selected from hydrogen, halogen, cyano, Alkyl, cycloalkyl, aliphatic heterocyclic group, said alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, alkyl, cycloalkyl, alicyclic.
  • R is not hydrogen
  • R5 is hydrogen and R6 is other than hydrogen.
  • Aromatic is selected from the following groups: Preferably, Aromatic.
  • a 3 is selected from CR 16 or N
  • a 6 is selected from CR 9 or N
  • a 7 is selected from CR 8 or N; preferably, selected from
  • a 1 is selected from CR 10 or N
  • a 3 is selected from CR 16 or N
  • a 4 is selected from CR 19 or N
  • a 5 is selected from N or S
  • a 7 is selected from CR 8 or N; preferably, for
  • a 1 is selected from CR 10 or N
  • a 3 is selected from CR 16 or N
  • a 4 is selected from CR 19 or N
  • a 7 is selected from CR 8 or N; preferably, for
  • a 1 is selected from CR 10 or N
  • a 3 is selected from CR 16 or N
  • a 4 is selected from CR 19 or N
  • a 7 is selected from NR 8 or S; preferably, selected from
  • a 1 is selected from CR 10 , CR 11 R 12 or N
  • a 2 is selected from CR 13 , CR 14 R 15 or N
  • a 3 is selected from CR 16 , CR 17 R 18 or N
  • a 4 is selected from CR 19 , CR 20 R 21 or N
  • a 1 and A 3 are not N at the same time.
  • Another aspect of the present invention provides a compound having a structure represented by formula I' having a structure represented by formula I or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable Salt, eutectic:
  • a 1 is selected from CR 10 , CR 11 R 12 or N
  • a 2 is selected from CR 13 , CR 14 R 15 or N
  • a 3 is selected from CR 16 , CR 17 R 18 or N
  • a 4 is selected from CR 19 , CR 20 R 21 or N, and A 1 and A 3 are not N at the same time;
  • B for The rings where B 1 and B 2 are located are 5-10 membered azacycloalkyl groups and are monocyclic, spiro or bridged rings, B 1 is selected from CR 22 or N, B 2 is selected from CR 23 or N, and B 1 , at least one of B2 is N;
  • R 7 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR n , -NR o R p , -C(O)R 24.
  • alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more halogen, Cyano, Alkyl, Cycloalkyl, Heteroalicyclic, -OR n , -NR o R p , -C(O)R 24 , -C(O)NR o R p , -C(O)OR n replace;
  • n 1 is selected from 0, 1, 2, 3, 4;
  • R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, alkyl, aliphatic heterocyclic group, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 25 , - S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C(O)OR a , and R 5 and R 6 not be hydrogen at the same time; optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 on the B ring to form a 4-12-membered aliphatic heterocyclic group; wherein, the Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 28 ;
  • R 28 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, -OR a , -NR b R c , -C(O)R 25 , -C(O)NR b R c , -C(O)OR a ;
  • R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aliphatic heterocyclic group, and -C(O)R 29 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally replaced by One or more of the following substituents are substituted: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic ring; when "-----" in ring E is a bond, R2 is none;
  • R 3 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g , -NR h R i , -C(O)R 30 , -C (O)R h R i , -C(O)OR g , when the "-----" in ring E is none, R 3 can also be the carbon atom connected to it to form a carbonyl group, wherein, the alkyl , cycloalkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 31 ;
  • R 31 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR g , -NR h R i , -C(O)R 32 , -C(O)NR h R i , -C(O)OR g ;
  • R is selected from alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl, wherein, alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally replaced by one or more R 33 replacement;
  • Each occurrence of R 33 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR j , -NR k R m , -C(O)R 34 , -C(O)NR k R m , -C(O)OR j , wherein, the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, heteroaryl group are optionally replaced by one or more R 35 replaced;
  • R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR j , -NR k R m , -C(O)R 36 , -C(O)NR k R m , -C(O)OR j ;
  • R 8 , R 9 , R 10 , R 13 , R 16 , R 19 , R 11 , R 12 , R 14 , R 15 , R 17 , R 18 , R 20 , R 21 , R 22 , and R 23 are independently selected from From hydrogen, halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR q , -NR r R s , -C(O)R 37 , -C(O) NR r R s , -C(O)OR q or none, wherein alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 38 ;
  • R 38 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR q , -NR r R s , -C(O)R 39 , -C(O)NR r R s , -C(O)OR q ;
  • R a , R b , R c , R g , R h , R i , R j , R k , R m , R n , R o , R p , R q , R r , R s are selected independently for each occurrence. from H, alkyl, cycloalkyl, aliphatic heterocyclic group, -C(O)R 40 , wherein the alkyl, cycloalkyl, aliphatic heterocyclic group is optionally substituted by one or more of the following substituents : Halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic heterocyclic;
  • R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , R 40 are each independently selected from hydrogen, halogen, cyano, Alkyl, cycloalkyl, aliphatic heterocyclic group, said alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, alkyl, cycloalkyl, alicyclic.
  • a 1 is selected from CR 10 and N
  • a 2 is selected from CR 13 and N
  • a 3 is selected from CR 16 and N
  • a 4 is selected from CR 19 and N
  • a 1 and A 3 are not N at the same time
  • B is The rings of B 1 and B 2 are 6-9 membered azacycloalkyl, 6-9 membered azacycloalkenyl, and the rings of B 1 and B 2 are monocyclic, spiro or bridged rings, B 1 selected from C, CR 22 or N, B 2 selected from CR 23 or N, and at least one of B 1 and B 2 is N.
  • B is The rings where B 1 and B 2 are located are 6-9 membered azacycloalkyl groups and are monocyclic or spiro rings;
  • B is The rings where B 1 and B 2 are located are 6-membered azamonocycloalkyl or 8-9 membered azaspirocycloalkyl;
  • R 22 is selected from hydrogen, halogen, C1 ⁇ C6 alkyl, preferably hydrogen, halogen, C1 ⁇ C3 alkyl, more preferably hydrogen;
  • R 23 is selected from hydrogen, halogen, C1-C6 alkyl, preferably hydrogen, halogen, C1-C3 alkyl, or R 23 and R 6 and their connected segments together form a 4-6 membered cycloalkenyl, preferably R 23 Together with R6 and the chain segment connected to it, it forms a 5-membered cycloalkenyl group;
  • B is The rings of B 1 and B 2 are 6-9 membered azabridged cycloalkyl groups, preferably 7-8 membered azabridged cycloalkyl groups, more preferably 8-membered azabridged cycloalkyl groups;
  • both B 1 and B 2 are N;
  • B is The rings where B 1 and B 2 are located are 6-9 membered azacycloalkenyl groups, and the rings where B 1 and B 2 are located are monocyclic, spiro or bridged rings, and B 1 is selected from C, CR 22 or N, B 2 is selected from CR 23 or N, and at least one of B 1 and B 2 is N;
  • the rings where B 1 and B 2 are located are 6-membered azacycloalkenyl groups, and the rings where B 1 and B 2 are located are monocyclic, B 1 is C, and B 2 is N;
  • n 1 is selected from 0, 1, 2, 3, preferably 0, 1, 2, more preferably 0 or 1.
  • R 1 and R 2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more of the following substituents Substitution: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, 3 ⁇ 6 membered aliphatic heterocyclic group; when "-----" in ring E is a bond, R2 is none;
  • R 1 and R 2 are independently selected from hydrogen, halogen, C1-C3 alkyl, wherein the alkyl and cycloalkyl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, C1 ⁇ C3 alkyl, C3 ⁇ C6 cycloalkyl; when "-----" in ring E is a bond, R2 is none;
  • R 1 and R 2 are independently selected from hydrogen or methyl; when "-----" in ring E is a bond, R 2 is none;
  • R 1 is hydrogen
  • R 5 and R 6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclic group, 6-10-membered aryl group, 5-10-membered heterocyclic group, Aryl, -C(O)R 25 , -S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C (O) OR a , and R 5 and R 6 are not hydrogen at the same time, wherein the alkyl, aliphatic heterocyclic group, aryl, heteroaryl is optionally substituted by one or more R 28 ;
  • R 28 is independently selected from halogen, cyano, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, -OR a , -NR b R c ;
  • R 6 when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 to form n 2 is selected from 0, 1, 2, 3, 4;
  • R 5 and R 6 are independently selected from hydrogen, halogen, C1-C3 alkyl, 5-6 membered heteroaryl, -C(O)R 25 , -S(O) 2 R 16 , -P( O) R 16 R 17 , and R 5 and R 6 are not hydrogen at the same time, wherein the alkyl and heteroaryl are optionally substituted by one or more R 28 ;
  • R 28 is independently selected from halogen, C1 ⁇ C3 alkyl, -OR a , -NR b R c ;
  • R 25 can be connected with any R 7 to form n 2 is selected from 1, 2;
  • R 5 and R 6 are independently selected from H, F, C1-C3 alkyl, -C(O)CH 3 , -C(O)CH 2 CH 2 CH 3 , -CH 2 N(CH 3 ) 2.
  • -CH 2 F, -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , and R 5 and R 6 are not hydrogen at the same time;
  • R 25 can be connected with any R 7 to form
  • R 5 is H
  • R 6 is -C(O)CH 3 , or R 6 is -C(O)CH 2 CH 2 CH 3 and is combined with any R 7 Preferably, R 6 is -C(O)CH 3 ;
  • each occurrence of R a , R b , and R c is independently selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R a , R b , and R c is independently selected from H, C1-C3 alkyl, wherein the alkyl is optionally substituted by one or more of the following substituents: halogen, C1-C3 alkyl;
  • each occurrence of R a , R b , and R c is independently selected from H, C1-C3 alkyl.
  • each occurrence of R 7 is independently selected from halogen, cyano, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, -OR n , -NR o R p , wherein alkyl, cycloalkane The group is optionally substituted by one or more substituents selected from halogen, cyano, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, -OR n , -NR o R p ;
  • R 7 is selected from C1 ⁇ C3 alkyl, -OR n , -NR o R p , wherein the alkyl is optionally replaced by one or more halogen, cyano, C1 ⁇ C3 alkyl, -OR n , -NR o R p substitution;
  • R 7 is selected from C1-C3 alkyl, preferably methyl.
  • each occurrence of R n , R o , and R p is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, C3 ⁇ C6 heterocycloalkyl;
  • each occurrence of R n , R o , and R p is independently selected from H, C1-C3 alkyl, wherein the alkyl is optionally substituted by one or more of the following substituents: halogen, C1-C3 Alkyl, 5-membered azacycloalkyl;
  • each occurrence of R n , R o , and R p is independently selected from H, C1-C3 alkyl.
  • R 3 is selected from hydrogen, halogen, cyano, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, 3 ⁇ 6 membered aliphatic heterocyclic group, -OR g , -NR h R i , when ring E When "-----" is none, R 3 can also be a carbonyl group formed by the carbon atoms connected to it, wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 31 , each occurrence of R 31 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -OR g , -NR h R i ;
  • R 3 is selected from hydrogen, halogen, C1 ⁇ C3 alkyl, -OR g , -NR h R i , when "-----" in ring E is none, the carbon atom to which R 3 is connected Together form a carbonyl group, wherein the alkyl group is optionally substituted by one or more R 31 , and each occurrence of R 31 is independently selected from halogen, cyano, C1 ⁇ C3 alkyl, -OR g , -NR h R i ;
  • R 3 is selected from hydrogen, F, Cl, Br, methyl, -OR g , -NR h R i , when the "-----" in ring E is none, the carbon to which R 3 is connected Atoms together form a carbonyl group;
  • R 3 is selected from hydrogen, C1 ⁇ 3 alkyl, -OR g , wherein the alkyl is optionally substituted by one or more halogens;
  • R 3 is -OR g .
  • each occurrence of R g , Rh , and R i is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R g , Rh , and R i is independently selected from H, C1-C3 alkyl, cyclopropyl, and cyclopentyl, wherein the alkyl and cyclopropyl are optionally replaced by one or A plurality of the following substituents are substituted: halogen, C1 ⁇ C3 alkyl;
  • each occurrence of R g , Rh , R i is independently selected from H, methyl, cyclopropyl, cyclopentyl, wherein said methyl is optionally substituted by one or more halogens.
  • R 3 is selected from methoxy, difluoromethoxy, trifluoromethoxy, preferably methoxy.
  • R 8 , R 9 , R 10 , R 16 , R 19 , R 11 , R 12 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 are independently selected from hydrogen, halogen, cyanide group, C1 ⁇ C6 alkyl group, C3 ⁇ C6 cycloalkyl group, -OR q , -NR r R s or none, wherein the alkyl group and cycloalkyl group are optionally substituted by one or more R 38 ;
  • Each occurrence of R 38 is independently selected from halogen, cyano, C1 ⁇ C6 alkyl, C3 ⁇ C6 cycloalkyl, -OR q , -NR r R s , -C(O)R 39 , -C(O) NR r R s , -C(O)OR q .
  • R 8 , R 9 , R 10 , R 16 , and R 19 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR q , -NR r R s , R q , R r , Each occurrence of R s is independently selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 38 , each occurrence of R 38 is independently selected from halogen; R 13 is selected from hydrogen, methyl;
  • R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, trifluoromethyl, hydroxyl, and methoxy , difluoromethoxy, trifluoromethoxy, amino, methylamino;
  • R 13 is selected from hydrogen, methyl;
  • R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl; R 13 is selected from hydrogen and methyl;
  • R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, fluorine, cyano, and methyl;
  • R 13 is selected from hydrogen, methyl;
  • R 8 is selected from hydrogen, fluorine, methyl; R 9 is selected from hydrogen, fluorine; R 10 is selected from hydrogen, fluorine, cyano; R 16 is selected from hydrogen, fluorine; R 19 is selected from hydrogen, fluorine; R 13 is hydrogen.
  • each occurrence of R q , R r , and R s is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
  • R 4 is selected from C1 ⁇ C6 alkyl, C3 ⁇ C9 cycloalkyl, 3 ⁇ 6 membered heterocycloalkyl, 6 ⁇ 10 membered aryl, 5 ⁇ 10 membered heteroaryl, wherein, alkyl, ring Alkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more R;
  • Each occurrence of R 33 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -OR j , -NR k R m , -C(O)R 27 , -C(O) NR k R m , -C(O)OR j , wherein the alkyl and cycloalkyl are optionally substituted by one or more R 35 ;
  • R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, -OR j , -NR k R m ;
  • R 4 is selected from C1 ⁇ C3 alkyl, C3 ⁇ C6 cycloalkyl, phenyl, 5 ⁇ 6 membered azaaryl, 5 ⁇ 6 membered thiaaryl, wherein, alkyl, cycloalkyl, Aryl, azaaryl, and thiaaryl are optionally substituted by 1 to 3 R33 ;
  • R 33 is independently selected from halogen, cyano, C1 ⁇ C3 alkyl, C3 ⁇ C6 cycloalkyl, -OR j , -NR k R m , wherein the alkyl and cycloalkyl are optionally replaced by one or more R35 ;
  • R 4 is selected from C1 ⁇ C3 alkyl, cyclohexyl, phenyl, pyridyl, thienyl, wherein, alkyl, cyclohexyl, phenyl, pyridyl, thienyl are optionally replaced by 1 to 3 R 33 replaced;
  • R 33 is independently selected from F, Cl, Br, C1-C3 alkyl, -OR j , preferably F, Cl, methyl, methoxy;
  • R 4 is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups, wherein the aryl and heteroaryl groups are optionally substituted by one or more R 33 ;
  • R 33 is independently selected from halogen, cyano, C1-C6 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
  • each occurrence of R is independently selected from halogen
  • R 4 is selected from phenyl, 5-6 membered heteroaryl, and said heteroaryl contains 1-2 heteroatoms selected from N and S, wherein, phenyl and heteroaryl are optionally replaced by 1 ⁇ 3 R33 substitutions;
  • R 33 is independently selected from halogen, cyano, C1-C3 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
  • each occurrence of R is independently selected from halogen
  • R 4 is selected from phenyl, pyridyl, thiazolyl, and the above groups are optionally substituted by 1 to 3 R 33 ;
  • R 33 is independently selected from halogen, cyano, C1-C3 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
  • each occurrence of R is independently selected from halogen
  • R 35 is F
  • each occurrence of R is independently selected from F, Cl, cyano, methyl, trifluoromethyl, methoxy;
  • R 4 is selected from phenyl and pyridyl, wherein, phenyl and pyridyl are optionally substituted by 1 to 3 R 33 ;
  • R 33 is independently selected from F, methyl each time it occurs;
  • R 4 is selected from methyl, cyclohexyl, phenyl,
  • R 4 is selected from
  • R is selected from methyl, cyclohexyl, phenyl,
  • R is selected from
  • each occurrence of R j , R k , and R m is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R j , R k , and R m is independently selected from H, C1-C3 alkyl, preferably C1-C3 alkyl, more preferably methyl.
  • each occurrence of R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 is independently selected from H, C1-C6 Alkyl, the alkyl is optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 is independently selected from H, C1-C3 Alkyl, said alkyl is optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, C1 ⁇ C3 alkyl;
  • R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 are each independently selected from C1-C3 alkyl groups. , preferably methyl, propyl.
  • the compound has the structure shown in formula II or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
  • each group of B, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R 25 is as defined above.
  • the compound has the structure shown in formula III or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
  • each group of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 25 is as defined above.
  • the compound has the structure shown in formula IV or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
  • each group of A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , and R 5 is as defined above.
  • the compound has the structure shown in formula V or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
  • each group of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , R 7 , and R 8 is as defined above.
  • compound structure is selected from one of the following:
  • the invention provides a kind of preparation method of pyridine derivative:
  • X2 is selected from CH, CR23 or NH
  • X1 is selected from groups that can react with X2 to form a covalent bond; for example, if X2 is NH, X1 is optionally capable of condensation reaction with NH OH;
  • the compound of formula C can be prepared by the following synthetic route:
  • X 3 and X 4 are selected from halogen atoms, boronic acid groups or borate ester groups; the condition is: when X 3 is selected from halogen atoms, X 4 is selected from boronic acid groups or borate ester groups, and when X 4 is selected from halogen atoms , X3 is selected from boric acid group or borate ester group;
  • the boronic acid group or borate ester group is selected from or -B(OH) 2 ;
  • B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R 1 , R 2 , R 3 , R 4 , R 7 , X 2 , n 1 , T are defined with the compound of formula I.
  • the invention provides a pharmaceutical composition, the active ingredient of which is selected from the compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co- One or a combination of two or more crystals.
  • the present invention provides the compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation of KRAS inhibitors and/or PI3K inhibitors use in pharmaceuticals;
  • KRAS inhibitor is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
  • the PI3K inhibitor is a PI3K ⁇ inhibitor and/or a PI3K ⁇ inhibitor.
  • the present invention provides the compound or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation for the treatment of KRAS and/or Use in medicine for PI3K-mediated diseases;
  • the disease is cancer or autoimmune disease.
  • the cancer is selected from: non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, breast cancer, Triple negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphatic cancer, blood cancer, esophageal cancer, urinary tract cancer, nasal cavity cancer.
  • the present invention provides the compound or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used in the preparation of anticancer agents use in medicines for drug-resistant diseases;
  • the anticancer agent is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
  • the KRAS G12C inhibitor in the anticancer agent is selected from AMG-510, MRTX-849, preferably AMG-510.
  • the present invention provides the compound or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pro- Use of the above pharmaceutical composition in the preparation of medicines for treating diseases that cause overexpression of PI3K protein and/or KRAS G12C protein.
  • the present invention provides the compound or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or the aforementioned pharmaceutical composition in the preparation of therapeutic PI3K protein and/or KRAS G12C Use in medicine for diseases caused by protein overexpression.
  • the present invention also provides a pharmaceutical composition, characterized in that the active ingredient of the pharmaceutical composition is selected from the above compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or one or a combination of two or more of the aforementioned pharmaceutical compositions.
  • the present invention also provides the above compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation of KRAS inhibitors and/or PI3K inhibitors use in pharmaceuticals.
  • the KRAS inhibitor is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
  • the PI3K inhibitors are PI3K ⁇ inhibitors and/or PI3K ⁇ inhibitors agent.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used for the treatment of KRAS and/or Use in medicine for PI3K-mediated diseases.
  • the present invention provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used in the preparation for the treatment of KRAS G12C Use in medicine for diseases mediated by one or more of PI3K ⁇ , PI3K ⁇ .
  • the disease is cancer or autoimmune disease.
  • the cancer includes but not limited to non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, breast cancer , triple negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphatic cancer, blood cancer, esophageal cancer, urethral cancer, nasal cavity cancer.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used in the preparation of anti-cancer agent production use in medicines for drug-resistant diseases;
  • the anticancer agent is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
  • the KRAS G12C inhibitor is selected from AMG-510, MRTX-849, preferably AMG-510.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation and treatment of PI3K protein and/or KRAS Use in medicine for diseases with overexpression of G12C protein.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation and treatment of PI3K protein excess and/or KRAS The use in medicine of diseases caused by G12C protein expression.
  • composition containing the compound of the present invention or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or the aforementioned pharmaceutical composition it may contain pharmaceutically acceptable Accessories.
  • the present invention also provides a method for treating diseases mediated by KRAS and/or PI3K, which comprises administering the aforementioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable Accepted salts, co-crystals or steps of the aforementioned pharmaceutical compositions.
  • the present invention also provides a method for treating a disease resistant to an anticancer agent, which comprises administering the aforementioned compound or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable compound to a patient in need. salt, co-crystal or the step of the aforementioned pharmaceutical composition.
  • the present invention also provides a method for treating diseases caused by overexpression of PI3K protein and/or KRAS G12C protein, which includes administering the aforementioned compound or its tautomer, stereoisomer, solvate, metabolite, Pharmaceutically acceptable salts, co-crystals or steps of the aforementioned pharmaceutical compositions.
  • “Pharmaceutically acceptable” in the present invention refers to any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.
  • the pharmaceutically acceptable adjuvant of the present invention is the general term for all additional materials in the drug except the main drug, and the adjuvant should have the following properties: (1) have no toxic effect on the human body, and have almost no side effects; (2) have stable chemical properties , not easily affected by temperature, pH, storage time, etc.; (3) no incompatibility with the main drug, does not affect the curative effect and quality inspection of the main drug; (4) does not interact with packaging materials.
  • auxiliary materials include but are not limited to fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, bacteriostats , emulsifier, disintegrant, etc.
  • salts refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine.
  • the above-mentioned acids and bases are Lewis acids and bases in a broad sense.
  • Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.
  • the administration mode of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the invention can likewise be used in injectable preparations.
  • the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (referring to molded tablet or machine-pressed tablet made by aseptic method of medicine, used for immediate use) Dissolved in water for injection, for subcutaneous or intramuscular injection).
  • the powder for injection contains at least excipients in addition to the above compounds.
  • the excipients mentioned in the present invention are ingredients intentionally added to the drug, which should not have pharmacological properties in the amount used, but the excipients can facilitate the processing, dissolution or dissolution of the drug, and pass through the target. to give Drug delivery may contribute to stability.
  • the "tautomer” mentioned in the present invention refers to the functional group isomers produced by the movement of an atom in the molecule at two positions, especially the presence of mobile hydrogen atoms in the molecule, such as the interconversion of keto and enol isomer.
  • stereoisomer in the present invention refers to isomers produced by atoms or atomic groups in the same order of interconnection but with different spatial arrangements, including cis-trans isomers, optical isomers, and conformational isomers.
  • the stereoisomers in the present invention also include mixtures of two or more stereoisomers, such as mixtures of enantiomers and/or diastereomers in any ratio.
  • solvate in the present invention refers to the association formed by one or more solvent molecules and the compound of the present invention, which is suitable for use as a drug.
  • Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and the like.
  • the “metabolite” in the present invention refers to the pharmaceutically acceptable metabolic derivative form of the compound of the present invention (or its salt).
  • co-crystal in the present invention refers to ionized or non-ionized formula (I) compound (or any other compound disclosed herein) and one or more non-ionized co-crystal formers (such as pharmaceutically acceptable salts) Molecular complexes linked by non-covalent interactions.
  • Optionally substituted by one or more means that it can be substituted by one or more specified substituents, and can also be unsubstituted; "multiple" in “one or more”, if not limited , then the minimum value is 2, and the maximum value is the value of the substitutable position of the substituted group.
  • substitution means that a hydrogen atom in a molecule is replaced by a different group.
  • Element means the number of skeleton atoms constituting the ring.
  • the "key” mentioned in the present invention means that there is only one connecting key, and it can also be understood as “none”.
  • hydrogen or “H” in chemical structures, unless otherwise stated, should be understood to include not only 1H, but also deuterium (2H, D), tritium (3H, T) or mixtures thereof.
  • Alkyl refers to an aliphatic hydrocarbon group and refers to a saturated hydrocarbon group.
  • the alkyl moiety may be straight-chain or branched-chain.
  • Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
  • C1 ⁇ Cn used in the present invention includes C1 ⁇ C2, C1 ⁇ C3...C1 ⁇ Cn, n is an integer greater than one; the prefix as a substituent indicates the minimum and maximum values of the number of carbon atoms in the substituent, for example , "C1-C6 alkyl” refers to a straight-chain or branched-chain alkyl group containing 1 to 6 carbon atoms.
  • Heteroalkyl refers to an alkyl group containing heteroatoms.
  • Ring refers to any covalently closed structure, including, for example, carbocycles (such as aryl or cycloalkyl), heterocycles (such as heteroaryl or heterocycloalkyl), aromatic groups (such as aryl or heteroaryl ), non-aromatic (such as cycloalkyl or heterocycloalkyl).
  • the "ring” mentioned in the present invention may be a single ring or a polycyclic ring, and may be a parallel ring, a spiro ring or a bridged ring.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon substituent.
  • Cycloalkenyl refers to a cyclic substituent having at least one carbon-carbon double bond in the ring skeleton.
  • Heterocycloalkyl refers to a saturated ring substituent containing a heteroatom in the ring backbone.
  • Azacycloalkyl refers to a cycloalkyl group containing a nitrogen atom in the ring skeleton, and the same applies to other similar cases.
  • Azamonocycloalkyl refers to an azacycloalkyl group with a monocyclic structure, and the same applies to other similar cases.
  • Azacycloalkenyl refers to a non-aromatic monocyclic or polycyclic group containing at least one double bond, in which at least one ring atom is a heteroatom nitrogen and the remaining ring atoms are carbon.
  • Examples of "5- to 10-membered azacycloalkenyl” can be, for example, As otherwise indicated, the azacycloalkenyl group is optionally substituted with one or more suitable substituents.
  • Alicyclic group refers to a cyclic substituent without aromaticity, which may be cycloalkyl, cycloalkenyl or aliphatic heterocyclic group.
  • Heteroalicyclic group refers to a substituent group formed by a heterocyclic compound containing at least one heteroatom in the ring skeleton and not possessing aromaticity, and “heterocycloalkyl” is included in “heteroalicyclic group”.
  • Typical heteroalicyclic groups include, but are not limited to:
  • Aryl means an aromatic monocyclic or polycyclic group whose planar ring has a delocalized ⁇ -electron system and contains 4n+2 ⁇ -electrons, where n is an integer; typical aryl groups include but not limited to phenyl Naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl, etc.
  • Heteroaryl refers to a monocyclic or polycyclic group containing heteroatoms and having aromaticity.
  • Typical heteroaryl groups include, but are not limited to:
  • alkyl, cycloalkyl, cycloalkenyl, alicyclic aliphatic, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, etc. mentioned in the article can be unsubstituted alkyl, cycloalkyl, cycloalkenyl , alicyclic aliphatic, heterocyclic, heterocycloalkyl, aryl, heteroaryl, etc., can also be substituted alkyl, cycloalkyl, cycloalkenyl, alicyclic aliphatic, heterocyclic, heteroaryl Cycloalkyl, aryl, heteroaryl, etc.
  • substitution means that the mentioned group can be replaced by one or more additional groups, the additional groups are each and independently selected from the common Substituent groups, such as halogen, cyano, hydroxyl, amino, carboxyl, alkyl, alkoxy, alkylamino, alkylthio, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. wait.
  • Alkoxy means -O-alkyl
  • Alkylamino means -NH-alkyl or -N-(alkyl)2.
  • Alkylthio means -S-alkyl.
  • Halogen or "halo" means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • the present invention provides a series of compounds with obvious inhibitory effects on KRAS and PI3K proteins, which have the advantages of high activity, good selectivity, and low toxicity and side effects, and have good pharmacokinetic properties in vivo. It provides a new solution for the treatment of diseases such as cancer with KRAS or PI3K as the target of treatment, which can be used to prepare drugs for the treatment of related diseases, and has broad application prospects.
  • the compound of the present invention is resistant to KRAS G12C inhibitors, especially AMG-510 drug-resistant cancer cells have a strong inhibitory effect, overcomes the problem of drug resistance caused by simple G12C inhibitors, and is expected to prolong the survival of patients .
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm).
  • the determination of NMR is carried out with AVANCE NEO 400MHz Bruker instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl sulfoxide trimethylsilane (TMS). MS was determined with an ISQ-EC Thermo Fisher LC-MS instrument.
  • Prep-HPLC is a GX-281 Gilson chromatograph, and the separation methods are: (method 1) Sun Fire Prep C18 OBDTM 5 ⁇ m, 30 ⁇ 150mm Column, 0.04% HCl aqueous solution/acetonitrile; (method 2) Xbridge Prep C18 OBDTM 5 ⁇ m, 30 x 150mm Column, 10mM NH 4 HCO 3 aqueous solution/acetonitrile.
  • the starting materials in the examples of the present invention are known and can be purchased in the market, or can be synthesized according to methods known in the art.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • DIPEA N,N-Diisopropylethylamine
  • BINAP 1,1'-binaphthyl-2,2'-bisdiphenylphosphine
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm).
  • the determination of NMR is carried out with AVANCE NEO 400MHz Bruker instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl sulfoxide trimethylsilane (TMS). MS was determined with an ISQ-EC Thermo Fisher LC-MS instrument.
  • Prep-HPLC is a GX-281 Gilson chromatograph, and the separation methods are: (method 1) Sun Fire Prep C18 OBDTM 5 ⁇ m, 30 ⁇ 150mm Column, 0.04% HCl aqueous solution/acetonitrile; (method 2) Xbridge Prep C18 OBDTM 5 ⁇ m, 30 ⁇ 150mm Column, 10mM NH 4 HCO 3 aqueous solution/acetonitrile.
  • the starting materials in the examples of the present invention are known and can be purchased in the market, or can be synthesized according to methods known in the art.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • Example 2 Referring to the preparation method of Example 1, the compounds in the following examples were prepared with corresponding raw materials.
  • the preparation method is the same as step a of Example 1.
  • Examples 4-10 Referring to the preparation method of Example 3, the compounds in the following examples were prepared with corresponding raw materials.
  • 6-Bromo-4-chloroquinolin-3-amine (700mg, 0.713mmol) was dissolved in tetrahydrofuran (8mL), fluoroboric acid (2.6mL) was added at 0°C, and sodium nitrite (206mg, 0.784 mmol) in aqueous solution (1.0 mL), after addition, react at 0-10°C for 2 h. After filtering, the filter cake was rinsed with ethyl acetate (10 mL ⁇ 2), and the filter cake was vacuum-dried to obtain 6-bromo-4-chloroquinoline-3-diazofluoroborate with a yield of 92.6%.
  • 6-bromo-4-chloroquinoline-3-diazofluoroborate (900mg, 2.521mmol) into a 250mL reaction flask, and react at 155°C for 1h.
  • 6-bromo-4-chloro-3-fluoroquinoline 160mg, 0.615mmol
  • 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (262mg, 0.615mmol)
  • Pd(dppf)Cl 2 45mg, 0.062mmol
  • N-(5-(4-bromo-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide 250mg, 0.477mmol
  • tert-butyl piperazine-1-carboxylate 134mg, 0.716mmol
  • Pd2 (dba) 3 88mg, 0.095mmol
  • RuPhos 67mg, 0.143mmol
  • cesium carbonate 469mg, 1.431mmol
  • Examples 14-15 Referring to the preparation method of Example 13, the compounds in the following examples were prepared with corresponding raw materials.
  • N-(5-(8-bromoquinolin-2-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide 200mg, 0.395mmol
  • piperazine-1 - tert-butyl formate 89 mg, 0.474 mmol
  • Pd 2 (dba) 3 73 mg, 0.079 mmol
  • RuPhos 56 mg, 0.119 mmol
  • cesium carbonate 391 mg, 1.185 mmol
  • 6-Bromo-4-chloroquinoline-3-carbonitrile (330mg, 1.233mmol), piperazine-1-carboxylic acid tert-butyl ester (270mg, 1.450mmol), triethylamine (370mg, 3.650mmol) were added N,N - Dimethylformamide (15 mL), heated to 60° C. for 2 h after addition. After the reaction, water (50ml) was added to the reaction solution, and stirred at room temperature for 30min.
  • Examples 22-24 Referring to the preparation method of Example 21, the compounds in the following examples were prepared with corresponding raw materials.
  • 6-Bromo-4-chloro-8-methylquinoline (320 mg, 1.247 mmol) and piperazine-1-carboxylic acid tert-butyl ester (303 mg, 1.634 mmol) were dissolved in DMSO (10 mL), and DIPEA (485 mg, 3.754mmol), after the addition was completed, the temperature was raised to 120°C and the reaction was stirred for 14h. After the reaction, cool to room temperature and add ice water (40mL) to quench the reaction, extract with ethyl acetate (40mL ⁇ 2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • DIPEA 485 mg, 3.754mmol
  • Examples 26-32 Referring to the preparation method of Example 25, the compounds in the following examples were prepared with corresponding raw materials.
  • 6-Bromo-4-chloro-3-fluoroquinoline 60mg, 0.231mmol
  • 2,6-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide 108mg, 0.254mmol
  • Pd(dppf)Cl 2 17mg, 0.023mmol
  • N-(5-(4-chloro-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide (100mg, 0.208mmol), tert-butyl piperazine-1-carboxylate (47mg, 0.250mmol), Pd2 (dba) 3 (38mg, 0.042mmol), RuPhos (29mg, 0.029mmol) and cesium carbonate (205mg, 0.624mmol) were added toluene (8mL) After the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen.
  • Examples 34-39 Referring to the preparation method of Example 33, the compounds in the following examples were prepared with corresponding raw materials.
  • Examples 41-42 Referring to the preparation method of Example 40, the compounds in the following examples were prepared with corresponding raw materials.
  • 6-bromo-4-chloro-8-fluoroquinoline (210.0mg, 0.806mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (379.8mg, 0.887mmol), Pd(dppf) Cl2 (59.3mg, 0.081mmol ), cesium carbonate (527.8mg, 1.612mmol), water (0.4mL) and 1,4-dioxane (2mL) were added into the reaction flask, replaced with nitrogen three times, and heated to 85°C under nitrogen protection for 1h reaction.
  • N-(5-(4-chloro-8-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (220.0mg, 0.458mmol) , tert-butyl piperazine-1-carboxylate (128.5mg, 0.687mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (42.9mg, 0.092mmol ), tris(dibenzylideneacetone)dipalladium (26.5mg, 0.046mmol), cesium carbonate (299.8mg, 0.916mmol) and toluene (2mL) were added into the reaction flask, heated to 110°C under nitrogen protection and stirred for 16h.
  • reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 4-(6-(5-((2,4-difluorophenyl)sulfonyl Amino)-6-methoxypyridin-3-yl)-8-fluoroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 58.7%; ESI-MS (m/z): 630.1[M+H] + .
  • Examples 45-47 Referring to the preparation method of Example 44, the compounds in the following examples were prepared with corresponding raw materials.
  • 6-bromo-4-chloroquinoline-3-cyano 200mg, 0.748mmol
  • 2,6-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide 319mg, 0.748mmol
  • Pd(dppf)Cl 2 109mg, 0.150mmol
  • Examples 49-50 Referring to the preparation method of Example 48, the compounds in the following examples were prepared with corresponding raw materials.
  • Step a): Preparation of N-(5-(4-chloro-5-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2-fluorobenzenesulfonamide 6-bromo-4 -Chloro-5-fluoroquinoline (300mg, 1.152mmol), 2-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (563 mg, 1.382 mmol), Pd(dppf)Cl 2 (84 mg, 0.115 mmol) and cesium carbonate (1.1 g, 3.456 mmol), Dioxane/water mixed solvent (10 mL, v/v 4:1) was added into the reaction flask, after the addition was completed, the temperature was raised to 80° C.
  • N-(5-(4-chloro-5-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2-fluorobenzenesulfonamide (350mg, 0.758mmol)
  • piperazine- tert-Butyl 1-carboxylate 212 mg, 1.137 mmol
  • Pd 2 (dba) 3 139 mg, 0.152 mmol
  • RuPhos 106 mg, 0.227 mmol
  • cesium carbonate 741 mg, 2.274 mmol
  • toluene (10 mL) were added to the reaction flask After the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen.
  • the preparation of tert-butyl 1-formate will be described in detail below.
  • N-(5-(4-chloroisoquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide 250mg, 0.541mmol
  • piperazine-1 - Dioxane 10mL
  • the temperature was raised to 110° C. and stirred overnight under the protection of nitrogen.
  • add water 50 mL to quench the reaction, extract with ethyl acetate (100 mL ⁇ 2), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • 6-Bromo-1,8-naphthyridin-4-ol (50mg, 0.222mmol) was dissolved in phosphorus oxychloride (5mL). After the addition was completed, the temperature was raised to 110°C under nitrogen protection and stirred for 3h.
  • reaction solution was concentrated under reduced pressure, and water (3 mL) was added to the concentrate to quench the reaction, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , to obtain 3-bromo-5-chloro-1,8-naphthyridine with a yield of 72.4%; ESI-MS (m/z): 242.9 [M+H] + .
  • 6-Chloro-1,5-naphthyridin-4-ol (50mg, 0.277mmol) was dissolved in phosphorus oxychloride (3mL). After the addition was completed, the temperature was raised to 110°C and stirred for 3h. After the reaction, the reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate (10 mL) was added to the concentrate to adjust the pH to 7-8. The aqueous phase was extracted with ethyl acetate (5 mL ⁇ 3), and the organic phase was washed with water (5 mL).
  • reaction solution was concentrated under reduced pressure, and water (3 mL) was added to the concentrate to quench the reaction, extracted with dichloromethane (10 mL), and the organic phases were combined, washed with water (5 mL ⁇ 2), and dried over anhydrous sodium sulfate.
  • 6-Bromo-4-chlorothieno[2,3-d]pyrimidine (320mg, 1.283mmol), tert-butyl piperazine-1-carboxylate (263mg, 1.411mmol), DIPEA (663mg, 5.132mmol) and acetonitrile (5 mL) was added into the reaction flask, and the temperature was raised to 80° C. for 1.5 h.
  • 6-Chloro-9-methyl-9H-purine 200mg, 0.808mmol
  • tert-butyl piperazine-1-carboxylate 226mg, 1.212mmol
  • DIPEA 209mg, 1.616mmol
  • DMF 4mL
  • 6-Bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid 700 mg, 2.723 mmol
  • phenylene ether-biphenyl cocrystal 10 mL
  • N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide 400mg, 1.055mmol
  • 4-(6-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 510mg, 1.161mmol
  • Pd(dppf)Cl 2 78mg, 0.106mmol
  • the positive reference compound of PI3K ⁇ inhibitor used in the present invention is Alpelisib (NVP-BYL-719), and the structure is as follows:
  • the positive reference compound of PI3K ⁇ inhibitor used in the present invention is Parsaclisib (IBI-376), the structure is as follows:
  • the KRAS G12C inhibitor positive reference compound used in the present invention is Sotorasib (AMG 510), and the structure is as follows:
  • Test Example 1 Determination of PI3K ⁇ inhibitory activity
  • the effect of the screening compounds on the PI3K ⁇ subtype enzyme activity was detected by ADP-Glo technology, so as to evaluate its inhibition level on PI3K protease activity.
  • the protein and detection reagents used were ADP-Glo TM Kinase Assay Kit (Promage). First, the 2mM test compound mother solution (dissolved in DMSO) was diluted with DMSO successively by 5-fold concentration to obtain the compound working solution 1 (200-fold). 8 concentrations.
  • IC 50 was calculated by fitting the inhibition rate with GraphPad Prism software and selecting log(inhibitor)vs.response—Variable Slope(four parameters) (Note: Negative means no inhibitor group; Blank means no enzyme group).
  • the test data of the compounds of the examples are shown in Table 1-Table 2.
  • Test Example 2 Determination of PI3K ⁇ Enzyme Inhibitory Activity
  • the effect of the screening compound on the enzyme activity of PI3K ⁇ subtype was detected by ADP-Glo technology, so as to evaluate its inhibition level on PI3K protease activity.
  • the protein and detection reagents used were ADP-Glo TM Kinase Assay Kit (Promage).
  • the 2mM test compound mother solution dissolved in DMSO
  • DMSO DMSO
  • 8 concentrations 8 concentrations.
  • 20-fold concentration gradient dilutions were performed on 8 concentrations of working solution 1 in turn, that is, 5 ⁇ L of working solution 1 was added to 95 ⁇ L ddH 2 O, and the vortex mixer was fully shaken to obtain compound working solution 2 (10 times).
  • IC 50 was calculated by fitting the inhibition rate with GraphPad Prism software and selecting log(inhibitor)vs.response—Variable Slope(four parameters) (Note: Negative means no inhibitor group; Blank means no enzyme group).
  • the test data of the compounds of the examples are shown in Table 1-Table 2.
  • PI3K ⁇ inhibitors Alpelisib and Parsaclisib are currently known PI3K ⁇ inhibitors and PI3K ⁇ inhibitors respectively. From the data in Table 1 to Table 2, it can be seen that the compounds of the present invention have obvious inhibitory effects on PI3K ⁇ and PI3K ⁇ , and the activity of some compounds is comparable to that of positive compounds. Compared with the invention, it has more advantages, can be used as a PI3K inhibitor, and has broad application prospects in the fields of cancer and other diseases mediated by PI3K protein.
  • KRAS-G12C inhibitor The effect of KRAS-G12C inhibitor on the interaction between KRAS-G12C and SOS1 protein was detected by HTRF technology, so as to evaluate its inhibitory activity on KRAS-G12C protein.
  • the protein and detection reagents used were KRAS G12C/SOS1 binding assay kits (Cisbio). Firstly, the 2mM test compound mother solution (dissolved in DMSO) was diluted with DMSO successively by 5-fold concentration to obtain the compound working solution 1 (200-fold). 8 concentrations.
  • % inhibition rate [(Rati Negative -Rati Compound )/(Rati Negative -Ratio Blank )] ⁇ 100
  • Negative means no inhibitor group
  • Blank means no enzyme group
  • IC 50 was calculated by fitting and calculating the inhibition rate by GraphPad Prism software, selecting log (inhibitor) vs. response working solution ribable Slope (four parameters).
  • the test data of the compounds of the examples are shown in Table 3 and Table 4.
  • the comparative examples do not have KRAS-G12C/SOS1 binding inhibitory activity, while the compounds of the present invention can effectively block the KRAS-G12C/SOS1 binding and can be used as KRAS G12C inhibitors , which has broad application prospects in the field of cancer and other diseases mediated by KRAS G12C protein and multi-target therapy.
  • Test Example 4 Determination of KRAS G12C Mutant Cell Line NCI-H358 Cells and MIA Paca-2 Cell Proliferation Inhibition
  • the reagent detects the number of viable cells to evaluate the inhibitory effect of the compound on cell proliferation.
  • Collect NCI-H358 cells in the logarithmic growth phase inoculate into a transparent bottom 96-well plate, 80 ⁇ L per well, density 4 ⁇ 10 3 cells/well, culture overnight at 37°C, 5% CO 2 ; Dilute to obtain 8 concentrations of gradient dilutions, then dilute with RPMI-640 (10% FBS) cell culture medium to obtain compound working solution (5 times), add 20 ⁇ L per well to the cell supernatant, 37 ° C, 5% The culture was continued for 3 days under CO 2 conditions.
  • the inhibition rate was calculated by the following formula:
  • IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group).
  • the test data of the compounds of the examples are shown in Table 5-Table 7.
  • the reagent detects the number of viable cells to evaluate the inhibitory effect of the compound on cell proliferation.
  • collected in the logarithmic growth phase MIA PaCa-2 cells were inoculated into a transparent bottom 384-well plate, 15 ⁇ L per well, at a density of 600 cells/well, and cultured overnight at 37°C, 5% CO 2 ; the compound was diluted 4-fold with DMSO to obtain 9 concentrations of serial dilutions solution, and then diluted with DMEM (10% FBS + 2.5% horse serum + 1% P/S) cell culture medium to obtain the compound working solution (2 times final concentration), add 15 ⁇ L per well to the cell supernatant, 37 ° C, Culture was continued for 3 days under 5% CO 2 condition.
  • the inhibition rate was calculated by the following formula:
  • IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 5 and Table 6.
  • Test example 5 NCI-H358-AMGR drug-resistant cell line construction method
  • NCI-H358 cells were inoculated into six-well plates, cultured in RPMI-640 (10% FBS) medium at 37°C and 5% CO 2 until the confluence was 50-70%, and AMG 510 was added for induction. Three initial concentration groups were established: 1nM, 10nM, and 50nM groups, and the culture medium containing the same concentration of AMG 510 was replaced every 3 days. When the cells reached 100% fusion, the AMG 510 concentration was increased by 3 times after every 2 passages, and so on until the AMG 510 concentration reached 1 ⁇ M.
  • the inhibition rate was calculated by the following formula:
  • IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 7 and Table 8.
  • Table 7 Test the inhibitory activity of the first batch of compounds on NCI-H358-AMGR drug-resistant cell proliferation
  • Test example 6 MIA PaCa-2-AMGR drug-resistant cell line construction method
  • MIA PaCa-2 cells were inoculated into six-well plates in DMEM (10% FBS+2.5% horse serum) medium, and cultured at 37°C and 5% CO2 until the confluence was 50-70%, and AMG 510 was added. To induce. Three initial concentration groups were established: 1nM, 10nM, and 50nM groups, and the culture medium containing the same concentration of AMG 510 was replaced every 3 days. When the cells reached 100% fusion, the AMG 510 concentration was increased by 3 times after every 2 passages, and so on until the AMG 510 concentration reached 1 ⁇ M. Comparing the inhibition rate of AMG510 on the drug-resistant cell line and the parental cell line, when the inhibition rate of the maximum administration concentration (10 ⁇ M) was less than 50%, it indicated that the MIA PaCa-2-AMGR drug-resistant cell line was successfully constructed.
  • the inhibition rate was calculated by the following formula:
  • IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 9 and Table 10.
  • the compound of the present invention has a strong inhibitory effect on KRAS-G12C inhibitors such as AMG 510 drug-resistant cancer cells, and can be used to overcome the problem of drug resistance caused by simple KRAS-G12C inhibitors .

Abstract

Disclosed are a pyridine derivative represented by formula I and use thereof. The compound has a significant inhibitory effect on KRAS and PI3K protein activities and can be used as a KRAS and/or PI3K protein inhibitor and in preparing a medicament for treating a disease such as a KRAS or PI3K protein-mediated cancer. The compound of the present application has an extremely strong inhibitory effect on cancer cells with resistance to KRAS G12C inhibitors such as AMG-510 and thus has broad application prospects.

Description

一种吡啶类衍生物及其用途A kind of pyridine derivative and its use
本申请要求申请日为2022年3月3日的中国专利申请202210208621.3、申请日为2022年8月12日的中国专利申请202210966140.9的优先权，本申请引用上述中国专利申请的全文。This application claims the priority of Chinese patent application 202210208621.3 with a filing date of March 3, 2022, and Chinese patent application 202210966140.9 with a filing date of August 12, 2022. This application cites the full text of the above-mentioned Chinese patent applications.
技术领域technical field
本发明涉及医药技术领域，特别是涉及一种用作KRAS G12C抑制剂和/或PI3K蛋白抑制剂的化合物及其用途。The invention relates to the field of medical technology, in particular to a compound used as a KRAS G12C inhibitor and/or PI3K protein inhibitor and its application.
背景技术Background technique
RAS蛋白是一类重要的信号分子，参与细胞增殖、分化、存活和运动等多种过程。RAS家族由KRAS、NRAS与HRAS等组成，它们在细胞内有两种状态：与GDP结合的非激活状态和与GTP结合的激活状态。当RAS被激活后，可以激活多条下游信号通路，其中包括MAPK信号通路，PI3K信号通路和Ral-GEFs信号通路，这些信号通路在促进细胞生存、增殖和细胞因子释放方面具有重要作用。RAS protein is an important class of signaling molecules involved in various processes such as cell proliferation, differentiation, survival and motility. The RAS family consists of KRAS, NRAS and HRAS, etc. They have two states in the cell: an inactive state bound to GDP and an activated state bound to GTP. When RAS is activated, it can activate multiple downstream signaling pathways, including MAPK signaling pathway, PI3K signaling pathway and Ral-GEFs signaling pathway, which play an important role in promoting cell survival, proliferation and cytokine release.
RAS的激活依赖于酪氨酸激酶受体结合信号分子后受体磷酸化，露出结合位点，鸟嘌呤核苷酸交换因子(GEF，如SOS1)与生长因子受体结合蛋白(Grb2)复合物结合到该位点上，通过Grb2的SH2结构域与之结合，形成RTK/Grb2/SOS复合物，SHP2可进一步促进此复合物结合到RAS上，促使其释放GDP，结合GTP，从而激活RAS。此外，值得注意的是，RAS在激活之前，需要结合到细胞膜内侧才能发挥其生理作用，其中法尼基转移酶起着关键作用，鞘磷脂合酶-1可能也参与调控RAS的定位。作为突变发生率最高的原癌基因，RAS家族分别有KRAS，NRAS和HRAS组成，而病人中KRAS的突变占84％，HRAS和NRAS突变则分别只有4％和12％。KRAS(Kirsten Rat Sarcoma virus)基因位于12号常染色体，由188-189个氨基酸组成，分子量为21.7kDa。RAS蛋白由6个β折叠和5个α螺旋组成，其中N端的166个氨基酸组成G结构域，而C端则膜结合区。G结构域(分G1-G5)为功能结构域，能直接与GDP/GTP结合，G2(Switch I)与GTP结合，而G3(Switch II)与GDP结合。KRAS在机体组织中广泛表达，其mRNA水平在几乎所有组织内都能检测到。KRAS在细胞中通过参与GTP水解而起作用，作为GTP酶在催化鸟嘌呤三核苷酸磷酸(Guanosine triphosphate,GTP)和鸟嘌呤二核苷酸磷酸(Guanosine diphosphate,GDP)转化中发挥功能，促进细胞生存、迁移和增殖。正常细胞中KRAS与GDP的结合为主，处于无活性状态，而鸟嘌呤核苷酸交换因子(Guanine Nucleotide Exchange Factor,GEF)如SOS1能促使其对GDP的释放而与GTP结合转变为激活状态，而其逆向转变则可通过GTP酶激活蛋白(GTPase-activating protein,GAP)，如RasGAP来实现。KRAS在RAS突变中占主要，KRAS的突变广泛发生在癌症病人之中，包括5-30％肺癌患者、36-40％结肠癌患者及约90％的胰腺癌患者，此外在其它肿瘤如，子宫内膜癌、皮肤癌、多发性骨髓瘤病人中也发现KRAS的突变。The activation of RAS depends on the phosphorylation of the receptor after the binding of signal molecules by tyrosine kinase receptors, exposing the binding site, and the complex of guanine nucleotide exchange factors (GEF, such as SOS1) and growth factor receptor binding protein (Grb2) Binding to this site, the SH2 domain of Grb2 binds to it to form a RTK/Grb2/SOS complex, and SHP2 can further promote the binding of this complex to RAS, prompting it to release GDP and bind GTP, thereby activating RAS. In addition, it is worth noting that before RAS is activated, it needs to be bound to the inner side of the cell membrane to play its physiological role, in which farnesyl transferase plays a key role, and sphingomyelin synthase-1 may also be involved in regulating the localization of RAS. As the proto-oncogene with the highest mutation incidence, the RAS family consists of KRAS, NRAS and HRAS respectively, and KRAS mutations account for 84% of patients, while HRAS and NRAS mutations are only 4% and 12% respectively. The KRAS (Kirsten Rat Sarcoma virus) gene is located on autosome 12, consists of 188-189 amino acids, and has a molecular weight of 21.7kDa. The RAS protein consists of 6 β sheets and 5 α helices, of which the 166 amino acids at the N-terminal form the G domain, while the C-terminal is the membrane binding region. The G domain (subdivided into G1-G5) is a functional domain that can directly bind to GDP/GTP, G2 (Switch I) binds to GTP, and G3 (Switch II) binds to GDP. KRAS is widely expressed in body tissues, and its mRNA level can be detected in almost all tissues. KRAS plays a role in the cell by participating in the hydrolysis of GTP. As a GTPase, it functions in catalyzing the conversion of guanine trinucleotide phosphate (GTP) and guanine dinucleotide phosphate (Guanosine diphosphate, GDP), promoting Cell survival, migration and proliferation. In normal cells, KRAS is mainly combined with GDP and is in an inactive state, while Guanine Nucleotide Exchange Factor (GEF) such as SOS1 can promote its release of GDP and change into an active state by combining with GTP. And its reverse transformation can be realized by GTPase-activating protein (GTPase-activating protein, GAP), such as RasGAP. KRAS is the main mutation in RAS, KRAS mutations widely occur in cancer patients, including 5-30% of lung cancer patients, 36-40% of colon cancer patients and about 90% of pancreatic cancer patients, in addition to other tumors such as uterus KRAS mutations have also been found in patients with endometrial cancer, skin cancer, and multiple myeloma.
在KRAS突变中，以G12位的突变为主，占83％，其次是G13占14％，此外还有Q61等；G12位突变中又以G12V，G12D，G12C为主。G12C突变在非小细胞肺癌患者中比例占14％，结肠癌占5％，胰腺导管腺癌2％。KRAS的突变能促进其与GTP的结合，并一直处于激活状态，持续激活细胞的生长，从而导致肿瘤的发生。这些都说明KRAS突变在临床治疗中具有重要价值。G12C突变是KRAS基因突变中比较常见的一个亚型，它是指12号甘氨酸突变为半胱氨酸。KRAS G12C突变在肺癌中也最为常见，根据文献(Cox,A.D.；et al.Nat.Rev.Drug Discov.2014,13,828-851)报道的数据推算，KRAS G12C突变占到所有肺癌患者的10％左右。三十多年来，寻找专一靶向KRAS的药物没有任何突破，所以KRAS被普遍认为是一个“不能成药”(Undruggable Target)的靶点。Among KRAS mutations, mutations at G12 are the main ones, accounting for 83%, followed by G13 at 14%, and Q61, etc.; G12 mutations are mainly G12V, G12D, and G12C. G12C mutations are present in 14% of patients with non-small cell lung cancer, 5% in colon cancer, and 2% in pancreatic ductal adenocarcinoma. The mutation of KRAS can promote its combination with GTP, and it is always in an activated state, continuously activating the growth of cells, thus leading to the occurrence of tumors. All these indicate that KRAS mutation has important value in clinical treatment. G12C mutation is a relatively common subtype of KRAS gene mutation, which refers to the mutation of glycine 12 to cysteine. KRAS G12C mutation is also the most common in lung cancer. According to the data reported in the literature (Cox, A.D.; et al. Nat. Rev. Drug Discov. 2014, 13, 828-851), KRAS G12C mutation accounts for about 10% of all lung cancer patients . For more than 30 years, there has been no breakthrough in the search for drugs that specifically target KRAS, so KRAS is generally considered an "undruggable target" (Undruggable Target).
近年来，KRAS G12C的成药性被发现，KRAS G12C抑制剂成为当前药物研发热点领域之一。文献(Ostrem,J.M.；et al.Nature.2013,503,548-551)报道了一类靶向KRAS G12C突变的共价结合抑制剂，但是这类化合物酶活性不高，在细胞水平没有表现出活性。文献(Lito,P.；et al.Science,2016,351,604-608；Patricelli,M.P.；et al.Cancer Discov.2016,6,316-329)报道的另一类化合物在细胞水平表现出了μΜ级别的抗细胞増殖活性，但是其代谢稳定性差，活性也很难进行进一步提高。寻找靶向RAS的药物非常困难。由于GTP与RAS的结合能力非常强，很难找到能够竞争性抑制它们结合的小分子；而且RAS蛋白的表面非常平滑，结构上缺乏让小分子或药物结合的结构空间。2013年，加州大学通过蛋白晶体学研究发现KRAS一个常见的突变KRAS G12C蛋白，在与GDP结合后会在分子表面形成了一个新口袋，小分子抑制剂在这个位点可与KRAS G12C蛋白共价结合从而将蛋白锁定在失活状态。近年来，AraxesPharma公司申请了数篇针对KRAS G12C抑制剂的专利，例如WO2016164675和WO2016168540就分别报道了一类具有较高的酶结合活性的喹唑啉衍生物和稠合的三环喹唑啉衍生物，且表现出μΜ级别的细胞抗増殖活性，其结构稳定，并有一定的选择性。Amgen(WO2018119183)与AstraZeneca(WO2018206539)公司在2018年分别有 关于KRAS G12C抑制剂的专利公开，且Amgen的KRASG12C抑制剂AMG-510在2018年7月份启动了一期临床研究。In recent years, the druggability of KRAS G12C has been discovered, and KRAS G12C inhibitors have become one of the current hot areas of drug development. The literature (Ostrem, JM; et al. Nature. 2013, 503, 548-551) reported a class of covalent binding inhibitors targeting the KRAS G12C mutation, but the enzymatic activity of these compounds is not high, and there is no activity at the cellular level. Another class of compounds reported in the literature (Lito, P.; et al. Science, 2016, 351, 604-608; Patricelli, MP; et al. Cancer Discov. 2016, 6, 316-329) exhibited μM-level anti-inflammatory activity at the cellular level. Cell proliferation activity, but its metabolic stability is poor, and activity is also difficult to further improve. Finding drugs that target RAS has been difficult. Due to the strong binding ability of GTP and RAS, it is difficult to find small molecules that can competitively inhibit their binding; moreover, the surface of RAS protein is very smooth, and the structure lacks structural space for small molecules or drugs to bind. In 2013, the University of California discovered through protein crystallography that a common mutant of KRAS, KRAS G12C protein, forms a new pocket on the surface of the molecule after binding to GDP, and small molecule inhibitors can covalently covalently bind to KRAS G12C protein at this site Binding locks the protein in an inactive state. In recent years, AraxesPharma has applied for several patents targeting KRAS G12C inhibitors. For example, WO2016164675 and WO2016168540 respectively reported a class of quinazoline derivatives and fused tricyclic quinazoline derivatives with high enzyme binding activity. and exhibits anti-proliferation activity at the μM level, with a stable structure and certain selectivity. Amgen (WO2018119183) and AstraZeneca (WO2018206539) respectively had The patent disclosure on KRAS G12C inhibitors, and Amgen's KRAS G12C inhibitor AMG-510 launched a phase 1 clinical study in July 2018.
纵观目前文献报道的KRAS G12C抑制剂，它们都有一个丙烯酰胺的片段，其作为迈克尔加成受体和KRAS G12C突变蛋白上的半胱氨酸残基作用形成共价结合复合物。2018年，Liu Yi等人在Cell(Janes,M.R.；et al.Cell.2018,172,578-589)上公开报道了靶向KRAS G12C突变的共价结合抑制剂ARS-1620，该化合物具有很好的代谢稳定性，在细胞水平表现出了nM级别的细胞抗増殖活性，且在胰腺癌MIA-Paca2细胞皮下异种移植肿瘤模型上能有效的抑制肿瘤生长。Throughout the current KRAS G12C inhibitors reported in the literature, they all have an acrylamide fragment, which acts as a Michael addition receptor and a cysteine residue on the KRAS G12C mutein to form a covalent binding complex. In 2018, Liu Yi et al. reported on Cell (Janes, M.R.; et al. Cell. 2018, 172, 578-589) the covalent binding inhibitor ARS-1620 targeting the KRAS G12C mutation. The compound has a good Metabolic stability, showing nM level of anti-proliferation activity at the cellular level, and can effectively inhibit tumor growth in the subcutaneous xenograft tumor model of pancreatic cancer MIA-Paca2 cells.
目前进展较快的在研KRAS G12C抑制剂主要包括Araxes公司的ARS-1620、Amgen公司的AMG-510和Mirati公司的MRTX-849(WO2020216190)。其中，AMG-510进展最快并于2021年获批上市，其在2018年就开始I期临床试验，是最早进入临床试验的KRAS G12C抑制剂。Currently, KRAS G12C inhibitors under development that are progressing rapidly mainly include ARS-1620 from Araxes, AMG-510 from Amgen, and MRTX-849 from Mirati (WO2020216190). Among them, AMG-510 has the fastest progress and will be approved for marketing in 2021. It started phase I clinical trials in 2018 and is the earliest KRAS G12C inhibitor to enter clinical trials.
然而，KRAS抑制剂的耐药性是癌症治疗的一大难题。安进最新的临床试验结果也表明接受KRAS G12C抑制剂AMG-510治疗的有些患者在缓解后疾病继续出现进展。由于KRAS G12C在活性和非活性构象之间循环，并且抑制剂仅与后者结合，Piro Lito等研究人员发现了一种对构象特异性KRAS G12C抑制的快速非均匀适应耐药机制。他们通过研究单细胞分辨率下的治疗效果来测试了同基因细胞群体是否以非均匀的方式反应，结果发现，在治疗后不久，一些癌细胞被变为静止状态，并具有较低的KRAS活性，而另一些则绕过这种作用以恢复增殖而产生耐药(XUE,J.Y.；et al.Nature.2020，577，421-425)。Adachi等最新研究表明上皮间质转化(EMT)才是AMG510固有和获得性耐药的原因(Adachi,Y.；et al.Clin.Cancer Res.2020,26,5962-5973)。虽然在AMG-510耐药机理方面还有其他研究发表，但对AMG-510等KRAS抑制剂的耐药问题目前临床上仍没有较好的切实可行的解决办法。因此，开发能够克服耐药问题的新治疗剂具有重要意义。However, resistance to KRAS inhibitors is a major problem in cancer treatment. Amgen's latest clinical trial results also show that some patients treated with KRAS G12C inhibitor AMG-510 continued to progress after remission. As KRASG12C cycles between active and inactive conformations, and inhibitors bind only to the latter, Piro Lito et al. discovered a mechanism of rapid heterogeneous adaptive resistance to conformation-specific KRASG12C inhibition. They tested whether isogenic cell populations responded in a heterogeneous manner by studying the effects of treatment at single-cell resolution, and found that shortly after treatment, some cancer cells were rendered quiescent and had lower KRAS activity , while others bypass this effect to restore proliferation and develop resistance (XUE, J.Y.; et al. Nature. 2020, 577, 421-425). The latest research by Adachi et al. shows that epithelial-mesenchymal transition (EMT) is the cause of AMG510 intrinsic and acquired drug resistance (Adachi, Y.; et al. Clin. Cancer Res. 2020, 26, 5962-5973). Although there are other studies published on the mechanism of AMG-510 resistance, there is still no clinically feasible solution to the problem of resistance to KRAS inhibitors such as AMG-510. Therefore, it is of great significance to develop new therapeutic agents that can overcome the problem of drug resistance.
发明内容Contents of the invention
本发明主要解决的技术问题是提供一种吡啶类衍生物，对PI3K具有强效的抑制作用。The technical problem mainly solved by the present invention is to provide a pyridine derivative, which has a strong inhibitory effect on PI3K.
为解决上述技术问题，本发明提供了一种化合物，具有式I所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
In order to solve the above-mentioned technical problems, the present invention provides a compound having the structure shown in formula I or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
其中：in:
T选自S(O)2、C＝O、CH2或NHS(O)2；T is selected from S(O) 2 , C=O, CH 2 or NHS(O) 2 ;
A1选自CR10、CR11R12或N，A2选自CR13、CR14R15或N，A3选自CR16、CR17R18或N，A4选自CR19、CR20R21或N，A5选自C、CR41、N或S，A6选自CR9、CR42R43、N或A6不存在，A7选自CR8、CR44R45、N、NR8或S，A8选自C、CR46或N，其中，当A1和A3同时为N时，A6不存在；A 1 is selected from CR 10 , CR 11 R 12 or N, A 2 is selected from CR 13 , CR 14 R 15 or N, A 3 is selected from CR 16 , CR 17 R 18 or N, A 4 is selected from CR 19 , CR 20 R 21 or N, A 5 is selected from C, CR 41 , N or S, A 6 is selected from CR 9 , CR 42 R 43 , N or A 6 is absent, A 7 is selected from CR 8 , CR 44 R 45 , N, NR 8 or S, A 8 is selected from C, CR 46 or N, wherein, when A 1 and A 3 are N at the same time, A 6 does not exist;
环C、环D、环E中的“-----”表示此处为一单键或无，且环C中任意两个相邻的“-----”不同时为单键；"-----" in Ring C, Ring D, and Ring E means that there is a single bond or none, and any two adjacent "-----" in Ring C are not single bonds at the same time;
B为B1、B2所在的环为5～10元氮杂环烷基、5～10元氮杂环烯基，且B1、B2所在的环为单环、螺环或桥环，B1选自C、CR22或N，B2选自C、CR23或N，且B1、B2中至少有一个为N；B for The rings of B 1 and B 2 are 5-10 membered azacycloalkyl groups, 5-10 membered azacycloalkenyl groups, and the rings of B 1 and B 2 are monocyclic, spiro or bridged rings, B 1 selected from C, CR 22 or N, B 2 selected from C, CR 23 or N, and at least one of B 1 and B 2 is N;
R7每次出现时分别独立选自卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORn、-NRoRp、-C(O)R24、-C(O)NRoRp、-C(O)ORn，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个卤素、氰基、烷基、环烷基、脂杂环基、-ORn、-NRoRp、-C(O)R24、-C(O)NRoRp、-C(O)ORn取代；Each occurrence of R 7 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR n , -NR o R p , -C(O)R 24. -C(O)NR o R p , -C(O)OR n , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more halogen, Cyano, Alkyl, Cycloalkyl, Heteroalicyclic, -OR n , -NR o R p , -C(O)R 24 , -C(O)NR o R p , -C(O)OR n replace;
n1选自0、1、2、3、4； n 1 is selected from 0, 1, 2, 3, 4;
R5、R6各自独立选自氢、卤素、氰基、烷基、脂杂环基、芳基、杂芳基、-ORa、-NRbRc、-C(O)R25、-S(O)R26、-S(O)2R26、-P(O)R26R27、-C(O)NRbRc、-C(O)ORa，且R5和R6不同时为氢；可选的，当R6选自-C(O)R25时，R25可与B环上任意一个R7相连共同组成4～12元脂杂环基；其中，所述烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R28取代；R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, alkyl, aliphatic heterocyclic group, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 25 , - S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C(O)OR a , and R 5 and R 6 not be hydrogen at the same time; optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 on the B ring to form a 4-12-membered aliphatic heterocyclic group; wherein, the Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 28 ;
R28每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORa、-NRbRc、-C(O)R25、-C(O)NRbRc、-C(O)ORa；Each occurrence of R 28 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, -OR a , -NR b R c , -C(O)R 25 , -C(O)NR b R c , -C(O)OR a ;
R1、R2分别独立选自氢、烷基、环烷基、脂杂环基、-C(O)R29，其中，所述烷基、环烷基、脂杂环基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基；当环E中的“-----”为一键时，R2为无；R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aliphatic heterocyclic group, and -C(O)R 29 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally replaced by One or more of the following substituents are substituted: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic ring; when "-----" in ring E is a bond, R2 is none ;
R3选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORg、-NRhRi、-C(O)R30、-C(O)RhRi、-C(O)ORg，当环E中的“-----”为无时，R3还可以是与其连接的碳原子共同组成羰基，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R31取代；R 3 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g , -NR h R i , -C(O)R 30 , -C (O)R h R i , -C(O)ORg, when the "-----" in ring E is none, R3 can also be the carbon atom connected to it to form a carbonyl group, wherein, alkyl, ring Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R;
R31每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORg、-NRhRi、-C(O)R32、-C(O)NRhRi、-C(O)ORg；Each occurrence of R 31 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR g , -NR h R i , -C(O)R 32 , -C(O)NR h R i , -C(O)OR g ;
R4选自烷基、环烷基、脂杂环基、芳基、杂芳基，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R33取代； R is selected from alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl, wherein, alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally replaced by one or more R 33 replacement;
R33每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORj、-NRkRm、-C(O)R34、-C(O)NRkRm、-C(O)ORj，其中，所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR j , -NR k R m , -C(O)R 34 , -C(O)NR k R m , -C(O)OR j , wherein, the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, heteroaryl group are optionally replaced by one or more R 35 replaced;
R35每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORj、-NRkRm、-C(O)R36、-C(O)NRkRm、-C(O)ORj；Each occurrence of R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR j , -NR k R m , -C(O)R 36 , -C(O)NR k R m , -C(O)OR j ;
R8、R9、R10、R16、R19、R11、R12、R17、R18、R20、R21、R22、R23、R41、R42、R43、R44、R45、R46分别独立选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORq、-NRrRs、-C(O)R37、-C(O)NRrRs、-C(O)ORq或无，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R38取代；R 8 , R 9 , R 10 , R 16 , R 19 , R 11 , R 12 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 are independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR q , -NR r R s , -C(O )R 37 , -C(O)NR r R s , -C(O)OR q or none, wherein the alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or Multiple R 38 substitutions;
R38每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORq、-NRrRs、-C(O)R39、-C(O)NRrRs、-C(O)ORq；Each occurrence of R 38 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR q , -NR r R s , -C(O)R 39 , -C(O)NR r R s , -C(O)OR q ;
R13、R14、R15分别独立选自氢、甲基；R 13 , R 14 , and R 15 are independently selected from hydrogen and methyl;
Ra、Rb、Rc、Rg、Rh、Ri、Rj、Rk、Rm、Rn、Ro、Rp、Rq、Rr、Rs每次出现时独立选自H、烷基、环烷基、脂杂环基、-C(O)R40，其中，所述烷基、环烷基、脂杂环基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基；R a , R b , R c , R g , R h , R i , R j , R k , R m , R n , R o , R p , R q , R r , R s are selected independently for each occurrence. from H, alkyl, cycloalkyl, aliphatic heterocyclic group, -C(O)R 40 , wherein the alkyl, cycloalkyl, aliphatic heterocyclic group is optionally substituted by one or more of the following substituents : Halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic heterocyclic;
R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时分别独立选自氢、卤素、氰基、烷基、环烷基、脂杂环基，所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基。R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , R 40 are each independently selected from hydrogen, halogen, cyano, Alkyl, cycloalkyl, aliphatic heterocyclic group, said alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, alkyl, cycloalkyl, alicyclic.
在一个实施方案中，R6不为氢。In one embodiment, R is not hydrogen.
在一个实施方案中，R5为氢，R6不为氢。In one embodiment, R5 is hydrogen and R6 is other than hydrogen.
进一步地，选自如下基团： 优选地，具有芳香性。further, selected from the following groups: Preferably, Aromatic.
进一步地，为其中，A3选自CR16或N，A6选自CR9或N，A7选自CR8或N；优选地，选自 further, for Wherein, A 3 is selected from CR 16 or N, A 6 is selected from CR 9 or N, A 7 is selected from CR 8 or N; preferably, selected from
进一步地，为其中，A1选自CR10或N，A3选自CR16或N，A4选自 CR19或N，A5选自N或S，A7选自CR8或N；优选地，为 further, for Wherein, A 1 is selected from CR 10 or N, A 3 is selected from CR 16 or N, A 4 is selected from CR 19 or N, A 5 is selected from N or S, A 7 is selected from CR 8 or N; preferably, for
进一步地，为其中，A1选自CR10或N，A3选自CR16或N，A4选自CR19或N，A7选自CR8或N；优选地，为 further, for Wherein, A 1 is selected from CR 10 or N, A 3 is selected from CR 16 or N, A 4 is selected from CR 19 or N, A 7 is selected from CR 8 or N; preferably, for
进一步地，为其中，A1选自CR10或N，A3选自CR16或N，A4选自CR19或N，A7选自NR8或S；优选地，选自 further, for Wherein, A 1 is selected from CR 10 or N, A 3 is selected from CR 16 or N, A 4 is selected from CR 19 or N, A 7 is selected from NR 8 or S; preferably, selected from
进一步地，为其中，A1选自CR10、CR11R12或N，A2选自CR13、CR14R15或N，A3选自CR16、CR17R18或N，A4选自CR19、CR20R21或N，且A1和A3不同时为N。further, for Among them, A 1 is selected from CR 10 , CR 11 R 12 or N, A 2 is selected from CR 13 , CR 14 R 15 or N, A 3 is selected from CR 16 , CR 17 R 18 or N, A 4 is selected from CR 19 , CR 20 R 21 or N, and A 1 and A 3 are not N at the same time.
本发明的另一方面，提供了一种化合物，具有式I’所示结构具有式I所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
Another aspect of the present invention provides a compound having a structure represented by formula I' having a structure represented by formula I or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable Salt, eutectic:
其中：in:
T选自S(O)2、C＝O、CH2或NHS(O)2；T is selected from S(O) 2 , C=O, CH 2 or NHS(O) 2 ;
A1选自CR10、CR11R12或N，A2选自CR13、CR14R15或N，A3选自CR16、CR17R18或N，A4选自CR19、CR20R21或N，且A1和A3不同时为N；A 1 is selected from CR 10 , CR 11 R 12 or N, A 2 is selected from CR 13 , CR 14 R 15 or N, A 3 is selected from CR 16 , CR 17 R 18 or N, A 4 is selected from CR 19 , CR 20 R 21 or N, and A 1 and A 3 are not N at the same time;
B为B1、B2所在的环为5～10元氮杂环烷基且为单环、螺环或桥环，B1选自CR22或N，B2选自CR23或N，且B1、B2中至少有一个为N； B for The rings where B 1 and B 2 are located are 5-10 membered azacycloalkyl groups and are monocyclic, spiro or bridged rings, B 1 is selected from CR 22 or N, B 2 is selected from CR 23 or N, and B 1 , at least one of B2 is N;
R7每次出现时分别独立选自卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORn、-NRoRp、-C(O)R24、-C(O)NRoRp、-C(O)ORn，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个卤素、氰基、烷基、环烷基、脂杂环基、-ORn、-NRoRp、-C(O)R24、-C(O)NRoRp、-C(O)ORn取代；Each occurrence of R 7 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR n , -NR o R p , -C(O)R 24. -C(O)NR o R p , -C(O)OR n , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more halogen, Cyano, Alkyl, Cycloalkyl, Heteroalicyclic, -OR n , -NR o R p , -C(O)R 24 , -C(O)NR o R p , -C(O)OR n replace;
n1选自0、1、2、3、4；n 1 is selected from 0, 1, 2, 3, 4;
R5、R6各自独立选自氢、卤素、氰基、烷基、脂杂环基、芳基、杂芳基、-ORa、-NRbRc、-C(O)R25、-S(O)R26、-S(O)2R26、-P(O)R26R27、-C(O)NRbRc、-C(O)ORa，且R5和R6不同时为氢；可选的，当R6选自-C(O)R25时，R25可与B环上任意一个R7相连共同组成4～12元脂杂环基；其中，所述烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R28取代；R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, alkyl, aliphatic heterocyclic group, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 25 , - S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C(O)OR a , and R 5 and R 6 not be hydrogen at the same time; optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 on the B ring to form a 4-12-membered aliphatic heterocyclic group; wherein, the Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 28 ;
R28每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORa、-NRbRc、-C(O)R25、-C(O)NRbRc、-C(O)ORa；Each occurrence of R 28 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, -OR a , -NR b R c , -C(O)R 25 , -C(O)NR b R c , -C(O)OR a ;
R1、R2分别独立选自氢、烷基、环烷基、脂杂环基、-C(O)R29，其中，所述烷基、环烷基、脂杂环基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基；当环E中的“-----”为一键时，R2为无；R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aliphatic heterocyclic group, and -C(O)R 29 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally replaced by One or more of the following substituents are substituted: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic ring; when "-----" in ring E is a bond, R2 is none;
R3选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORg、-NRhRi、-C(O)R30、-C(O)RhRi、-C(O)ORg，当环E中的“-----”为无时，R3还可以是与其连接的碳原子共同组成羰基，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R31取代；R 3 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g , -NR h R i , -C(O)R 30 , -C (O)R h R i , -C(O)OR g , when the "-----" in ring E is none, R 3 can also be the carbon atom connected to it to form a carbonyl group, wherein, the alkyl , cycloalkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 31 ;
R31每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORg、-NRhRi、-C(O)R32、-C(O)NRhRi、-C(O)ORg；Each occurrence of R 31 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR g , -NR h R i , -C(O)R 32 , -C(O)NR h R i , -C(O)OR g ;
R4选自烷基、环烷基、脂杂环基、芳基、杂芳基，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R33取代； R is selected from alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl, wherein, alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally replaced by one or more R 33 replacement;
R33每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORj、-NRkRm、-C(O)R34、-C(O)NRkRm、-C(O)ORj，其中，所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR j , -NR k R m , -C(O)R 34 , -C(O)NR k R m , -C(O)OR j , wherein, the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, heteroaryl group are optionally replaced by one or more R 35 replaced;
R35每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORj、-NRkRm、-C(O)R36、-C(O)NRkRm、-C(O)ORj；Each occurrence of R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR j , -NR k R m , -C(O)R 36 , -C(O)NR k R m , -C(O)OR j ;
R8、R9、R10、R13、R16、R19、R11、R12、R14、R15、R17、R18、R20、R21、R22、R23分别独立选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORq、-NRrRs、-C(O)R37、-C(O)NRrRs、-C(O)ORq或无，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R38取代；R 8 , R 9 , R 10 , R 13 , R 16 , R 19 , R 11 , R 12 , R 14 , R 15 , R 17 , R 18 , R 20 , R 21 , R 22 , and R 23 are independently selected from From hydrogen, halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR q , -NR r R s , -C(O)R 37 , -C(O) NR r R s , -C(O)OR q or none, wherein alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 38 ;
R38每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORq、-NRrRs、-C(O)R39、-C(O)NRrRs、-C(O)ORq；Each occurrence of R 38 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR q , -NR r R s , -C(O)R 39 , -C(O)NR r R s , -C(O)OR q ;
Ra、Rb、Rc、Rg、Rh、Ri、Rj、Rk、Rm、Rn、Ro、Rp、Rq、Rr、Rs每次出现时独立选自H、烷基、环烷基、脂杂环基、-C(O)R40，其中，所述烷基、环烷基、脂杂环基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基；R a , R b , R c , R g , R h , R i , R j , R k , R m , R n , R o , R p , R q , R r , R s are selected independently for each occurrence. from H, alkyl, cycloalkyl, aliphatic heterocyclic group, -C(O)R 40 , wherein the alkyl, cycloalkyl, aliphatic heterocyclic group is optionally substituted by one or more of the following substituents : Halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic heterocyclic;
R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时分别独立选自氢、卤素、氰基、烷基、环烷基、脂杂环基，所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基。R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , R 40 are each independently selected from hydrogen, halogen, cyano, Alkyl, cycloalkyl, aliphatic heterocyclic group, said alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, alkyl, cycloalkyl, alicyclic.
进一步地，选自如下基团：further, selected from the following groups:
优选更优选 preferred more preferred
在一个实施方案中，选自如下基团：
In one embodiment, selected from the following groups:
或者，为其中，A1选自CR10、N，A2选自CR13、N，A3选自CR16、N，A4选自CR19、N，且A1和A3不同时为N；or, for Wherein, A 1 is selected from CR 10 and N, A 2 is selected from CR 13 and N, A 3 is selected from CR 16 and N, A 4 is selected from CR 19 and N, and A 1 and A 3 are not N at the same time;
进一步地，选自如下基团： 优选 优选 更优选 further, selected from the following groups: preferred preferred more preferred
在部分实施方案中，B为B1、B2所在的环为6～9元氮杂环烷基、6～9元氮杂环烯基，且B1、B2所在的环为单环、螺环或桥环，B1选自C、CR22或N，B2选自CR23或N，且B1、B2中至少有一个为N。In some embodiments, B is The rings of B 1 and B 2 are 6-9 membered azacycloalkyl, 6-9 membered azacycloalkenyl, and the rings of B 1 and B 2 are monocyclic, spiro or bridged rings, B 1 selected from C, CR 22 or N, B 2 selected from CR 23 or N, and at least one of B 1 and B 2 is N.
进一步地，B为B1、B2所在的环为6～9元氮杂环烷基且为单环或螺环；Further, B is The rings where B 1 and B 2 are located are 6-9 membered azacycloalkyl groups and are monocyclic or spiro rings;
进一步地，B为B1、B2所在的环为6元氮杂单环烷基或8～9元氮杂螺环烷基；Further, B is The rings where B 1 and B 2 are located are 6-membered azamonocycloalkyl or 8-9 membered azaspirocycloalkyl;
进一步地，选自如下基团：
further, selected from the following groups:
R22选自氢、卤素、C1～C6烷基，优选氢、卤素、C1～C3烷基，更优选氢；R 22 is selected from hydrogen, halogen, C1～C6 alkyl, preferably hydrogen, halogen, C1～C3 alkyl, more preferably hydrogen;
R23选自氢、卤素、C1～C6烷基，优选氢、卤素、C1～C3烷基，或R23与R6及其相连的链段共同组成4～6元环烯基，优选R23与R6及其相连的链段共同组成5元环烯基；R 23 is selected from hydrogen, halogen, C1-C6 alkyl, preferably hydrogen, halogen, C1-C3 alkyl, or R 23 and R 6 and their connected segments together form a 4-6 membered cycloalkenyl, preferably R 23 Together with R6 and the chain segment connected to it, it forms a 5-membered cycloalkenyl group;
进一步地，选自优选 further, selected from preferred
在部分实施方案中，B为B1、B2所在的环为6～9元氮杂桥环烷基，优选为7～8元氮杂桥环烷基，更优选为8元氮杂桥环烷基；In some embodiments, B is The rings of B 1 and B 2 are 6-9 membered azabridged cycloalkyl groups, preferably 7-8 membered azabridged cycloalkyl groups, more preferably 8-membered azabridged cycloalkyl groups;
进一步地，B1、B2均为N；Further, both B 1 and B 2 are N;
进一步地，为 further, for
在部分实施方案中，B为B1、B2所在的环为6～9元氮杂环烯基，且B1、B2所在的环为单环、螺环或桥环，B1选自C、CR22或N，B2选自CR23或N，且B1、B2中至少有一个为N；In some embodiments, B is The rings where B 1 and B 2 are located are 6-9 membered azacycloalkenyl groups, and the rings where B 1 and B 2 are located are monocyclic, spiro or bridged rings, and B 1 is selected from C, CR 22 or N, B 2 is selected from CR 23 or N, and at least one of B 1 and B 2 is N;
优选地，B1、B2所在的环为6元氮杂环烯基，且B1、B2所在的环为单环，B1为C，B2为N；Preferably, the rings where B 1 and B 2 are located are 6-membered azacycloalkenyl groups, and the rings where B 1 and B 2 are located are monocyclic, B 1 is C, and B 2 is N;
优选地，为 Preferably, for
进一步地，n1选自0、1、2、3，优选0、1、2，更优选0或1。Further, n 1 is selected from 0, 1, 2, 3, preferably 0, 1, 2, more preferably 0 or 1.
进一步地，T选自S(O)2或C＝O，优选S(O)2。Further, T is selected from S(O) 2 or C=O, preferably S(O) 2 .
进一步地，R1、R2分别独立选自氢、卤素、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基、C3～C6环烷基、3～6元脂杂环基；当环E中的“-----”为一键时，R2为无；Further, R 1 and R 2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more of the following substituents Substitution: halogen, cyano, hydroxyl, amino, C1~C6 alkyl, C3~C6 cycloalkyl, 3~6 membered aliphatic heterocyclic group; when "-----" in ring E is a bond, R2 is none;
进一步地，R1、R2分别独立选自氢、卤素、C1～C3烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C3烷基、C3～C6环烷基；当环E中的“-----”为一键时，R2为无；Further, R 1 and R 2 are independently selected from hydrogen, halogen, C1-C3 alkyl, wherein the alkyl and cycloalkyl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, C1~C3 alkyl, C3~C6 cycloalkyl; when "-----" in ring E is a bond, R2 is none;
R1、R2分别独立选自氢或甲基；当环E中的“-----”为一键时，R2为无；R 1 and R 2 are independently selected from hydrogen or methyl; when "-----" in ring E is a bond, R 2 is none;
更进一步地，R1为氢；Further, R 1 is hydrogen;
更进一步地，环E中的“-----”为一单键且R2为无，或者，环E中的“-----”为无且R2为氢；Furthermore, "-----" in ring E is a single bond and R 2 is nothing, or, "-----" in ring E is nothing and R 2 is hydrogen;
更进一步地，环E中的“-----”为一键且R2为无。Furthermore, "-----" in ring E is a bond and R 2 is nothing.
进一步地，R5、R6分别独立选自氢、卤素、C1～C6烷基、C3～C6环烷基、3～6元脂杂环基、6～10元芳基、5～10元杂芳基、-C(O)R25、-S(O)R26、-S(O)2R26、-P(O)R26R27、-C(O)NRbRc、-C(O)ORa，且R5和R6不同时为氢，其中，所述烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R28取代；Further, R 5 and R 6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclic group, 6-10-membered aryl group, 5-10-membered heterocyclic group, Aryl, -C(O)R 25 , -S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C (O) OR a , and R 5 and R 6 are not hydrogen at the same time, wherein the alkyl, aliphatic heterocyclic group, aryl, heteroaryl is optionally substituted by one or more R 28 ;
R28每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORa、-NRbRc；Each occurrence of R 28 is independently selected from halogen, cyano, C1～C6 alkyl, C3～C6 cycloalkyl, -OR a , -NR b R c ;
可选地，当R6选自-C(O)R25时，R25可与任意一个R7相连共同组成n2选自0、1、2、3、4；Optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 to form n 2 is selected from 0, 1, 2, 3, 4;
进一步地，R5、R6分别独立选自氢、卤素、C1～C3烷基、5～6元杂芳基、-C(O)R25、-S(O)2R16、-P(O)R16R17，且R5和R6不同时为氢，其中，所述烷基、杂芳基任选地被一个或多个R28取代；Further, R 5 and R 6 are independently selected from hydrogen, halogen, C1-C3 alkyl, 5-6 membered heteroaryl, -C(O)R 25 , -S(O) 2 R 16 , -P( O) R 16 R 17 , and R 5 and R 6 are not hydrogen at the same time, wherein the alkyl and heteroaryl are optionally substituted by one or more R 28 ;
R28每次出现时独立选自卤素、C1～C3烷基、-ORa、-NRbRc；Each occurrence of R 28 is independently selected from halogen, C1～C3 alkyl, -OR a , -NR b R c ;
可选地，当R6选自-C(O)R25时，R25可与任意一个R7相连共同组成n2选自1、2；Optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 to form n 2 is selected from 1, 2;
进一步地，R5、R6分别独立选自H、F、C1～C3烷基、-C(O)CH3、-C(O)CH2CH2CH3、-CH2N(CH3)2、-CH2F、-S(O)2CH3、-P(O)(CH3)2，且R5和R6不同时为氢； Further, R 5 and R 6 are independently selected from H, F, C1-C3 alkyl, -C(O)CH 3 , -C(O)CH 2 CH 2 CH 3 , -CH 2 N(CH 3 ) 2. -CH 2 F, -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , and R 5 and R 6 are not hydrogen at the same time;
可选地，当R6选自-C(O)CH2CH2CH3时，R25可与任意一个R7相连共同组成 Optionally, when R 6 is selected from -C(O)CH 2 CH 2 CH 3 , R 25 can be connected with any R 7 to form
进一步地，R5为H；Further, R 5 is H;
R6为-C(O)CH3，或者R6为-C(O)CH2CH2CH3且与任意一个R7相连共同组成优选地，R6为-C(O)CH3；R 6 is -C(O)CH 3 , or R 6 is -C(O)CH 2 CH 2 CH 3 and is combined with any R 7 Preferably, R 6 is -C(O)CH 3 ;
进一步地，的构型为 further, is configured as
进一步地，Ra、Rb、Rc每次出现时独立选自H、C1～C6烷基，其中，所述烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基；Further, each occurrence of R a , R b , and R c is independently selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, C1~C6 alkyl;
进一步地，Ra、Rb、Rc每次出现时独立选自H、C1～C3烷基，其中，所述烷基任选地被一个或多个如下取代基取代：卤素、C1～C3烷基；Further, each occurrence of R a , R b , and R c is independently selected from H, C1-C3 alkyl, wherein the alkyl is optionally substituted by one or more of the following substituents: halogen, C1-C3 alkyl;
更进一步地，Ra、Rb、Rc每次出现时独立选自H、C1～C3烷基。Furthermore, each occurrence of R a , R b , and R c is independently selected from H, C1-C3 alkyl.
进一步地，R7每次出现时分别独立选自选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORn、-NRoRp，其中，烷基、环烷基任选地被一个或多个选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORn、-NRoRp的取代基取代；Further, each occurrence of R 7 is independently selected from halogen, cyano, C1~C6 alkyl, C3~C6 cycloalkyl, -OR n , -NR o R p , wherein alkyl, cycloalkane The group is optionally substituted by one or more substituents selected from halogen, cyano, C1~C6 alkyl, C3~C6 cycloalkyl, -OR n , -NR o R p ;
进一步地，R7选自C1～C3烷基、-ORn、-NRoRp，其中，烷基任选地被一个或多个卤素、氰基、C1～C3烷基、-ORn、-NRoRp取代；Further, R 7 is selected from C1～C3 alkyl, -OR n , -NR o R p , wherein the alkyl is optionally replaced by one or more halogen, cyano, C1～C3 alkyl, -OR n , -NR o R p substitution;
进一步地，R7选自C1～C3烷基，优选甲基。Further, R 7 is selected from C1-C3 alkyl, preferably methyl.
进一步地，Rn、Ro、Rp每次出现时独立选自H、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基、C3～C6环烷基、C3～C6杂环烷基；Further, each occurrence of R n , R o , and R p is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl, C3~C6 cycloalkyl, C3~C6 heterocycloalkyl;
进一步地，Rn、Ro、Rp每次出现时独立选自H、C1～C3烷基，其中，所述烷基任选地被一个或多个如下取代基取代：卤素、C1～C3烷基、5元氮杂环烷基；Further, each occurrence of R n , R o , and R p is independently selected from H, C1-C3 alkyl, wherein the alkyl is optionally substituted by one or more of the following substituents: halogen, C1-C3 Alkyl, 5-membered azacycloalkyl;
更进一步地，Rn、Ro、Rp每次出现时独立选自H、C1～C3烷基。Furthermore, each occurrence of R n , R o , and R p is independently selected from H, C1-C3 alkyl.
进一步地，R3选自氢、卤素、氰基、C1～C6烷基、C3～C6环烷基、3～6元脂杂环基、-ORg、-NRhRi，当环E中的“-----”为无时，R3还可以是与其连接的碳原子共同组成羰基，其中，烷基、环烷基、脂杂环基任选地被一个或多个R31取代，所述R31每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORg、-NRhRi；Further, R 3 is selected from hydrogen, halogen, cyano, C1~C6 alkyl, C3~C6 cycloalkyl, 3~6 membered aliphatic heterocyclic group, -OR g , -NR h R i , when ring E When "-----" is none, R 3 can also be a carbonyl group formed by the carbon atoms connected to it, wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 31 , each occurrence of R 31 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -OR g , -NR h R i ;
进一步地，R3选自氢、卤素、C1～C3烷基、-ORg、-NRhRi，当环E中的“-----”为无时，R3与其连接的碳原子共同组成羰基，其中，烷基任选地被一个或多个R31取代，R31每次出现时独立选自卤素、氰基、C1～C3烷基、-ORg、-NRhRi；Further, R 3 is selected from hydrogen, halogen, C1~C3 alkyl, -OR g , -NR h R i , when "-----" in ring E is none, the carbon atom to which R 3 is connected Together form a carbonyl group, wherein the alkyl group is optionally substituted by one or more R 31 , and each occurrence of R 31 is independently selected from halogen, cyano, C1～C3 alkyl, -OR g , -NR h R i ;
进一步地，R3选自氢、F、Cl、Br、甲基、-ORg、-NRhRi，当环E中的“-----”为无时，R3与其连接的碳原子共同组成羰基；Further, R 3 is selected from hydrogen, F, Cl, Br, methyl, -OR g , -NR h R i , when the "-----" in ring E is none, the carbon to which R 3 is connected Atoms together form a carbonyl group;
进一步地，R3选自氢、C1～3烷基、-ORg，其中，所述烷基任选地被一个或多个卤素取代；Further, R 3 is selected from hydrogen, C1~3 alkyl, -OR g , wherein the alkyl is optionally substituted by one or more halogens;
进一步地，R3为-ORg。Further, R 3 is -OR g .
进一步地，Rg、Rh、Ri每次出现时独立选自H、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基；Further, each occurrence of R g , Rh , and R i is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
进一步地，Rg、Rh、Ri每次出现时独立选自H、C1～C3烷基、环丙基、环戊基，其中，所述烷基、环丙基任选地被一个或多个如下取代基取代：卤素、C1～C3烷基；Further, each occurrence of R g , Rh , and R i is independently selected from H, C1-C3 alkyl, cyclopropyl, and cyclopentyl, wherein the alkyl and cyclopropyl are optionally replaced by one or A plurality of the following substituents are substituted: halogen, C1～C3 alkyl;
更进一步地，Rg、Rh、Ri每次出现时独立选自H、甲基、环丙基、环戊基，其中，所述甲基任选地被一个或多个卤素取代。Further, each occurrence of R g , Rh , R i is independently selected from H, methyl, cyclopropyl, cyclopentyl, wherein said methyl is optionally substituted by one or more halogens.
进一步地，R3选自甲氧基、二氟甲氧基、三氟甲氧基，优选为甲氧基。Further, R 3 is selected from methoxy, difluoromethoxy, trifluoromethoxy, preferably methoxy.
进一步地，R8、R9、R10、R16、R19、R11、R12、R17、R18、R20、R21、R22、R23分别独立选自氢、卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORq、-NRrRs或无，其中，烷基、环烷基任选地被一个或多个R38取代；Further, R 8 , R 9 , R 10 , R 16 , R 19 , R 11 , R 12 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 are independently selected from hydrogen, halogen, cyanide group, C1~C6 alkyl group, C3~C6 cycloalkyl group, -OR q , -NR r R s or none, wherein the alkyl group and cycloalkyl group are optionally substituted by one or more R 38 ;
R38每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORq、-NRrRs、-C(O)R39、-C(O)NRrRs、-C(O)ORq。Each occurrence of R 38 is independently selected from halogen, cyano, C1～C6 alkyl, C3～C6 cycloalkyl, -OR q , -NR r R s , -C(O)R 39 , -C(O) NR r R s , -C(O)OR q .
进一步地，R8、R9、R10、R16、R19分别独立选自氢、卤素、氰基、C1～C6烷基、-ORq、-NRrRs，Rq、Rr、Rs每次出现时独立选自H、C1～C6烷基，其中，烷基任选地被一个或多个R38取代，R38每次出现时独立选自卤素；R13选自氢、甲基；Further, R 8 , R 9 , R 10 , R 16 , and R 19 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR q , -NR r R s , R q , R r , Each occurrence of R s is independently selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 38 , each occurrence of R 38 is independently selected from halogen; R 13 is selected from hydrogen, methyl;
优选地，R8、R9、R10、R16、R19分别独立选自氢、氟、氯、溴、氰基、甲基、二氟甲基、三氟甲基、羟基、甲氧基、二氟甲氧基、三氟甲氧基、氨基、甲氨基；R13选自氢、甲基；Preferably, R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, trifluoromethyl, hydroxyl, and methoxy , difluoromethoxy, trifluoromethoxy, amino, methylamino; R 13 is selected from hydrogen, methyl;
进一步地，R8、R9、R10、R16、R19分别独立选自氢、卤素、氰基、C1～C6烷基；R13选自氢、甲基； Further, R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl; R 13 is selected from hydrogen and methyl;
优选地，R8、R9、R10、R16、R19分别独立选自氢、氟、氰基、甲基；R13选自氢、甲基；Preferably, R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, fluorine, cyano, and methyl; R 13 is selected from hydrogen, methyl;
更优选地，R8选自氢、氟、甲基；R9选自氢、氟；R10选自氢、氟、氰基；R16选自氢、氟；R19选自氢、氟；R13为氢。More preferably, R 8 is selected from hydrogen, fluorine, methyl; R 9 is selected from hydrogen, fluorine; R 10 is selected from hydrogen, fluorine, cyano; R 16 is selected from hydrogen, fluorine; R 19 is selected from hydrogen, fluorine; R 13 is hydrogen.
进一步地，Rq、Rr、Rs每次出现时独立选自H、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基。Further, each occurrence of R q , R r , and R s is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
进一步地，R4选自C1～C6烷基、C3～C9环烷基、3～6元杂环烷基、6～10元芳基、5～10元杂芳基，其中，烷基、环烷基、杂环烷基、芳基、杂芳基任选地被一个或多个R33取代；Further, R 4 is selected from C1～C6 alkyl, C3～C9 cycloalkyl, 3～6 membered heterocycloalkyl, 6～10 membered aryl, 5～10 membered heteroaryl, wherein, alkyl, ring Alkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more R;
R33每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORj、-NRkRm、-C(O)R27、-C(O)NRkRm、-C(O)ORj，其中，所述烷基、环烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -OR j , -NR k R m , -C(O)R 27 , -C(O) NR k R m , -C(O)OR j , wherein the alkyl and cycloalkyl are optionally substituted by one or more R 35 ;
R35每次出现时独立选自卤素、氰基、烷基、环烷基、-ORj、-NRkRm；Each occurrence of R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, -OR j , -NR k R m ;
进一步地，R4选自C1～C3烷基、C3～C6环烷基、苯基、5～6元氮杂芳基、5～6元硫杂芳基，其中，烷基、环烷基、芳基、氮杂芳基、硫杂芳基任选地被1～3个R33取代；Further, R 4 is selected from C1～C3 alkyl, C3～C6 cycloalkyl, phenyl, 5～6 membered azaaryl, 5～6 membered thiaaryl, wherein, alkyl, cycloalkyl, Aryl, azaaryl, and thiaaryl are optionally substituted by 1 to 3 R33 ;
R33每次出现时独立选自卤素、氰基、C1～C3烷基、C3～C6环烷基、-ORj、-NRkRm，其中，所述烷基、环烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1～C3 alkyl, C3～C6 cycloalkyl, -OR j , -NR k R m , wherein the alkyl and cycloalkyl are optionally replaced by one or more R35 ;
进一步地，R4选自C1～C3烷基、环己基、苯基、吡啶基、噻吩基，其中，烷基、环己基、苯基、吡啶基、噻吩基任选地被1～3个R33取代；Further, R 4 is selected from C1～C3 alkyl, cyclohexyl, phenyl, pyridyl, thienyl, wherein, alkyl, cyclohexyl, phenyl, pyridyl, thienyl are optionally replaced by 1 to 3 R 33 replaced;
R33每次出现时独立选自F、Cl、Br、C1～C3烷基、-ORj，优选F、Cl、甲基、甲氧基；Each occurrence of R 33 is independently selected from F, Cl, Br, C1-C3 alkyl, -OR j , preferably F, Cl, methyl, methoxy;
进一步地，R4选自6～10元芳基、5～10元杂芳基，其中，芳基、杂芳基任选地被一个或多个R33取代；Further, R 4 is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups, wherein the aryl and heteroaryl groups are optionally substituted by one or more R 33 ;
R33每次出现时独立选自卤素、氰基、C1～C6烷基、-ORj，其中，所述烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C6 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
R35每次出现时独立选自卤素；each occurrence of R is independently selected from halogen;
进一步地，R4选自苯基、5～6元杂芳基，所述杂芳基含有1～2个选自N、S的杂原子，其中，苯基、杂芳基任选地被1～3个R33取代；Further, R 4 is selected from phenyl, 5-6 membered heteroaryl, and said heteroaryl contains 1-2 heteroatoms selected from N and S, wherein, phenyl and heteroaryl are optionally replaced by 1 ~3 R33 substitutions;
R33每次出现时独立选自卤素、氰基、C1～C3烷基、-ORj，其中，所述烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C3 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
R35每次出现时独立选自卤素；each occurrence of R is independently selected from halogen;
进一步地，R4选自苯基、吡啶基、噻唑基，上述基团任选地被1～3个R33取代；Further, R 4 is selected from phenyl, pyridyl, thiazolyl, and the above groups are optionally substituted by 1 to 3 R 33 ;
R33每次出现时独立选自卤素、氰基、C1～C3烷基、-ORj，其中，所述烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C3 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
R35每次出现时独立选自卤素；each occurrence of R is independently selected from halogen;
进一步地，R35为F；Further, R 35 is F;
进一步地，R33每次出现时独立选自F、Cl、氰基、甲基、三氟甲基、甲氧基；Further, each occurrence of R is independently selected from F, Cl, cyano, methyl, trifluoromethyl, methoxy;
进一步地，R4选自苯基、吡啶基，其中，苯基、吡啶基任选地被1～3个R33取代；Further, R 4 is selected from phenyl and pyridyl, wherein, phenyl and pyridyl are optionally substituted by 1 to 3 R 33 ;
R33每次出现时独立选自F、甲基；R 33 is independently selected from F, methyl each time it occurs;
进一步地，R4选自甲基、环己基、苯基、 Further, R 4 is selected from methyl, cyclohexyl, phenyl,
进一步地，R4选自 Further, R 4 is selected from
在一些具体实施方案中，R4选自甲基、环己基、苯基、 In some embodiments, R is selected from methyl, cyclohexyl, phenyl,
在一些具体实施方案中，R4选自 In some embodiments, R is selected from
进一步地，Rj、Rk、Rm每次出现时独立选自H、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基；Further, each occurrence of R j , R k , and R m is independently selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
进一步地，Rj、Rk、Rm每次出现时独立选自H、C1～C3烷基，优选C1～C3烷基，更优选甲基。Further, each occurrence of R j , R k , and R m is independently selected from H, C1-C3 alkyl, preferably C1-C3 alkyl, more preferably methyl.
进一步地，R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时独立选自H、C1～C6烷基，所述烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基；Further, each occurrence of R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 is independently selected from H, C1-C6 Alkyl, the alkyl is optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1～C6 alkyl;
进一步地，R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时独立选自H、C1～C3烷基，所述烷基任选地被一个或多个如下取代基取代：卤素、羟基、氨基、C1～C3烷基；Further, each occurrence of R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 is independently selected from H, C1-C3 Alkyl, said alkyl is optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, C1～C3 alkyl;
进一步地，R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时独立选自C1～C3烷基，优选甲基、丙基。Further, R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 are each independently selected from C1-C3 alkyl groups. , preferably methyl, propyl.
进一步地，所述化合物具有式II所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
Further, the compound has the structure shown in formula II or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
其中，B、A1、A2、A3、A4、R1、R2、R3、R4、R5、R8、R9、R25各基团如前所定义。Wherein, each group of B, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and R 25 is as defined above.
进一步地，所述化合物有式III所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
Further, the compound has the structure shown in formula III or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
其中，B1、B2、A1、A2、A3、A4、R1、R3、R4、R5、R7、R8、R25各基团如前所定义。Wherein, each group of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 25 is as defined above.
进一步地，所述化合物具有式IV所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
Further, the compound has the structure shown in formula IV or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
其中，A1、A2、A3、A4、R1、R3、R4、R5各基团如前所定义。Wherein, each group of A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , and R 5 is as defined above.
进一步地，所述化合物有式V所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
Further, the compound has the structure shown in formula V or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, and co-crystals:
其中，B1、B2、A1、A2、A3、A4、R1、R3、R4、R7、R8各基团如前所定义。 Wherein, each group of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , R 7 , and R 8 is as defined above.
进一步地，所述化合物结构选自如下之一：





Further, the compound structure is selected from one of the following:





本发明提供一种吡啶衍生物的制备方法：
The invention provides a kind of preparation method of pyridine derivative:
式A化合物与式B化合物反应得到式C化合物；The compound of formula A is reacted with the compound of formula B to obtain the compound of formula C;
式中，X2选自CH、CR23或NH，X1选自可与X2反应形成共价键的基团；例如，若X2为NH，X1为可选为能与NH缩合反应的OH；In the formula, X2 is selected from CH, CR23 or NH, and X1 is selected from groups that can react with X2 to form a covalent bond; for example, if X2 is NH, X1 is optionally capable of condensation reaction with NH OH;
B1、B2、A1、A2、A3、A4、A5、A6、A7、A8、R1、R2、R3、R4、R5、R6、T定义同式I化合物。Definition of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , T Same formula I compound.
任选地，式C化合物可选通过以下合成路线制备得到：
Optionally, the compound of formula C can be prepared by the following synthetic route:
式D化合物与式E化合物Suzuki偶联反应得到式C化合物；Formula D compound and formula E compound Suzuki coupling reaction to obtain formula C compound;
其中，X3和X4选自卤素原子、硼酸基或硼酸酯基；条件是：X3选自卤素原子时，X4选自硼酸基或硼酸酯基，X4选自卤素原子时，X3选自硼酸基或硼酸酯基；Wherein, X 3 and X 4 are selected from halogen atoms, boronic acid groups or borate ester groups; the condition is: when X 3 is selected from halogen atoms, X 4 is selected from boronic acid groups or borate ester groups, and when X 4 is selected from halogen atoms , X3 is selected from boric acid group or borate ester group;
所述硼酸基或硼酸酯基选自或-B(OH)2；The boronic acid group or borate ester group is selected from or -B(OH) 2 ;
B1、B2、A1、A2、A3、A4、A5、A6、A7、A8、R1、R2、R3、R4、R7、X2、n1、T定义同式I化合物。B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , R 1 , R 2 , R 3 , R 4 , R 7 , X 2 , n 1 , T are defined with the compound of formula I.
本发明提供了一种药用组合物，该药用组合物活性成份选自所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶中的一种或两种以上的组合。The invention provides a pharmaceutical composition, the active ingredient of which is selected from the compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co- One or a combination of two or more crystals.
本发明提供了所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备KRAS抑制剂和/或PI3K抑制剂中的用途；The present invention provides the compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation of KRAS inhibitors and/or PI3K inhibitors use in pharmaceuticals;
进一步地，所述KRAS抑制剂选自KRAS G12C抑制剂、KRAS G12V抑制剂、KRAS G12D抑制剂、KRAS G12S抑制剂，优选KRAS G12C抑制剂；Further, the KRAS inhibitor is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
所述PI3K抑制剂为PI3Kα抑制剂和/或PI3Kδ抑制剂。The PI3K inhibitor is a PI3Kα inhibitor and/or a PI3Kδ inhibitor.
本发明提供了所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备用于治疗由KRAS和/或PI3K介导的疾病的药物中的用途；The present invention provides the compound or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation for the treatment of KRAS and/or Use in medicine for PI3K-mediated diseases;
进一步地，是制备用于治疗由KRAS G12C、PI3Kα、PI3Kδ中的一种或多种介导的疾病的药物中的用途。Further, it is the use in preparing medicines for treating diseases mediated by one or more of KRAS G12C, PI3Kα, and PI3Kδ.
进一步地，所述疾病为癌症或自身免疫性疾病。Further, the disease is cancer or autoimmune disease.
进一步地，所述癌症选自：非小细胞肺癌、肺癌、胰腺癌、卵巢癌、膀胱癌、***癌、慢性粒细胞白血病、结直肠癌、脑癌、肝癌、肾癌、胃癌、乳腺癌、三阴性乳腺癌、皮肤癌、黑色素癌、头颈癌、骨癌、***、盆腔癌、***癌、口腔癌、淋巴癌、血癌、食管癌、尿道癌、鼻腔癌。Further, the cancer is selected from: non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, breast cancer, Triple negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphatic cancer, blood cancer, esophageal cancer, urinary tract cancer, nasal cavity cancer.
本发明提供了所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备用于治疗对抗癌剂产生耐药的疾病的药物中的用途；The present invention provides the compound or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used in the preparation of anticancer agents use in medicines for drug-resistant diseases;
进一步地，所述抗癌剂选自KRAS G12C抑制剂、KRAS G12V抑制剂、KRAS G12D抑制剂、KRAS G12S抑制剂，优选KRAS G12C抑制剂；Further, the anticancer agent is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
进一步地，所述抗癌剂中的KRAS G12C抑制剂选自AMG-510、MRTX-849，优选AMG-510。Further, the KRAS G12C inhibitor in the anticancer agent is selected from AMG-510, MRTX-849, preferably AMG-510.
本发明提供了所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前 述药物组合物在制备治疗致使PI3K蛋白和/或KRAS G12C蛋白过度表达的疾病的药物中的用途。The present invention provides the compound or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pro- Use of the above pharmaceutical composition in the preparation of medicines for treating diseases that cause overexpression of PI3K protein and/or KRAS G12C protein.
本发明提供了所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备治疗PI3K蛋白和/或KRAS G12C蛋白过度表达所致疾病的药物中的用途。The present invention provides the compound or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or the aforementioned pharmaceutical composition in the preparation of therapeutic PI3K protein and/or KRAS G12C Use in medicine for diseases caused by protein overexpression.
本发明还提供了一种药用组合物，其特征在于，该药用组合物活性成份选自上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物中的一种或两种以上的组合。The present invention also provides a pharmaceutical composition, characterized in that the active ingredient of the pharmaceutical composition is selected from the above compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or one or a combination of two or more of the aforementioned pharmaceutical compositions.
本发明还提供了上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备KRAS抑制剂和/或PI3K抑制剂中的用途。The present invention also provides the above compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation of KRAS inhibitors and/or PI3K inhibitors use in pharmaceuticals.
进一步地，所述KRAS抑制剂选自KRAS G12C抑制剂、KRAS G12V抑制剂、KRAS G12D抑制剂、KRAS G12S抑制剂，优选KRAS G12C抑制剂；所述PI3K抑制剂为PI3Kα抑制剂和/或PI3Kδ抑制剂。Further, the KRAS inhibitor is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors; the PI3K inhibitors are PI3Kα inhibitors and/or PI3Kδ inhibitors agent.
本发明还提供了上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备用于治疗由KRAS和/或PI3K介导的疾病的药物中的用途。The present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used for the treatment of KRAS and/or Use in medicine for PI3K-mediated diseases.
进一步地，本发明提供了上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备用于治疗由KRAS G12C、PI3Kα、PI3Kδ中的一种或多种介导的疾病的药物中的用途。Further, the present invention provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used in the preparation for the treatment of KRAS G12C Use in medicine for diseases mediated by one or more of PI3Kα, PI3Kδ.
进一步地，所述疾病为癌症或自身免疫性疾病。Further, the disease is cancer or autoimmune disease.
进一步地，所述癌症包括但不限于非小细胞肺癌、肺癌、胰腺癌、卵巢癌、膀胱癌、***癌、慢性粒细胞白血病、结直肠癌、脑癌、肝癌、肾癌、胃癌、乳腺癌、三阴性乳腺癌、皮肤癌、黑色素癌、头颈癌、骨癌、***、盆腔癌、***癌、口腔癌、淋巴癌、血癌、食管癌、尿道癌、鼻腔癌。Further, the cancer includes but not limited to non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myeloid leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, breast cancer , triple negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphatic cancer, blood cancer, esophageal cancer, urethral cancer, nasal cavity cancer.
本发明还提供了上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备用于治疗对抗癌剂产生耐药的疾病的药物中的用途；The present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions used in the preparation of anti-cancer agent production use in medicines for drug-resistant diseases;
进一步地，所述抗癌剂选自KRAS G12C抑制剂、KRAS G12V抑制剂、KRAS G12D抑制剂、KRAS G12S抑制剂，优选KRAS G12C抑制剂；Further, the anticancer agent is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
进一步地，所述KRAS G12C抑制剂选自AMG-510、MRTX-849，优选AMG-510。Further, the KRAS G12C inhibitor is selected from AMG-510, MRTX-849, preferably AMG-510.
本发明还提供了上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备治疗致使PI3K蛋白和/或KRAS G12C蛋白过度表达的疾病的药物中的用途。The present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation and treatment of PI3K protein and/or KRAS Use in medicine for diseases with overexpression of G12C protein.
本发明还提供了上述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物在制备治疗PI3K蛋白过度和/或KRAS G12C蛋白表达所致疾病的药物中的用途。The present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals or the aforementioned pharmaceutical compositions in the preparation and treatment of PI3K protein excess and/or KRAS The use in medicine of diseases caused by G12C protein expression.
含有本发明化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物的药物组合物中，可以含有药学上可接受的辅料。In the pharmaceutical composition containing the compound of the present invention or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or the aforementioned pharmaceutical composition, it may contain pharmaceutically acceptable Accessories.
本发明还提供治疗由KRAS和/或PI3K介导的疾病的方法，其包括向有需要的患者施用前述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物的步骤。The present invention also provides a method for treating diseases mediated by KRAS and/or PI3K, which comprises administering the aforementioned compounds or their tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable Accepted salts, co-crystals or steps of the aforementioned pharmaceutical compositions.
本发明还提供治疗对抗癌剂产生耐药的疾病的方法，其包括向有需要的患者施用前述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物的步骤。The present invention also provides a method for treating a disease resistant to an anticancer agent, which comprises administering the aforementioned compound or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable compound to a patient in need. salt, co-crystal or the step of the aforementioned pharmaceutical composition.
本发明还提供治疗PI3K蛋白和/或KRAS G12C蛋白过度表达所致疾病的方法，其包括向有需要的患者施用前述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或前述药物组合物的步骤。本发明中所述“药学上可接受的”是指包括任意不干扰活性成分的生物活性的有效性且对它被给予的宿主无毒性的物质。The present invention also provides a method for treating diseases caused by overexpression of PI3K protein and/or KRAS G12C protein, which includes administering the aforementioned compound or its tautomer, stereoisomer, solvate, metabolite, Pharmaceutically acceptable salts, co-crystals or steps of the aforementioned pharmaceutical compositions. "Pharmaceutically acceptable" in the present invention refers to any substance that does not interfere with the effectiveness of the biological activity of the active ingredient and is non-toxic to the host to which it is administered.
本发明所述药学上可接受的辅料，是药物中除主药以外的一切附加材料的总称，辅料应当具备如下性质：(1)对人体无毒害作用，几无副作用；(2)化学性质稳定，不易受温度、pH、保存时间等的影响；(3)与主药无配伍禁忌，不影响主药的疗效和质量检查；(4)不与包装材料相互发生作用。本发明中辅料包括但不仅限于填充剂(稀释剂)、润滑剂(助流剂或抗粘着剂)、分散剂、湿润剂、粘合剂、调节剂、增溶剂、抗氧剂、抑菌剂、乳化剂、崩解剂等。The pharmaceutically acceptable adjuvant of the present invention is the general term for all additional materials in the drug except the main drug, and the adjuvant should have the following properties: (1) have no toxic effect on the human body, and have almost no side effects; (2) have stable chemical properties , not easily affected by temperature, pH, storage time, etc.; (3) no incompatibility with the main drug, does not affect the curative effect and quality inspection of the main drug; (4) does not interact with packaging materials. In the present invention, auxiliary materials include but are not limited to fillers (diluents), lubricants (glidants or anti-adhesives), dispersants, wetting agents, adhesives, regulators, solubilizers, antioxidants, bacteriostats , emulsifier, disintegrant, etc.
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。上述酸碱为广义的路易斯酸碱。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸、苯磺酸等有机酸；以及天冬氨酸、谷氨酸等酸性氨基酸。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or a base which is suitable for use as a medicine. The above-mentioned acids and bases are Lewis acids and bases in a broad sense. Acids suitable for forming salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenemethanesulfonic acid, benzenesulfonic acid and other organic acids; and acidic amino acids such as aspartic acid and glutamic acid.
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)和局部给药。The administration mode of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration modes include (but not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
本发明化合物同样可以用于注射制剂。其中，所述注射剂选自液体注射剂(水针)、注射用无菌粉末(粉针)或注射用片剂(系指药物用无菌操作法制成的模印片或机压片，临用时用注射用水溶解，供皮下或肌肉注射之用)。The compounds of the invention can likewise be used in injectable preparations. Wherein, the injection is selected from liquid injection (water injection), sterile powder for injection (powder injection) or tablet for injection (referring to molded tablet or machine-pressed tablet made by aseptic method of medicine, used for immediate use) Dissolved in water for injection, for subcutaneous or intramuscular injection).
其中，所述注射用粉剂的中除含有上述化合物外，还至少含有赋形剂。本发明中所述赋形剂，为有意加到药物中的成分，其在所用的量上不应具有药理学特性，但是，赋形剂可以有助于药物的加工、溶解或溶出、通过靶向给 药途径递药或有助于稳定性。Wherein, the powder for injection contains at least excipients in addition to the above compounds. The excipients mentioned in the present invention are ingredients intentionally added to the drug, which should not have pharmacological properties in the amount used, but the excipients can facilitate the processing, dissolution or dissolution of the drug, and pass through the target. to give Drug delivery may contribute to stability.
本发明所述“互变异构体”是指因分子中某原子在两个位置移动而产生的官能团异构体，尤其是分子中存在机动的氢原子，例如酮式和烯醇式互变异构体。The "tautomer" mentioned in the present invention refers to the functional group isomers produced by the movement of an atom in the molecule at two positions, especially the presence of mobile hydrogen atoms in the molecule, such as the interconversion of keto and enol isomer.
本发明所述“立体异构体”是指分子中原子或原子团互相连接次序相同，但空间排列不同而产生的异构体，包括顺反异构体、旋光异构体、构象异构体。本发明所述立体异构体还包括两种或多种立体异构体的混合物形式，例如对映异构体和/或非对映异构体的任何比例的混合物。The term "stereoisomer" in the present invention refers to isomers produced by atoms or atomic groups in the same order of interconnection but with different spatial arrangements, including cis-trans isomers, optical isomers, and conformational isomers. The stereoisomers in the present invention also include mixtures of two or more stereoisomers, such as mixtures of enantiomers and/or diastereomers in any ratio.
本发明所述“溶剂化物”表示一个或多个溶剂分子与本发明化合物所形成的适合用作药物的缔合物。形成溶剂化物的溶剂包括但不限于水、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜等。The "solvate" in the present invention refers to the association formed by one or more solvent molecules and the compound of the present invention, which is suitable for use as a drug. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethylsulfoxide, and the like.
本发明所述“代谢产物”是指本发明化合物(或者其盐)的药学上可接受的新陈代谢衍生物形式。The "metabolite" in the present invention refers to the pharmaceutically acceptable metabolic derivative form of the compound of the present invention (or its salt).
本发明所述“共晶”是指离子化或非离子化式(I)化合物(或本文公开的任何其它化合物)和一个或多个非离子化共晶形成物(如药物可接受的盐)通过非共价相互作用连接的分子复合物。The "co-crystal" in the present invention refers to ionized or non-ionized formula (I) compound (or any other compound disclosed herein) and one or more non-ionized co-crystal formers (such as pharmaceutically acceptable salts) Molecular complexes linked by non-covalent interactions.
“任选地被一个或多个···取代”是指可以被一个或多个指定的取代基取代，也可以为非取代；“一个或多个”中的“多个”，若未限定，则最小值为2，最大值为被取代基团的可取代位点的数值。"Optionally substituted by one or more" means that it can be substituted by one or more specified substituents, and can also be unsubstituted; "multiple" in "one or more", if not limited , then the minimum value is 2, and the maximum value is the value of the substitutable position of the substituted group.
“取代”是指分子中的氢原子被其它不同的基团所替换。"Substitution" means that a hydrogen atom in a molecule is replaced by a different group.
“元”是表示构成环的骨架原子的个数。"Element" means the number of skeleton atoms constituting the ring.
本发明中所述“键”，指该处仅为一个连接键，亦可理解为“无”。The "key" mentioned in the present invention means that there is only one connecting key, and it can also be understood as "none".
本文所用的化学结构中的术语“氢”或“H”，除非另有说明外，应当被理解为不仅包括1H，还包括氘(2H，D)、氚(3H，T)或其混合。As used herein, the terms "hydrogen" or "H" in chemical structures, unless otherwise stated, should be understood to include not only 1H, but also deuterium (2H, D), tritium (3H, T) or mixtures thereof.
“烷基”，是指脂肪族烃基团，指饱和烃基。烷基部分可以是直链烷基，亦可以是支链烷基。典型的烷基包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、己基等。"Alkyl" refers to an aliphatic hydrocarbon group and refers to a saturated hydrocarbon group. The alkyl moiety may be straight-chain or branched-chain. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.
本发明中使用的C1～Cn包括C1～C2、C1～C3……C1～Cn，n为大于一的整数；作为取代基的前缀表示取代基中碳原子个数的最小值和最大值，例如，“C1～C6烷基”是指含有1个至6个碳原子的直链或支链的烷基。C1～Cn used in the present invention includes C1～C2, C1～C3...C1～Cn, n is an integer greater than one; the prefix as a substituent indicates the minimum and maximum values of the number of carbon atoms in the substituent, for example , "C1-C6 alkyl" refers to a straight-chain or branched-chain alkyl group containing 1 to 6 carbon atoms.
“杂烷基”是指含有杂原子的烷基。"Heteroalkyl" refers to an alkyl group containing heteroatoms.
“环”是指任意的共价封闭结构，包括例如碳环(例如芳基或环烷基)、杂环(例如杂芳基或杂环烷基)、芳香基(如芳基或杂芳基)、非芳香基(如环烷基或杂环烷基)。本发明中所述“环”可以是单环也可以是多环，可以是并环、螺环或桥环。"Ring" refers to any covalently closed structure, including, for example, carbocycles (such as aryl or cycloalkyl), heterocycles (such as heteroaryl or heterocycloalkyl), aromatic groups (such as aryl or heteroaryl ), non-aromatic (such as cycloalkyl or heterocycloalkyl). The "ring" mentioned in the present invention may be a single ring or a polycyclic ring, and may be a parallel ring, a spiro ring or a bridged ring.
“环烷基”指饱和的环状烃取代基。"Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent.
“环烯基”指环骨架上至少含有一个碳碳双键的环状取代基。"Cycloalkenyl" refers to a cyclic substituent having at least one carbon-carbon double bond in the ring skeleton.
“杂环烷基”指环骨架上含有杂原子的饱和环取代基。"Heterocycloalkyl" refers to a saturated ring substituent containing a heteroatom in the ring backbone.
“氮杂环烷基”指环骨架上含有氮原子的环烷基，其余类似情况同理。"Azacycloalkyl" refers to a cycloalkyl group containing a nitrogen atom in the ring skeleton, and the same applies to other similar cases.
“氮杂单环烷基”是指为氮杂环烷基且为单环结构，其余类似情况同理。"Azamonocycloalkyl" refers to an azacycloalkyl group with a monocyclic structure, and the same applies to other similar cases.
“氮杂环烯基”指含有至少一个双键的非芳族的单环或多环基团，且其中至少有一个环原子为杂原子氮，其余环原子为碳。“5～10元氮杂环烯基”的实例例如可以是如另外指明，所述氮杂环烯基可选地被一个或多个适合的取代基所取代。"Azacycloalkenyl" refers to a non-aromatic monocyclic or polycyclic group containing at least one double bond, in which at least one ring atom is a heteroatom nitrogen and the remaining ring atoms are carbon. Examples of "5- to 10-membered azacycloalkenyl" can be, for example, As otherwise indicated, the azacycloalkenyl group is optionally substituted with one or more suitable substituents.
“脂环基”指不具备芳香性的环状取代基，可以是环烷基、环烯基或脂杂环基。"Alicyclic group" refers to a cyclic substituent without aromaticity, which may be cycloalkyl, cycloalkenyl or aliphatic heterocyclic group.
“脂杂环基”指环骨架上含有至少一个杂原子且不具备芳香性的杂环化合物形成的取代基团，“脂杂环基”中包含“杂环烷基”。"Heteroalicyclic group" refers to a substituent group formed by a heterocyclic compound containing at least one heteroatom in the ring skeleton and not possessing aromaticity, and "heterocycloalkyl" is included in "heteroalicyclic group".
典型的脂杂环基包括但不限于：
Typical heteroalicyclic groups include, but are not limited to:
“芳基”，是指具有芳香性的单环或多环基团，其平面环具有离域的π电子***并且含有4n+2个π电子，其中n是整数；典型的芳基包括但不限于苯基萘基、菲基、蒽基、芴基和茚基等。"Aryl" means an aromatic monocyclic or polycyclic group whose planar ring has a delocalized π-electron system and contains 4n+2 π-electrons, where n is an integer; typical aryl groups include but not limited to phenyl Naphthyl, phenanthrenyl, anthracenyl, fluorenyl and indenyl, etc.
“杂芳基”是指含有杂原子并具有芳香性的单环或多环基团。"Heteroaryl" refers to a monocyclic or polycyclic group containing heteroatoms and having aromaticity.
典型的杂芳基包括但不限于：
Typical heteroaryl groups include, but are not limited to:
文中所述烷基、环烷基、环烯基、脂环基脂、杂环基、杂环烷基、芳基、杂芳基等，可以是非取代的烷基、环烷基、环烯基、脂环基脂、杂环基、杂环烷基、芳基、杂芳基等，也可以是被取代的烷基、环烷基、环烯基、脂环基脂、杂环基、杂环烷基、芳基、杂芳基等。The alkyl, cycloalkyl, cycloalkenyl, alicyclic aliphatic, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, etc. mentioned in the article can be unsubstituted alkyl, cycloalkyl, cycloalkenyl , alicyclic aliphatic, heterocyclic, heterocycloalkyl, aryl, heteroaryl, etc., can also be substituted alkyl, cycloalkyl, cycloalkenyl, alicyclic aliphatic, heterocyclic, heteroaryl Cycloalkyl, aryl, heteroaryl, etc.
上文中，除已经指明的外，所述“取代”是指所提及的基团可以被一个或多个额外的基团取代，所述额外的基团各自并且独立地选自本领域常见的取代基团，如卤素、氰基、羟基、氨基、羧基、烷基、烷氧基、烷胺基、烷硫基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基等等。In the above, unless otherwise specified, the "substitution" means that the mentioned group can be replaced by one or more additional groups, the additional groups are each and independently selected from the common Substituent groups, such as halogen, cyano, hydroxyl, amino, carboxyl, alkyl, alkoxy, alkylamino, alkylthio, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. wait.
其中，当T为NHS(O)2时，结构片段为 Wherein, when T is NHS (O) 2, the structural fragment for
“烷氧基”是指-O-烷基。"Alkoxy" means -O-alkyl.
“烷胺基”是指-NH-烷基或-N-(烷基)2。"Alkylamino" means -NH-alkyl or -N-(alkyl)2.
“烷硫基”是指-S-烷基。"Alkylthio" means -S-alkyl.
“卤素”或“卤”是指氟、氯、溴或碘。"Halogen" or "halo" means fluorine, chlorine, bromine or iodine.
“氰基”是指-CN。"Cyano" means -CN.
“氨基”是指-NH2。"Amino" refers to -NH2 .
“羟基”是指-OH。"Hydroxy" means -OH.
“(O)”是指＝O，如-C(O)R13是指其余类似情况同理。"(O)" means =O, such as -C(O)R13 means The rest of the similar situations are the same.
C＝O是指 C=O means
“吡啶”结构式为 The structural formula of "pyridine" is
“噻吩”结构式为 The structural formula of "thiophene" is
“吡咯”结构式为 The structural formula of "pyrrole" is
本发明的有益效果是：The beneficial effects of the present invention are:
(1)本发明提供了一系列对KRAS和PI3K蛋白具有明显的抑制作用的化合物，具有活性高、选择性好且毒副作用低等优点，且在体内具有较好的药代动力学性能，为以KRAS或PI3K为治疗的靶点的疾病如癌症等的治疗提供新的方案，可用于制备治疗相关疾病的药物，具有广阔的应用前景。(1) The present invention provides a series of compounds with obvious inhibitory effects on KRAS and PI3K proteins, which have the advantages of high activity, good selectivity, and low toxicity and side effects, and have good pharmacokinetic properties in vivo. It provides a new solution for the treatment of diseases such as cancer with KRAS or PI3K as the target of treatment, which can be used to prepare drugs for the treatment of related diseases, and has broad application prospects.
(2)本发明化合物对KRAS G12C抑制剂耐药，尤其是AMG-510耐药的癌细胞具有极强的抑制作用，克服了由单纯G12C抑制剂产生的耐药问题，有望延长患者的生存期。(2) The compound of the present invention is resistant to KRAS G12C inhibitors, especially AMG-510 drug-resistant cancer cells have a strong inhibitory effect, overcomes the problem of drug resistance caused by simple G12C inhibitors, and is expected to prolong the survival of patients .
具体实施方式Detailed ways
下面对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions of the present invention are clearly and completely described below, and obviously, the described embodiments are part of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR的化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用AVANCE NEO 400MHz Bruker仪器，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。MS的测定是用ISQ-EC Thermo Fisher LC-MS仪器。Prep-HPLC是GX-281 Gilson色谱仪，分离方法有：(方法1)Sun Fire Prep C18 OBDTM 5μm，30×150mm Column，0.04％HCl水溶液/乙腈；(方法2)Xbridge Prep C18 OBDTM 5μm，30 x 150mm Column，10mM NH4HCO3水溶液/乙腈。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). The determination of NMR is carried out with AVANCE NEO 400MHz Bruker instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl sulfoxide trimethylsilane (TMS). MS was determined with an ISQ-EC Thermo Fisher LC-MS instrument. Prep-HPLC is a GX-281 Gilson chromatograph, and the separation methods are: (method 1) Sun Fire Prep C18 OBDTM 5 μm, 30 × 150mm Column, 0.04% HCl aqueous solution/acetonitrile; (method 2) Xbridge Prep C18 OBDTM 5 μm, 30 x 150mm Column, 10mM NH 4 HCO 3 aqueous solution/acetonitrile.
本发明实施例中的起始原料是已知的，并且可以在市场上买到，或者可以按照本领域的已知方法合成得到。The starting materials in the examples of the present invention are known and can be purchased in the market, or can be synthesized according to methods known in the art.
本发明所使用的溶剂，若无特殊说明，是指可经市售获得。The solvents used in the present invention are commercially available unless otherwise specified.
实施例中若无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
本发明中涉及的化学缩写简称具有以下意义：The chemical abbreviations involved in the present invention have the following meanings:
TFA：三氟乙酸 TFA: Trifluoroacetic acid
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
THF：四氢呋喃THF: Tetrahydrofuran
HOBT：1-羟基苯并***HOBT: 1-Hydroxybenzotriazole
EDCI：1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐EDCI: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
DIPEA：N,N-二异丙基乙胺DIPEA: N,N-Diisopropylethylamine
HATU：O-(7-氮杂苯并***-1-基)-N,N,N′,N′-四甲基脲HATU: O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethylurea
T3P：1-丙基磷酸酐T 3 P: 1-propyl phosphoric anhydride
BINAP：1,1'-联萘-2,2'-双二苯膦BINAP: 1,1'-binaphthyl-2,2'-bisdiphenylphosphine
Prep-HPLC：制备型高效液相色谱仪Prep-HPLC: Preparative High Performance Liquid Chromatography
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.
本发明的化合物结构是通过核磁共振(NMR)或/和液质联用色谱(LC-MS)来确定的。NMR的化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用AVANCE NEO 400MHz Bruker仪器，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。MS的测定是用ISQ-EC Thermo Fisher LC-MS仪器。Prep-HPLC是GX-281 Gilson色谱仪，分离方法有：(方法1)Sun Fire Prep C18 OBDTM 5μm，30×150mm Column，0.04％HCl水溶液/乙腈；(方法2)Xbridge Prep C18 OBDTM 5μm，30×150mm Column，10mM NH4HCO3水溶液/乙腈。The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass chromatography (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). The determination of NMR is carried out with AVANCE NEO 400MHz Bruker instrument, the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl sulfoxide trimethylsilane (TMS). MS was determined with an ISQ-EC Thermo Fisher LC-MS instrument. Prep-HPLC is a GX-281 Gilson chromatograph, and the separation methods are: (method 1) Sun Fire Prep C18 OBDTM 5 μm, 30 × 150mm Column, 0.04% HCl aqueous solution/acetonitrile; (method 2) Xbridge Prep C18 OBDTM 5 μm, 30 × 150mm Column, 10mM NH 4 HCO 3 aqueous solution/acetonitrile.
本发明实施例中的起始原料是已知的，并且可以在市场上买到，或者可以按照本领域的已知方法合成得到。The starting materials in the examples of the present invention are known and can be purchased in the market, or can be synthesized according to methods known in the art.
本发明所使用的溶剂，若无特殊说明，是指可经市售获得。The solvents used in the present invention are commercially available unless otherwise specified.
实施例中若无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
本发明中涉及的化学缩写简称具有以下意义：The chemical abbreviations involved in the present invention have the following meanings:
TFA：三氟乙酸TFA: Trifluoroacetic acid
DMF：N,N-二甲基甲酰胺DMF: N,N-Dimethylformamide
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
T3P：1-丙基磷酸酐T 3 P: 1-propyl phosphoric anhydride
Prep-HPLC：制备型高效液相色谱仪Prep-HPLC: Preparative High Performance Liquid Chromatography
实施例1Example 1
(E)-2，4，6-三氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinone Preparation of olin-6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(6-溴喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromoquinolin-4-yl)piperazine-1-carboxylate
将6-溴-4-氯喹啉(300mg,1.235mmol)和DMSO(10mL)加入反应瓶中，搅拌溶解，加入三乙胺(187mg,1.853mmol)和哌嗪-1-甲酸叔丁酯(253mg,1.359mmol)，加毕，升温120℃反应2h。反应结束后，加水(50mL)淬灭反应，以二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯＝2/1到1/2)，得4-(6-溴喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率82.6％；ESI-MS(m/z)：392.0[M+H]+。Add 6-bromo-4-chloroquinoline (300mg, 1.235mmol) and DMSO (10mL) into the reaction flask, stir to dissolve, add triethylamine (187mg, 1.853mmol) and piperazine-1-carboxylic acid tert-butyl ester (253mg , 1.359mmol), after the addition was completed, the temperature was raised to 120°C for 2h. After the reaction, add water (50mL) to quench the reaction, extract with dichloromethane (100mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=2/1 to 1/2) to obtain 4-(6-bromoquinolin-4-yl)piperazine-1- Tert-butyl formate, yield 82.6%; ESI-MS (m/z): 392.0 [M+H] + .
步骤b)：4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine- Preparation of tert-butyl 1-formate
将4-(6-溴喹啉-4-基)哌嗪-1-甲酸叔丁酯(170mg,0.434mmol)、双联频哪醇硼酸酯(132mg,0.521mmol)、Pd(dppf)Cl2(32mg,0.043mmol)和醋酸钾(127mg,1.302mmol)加入二氧六环(10mL)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2次)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率96.8％；ESI-MS(m/z)：440.3[M+H]+。4-(6-Bromoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (170mg, 0.434mmol), double pinacol borate (132mg, 0.521mmol), Pd(dppf)Cl 2 (32mg, 0.043mmol) and potassium acetate (127mg, 1.302mmol) were added into dioxane (10mL). After the addition was complete, the temperature was raised to 110°C under nitrogen protection and stirred for 2h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2 times), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 4-(6-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 96.8%; ESI-MS (m/z): 440.3 [M +H] + .
步骤c)：4-(6-(6-甲氧基-5-((2,4,6-三氟苯基)磺酰氨基)吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step c): 4-(6-(6-methoxy-5-((2,4,6-trifluorophenyl)sulfonylamino)pyridin-3-yl)quinolin-4-yl)piperazine - Preparation of tert-butyl formate
将4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(185mg,0.420mmol)、N-(5- 溴-2-甲氧基吡啶-3-基)-2,4,6-三氟苯磺酰胺(200mg,0.504mmol)、Pd(dppf)Cl2(31mg,0.042mmol)和碳酸铯(411mg,1.260mmol)加入二氧六环/水混合溶剂(10mL，v/v＝4:1)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2次)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-(6-甲氧基-5-((2,4,6-三氟苯基)磺酰氨基)吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率94.3％；ESI-MS(m/z)：630.1[M+H]+。4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (185mg, 0.420mmol), N-(5- Bromo-2-methoxypyridin-3-yl)-2,4,6-trifluorobenzenesulfonamide (200mg, 0.504mmol), Pd(dppf)Cl 2 (31mg, 0.042mmol) and cesium carbonate (411mg, 1.260 mmol) was added into dioxane/water mixed solvent (10 mL, v/v=4:1), after the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2 times), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 4-(6-(6-methoxy-5-((2,4, 6-trifluorophenyl)sulfonylamino)pyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 94.3%; M+H] + .
步骤d)：2,4,6-三氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step d): 2,4,6-Trifluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonate Preparation of amide trifluoroacetate
将4-(6-(6-甲氧基-5-((2,4,6-三氟苯基)磺酰氨基)吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(250mg,0.403mmol)溶于二氯甲烷(4mL)中，在冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入甲基叔丁基醚，搅拌析出固体，过滤，得2,4,6-三氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：530.1[M+H]+。4-(6-(6-methoxy-5-((2,4,6-trifluorophenyl)sulfonylamino)pyridin-3-yl)quinolin-4-yl)piperazine-1- Tert-butyl formate (250mg, 0.403mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether to the crude product, stir to precipitate a solid, filter to obtain 2,4,6-trifluoro-N-(2-methoxy-5-(4-( Piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 530.1 [M+H] + .
步骤e)：(E)-2,4,6-三氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备Step e): (E)-2,4,6-Trifluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazine-1 Preparation of -yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide
将2,4,6-三氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(150mg,0.239mmol)溶于四氢呋喃(6mL)中，将反应体系降温-78℃，依次加入N,N-二异丙基乙胺(155mg,1.195mmol)、(E)-4-氧代戊-2-烯酸(41mg,0.359mmol)和50％的T3P乙酸乙酯溶液(304mg,0.478mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,4,6-三氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺,产率31.0％；1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.73(d,J＝4.8Hz,1H),8.50(d,J＝2.4Hz,1H),8.19(d,J＝2.4Hz,1H),8.10-8.04(m,2H),8.00(dd,J1＝8.8,J2＝2.0Hz,1H),7.50(d,J＝15.6Hz,1H),7.47-7.38(m,2H),7.07(d,J＝5.2Hz,1H),6.73(d,J＝16.0Hz,1H),4.02-3.82(m,4H),3.70(s,3H),3.32-3.21(m,4H),2.38(s,3H)；ESI-MS(m/z)：626.0[M+H]+。2,4,6-trifluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoro Acetate (150mg, 0.239mmol) was dissolved in tetrahydrofuran (6mL), the reaction system was cooled to -78°C, and N,N-diisopropylethylamine (155mg, 1.195mmol), (E)-4- Oxopent-2-enoic acid (41mg, 0.359mmol) and 50% T 3 P ethyl acetate solution (304mg, 0.478mmol, 50%wt) were added, and stirred at -78°C for 1h. After the reaction, quench the reaction with saturated ammonium chloride solution (50mL) at -78°C, extract with dichloromethane (100mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), and anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure, the obtained crude product was purified by Prep-HPLC (method 2) to obtain (E)-2,4,6-trifluoro-N-(2-methoxy-5-(4-( 4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 31.0%; 1H NMR (400MHz, DMSO- d 6 )δ10.79(s,1H),8.73(d,J=4.8Hz,1H),8.50(d,J=2.4Hz,1H),8.19(d,J=2.4Hz,1H),8.10- 8.04(m,2H),8.00(dd,J1=8.8,J2=2.0Hz,1H),7.50(d,J=15.6Hz,1H),7.47-7.38(m,2H),7.07(d,J= 5.2Hz, 1H), 6.73(d, J=16.0Hz, 1H), 4.02-3.82(m, 4H), 3.70(s, 3H), 3.32-3.21(m, 4H), 2.38(s, 3H); ESI-MS (m/z): 626.0 [M+H] + .
实施例2参考实施例1的制备方法，以相应的原料，制得了以下实施例中的化合物。
Example 2 Referring to the preparation method of Example 1, the compounds in the following examples were prepared with corresponding raw materials.
实施例3Example 3
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline- Preparation of 6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(6-溴喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromoquinolin-4-yl)piperazine-1-carboxylate
制备方法同实施例1的步骤a。The preparation method is the same as step a of Example 1.
步骤b)：4-(6-(5-((2,4-二氟苯基)磺酰氨基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,4-difluorophenyl)sulfonylamino)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1 -Preparation of tert-butyl formate
将4-(6-溴喹啉-4-基)哌嗪-1-甲酸叔丁酯(400mg,1.020mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(522mg,1.224mmol)、Pd(dppf)Cl2(75mg,0.102mmol)和碳酸铯(998 mg,3.060mmol)加入二氧六环/水混合溶剂中(10mL，v/v＝4:1)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2次)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-(5-((2,4-二氟苯基)磺酰氨基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率64.1％；ESI-MS(m/z)：612.6[M+H]+。4-(6-bromoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (400mg, 1.020mmol), 2,4-difluoro-N-(2-methoxy-5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (522mg, 1.224mmol), Pd(dppf)Cl 2 (75mg, 0.102mmol) and cesium carbonate (998 mg, 3.060mmol) was added to dioxane/water mixed solvent (10mL, v/v=4:1), after the addition was completed, the temperature was raised to 110°C under nitrogen protection and stirred for 2h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2 times), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 4-(6-(5-((2,4-difluorophenyl)sulfonyl Amino)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 64.1%; ESI-MS (m/z): 612.6 [M+ H] + .
步骤c)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide tris Preparation of fluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰氨基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(400mg,0.195mmol)溶于二氯甲烷(4mL)中，在冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入甲基叔丁基醚，搅拌析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：512.0[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonylamino)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert Butyl ester (400mg, 0.195mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether to the crude product, stir to precipitate a solid, filter to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piperazine -1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 512.0 [M+H] + .
步骤d)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) quinoline-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(150mg,0.246mmol)溶于四氢呋喃(5mL)中，将反应体系降温-78℃，依次加入N,N-二异丙基乙胺(160mg,1.230mmol)、(E)-4-氧代戊-2-烯酸(42mg,0.369mmol)和50％的T3P乙酸乙酯溶液(313mg，0.492mmol，50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺,产率13.1％；1HNMR(400MHz,DMSO-d6)δ10.35(s,1H),8.74(d,J＝8.0Hz,1H),8.48(s,1H),8.19(s,1H),8.08-7.98(m,3H),7.80-7.78(m,1H),7.57-7.54(m,1H),7.50(d,J＝16.0Hz,1H),7.27-7.23(m,1H),7.07-7.06(m,1H),6.76(d,J＝16.0Hz,1H),3.97-3.88(m,4H),3.70(s,3H),3.27-3.26(m,4H),2.38(s,3H)；ESI-MS(m/z)：608.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetic acid Salt (150mg, 0.246mmol) was dissolved in tetrahydrofuran (5mL), the temperature of the reaction system was lowered to -78°C, and N,N-diisopropylethylamine (160mg, 1.230mmol), (E)-4-oxo Pent-2-enoic acid (42mg, 0.369mmol) and 50% T 3 P ethyl acetate solution (313mg, 0.492mmol, 50%wt) were added, and stirred at -78°C for 1h. After the reaction, quench the reaction with saturated ammonium chloride solution (50mL) at -78°C, extract with dichloromethane (100mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), and anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure, the obtained crude product was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(4-(4- (4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 13.1%; 1 HNMR (400MHz, DMSO-d 6 )δ10.35(s,1H),8.74(d,J＝8.0Hz,1H),8.48(s,1H),8.19(s,1H),8.08-7.98(m,3H),7.80-7.78(m ,1H),7.57-7.54(m,1H),7.50(d,J=16.0Hz,1H),7.27-7.23(m,1H),7.07-7.06(m,1H),6.76(d,J=16.0 Hz, 1H), 3.97-3.88(m, 4H), 3.70(s, 3H), 3.27-3.26(m, 4H), 2.38(s, 3H); ESI-MS(m/z): 608.0[M+ H] + .
实施例4-10参考实施例3的制备方法，以相应的原料，制得了以下实施例中的化合物。

Examples 4-10 Referring to the preparation method of Example 3, the compounds in the following examples were prepared with corresponding raw materials.

实施例11Example 11
(E)-N-(5-(3-氰基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2，4-二氟苯磺酰胺的制备
(E)-N-(5-(3-cyano-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)-2-methyl Preparation of oxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
步骤a)：4-(6-溴-3-氰基喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromo-3-cyanoquinolin-4-yl)piperazine-1-carboxylate
将6-溴-4-氯喹啉-3-甲腈(300mg，1.121mmol)、哌嗪-1-甲酸叔丁酯(209mg，1.121mmol)、三乙胺(340mg,3.363mmol)加入N,N-二甲基甲酰胺(5mL)中，加完升温至60℃反应2h。反应结束后，加水(30mL)淬灭反应液，加乙酸乙酯(50mL×2)萃取，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/20到1/5)，得4-(6-溴-3-氰基喹唑啉-4-基)哌嗪-1- 甲酸叔丁酯，产率96.3％；ESI-MS(m/z)：417.1[M+H]+。Add 6-bromo-4-chloroquinoline-3-carbonitrile (300mg, 1.121mmol), piperazine-1-carboxylic acid tert-butyl ester (209mg, 1.121mmol), triethylamine (340mg, 3.363mmol) into N,N - Dimethylformamide (5 mL), heated to 60° C. for 2 h after addition. After the reaction, add water (30mL) to quench the reaction solution, add ethyl acetate (50mL×2) for extraction, combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product Purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20 to 1/5) to obtain 4-(6-bromo-3-cyanoquinazolin-4-yl)piperazine- 1- Tert-butyl formate, yield 96.3%; ESI-MS (m/z): 417.1 [M+H] + .
步骤b-d)：(E)-N-(5-(3-氰基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step b-d): (E)-N-(5-(3-cyano-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl) Preparation of -2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
制备方法参考实施例3的步骤b-d)，得(E)-N-(5-(3-氰基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率19.9％；1H NMR(400MHz,DMSO-d6)δ10.28(brs,1H),8.81(s,1H),8.49-8.33(m,1H),8.21(s,1H),8.16-8.05(m,2H),8.04-7.95(m,1H),7.82-7.73(m,1H),7.54(d,J＝16.0Hz,2H),7.17(d,J＝8.0Hz,1H),6.73(d,J＝16.0Hz,1H),4.06-3.72(m,8H),3.71(s,3H),2.39(s,3H)；ESI-MS(m/z)：633.0[M+H]+。The preparation method refers to step bd) of Example 3 to obtain (E)-N-(5-(3-cyano-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl) )quinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 19.9%; 1 H NMR (400MHz, DMSO-d 6 )δ10.28 (brs,1H),8.81(s,1H),8.49-8.33(m,1H),8.21(s,1H),8.16-8.05(m,2H),8.04-7.95(m,1H),7.82-7.73 (m,1H),7.54(d,J=16.0Hz,2H),7.17(d,J=8.0Hz,1H),6.73(d,J=16.0Hz,1H),4.06-3.72(m,8H) , 3.71 (s, 3H), 2.39 (s, 3H); ESI-MS (m/z): 633.0 [M+H] + .
实施例12Example 12
(E)-2，4-二氟-N-(5-(3-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(5-(3-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline-6- The preparation of -2-methoxypyridin-3-yl)benzenesulfonamide
步骤a)：6-溴-4-氯喹啉-3-胺的制备Step a): Preparation of 6-bromo-4-chloroquinolin-3-amine
将6-溴-4-氯-3-硝基喹啉(1g,3.484mmol)溶于甲醇(30mL)和水(10mL)中，加入铁粉(3.9g，69.686mmol)和氯化铵(1.9g，34.840mmol)，加毕，室温搅拌4h。反应结束后，将反应液过滤，滤液减压蒸除甲醇，残余物用二氯甲烷(100mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1到1/1)，得6-溴-4-氯喹啉-3-胺，产率78.7％；ESI-MS(m/z)：258.9[M+H]+。Dissolve 6-bromo-4-chloro-3-nitroquinoline (1 g, 3.484 mmol) in methanol (30 mL) and water (10 mL), add iron powder (3.9 g, 69.686 mmol) and ammonium chloride (1.9 g, 34.840mmol), after addition, stirred at room temperature for 4h. After the reaction, the reaction solution was filtered, the filtrate was evaporated under reduced pressure to remove methanol, the residue was extracted with dichloromethane (100mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel Purified by column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to obtain 6-bromo-4-chloroquinolin-3-amine with a yield of 78.7%; ESI-MS (m/ z): 258.9 [M+H] + .
步骤b)：6-溴-4-氯喹啉-3-重氮氟硼酸盐的制备Step b): Preparation of 6-bromo-4-chloroquinoline-3-diazofluoroborate
将6-溴-4-氯喹啉-3-胺(700mg，0.713mmol)溶于四氢呋喃(8mL)中，在0℃下加入氟硼酸(2.6mL)，并缓慢滴加亚硝酸钠(206mg，0.784mmol)的水溶液(1.0mL)，加毕，在0～10℃反应2h。过滤，滤饼用乙酸乙酯(10mL×2)淋洗，滤饼真空干燥得6-溴-4-氯喹啉-3-重氮氟硼酸盐，产率92.6％。6-Bromo-4-chloroquinolin-3-amine (700mg, 0.713mmol) was dissolved in tetrahydrofuran (8mL), fluoroboric acid (2.6mL) was added at 0°C, and sodium nitrite (206mg, 0.784 mmol) in aqueous solution (1.0 mL), after addition, react at 0-10°C for 2 h. After filtering, the filter cake was rinsed with ethyl acetate (10 mL×2), and the filter cake was vacuum-dried to obtain 6-bromo-4-chloroquinoline-3-diazofluoroborate with a yield of 92.6%.
步骤c)：6-溴-4-氯-3-氟喹啉的制备Step c): Preparation of 6-bromo-4-chloro-3-fluoroquinoline
将6-溴-4-氯喹啉-3-重氮氟硼酸盐(900mg，2.521mmol)加入到250mL反应瓶中，155℃反应1h。将反应液冷却至室温，粗品经硅胶柱层析纯化(二氯甲烷/乙酸乙酯＝10/1到2/1)得6-溴-4-氯-3-氟喹啉，产率31.2％；ESI-MS(m/z)：259.9[M+H]+。Add 6-bromo-4-chloroquinoline-3-diazofluoroborate (900mg, 2.521mmol) into a 250mL reaction flask, and react at 155°C for 1h. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography (dichloromethane/ethyl acetate=10/1 to 2/1) to obtain 6-bromo-4-chloro-3-fluoroquinoline with a yield of 31.2% ; ESI-MS (m/z): 259.9 [M+H] + .
步骤d)：N-(5-(4-溴-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step d): Preparation of N-(5-(4-bromo-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
将6-溴-4-氯-3-氟喹啉(160mg,0.615mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(262mg,0.615mmol)、Pd(dppf)Cl2(45mg,0.062mmol)和碳酸铯(596mg,1.845mmol)加入二氧六环/水混合溶剂(10mL，v/v＝4:1)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得N-(5-(4-溴-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率91.5％；ESI-MS(m/z)：480.0[M+H]+。6-bromo-4-chloro-3-fluoroquinoline (160mg, 0.615mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (262mg, 0.615mmol), Pd(dppf)Cl 2 (45mg, 0.062mmol) and carbonic acid Cesium (596mg, 1.845mmol) was added into dioxane/water mixed solvent (10mL, v/v=4:1). After the addition was completed, the temperature was raised to 110°C under nitrogen protection and stirred for 2h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain N-(5-(4-bromo-3-fluoroquinolin-6-yl)- 2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 91.5%; ESI-MS (m/z): 480.0 [M+H] + .
步骤e)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step e): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl) Preparation of tert-butyl piperazine-1-carboxylate
将N-(5-(4-溴-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(250mg，0.477mmol)、哌嗪-1-甲酸叔丁酯(134mg,0.716mmol)、Pd2(dba)3(88mg,0.095mmol)、RuPhos(67mg，0.143mmol)和碳酸铯(469mg，1.431mmol)加入甲苯(8mL)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2次)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率90.0％；ESI-MS(m/z)：630.2[M+H]+。N-(5-(4-bromo-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (250mg, 0.477mmol), tert-butyl piperazine-1-carboxylate (134mg, 0.716mmol), Pd2 (dba) 3 (88mg, 0.095mmol), RuPhos (67mg, 0.143mmol) and cesium carbonate (469mg, 1.431mmol) were added toluene (8mL) After the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2 times), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 4-(6-(5-((2,4-difluorophenyl)sulfonyl Amino)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 90.0%; ESI-MS (m/z): 630.2[M+H] + .
步骤f)：2,4-二氟-N-(5-(3-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step f): 2,4-Difluoro-N-(5-(3-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl) Preparation of Benzenesulfonamide Trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯(270mg，0.429mmol)溶于二氯甲烷(6mL)中，在冰浴下缓慢滴加TFA(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入甲基叔丁基醚，搅拌析出固体，过滤，得2,4-二氟-N-(5-(3-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：530.0[M+H]+。 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl)piperazine- tert-Butyl 1-carboxylate (270 mg, 0.429 mmol) was dissolved in dichloromethane (6 mL), and TFA (2 mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1 h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether to the crude product, stir to precipitate a solid, filter to obtain 2,4-difluoro-N-(5-(3-fluoro-4-(piperazine-1 -yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 530.0 [M+H] + .
步骤g)：(E)-2,4-二氟-N-(5-(3-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备Step g): (E)-2,4-difluoro-N-(5-(3-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinone Preparation of phen-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
将2,4-二氟-N-(5-(3-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐(150mg,0.239mmol)溶于四氢呋喃(6mL)中，将反应体系降温-78℃，依次加入N,N-二异丙基乙胺(155mg,1.195mmol)、(E)-4-氧代戊-2-烯酸(41mg,0.359mmol)和50％的T3P乙酸乙酯溶液(304mg,0.478mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(100mL×2次)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(5-(3-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺,产率19.5％；1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.81(d,J＝4.4Hz,1H),8.51(d,J＝2.4Hz,1H),8.27(s,1H),8.11-8.01(m,3H),7.81-7.79(m,1H),7.59-7.49(m,2H),7.23-7.19(m,1H),6.74(d,J＝15.6Hz,1H),3.95-3.89(m,4H),3.70(s,3H),3.42-3.38(m,4H),2.37(s,3H))；ESI-MS(m/z)：626.0[M+H]+。2,4-Difluoro-N-(5-(3-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide Trifluoroacetate (150mg, 0.239mmol) was dissolved in tetrahydrofuran (6mL), the reaction system was cooled to -78°C, and N,N-diisopropylethylamine (155mg, 1.195mmol), (E)- 4-Oxopent-2-enoic acid (41mg, 0.359mmol) and 50% T 3 P ethyl acetate solution (304mg, 0.478mmol, 50%wt) were added, and stirred at -78°C for 1h. After the reaction, quench the reaction with saturated ammonium chloride solution (50mL) at -78°C, extract with dichloromethane (100mL×2 times), combine the organic phases, wash the organic phase with saturated brine (100mL), and wash with anhydrous sulfuric acid Na-dried, filtered, and the filtrate concentrated under reduced pressure, the resulting crude product was purified by Prep-HPLC (Method 2) to give (E)-2,4-difluoro-N-(5-(3-fluoro-4-(4-( 4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 19.5%; 1 H NMR ( 400MHz,DMSO-d 6 )δ10.36(s,1H),8.81(d,J＝4.4Hz,1H),8.51(d,J＝2.4Hz,1H),8.27(s,1H),8.11-8.01 (m,3H),7.81-7.79(m,1H),7.59-7.49(m,2H),7.23-7.19(m,1H),6.74(d,J＝15.6Hz,1H),3.95-3.89(m ,4H), 3.70(s,3H), 3.42-3.38(m,4H), 2.37(s,3H)); ESI-MS (m/z): 626.0[M+H] + .
实施例13Example 13
(S，E)-2，4，6-三氟-N-(2-甲氧基-5-(4-(2-甲基-4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备
(S, E)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(2-methyl-4-(4-oxopent-2-enoyl)piperene) Preparation of oxazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：2-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶的制备Step a): 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine preparation
将5-溴-2-甲氧基-3-硝基砒啶(850mg，3.648mmol)和联硼酸频那醇酯(1.39g，5.474mmol)和二氧六环(10mL)加入反应瓶中，再加入Pd(dppf)Cl2(130mg,0.178mmol)和醋酸钾(1.07g,10.903mmol)，加毕，75℃反应4h。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯(60mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100：1)，得2-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶，产率97.8％；ESI-MS(m/z)：281.0[M+H]+。5-Bromo-2-methoxy-3-nitropyridine (850 mg, 3.648 mmol) and pinacol diborate (1.39 g, 5.474 mmol) and dioxane (10 mL) were added to the reaction flask, Then Pd(dppf)Cl 2 (130mg, 0.178mmol) and potassium acetate (1.07g, 10.903mmol) were added, after the addition was completed, the mixture was reacted at 75°C for 4h. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (60mL×2), combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography Purification (eluent: dichloromethane/methanol=100:1) to obtain 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)pyridine, yield 97.8%; ESI-MS (m/z): 281.0 [M+H] + .
步骤b)：4-氯-6-(6-甲氧基-5-硝基吡啶-3-基)喹啉的制备Step b): Preparation of 4-chloro-6-(6-methoxy-5-nitropyridin-3-yl)quinoline
将6-溴-4-氯喹啉(727mg，2.998mmol)、2-甲氧基-3-硝基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶(840mg，2.999mmol)、Pd(dppf)Cl2(219mg，0.299mmol)和碳酸铯(2.0g，6.138mmol)溶于二氧六环/水混合溶剂中(10mL，v/v＝5:1)中，加毕，氮气保护下升温至90℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1到1/2)，得4-氯-6-(6-甲氧基-5-硝基吡啶-3-基)喹啉，产率95.7％；ESI-MS(m/z)：316.0[M+H]+。6-Bromo-4-chloroquinoline (727mg, 2.998mmol), 2-methoxy-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxo Borolan-2-yl)pyridine (840mg, 2.999mmol), Pd(dppf) Cl2 (219mg, 0.299mmol) and cesium carbonate (2.0g, 6.138mmol) were dissolved in dioxane/water mixed solvent (10 mL, v/v=5:1), after the addition was complete, the temperature was raised to 90° C. and stirred for 2 h under the protection of nitrogen. After the reaction, add water (50mL) to quench the reaction, extract with ethyl acetate (100mL×2), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1 to 1/2), obtain 4-chloro-6-(6-methoxy-5-nitropyridin-3-yl) quinoline, yield 95.7%; ESI-MS (m/z): 316.0 [M+H] + .
步骤c)：(S)-4-(6-(6-甲氧基-5-硝基吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯的制备Step c): (S)-4-(6-(6-methoxy-5-nitropyridin-3-yl)quinolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl Preparation of esters
将4-氯-6-(6-甲氧基-5-硝基吡啶-3-基)喹啉(720mg，2.281mmol)、(S)-3-甲基哌嗪-1-甲酸叔丁酯(914mg，4.564mmol)、RuPhos(319mg，0.684mmol)、Pd2(dba)3(418mg，0.456mmol)、碳酸铯(2.2g,6.752mmol)和甲苯(25mL)加入反应瓶中，加毕，氮气保护下升温至110℃搅拌16h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到20/1)，得(S)-4-(6-(6-甲氧基-5-硝基吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯，产率42.1％；ESI-MS(m/z)：480.5[M+H]+。4-Chloro-6-(6-methoxy-5-nitropyridin-3-yl)quinoline (720mg, 2.281mmol), (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (914mg, 4.564mmol), RuPhos (319mg, 0.684mmol), Pd 2 (dba) 3 (418mg, 0.456mmol), cesium carbonate (2.2g, 6.752mmol) and toluene (25mL) were added in the reaction flask, and the addition was completed. Under nitrogen protection, the temperature was raised to 110° C. and stirred for 16 h. After the reaction, add water (50mL) to quench the reaction, extract with ethyl acetate (100mL×2), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (Eluent: dichloromethane/methanol=100/1 to 20/1), (S)-4-(6-(6-methoxy-5-nitropyridin-3-yl)quinoline- 4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, yield 42.1%; ESI-MS (m/z): 480.5[M+H] + .
步骤d)：(S)-4-(6-(5-氨基-6-甲氧基吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯的制备Step d): (S)-tert-butyl 4-(6-(5-amino-6-methoxypyridin-3-yl)quinolin-4-yl)-3-methylpiperazine-1-carboxylate preparation of
将(S)-4-(6-(6-甲氧基-5-硝基吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(460mg，0.959mmol)溶于乙醇中(8mL)中，加毕，氢气置换3次，在氢气氛围下升温至40℃反应2h。反应结束后，硅藻土过滤，甲醇冲洗滤饼，收集滤液，滤液减压浓缩，得(S)-4-(6-(5-氨基-6-甲氧基吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯，产率92.8％；ESI-MS(m/z)：450.1[M+H]+。(S)-4-(6-(6-methoxy-5-nitropyridin-3-yl)quinolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (460mg , 0.959mmol) was dissolved in ethanol (8mL), after the addition was completed, hydrogen was replaced 3 times, and the temperature was raised to 40°C under hydrogen atmosphere to react for 2h. After the reaction, filter with diatomaceous earth, wash the filter cake with methanol, collect the filtrate, and concentrate the filtrate under reduced pressure to obtain (S)-4-(6-(5-amino-6-methoxypyridin-3-yl)quinoline -4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, yield 92.8%; ESI-MS (m/z): 450.1 [M+H] + .
步骤e)：(S)-4-(6-(6-甲氧基-5-((2,4,6-三氟苯基)磺酰胺基)吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯的制备Step e): (S)-4-(6-(6-methoxy-5-((2,4,6-trifluorophenyl)sulfonamido)pyridin-3-yl)quinoline-4- base)-3-methylpiperazine-1-carboxylate tert-butyl ester
将(S)-4-(6-(5-氨基-6-甲氧基吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(80mg，0.178mmol)、吡啶(28 mg，0.354mmol)和4-二甲氨基吡啶(2mg，0.016mmol)溶于二氯甲烷(3mL)中，冷却至0℃，滴加2,4,6-三氟苯磺酰氯(98mg，0.425mmol)，加毕，升温至30℃反应4h。反应结束后，加水(30mL)淬灭反应，用二氯甲烷(60mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1到0/1)，得(S)-4-(6-(6-甲氧基-5-((2,4,6-三氟苯基)磺酰胺基)吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯，产率69.9％；ESI-MS(m/z)：644.0[M+H]+。(S)-4-(6-(5-amino-6-methoxypyridin-3-yl)quinolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester (80mg, 0.178mmol), pyridine (28 mg, 0.354mmol) and 4-dimethylaminopyridine (2mg, 0.016mmol) were dissolved in dichloromethane (3mL), cooled to 0°C, and 2,4,6-trifluorobenzenesulfonyl chloride (98mg, 0.425 mmol), the addition was completed, and the temperature was raised to 30° C. for 4 h. After the reaction, add water (30mL) to quench the reaction, extract with dichloromethane (60mL×2), combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate = 5/1 to 0/1) gave (S)-4-(6-(6-methoxy-5-((2,4,6-tri Fluorophenyl)sulfonamido)pyridin-3-yl)quinolin-4-yl)-3-methylpiperazine-1-carboxylic acid tert-butyl ester, yield 69.9%; ESI-MS (m/z): 644.0[M+H] + .
步骤f)：(S)-2,4,6-三氟-N-(2-甲氧基-5-(4-(2-甲基哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step f): (S)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(2-methylpiperazin-1-yl)quinolin-6-yl) Preparation of pyridin-3-yl)benzenesulfonamide trifluoroacetate
将(S)-4-(6-(6-甲氧基-5-((2,4,6-三氟苯基)磺酰胺基)吡啶-3-基)喹啉-4-基)-3-甲基哌嗪-1-甲酸叔丁酯(50mg，0.078mmol)溶于二氯甲烷(2mL)中，冰浴下缓慢滴加TFA(0.7mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，得(S)-2,4,6-三氟-N-(2-甲氧基-5-(4-(2-甲基哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐，产率78.4％；ESI-MS(m/z)：544.1[M+H]+。(S)-4-(6-(6-methoxy-5-((2,4,6-trifluorophenyl)sulfonamido)pyridin-3-yl)quinolin-4-yl)- 3-Methylpiperazine-1-carboxylic acid tert-butyl ester (50mg, 0.078mmol) was dissolved in dichloromethane (2mL), and TFA (0.7mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure to obtain (S)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(2-methylpiperazin-1-yl)quinoline -6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate salt, yield 78.4%; ESI-MS (m/z): 544.1 [M+H] + .
步骤g)：(S,E)-2,4,6-三氟-N-(2-甲氧基-5-(4-(2-甲基-4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备Step g): (S,E)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(2-methyl-4-(4-oxopent-2- Preparation of enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide
制备方法参考实施例3的步骤d，得(S,E)-2,4,6-三氟-N-(2-甲氧基-5-(4-(2-甲基-4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺，产率19.9％；1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.75(s,1H),8.53-8.51(m,1H),8.25(s,1H),8.10-8.04(m,3H),7.55-7.39(m,3H),7.20-7.12(m,1H),6.79-6.72(m,1H),4.20-3.95(m,3H),3.84-3.72(m,1H),3.70(s,3H),3.62-3.50(m,2H),3.25-3.14(m,1H),2.38(d,J＝8.0Hz,3H),1.04-0.96(m,3H)；ESI-MS(m/z)：640.2[M+H]+。The preparation method refers to step d of Example 3 to obtain (S,E)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(2-methyl-4-(4 -Oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 19.9%; 1 H NMR (400MHz, DMSO-d 6 ) δ10.76(s,1H),8.75(s,1H),8.53-8.51(m,1H),8.25(s,1H),8.10-8.04(m,3H),7.55-7.39(m,3H), 7.20-7.12(m,1H),6.79-6.72(m,1H),4.20-3.95(m,3H),3.84-3.72(m,1H),3.70(s,3H),3.62-3.50(m,2H ), 3.25-3.14 (m, 1H), 2.38 (d, J=8.0Hz, 3H), 1.04-0.96 (m, 3H); ESI-MS (m/z): 640.2 [M+H] + .
实施例14-15参考实施例13的制备方法，以相应的原料，制得了以下实施例中的化合物。
Examples 14-15 Referring to the preparation method of Example 13, the compounds in the following examples were prepared with corresponding raw materials.
实施例16Example 16
(E)-N-(5-(4-氰基-1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)-2，4-二氟苯磺酰胺的制备
(E)-N-(5-(4-cyano-1-(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinolin-7-yl)-2- Preparation of methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
步骤a)：7-溴-4-氯异喹啉-1-醇的制备Step a): Preparation of 7-bromo-4-chloroisoquinolin-1-ol
将7-溴喹啉-1-醇(500mg，2.232mmol)、N-氯代丁二酰亚胺(358mg，2.678mmol)和乙腈(10mL)加入反应瓶中，升温至90℃搅拌反应过夜。反应结束后，将反应液冷却至室温，搅拌1h有晶体析出，过滤，滤饼用乙腈(20mL×2)洗涤，50℃减压真空干燥2h，得7-溴-4-氯异喹啉-1-醇，产率61.2％；ESI-MS(m/z)：259.9[M+H]+。Add 7-bromoquinolin-1-ol (500mg, 2.232mmol), N-chlorosuccinimide (358mg, 2.678mmol) and acetonitrile (10mL) into the reaction flask, heat up to 90°C and stir the reaction overnight. After the reaction, the reaction solution was cooled to room temperature, stirred for 1 h, crystals precipitated, filtered, the filter cake was washed with acetonitrile (20 mL×2), and dried under reduced pressure at 50°C for 2 h to obtain 7-bromo-4-chloroisoquinoline- 1-alcohol, yield 61.2%; ESI-MS (m/z): 259.9 [M+H] + .
步骤b)：7-溴-1,4-二氯异喹啉的制备Step b): Preparation of 7-bromo-1,4-dichloroisoquinoline
将7-溴-4-氯异喹啉-1-醇(200mg，0.774mmol)加入乙腈(5mL)中，室温下加入三氯氧磷(154mg，1.006mmol)，加毕，升温至90℃搅拌3h。反应结束后，加水(30mL)淬灭反应，饱和碳酸氢钠水溶液调pH至中性，乙酸乙酯(50mL×2次)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得7-溴-1,4-二氯异喹啉，产率98.6％；ESI-MS(m/z)：277.9[M+H]+。Add 7-bromo-4-chloroisoquinolin-1-ol (200mg, 0.774mmol) into acetonitrile (5mL), add phosphorus oxychloride (154mg, 1.006mmol) at room temperature, after the addition is complete, heat up to 90°C and stir 3h. After the reaction was finished, add water (30mL) to quench the reaction, adjust the pH to neutral with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (50mL×2 times), combine the organic phases, and wash the organic phases with saturated brine (30mL). Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 7-bromo-1,4-dichloroisoquinoline with a yield of 98.6%; ESI-MS (m/z): 277.9 [M+H] + .
步骤c)：4-(7-溴-4-氯异喹啉-1-基)哌嗪-1-甲酸叔丁酯的制备Step c): Preparation of tert-butyl 4-(7-bromo-4-chloroisoquinolin-1-yl)piperazine-1-carboxylate
将7-溴-1,4-二氯异喹啉(150mg，0.542mmol)、哌嗪-1-甲酸叔丁酯(101mg，0.542mmol)、N,N-二异丙基乙胺(210mg，1.626mmol)加入DMSO(5mL)中，加毕，升温至100℃搅拌反应过夜。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/50)，得4-(7-溴-4-氯异喹啉-1-基)哌嗪-1-甲酸叔丁酯，产率95.6％；ESI-MS(m/z)：428.1[M+H]+。7-bromo-1,4-dichloroisoquinoline (150mg, 0.542mmol), piperazine-1-carboxylic acid tert-butyl ester (101mg, 0.542mmol), N,N-diisopropylethylamine (210mg, 1.626 mmol) was added into DMSO (5 mL). After the addition was completed, the temperature was raised to 100° C. and the reaction was stirred overnight. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product Purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/50) to obtain 4-(7-bromo-4-chloroisoquinolin-1-yl)piperazine-1- Tert-butyl formate, yield 95.6%; ESI-MS (m/z): 428.1 [M+H] + .
步骤d)：4-(4-氯-7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯的制备Step d): 4-(4-Chloro-7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-1-yl ) Preparation of piperazine-1-formic acid tert-butyl ester
将4-(7-溴-4-氯异喹啉-1-基)哌嗪-1-甲酸叔丁酯(200mg,0.469mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(272mg,0.469mmol)、Pd(dppf)Cl2(47mg,0.064mmol)和碳酸铯(623mg,1.911mmol)加入二氧六环/水混合溶剂中(10mL，v/v＝10:1)中加毕，升温至100℃搅拌反应3h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2次)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/50)，得4-(7-溴-4-氯异喹啉-1-基)哌嗪-1-甲酸叔丁酯，产率95.6％；ESI-MS(m/z)：646.2[M+H]+。4-(7-bromo-4-chloroisoquinolin-1-yl)piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.469mmol), 2,4-difluoro-N-(2-methoxy -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (272mg, 0.469mmol), Pd(dppf)Cl 2 (47mg, 0.064mmol) and cesium carbonate (623mg, 1.911mmol) were added into dioxane/water mixed solvent (10mL, v/v=10:1) and the temperature was raised to 100°C The reaction was stirred for 3h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2 times), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/50) to obtain 4-(7-bromo-4-chloroisoquinolin-1-yl)piperazine - tert-butyl 1-carboxylate, yield 95.6%; ESI-MS (m/z): 646.2 [M+H] + .
步骤e)：4-(4-氰基-7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯的制备Step e): 4-(4-cyano-7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinoline-1- Base) preparation of piperazine-1-carboxylic acid tert-butyl ester
将4-(7-溴-4-氯异喹啉-1-基)哌嗪-1-甲酸叔丁酯(100mg,0.155mmol)、氰化锌(36mg,0.310mmol)、三(二亚苄基丙酮)二钯(43mg,0.047mmol)、2-二环己基膦-2',4',6'-三异丙基联苯(44mg,0.093mmol)加入N,N-二甲基甲酰胺(5mL)和水(0.1mL)混合溶剂中，加毕，氮气保护下微波150℃反应30min。反应结束后，加饱和碳酸氢钠水溶液(30mL)淬灭反应，乙酸乙酯(50mL×2次)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/30)，得4-(4-氰基-7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯，产率90.1％；ESI-MS(m/z)：637.2[M+H]+ 4-(7-Bromo-4-chloroisoquinolin-1-yl)piperazine-1-carboxylic acid tert-butyl ester (100mg, 0.155mmol), zinc cyanide (36mg, 0.310mmol), three (dibenzylidene Dipalladium (43mg, 0.047mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (44mg, 0.093mmol) were added to N,N-dimethylformamide (5mL) and water (0.1mL) in a mixed solvent, after the addition was complete, microwave reaction at 150°C for 30min under the protection of nitrogen. After the reaction, add saturated aqueous sodium bicarbonate (30 mL) to quench the reaction, extract with ethyl acetate (50 mL×2 times), combine the organic phases, wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, and filter , and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/30) to obtain 4-(4-cyano-7-(5-(( 2,4-Difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-1-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 90.1%; ESI- MS(m/z): 637.2[M+H] +
步骤f)：N-(5-(4-氰基-1-(哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺三氟乙酸盐的制备Step f): N-(5-(4-cyano-1-(piperazin-1-yl)isoquinolin-7-yl)-2-methoxypyridin-3-yl)-2,4- Preparation of difluorobenzenesulfonamide trifluoroacetate
将4-(4-氰基-7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯(80mg,0.126mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得N-(5-(4-氰基-1-(哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺三氟乙酸盐，产率86.2％；ESI-MS(m/z)：536.2[M+H]+。4-(4-cyano-7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-1-yl)piper Tert-butyloxine-1-carboxylate (80mg, 0.126mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5 mL), and the solid was precipitated and filtered to obtain N-(5-(4-cyano-1-(piperazin-1-yl)isoquinone Phenyl-7-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide trifluoroacetate, yield 86.2%; ESI-MS (m/z): 536.2[ M+H] + .
步骤g)：(E)-N-(5-(4-氰基-1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰 胺的制备Step g): (E)-N-(5-(4-cyano-1-(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinolin-7-yl )-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonyl Amine preparation
操作步骤同实施例3的步骤d，得(E)-N-(5-(4-氰基-1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率28.9％；1H NMR(400MHz,DMSO-d6)δ10.37(brs,1H),8.63(s,1H),8.49(d,J＝2.4Hz,1H),8.26(d,J＝2.0Hz,1H),8.22-8.16(m,1H),8.07-7.99(m,2H),7.82-7.74(m,1H),7.60-7.53(m,1H),7.46(d,J＝16.0Hz,1H),7.25-7.18(m,1H),6.73(d,J＝16.0Hz,1H),4.01-3.75(m,8H),3.69(s,3H),2.37(s,3H)；ESI-MS(m/z)：633.0[M+H]+。The operating steps are the same as step d of Example 3 to obtain (E)-N-(5-(4-cyano-1-(4-(4-oxopent-2-enoyl)piperazin-1-yl) Isoquinolin-7-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 28.9%; 1 H NMR (400MHz, DMSO-d 6 )δ10.37 (brs,1H),8.63(s,1H),8.49(d,J=2.4Hz,1H),8.26(d,J=2.0Hz,1H),8.22-8.16(m,1H),8.07-7.99( m,2H),7.82-7.74(m,1H),7.60-7.53(m,1H),7.46(d,J＝16.0Hz,1H),7.25-7.18(m,1H),6.73(d,J＝ 16.0Hz, 1H), 4.01-3.75(m, 8H), 3.69(s, 3H), 2.37(s, 3H); ESI-MS (m/z): 633.0[M+H] + .
实施例17Example 17
(E)-2，4-二氟-N-(2-甲氧基-5-(1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(1-(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinoline Preparation of -7-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(7-溴异喹啉-1-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(7-bromoisoquinolin-1-yl)piperazine-1-carboxylate
将7-溴-1-氯异喹啉(250mg，1.031mmol)、哌嗪-1-甲酸叔丁酯(192mg，1.031mmol)、三乙胺(313mg，3.093mmol)和DMSO(5mL)加入反应瓶中，加毕，升温至110℃反应过夜。反应结束后，加水(30mL)淬灭反应液，加乙酸乙酯(50mL×2)萃取，合并有机相，以饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/30)，得4-(7-溴异喹啉-1-基)哌嗪-1-甲酸叔丁酯，产率62.8％；ESI-MS(m/z)：392.1[M+H]+。7-Bromo-1-chloroisoquinoline (250 mg, 1.031 mmol), tert-butyl piperazine-1-carboxylate (192 mg, 1.031 mmol), triethylamine (313 mg, 3.093 mmol) and DMSO (5 mL) were added to the reaction In the bottle, after the addition, the temperature was raised to 110°C to react overnight. After the reaction, add water (30 mL) to quench the reaction solution, add ethyl acetate (50 mL×2) to extract, combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain The crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/30) to obtain tert-butyl 4-(7-bromoisoquinolin-1-yl)piperazine-1-carboxylate Ester, yield 62.8%; ESI-MS (m/z): 392.1 [M+H] + .
步骤b)：4-(7-(5-((2,4-二氟苯基)磺酰氨基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(7-(5-((2,4-difluorophenyl)sulfonylamino)-6-methoxypyridin-3-yl)isoquinolin-1-yl)piperazine- Preparation of tert-butyl 1-formate
将4-(7-溴异喹啉-1-基)哌嗪-1-甲酸叔丁酯(250mg，0.637mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(272mg，0.637mmol)、Pd(dppf)Cl2(47mg，0.064mmol)和碳酸铯(623mg，1.911mmol)加入二氧六环/水混合溶剂中(10mL，v/v＝10:1)中，加毕，氮气保护下升温至100℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL次)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/50)，得4-(7-(5-((2,4-二氟苯基)磺酰氨基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯，产率61.1％；ESI-MS(m/z)：612.2[M+H]+。4-(7-Bromoisoquinolin-1-yl)piperazine-1-carboxylic acid tert-butyl ester (250 mg, 0.637 mmol), 2,4-difluoro-N-(2-methoxy-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (272mg, 0.637mmol), Pd(dppf) Add Cl 2 (47mg, 0.064mmol) and cesium carbonate (623mg, 1.911mmol) into dioxane/water mixed solvent (10mL, v/v=10:1), after the addition is complete, heat up to 100°C under nitrogen protection Stir for 2h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL times), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane = 1/100 to 1/50) to obtain 4-(7-(5-((2,4-difluorophenyl)sulfonyl Amino)-6-methoxypyridin-3-yl)isoquinolin-1-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 61.1%; ESI-MS (m/z): 612.2 [M +H] + .
步骤c)：2,4-二氟-N-(2-甲氧基-5-(1-(哌嗪-1-基)异喹啉-7-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-Difluoro-N-(2-methoxy-5-(1-(piperazin-1-yl)isoquinolin-7-yl)pyridin-3-yl)benzenesulfonamide Preparation of trifluoroacetate
将4-(7-(5-((2,4-二氟苯基)磺酰氨基)-6-甲氧基吡啶-3-基)异喹啉-1-基)哌嗪-1-甲酸叔丁酯(200mg,0.327mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(1-(哌嗪-1-基)异喹啉-7-基)吡啶-3-基)苯磺酰胺三氟乙酸盐，产率88.8％；ESI-MS(m/z)：512.2[M+H]+。4-(7-(5-((2,4-difluorophenyl)sulfonylamino)-6-methoxypyridin-3-yl)isoquinolin-1-yl)piperazine-1-carboxylic acid Tert-butyl ester (200mg, 0.327mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(2-methoxy-5-(1-(piper Oxyzin-1-yl)isoquinolin-7-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate salt, yield 88.8%; ESI-MS (m/z): 512.2[M+H] + .
步骤d)：(E)-2,4-二氟-N-(2-甲氧基-5-(1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-Difluoro-N-(2-methoxy-5-(1-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) isoquinolin-7-yl) pyridin-3-yl) preparation of benzenesulfonamide
操作步骤同实施例3步骤d，得(E)-2,4-二氟-N-(2-甲氧基-5-(1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)吡啶-3-基)苯磺酰胺，产率23.5％；1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),8.48(s,1H),8.23(s,1H),8.15(d,J＝6.0Hz,1H),8.06-7.97(m,3H),7.83-7.73(m,1H),7.63-7.53(m,1H),7.54-7.45(m,2H),7.27-7.17(m,1H),6.73(d,J＝16.0Hz,1H),3.95-3.83(m,4H),3.46-3.36(m,4H),3.36(s,3H),2.37(s,3H)；ESI-MS(m/z)：608.0[M+H]+。The operation steps are the same as step d of Example 3 to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(1-(4-(4-oxopent-2-enoyl) Piperazin-1-yl)isoquinolin-7-yl)pyridin-3-yl)benzenesulfonamide, yield 23.5%; 1 H NMR (400MHz, DMSO-d 6 )δ10.39(s,1H), 8.48(s,1H),8.23(s,1H),8.15(d,J＝6.0Hz,1H),8.06-7.97(m,3H),7.83-7.73(m,1H),7.63-7.53(m, 1H),7.54-7.45(m,2H),7.27-7.17(m,1H),6.73(d,J＝16.0Hz,1H),3.95-3.83(m,4H),3.46-3.36(m,4H) , 3.36 (s, 3H), 2.37 (s, 3H); ESI-MS (m/z): 608.0 [M+H] + .
实施例18Example 18
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)噌啉-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)cinnoline- Preparation of 6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(6-溴噌啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromocinnolin-4-yl)piperazine-1-carboxylate
将4-氯-6-溴噌啉(300mg，1.232mmol)和哌嗪-1-甲酸叔丁酯(241mg，1.294mmol)溶于DMF(5mL)中，加入N,N-二异丙基乙胺(478g，3.699mmol)，加毕，60℃反应过夜。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯(60mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1到1/2)，得4-(6-溴噌啉-4-基)哌嗪-1-甲酸叔丁酯，产率97.0％；ESI-MS(m/z)：393.0[M+H]+。Dissolve 4-chloro-6-bromocinnoline (300mg, 1.232mmol) and piperazine-1-carboxylic acid tert-butyl ester (241mg, 1.294mmol) in DMF (5mL), add N,N-diisopropylethyl Amine (478g, 3.699mmol) was added and reacted overnight at 60°C. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (60mL×2), combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate = 3/1 to 1/2) gave tert-butyl 4-(6-bromocinnolin-4-yl)piperazine-1-carboxylate with a yield of 97.0% ; ESI-MS (m/z): 393.0 [M+H] + .
步骤b)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)噌啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)cinnolin-4-yl)piperazine-1 -Preparation of tert-butyl formate
将4-(6-溴噌啉-4-基)哌嗪-1-甲酸叔丁酯(300mg，0.763mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(358mg，0.84mmol)、Pd(dppf)Cl2(56mg，0.077mmol)和碳酸铯(746mg，2.29mmol)溶于二氧六环/水混合溶剂中(5mL，v/v＝5:1)中，加毕，氮气保护下升温至100℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1到1/4)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)噌啉-4-基)哌嗪-1-甲酸叔丁酯，产率89.9％；ESI-MS(m/z)：613.2[M+H]+。4-(6-bromocinnolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (300mg, 0.763mmol), 2,4-difluoro-N-(2-methoxy-5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (358mg, 0.84mmol), Pd(dppf)Cl 2 (56mg, 0.077mmol) and cesium carbonate (746mg, 2.29mmol) were dissolved in dioxane/water mixed solvent (5mL, v/v=5:1), after addition, the temperature was raised to 100°C under nitrogen protection Stir for 2h. After the reaction, add water (50mL) to quench the reaction, extract with ethyl acetate (100mL×2), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (Eluent: Petroleum ether/ethyl acetate=5/1 to 1/4), to get 4-(6-(5-((2,4-difluorophenyl)sulfonyl)-6-methoxy tert-butyl pyridin-3-yl)cinnolin-4-yl)piperazine-1-carboxylate, yield 89.9%; ESI-MS (m/z): 613.2[M+H] + .
步骤c)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)噌啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-Difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)cinnolin-6-yl)pyridin-3-yl)benzenesulfonamide tris Preparation of fluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)噌啉-4-基)哌嗪-1-甲酸叔丁酯(170mg,0.277mmol)溶于二氯甲烷(3mL)中，冰浴下缓慢滴加TFA(0.7mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)噌啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐，产率80.5％；ESI-MS(m/z)：513.1[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)cinnolin-4-yl)piperazine-1-carboxylic acid tert Butyl ester (170mg, 0.277mmol) was dissolved in dichloromethane (3mL), and TFA (0.7mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)cinnolin-6-yl)pyridin-3-yl ) Benzenesulfonamide trifluoroacetate, yield 80.5%; ESI-MS (m/z): 513.1 [M+H] + .
步骤d)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)噌啉-6-基)吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) cinnolin-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
操作步骤同实施例3，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)噌啉-6-基)吡啶-3-基)苯磺酰胺，产率22.1％；1H NMR(400MHz,DMSO-d6)δ10.43(brs,1H),9.01(s,1H),8.56(d,J＝8.0Hz,1H),8.44-8.41(m,1H),8.19-8.14(m,2H),8.11-8.09(m,1H),7.81-7.74(m,1H),7.62-7.56(m,1H),7.50(d,J＝16.0Hz,1H),7.25-7.19(m,1H),6.73(d,J＝16.0Hz,1H),3.98-3.93(m,2H),3.91-3.86(m,2H),3.69(s,3H),3.53-3.47(m,4H),2.38(s,3H)；ESI-MS(m/z)：609.0[M+H]+。The operation steps are the same as in Example 3 to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazine) -1-yl)cinnolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 22.1%; 1 H NMR (400MHz, DMSO-d 6 )δ10.43(brs,1H), 9.01(s ,1H),8.56(d,J＝8.0Hz,1H),8.44-8.41(m,1H),8.19-8.14(m,2H),8.11-8.09(m,1H),7.81-7.74(m,1H ),7.62-7.56(m,1H),7.50(d,J=16.0Hz,1H),7.25-7.19(m,1H),6.73(d,J=16.0Hz,1H),3.98-3.93(m, 2H), 3.91-3.86(m,2H), 3.69(s,3H), 3.53-3.47(m,4H), 2.38(s,3H); ESI-MS(m/z): 609.0[M+H] + .
实施例19Example 19
(E)-2，4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)萘-2-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl)naphthalene-2 Preparation of -yl)pyridin-3-yl)benzenesulfonamide
步骤a)：8-溴萘-2-乙酯的制备 Step a): Preparation of 8-bromonaphthalene-2-ethyl ester
将8-溴-2-羟基-萘(200mg，0.900mmol)和二氯甲烷(5mL)加入反应瓶中，降温至0℃，依次滴加三乙胺(270mg，2.660mmol)和乙酰氯(110mg，1.340mmol)，加毕，0℃搅拌1h。反应结束后，加水(1mL)淬灭反应，以二氯甲烷(5mL×3)萃取，合并有机相，无水硫酸钠干燥、过滤、滤液减压浓缩，得8-溴萘-2-乙酯，产率61.7％；ESI-MS(m/z)：265.9[M+H]+。Add 8-bromo-2-hydroxy-naphthalene (200mg, 0.900mmol) and dichloromethane (5mL) into the reaction flask, cool down to 0°C, add triethylamine (270mg, 2.660mmol) and acetyl chloride (110mg , 1.340mmol), after addition, stirred at 0°C for 1h. After the reaction, add water (1 mL) to quench the reaction, extract with dichloromethane (5 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 8-bromonaphthalene-2-ethyl ester , yield 61.7%; ESI-MS (m/z): 265.9 [M+H] + .
步骤b)：4-(7-羟基萘-1-基)哌嗪-1-甲酸叔丁酯的制备Step b): Preparation of tert-butyl 4-(7-hydroxynaphthalen-1-yl)piperazine-1-carboxylate
将8-溴萘-2-乙酯(180mg,0.680mmol)、哌嗪-1-甲酸叔丁酯(250mg,1.360mmol)、三(二亚苄基丙酮)二钯(120mg,0.140mmol)、碳酸铯(660mg,2.040mmol)、2-二环己基膦-2′，6′-二异丙氧基联苯(95mg,0.200mmol)和甲苯(3mL)加入反应瓶中，加毕，氮气保护下升温至110℃搅拌反应12h。反应结束后，过滤，滤液加水(3mL)淬灭反应，以乙酸乙酯(10mL×3次)萃取，合并有机相，无水硫酸钠干燥、过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1到1/1)，得4-(7-羟基萘-1-基)哌嗪-1-甲酸叔丁酯，产率73.2％；ESI-MS(m/z)：329.1[M+H]+。8-bromonaphthalene-2-ethyl ester (180mg, 0.680mmol), piperazine-1-carboxylic acid tert-butyl ester (250mg, 1.360mmol), tris(dibenzylideneacetone)dipalladium (120mg, 0.140mmol), Cesium carbonate (660mg, 2.040mmol), 2-dicyclohexylphosphine-2', 6'-diisopropoxybiphenyl (95mg, 0.200mmol) and toluene (3mL) were added to the reaction flask, after the addition was complete, nitrogen protection The temperature was raised to 110°C and the reaction was stirred for 12h. After the reaction, filter, add water (3mL) to the filtrate to quench the reaction, extract with ethyl acetate (10mL×3 times), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification by analysis (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) gave tert-butyl 4-(7-hydroxynaphthalen-1-yl)piperazine-1-carboxylate with a yield of 73.2% ; ESI-MS (m/z): 329.1 [M+H] + .
步骤c)：4-(7-(((三氟甲基)磺酰基)氧基)萘-1-基)哌嗪-1-甲酸叔丁酯的制备Step c): Preparation of tert-butyl 4-(7-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)piperazine-1-carboxylate
将4-(7-羟基萘-1-基)哌嗪-1-甲酸叔丁酯(50mg，0.150mmol)和二氯甲烷(3mL)加入反应瓶中，降温至0℃，依次滴加三乙胺(31mg，0.300mmol)和三氟甲磺酸酐(63mg，0.220mmol)，加毕，0℃搅拌1h。反应结束后，加水(1mL)淬灭反应，以二氯甲烷(5mL×3)萃取，合并有机相，无水硫酸钠干燥、过滤、滤液减压浓缩，得4-(7-(((三氟甲基)磺酰基)氧基)萘-1-基)哌嗪-1-甲酸叔丁酯。无需进一步纯化直接用于下一步反应；ESI-MS(m/z)：461.6[M+H]+。Add tert-butyl 4-(7-hydroxynaphthalen-1-yl)piperazine-1-carboxylate (50mg, 0.150mmol) and dichloromethane (3mL) into the reaction flask, cool down to 0°C, and add triethyl Add amine (31mg, 0.300mmol) and trifluoromethanesulfonic anhydride (63mg, 0.220mmol) and stir at 0°C for 1h. After the reaction was completed, add water (1 mL) to quench the reaction, extract with dichloromethane (5 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 4-(7-(((three fluoromethyl)sulfonyl)oxy)naphthalen-1-yl)piperazine-1-carboxylic acid tert-butyl ester. It was directly used in the next reaction without further purification; ESI-MS (m/z): 461.6[M+H] + .
步骤d)：4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)萘-1-基)哌嗪-1-甲酸叔丁酯的制备Step d): 4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)naphthalen-1-yl)piperazine-1- Preparation of tert-butyl formate
将4-(7-(((三氟甲基)磺酰基)氧基)萘-1-基)哌嗪-1-甲酸叔丁酯(70mg,0.150mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(64mg，0.150mmol)、Pd(dppf)Cl2(22mg，0.030mmol)和碳酸铯(98mg，0.300mmol)溶于二氧六环/水(3.3mL，v/v＝10:1)中，加毕，氮气保护下100℃搅拌3h。反应结束后，加水(3mL)淬灭反应，用二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷)，得4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)萘-1-基)哌嗪-1-甲酸叔丁酯,产率66.6％。ESI-MS(m/z)：611.1[M+H]+。4-(7-(((trifluoromethyl)sulfonyl)oxy)naphthalen-1-yl)piperazine-1-carboxylic acid tert-butyl ester (70mg, 0.150mmol), 2,4-difluoro-N -(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (64mg, 0.150mmol), Pd(dppf) Cl2 (22mg, 0.030mmol) and cesium carbonate (98mg, 0.300mmol) were dissolved in dioxane/water (3.3mL, v/v=10:1), After the addition was complete, the mixture was stirred at 100° C. for 3 h under nitrogen protection. After the reaction, add water (3mL) to quench the reaction, extract with dichloromethane (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (washing Removal agent: dichloromethane) to get 4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)naphthalene-1-yl) Piperazine-1-carboxylic acid tert-butyl ester, yield 66.6%. ESI-MS (m/z): 611.1 [M+H] + .
步骤e):2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)萘-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step e): 2,4-difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl)naphthalene-2-yl)pyridin-3-yl)benzenesulfonamide trifluoro Preparation of acetate
将4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)萘-1-基)哌嗪-1-甲酸叔丁酯(80mg，0.130mmol)溶于二氯甲烷(4mL)中，冷却至0℃，缓慢滴加三氟乙酸(2mL)，加完自然升温至室温反应0.5h。反应结束后，减压浓缩，加入甲基叔丁醚(4mL)打浆，过滤，得2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)萘-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：511.0[M+H]+。4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)naphthalene-1-yl)piperazine-1-carboxylic acid tert-butyl The ester (80mg, 0.130mmol) was dissolved in dichloromethane (4mL), cooled to 0°C, and trifluoroacetic acid (2mL) was slowly added dropwise. After the addition, the reaction was naturally warmed to room temperature for 0.5h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether (4mL) for slurry, and filter to obtain 2,4-difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl )naphthalen-2-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 511.0 [M+H] + .
步骤f)：(E)-2,4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)萘-2-基)吡啶-3-基)苯磺酰胺的制备Step f): (E)-2,4-difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) Naphthalene-2-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)萘-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(70mg，0.110mmol)溶于四氢呋喃(2mL)中，将反应体系降温-78℃，依次加入N,N-二异丙基乙胺(85mg,0.660mmol)、(E)-4-氧代戊-2-烯酸(13mg,0.110mmol)和50％的T3P乙酸乙酯溶液(70mg,0.110mmol)，加毕，在-78℃搅拌1h。反应结束后，加入乙腈(1mL)稀释，将反应体系经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)萘-2-基)吡啶-3-基)苯磺酰胺，产率19.4％；1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.46(s,1H),8.32(s,1H),8.03-8.01(m,2H),7.81-7.75(m,2H),7.67(d,J＝8.0Hz,1H),7.62-7.54(m,1H),7.52-7.44(m,2H),7.24-7.18(m,2H),6.72(d,J＝16.0Hz,1H),4.29-3.55(m,7H),3.23-2.86(m,4H),2.37(s,3H)；ESI-MS(m/z)：607.0[M+H]+。2,4-Difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl)naphthalene-2-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate (70mg, 0.110mmol) was dissolved in tetrahydrofuran (2mL), the temperature of the reaction system was lowered to -78°C, and N,N-diisopropylethylamine (85mg, 0.660mmol) and (E)-4-oxopentylamine were added in sequence -2-enoic acid (13mg, 0.110mmol) and 50% T 3 P ethyl acetate solution (70mg, 0.110mmol) were added, and stirred at -78°C for 1h. After the reaction was completed, acetonitrile (1 mL) was added for dilution, and the reaction system was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(8- (4-(4-oxopent-2-enoyl)piperazin-1-yl)naphthalene-2-yl)pyridin-3-yl)benzenesulfonamide, yield 19.4%; 1 H NMR (400MHz, DMSO -d 6 )δ10.36(s,1H),8.46(s,1H),8.32(s,1H),8.03-8.01(m,2H),7.81-7.75(m,2H),7.67(d,J =8.0Hz,1H),7.62-7.54(m,1H),7.52-7.44(m,2H),7.24-7.18(m,2H),6.72(d,J=16.0Hz,1H),4.29-3.55( m, 7H), 3.23-2.86 (m, 4H), 2.37 (s, 3H); ESI-MS (m/z): 607.0 [M+H] + .
实施例20Example 20
(E)-2，4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-2-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline- Preparation of 2-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：N-(5-(8-溴喹啉-2-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step a): Preparation of N-(5-(8-bromoquinolin-2-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
将8-溴-2-氯喹啉(200mg，0.823mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(419mg，0.988mmol)、Pd(PPh3)4(47mg，0.082mmol)和碳酸钠(261mg，2.469mmol)加入乙二醇二甲醚/水混合溶剂(12mL，v/v＝5:1)中中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得N-(5-(8-溴喹啉-2-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率96.2％；ESI-MS(m/z)：505.9[M+H]+。8-Bromo-2-chloroquinoline (200mg, 0.823mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (419mg, 0.988mmol), Pd(PPh 3 ) 4 (47mg, 0.082mmol) and sodium carbonate (261mg, 2.469 mmol) was added to ethylene glycol dimethyl ether/water mixed solvent (12 mL, v/v=5:1), after the addition was complete, the mixture was heated to 110° C. and stirred for 2 h under nitrogen protection. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain N-(5-(8-bromoquinolin-2-yl)-2-methoxy ylpyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 96.2%; ESI-MS (m/z): 505.9 [M+H] + .
步骤b)：4-(2-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-8-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(2-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-8-yl)piperazine-1 -Preparation of tert-butyl formate
将N-(5-(8-溴喹啉-2-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(200mg，0.395mmol)、哌嗪-1-甲酸叔丁酯(89mg，0.474mmol)、Pd2(dba)3(73mg，0.079mmol)、RuPhos(56mg，0.119mmol)和碳酸铯(391mg，1.185mmol)加入N,N-二甲基甲酰胺(8mL)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯＝100/1到10/1)，得4-(2-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-8-基)哌嗪-1-甲酸叔丁酯，产率82.6％；ESI-MS(m/z)：612.0[M+H]+。N-(5-(8-bromoquinolin-2-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (200mg, 0.395mmol), piperazine-1 - tert-butyl formate (89 mg, 0.474 mmol), Pd 2 (dba) 3 (73 mg, 0.079 mmol), RuPhos (56 mg, 0.119 mmol) and cesium carbonate (391 mg, 1.185 mmol) were added to N,N-dimethylformaldehyde Amide (8 mL), after the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=100/1 to 10/1) to obtain 4-(2-(5-((2,4-difluorophenyl) Sulfonamido)-6-methoxypyridin-3-yl)quinolin-8-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 82.6%; ESI-MS (m/z): 612.0 [M +H] + .
步骤c)：2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)喹啉-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-Difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl)quinolin-2-yl)pyridin-3-yl)benzenesulfonamide tris Preparation of fluoroacetate
将4-(2-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-8-基)哌嗪-1-甲酸叔丁酯(200mg，0.327mmol)溶于二氯甲烷(6mL)中，在冰浴下缓慢滴加TFA(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入甲基叔丁基醚，搅拌析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)喹啉-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：512.1[M+H]+。4-(2-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-8-yl)piperazine-1-carboxylic acid tert Butyl ester (200mg, 0.327mmol) was dissolved in dichloromethane (6mL), and TFA (2mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether to the crude product, stir to precipitate a solid, filter to obtain 2,4-difluoro-N-(2-methoxy-5-(8-(piperazine -1-yl)quinolin-2-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 512.1 [M+H] + .
步骤d)：(E)-2,4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-2-基)吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) quinoline-2-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)喹啉-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(150mg，0.246mmol)溶于四氢呋喃(6mL)中，将反应体系降温-78℃，依次加入N,N-二异丙基乙胺(160mg，1.230mmol)、(E)-4-氧代戊-2-烯酸(42mg，0.369mmol)和50％的T3P乙酸乙酯溶液(313mg,，0.492mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,5-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺,产率22.2％；1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.88(s,1H),8.55(s,1H),8.41(d,J＝8.8Hz,1H),8.16(d,J＝8.8Hz,1H),7.78-7.71(m,1H),7.58-7.46(m,4H),7.21-7.15(m,2H),6.74(d,J＝16.0Hz,1H),3.96-3.88(m,4H),3.72(s,3H),3.46-3.42(m,4H),2.37(s,3H)；ESI-MS(m/z)：608.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl)quinolin-2-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetic acid Salt (150mg, 0.246mmol) was dissolved in tetrahydrofuran (6mL), the reaction system was cooled to -78°C, and N,N-diisopropylethylamine (160mg, 1.230mmol), (E)-4-oxo Pent-2-enoic acid (42 mg, 0.369 mmol) and 50% T 3 P ethyl acetate solution (313 mg, 0.492 mmol, 50% wt) were added, and stirred at -78°C for 1 h. After the reaction, quench the reaction with saturated ammonium chloride solution (50mL) at -78°C, extract with dichloromethane (100mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), and anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure, the obtained crude product was purified by Prep-HPLC (method 2) to obtain (E)-2,5-difluoro-N-(2-methoxy-5-(4-(4- (4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 22.2%; 1H NMR (400MHz, DMSO-d 6 )δ10.33(s,1H),8.88(s,1H),8.55(s,1H),8.41(d,J＝8.8Hz,1H),8.16(d,J＝8.8Hz,1H),7.78- 7.71(m,1H),7.58-7.46(m,4H),7.21-7.15(m,2H),6.74(d,J=16.0Hz,1H),3.96-3.88(m,4H),3.72(s, 3H), 3.46-3.42 (m, 4H), 2.37 (s, 3H); ESI-MS (m/z): 608.0 [M+H] + .
实施例21Example 21
(E)-N-(5-(3-氰基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2，6-二氟苯磺酰胺的制备
(E)-N-(5-(3-cyano-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)-2-methyl Preparation of oxypyridin-3-yl)-2,6-difluorobenzenesulfonamide
步骤a)：4-(6-溴-3-氰基喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromo-3-cyanoquinolin-4-yl)piperazine-1-carboxylate
将6-溴-4-氯喹啉-3-甲腈(330mg,1.233mmol)、哌嗪-1-甲酸叔丁酯(270mg,1.450mmol)、三乙胺(370mg,3.650mmol)加入N,N-二甲基甲酰胺(15mL)中，加完升温至60℃反应2h。反应结束后，向反应液中加入水(50ml)，于室温下搅拌30min。抽滤，收集滤饼，干燥，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-溴-3-氰基喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率85.7％；ESI-MS(m/z)：417.1[M+H]+。6-Bromo-4-chloroquinoline-3-carbonitrile (330mg, 1.233mmol), piperazine-1-carboxylic acid tert-butyl ester (270mg, 1.450mmol), triethylamine (370mg, 3.650mmol) were added N,N - Dimethylformamide (15 mL), heated to 60° C. for 2 h after addition. After the reaction, water (50ml) was added to the reaction solution, and stirred at room temperature for 30min. Suction filtration, filter cake was collected, dried, and the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 4-(6-bromo-3-cyanoquinone tert-butyl piperazine-1-carboxylate, yield 85.7%; ESI-MS (m/z): 417.1 [M+H] + .
步骤b)：4-(3-氰基-6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(3-cyano-6-(5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl ) Preparation of piperazine-1-formic acid tert-butyl ester
将4-(6-溴-3-氰基喹啉-4-基)哌嗪-1-甲酸叔丁酯(160mg,0.380mmol)、2,6-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(196.1mg,0.460mmol)、Pd(dppf)Cl2(56mg,0.077mmol)和碳酸铯(249.9mg,0.770mmol)加入二氧六环/水混合溶剂中(22mL，v/v＝10:1)中，加毕，氮气保护下升温至100℃搅拌3.5h。反应结束后，向反应液中加水(30mL)，乙酸乙酯(30mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(3-氰基-6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率81.9％；ESI-MS(m/z)：637.2[M+H]+。4-(6-bromo-3-cyanoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (160mg, 0.380mmol), 2,6-difluoro-N-(2-methoxy -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (196.1mg, 0.460mmol) , Pd(dppf)Cl 2 (56mg, 0.077mmol) and cesium carbonate (249.9mg, 0.770mmol) were added to dioxane/water mixed solvent (22mL, v/v=10:1), after the addition, nitrogen Under protection, the temperature was raised to 100°C and stirred for 3.5h. After the reaction, add water (30mL) to the reaction solution, extract with ethyl acetate (30mL×2), combine the organic phases, wash the organic phase with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 4-(3-cyano-6-(5-((2,6-di Fluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 81.9%; ESI-MS (m/z) : 637.2[M+H] + .
步骤c)：N-(5-(3-氰基-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺三氟乙酸盐的制备 Step c): N-(5-(3-cyano-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-di Preparation of Fluorbenzenesulfonamide Trifluoroacetate
将4-(3-氰基-6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(200mg,0.31mmol)溶于二氯甲烷(20mL)中，缓慢滴加TFA(3mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(30mL)打浆，析出固体，过滤，得N-(5-(3-氰基-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺三氟乙酸盐，产率96.2％；ESI-MS(m/z)：537.2[M+H]+。4-(3-cyano-6-(5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine - tert-Butyl 1-carboxylate (200mg, 0.31mmol) was dissolved in dichloromethane (20mL), and TFA (3mL) was slowly added dropwise. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (30mL), and the solid was precipitated and filtered to obtain N-(5-(3-cyano-4-(piperazin-1-yl)quinoline -6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide trifluoroacetate, yield 96.2%; ESI-MS (m/z): 537.2 [M +H] + .
步骤d)：(E)-N-(5-(3-氰基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺的制备Step d): (E)-N-(5-(3-cyano-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl) Preparation of -2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide
将N-(5-(3-氰基-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺三氟乙酸盐(160.0mg,0.246mmol)溶于四氢呋喃(15.0mL)中，将反应体系降温-70℃，依次加入N,N-二异丙基乙胺(230mg,1.800mmol)、(E)-4-氧代戊-2-烯酸(41.0mg,0.36mmol)和50％的丙基磷酸酐的乙酸乙酯溶液(382mg,0.60mmol)，加毕，在-70℃搅拌30min。反应结束后，向反应液中加入自来水(20ml)，乙酸乙酯(30.0mL×2)萃取，分液，依次用饱和氯化钠洗涤，无水硫酸钠干燥，浓缩，经Prep-HPLC(方法2)制备纯化，得(E)-N-(5-(3-氰基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺，产率52.7％；1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.81(s,1H),8.47(s,1H),8.23(s,1H),8.16-8.00(m,3H),7.68(s,1H),7.54(d,J＝15.6Hz,1H),7.25(t,J＝9.2Hz,2H),6.73(d,J＝15.6Hz,1H),3.93-3.80(m,4H),3.75-3.70(m,4H),3.67(s,3H),2.38(s,3H)；ESI-MS(m/z)：633.0[M+H]+。N-(5-(3-cyano-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonic Amide trifluoroacetate (160.0mg, 0.246mmol) was dissolved in tetrahydrofuran (15.0mL), the reaction system was cooled to -70°C, and N,N-diisopropylethylamine (230mg, 1.800mmol), ( E) Add 4-oxopent-2-enoic acid (41.0mg, 0.36mmol) and 50% ethyl acetate solution of propylphosphoric anhydride (382mg, 0.60mmol), and stir at -70°C for 30min. After the reaction, tap water (20ml) was added to the reaction solution, extracted with ethyl acetate (30.0mL×2), separated, washed with saturated sodium chloride successively, dried over anhydrous sodium sulfate, concentrated, and analyzed by Prep-HPLC (Method 2) Preparation and purification to obtain (E)-N-(5-(3-cyano-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline-6- yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide, yield 52.7%; 1H NMR (400MHz, DMSO-d 6 )δ10.61(s,1H), 8.81 (s,1H),8.47(s,1H),8.23(s,1H),8.16-8.00(m,3H),7.68(s,1H),7.54(d,J=15.6Hz,1H),7.25( t,J=9.2Hz,2H),6.73(d,J=15.6Hz,1H),3.93-3.80(m,4H),3.75-3.70(m,4H),3.67(s,3H),2.38(s ,3H); ESI-MS (m/z): 633.0 [M+H] + .
实施例22-24参考实施例21的制备方法，以相应的原料，制得了以下实施例中的化合物。
Examples 22-24 Referring to the preparation method of Example 21, the compounds in the following examples were prepared with corresponding raw materials.
实施例25Example 25
(E)-2-氟-N-(2-甲氧基-5-(8-甲基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2-fluoro-N-(2-methoxy-5-(8-methyl-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinone Preparation of olin-6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(6-溴-8-甲基喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromo-8-methylquinolin-4-yl)piperazine-1-carboxylate
将6-溴-4-氯-8-甲基喹啉(320mg,1.247mmol)和哌嗪-1-甲酸叔丁酯(303mg,1.634mmol)溶于DMSO(10mL)中，加入DIPEA(485mg，3.754mmol)，加毕，升温至120℃搅拌反应14h。反应结束后，冷却至室温后加冰水(40mL)淬灭反应，用乙酸乙酯(40mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到35/1)，得4-(6-溴-8-甲基喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率51.5％；ESI-MS(m/z)：406.0[M+H]+。6-Bromo-4-chloro-8-methylquinoline (320 mg, 1.247 mmol) and piperazine-1-carboxylic acid tert-butyl ester (303 mg, 1.634 mmol) were dissolved in DMSO (10 mL), and DIPEA (485 mg, 3.754mmol), after the addition was completed, the temperature was raised to 120°C and the reaction was stirred for 14h. After the reaction, cool to room temperature and add ice water (40mL) to quench the reaction, extract with ethyl acetate (40mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by column chromatography (eluent: dichloromethane/methanol=1/0 to 35/1) to obtain 4-(6-bromo-8-methylquinolin-4-yl)piperazine-1-carboxylic acid tert Butyl ester, yield 51.5%; ESI-MS (m/z): 406.0 [M+H] + .
步骤b)：4-(6-(5-((2-氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-8-甲基喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2-fluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-8-methylquinolin-4-yl)piperazine - Preparation of tert-butyl formate
将4-(6-溴-8-甲基喹啉-4-基)哌嗪-1-甲酸叔丁酯(98mg,0.242mmol)、2-氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(98mg,0.242mmol)、Pd(dppf)Cl2(18mg,0.024mmol)、碳酸铯(235mg,0.722mmol)和二氧六环(9mL)与水(2mL)的混合溶剂加入反应瓶中，加毕，氮气保护下100℃搅拌反应3h。反应结束后，冷却至室温，加饱和氯化铵(40mL)淬灭反应，用乙酸乙酯(40mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到35/1)，得4-(6-(5-((2-氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-8-甲基喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率64.8％；ESI-MS(m/z)：608.2[M+H]+。4-(6-bromo-8-methylquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (98mg, 0.242mmol), 2-fluoro-N-(2-methoxy-5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (98mg, 0.242mmol), Pd(dppf )Cl 2 (18mg, 0.024mmol), cesium carbonate (235mg, 0.722mmol) and a mixed solvent of dioxane (9mL) and water (2mL) were added to the reaction flask, and after the addition was complete, the reaction was stirred at 100°C under nitrogen protection for 3h . After the reaction, cool to room temperature, add saturated ammonium chloride (40mL) to quench the reaction, extract with ethyl acetate (40mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product Purified by silica gel column chromatography (eluent: dichloromethane/methanol = 1/0 to 35/1) to obtain 4-(6-(5-((2-fluorophenyl)sulfonamido)-6- Methoxypyridin-3-yl)-8-methylquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 64.8%; ESI-MS (m/z): 608.2 [M+H ] + .
步骤c)：2-氟-N-(2-甲氧基-5-(8-甲基-4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2-fluoro-N-(2-methoxy-5-(8-methyl-4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonate Preparation of amide trifluoroacetate
将4-(6-(5-((2-氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-8-甲基喹啉-4-基)哌嗪-1-甲酸叔丁酯(105mg,0.170mmol)溶于二氯甲烷(3mL)中，冰浴下缓慢滴加三氟乙酸(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，所得粗品分散于甲基叔丁基醚(10mL)中，室温搅拌0.5h，过滤，滤饼干燥，得2-氟-N-(2-甲氧基-5-(8-甲基-4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐，产率96.9％；ESI-MS(m/z)：508.3[M+H]+。4-(6-(5-((2-fluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-8-methylquinolin-4-yl)piperazine-1- Tert-butyl formate (105mg, 0.170mmol) was dissolved in dichloromethane (3mL), and trifluoroacetic acid (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrated under reduced pressure, the obtained crude product was dispersed in methyl tert-butyl ether (10 mL), stirred at room temperature for 0.5 h, filtered, and the filter cake was dried to obtain 2-fluoro-N-(2-methoxy-5- (8-Methyl-4-(piperazin-1-yl) quinoline-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate, yield 96.9%; ESI-MS (m/z ): 508.3[M+H] + .
步骤d)：(E)-2-氟-N-(2-甲氧基-5-(8-甲基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺的制备Step d): (E)-2-fluoro-N-(2-methoxy-5-(8-methyl-4-(4-(4-oxopent-2-enoyl)piperazine-1 Preparation of -yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide
将2-氟-N-(2-甲氧基-5-(8-甲基-4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(140mg,0.225mmol)、(E)-4-氧代戊-2-烯酸(39mg,0.342mmol)、DIPEA(181mg,1.404mmol)溶于四氢呋喃(2mL)中，-78℃温度下缓慢加入1-丙基磷酸酐(214mg,0.341mmol,50％wt)加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(20mL)淬灭反应，用二氯甲烷(20mL×2)萃取，合并有机相，用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2-氟-N-(2-甲氧基-5-(8-甲基-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺，产率26.4％；1H NMR(400MHz,DMSO-d6)δ10.23(s,1H),8.75(d,J＝5.2Hz,1H),8.45(d,J＝2.4Hz,1H),8.08-7.97(m,2H),7.88-7.81(m,1H),7.78-7.66(m,2H),7.54-7.42(m,2H),7.34(td,J＝7.6,1.2Hz,1H),7.08(d,J＝5.2Hz,1H),6.73(d,J＝15.6Hz,1H),3.99-3.84(m,4H),3.68(s,3H),3.29-3.19(m,4H),2.77(s,3H),2.38(s,3H)；ESI-MS(m/z)：604.0[M+H]+。2-fluoro-N-(2-methoxy-5-(8-methyl-4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoro Acetate (140mg, 0.225mmol), (E)-4-oxopent-2-enoic acid (39mg, 0.342mmol), DIPEA (181mg, 1.404mmol) were dissolved in tetrahydrofuran (2mL), and the temperature was -78°C 1-Propylphosphoric anhydride (214mg, 0.341mmol, 50%wt) was added slowly under low temperature, and the mixture was stirred at -78°C for 1h. After the reaction was completed, the reaction was quenched with saturated ammonium chloride solution (20 mL) at -78°C, extracted with dichloromethane (20 mL×2), the organic phases were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (E)-2-fluoro-N-(2-methoxy-5-(8-methyl-4-(4 -(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 26.4%; 1 H NMR (400MHz, DMSO- d 6 )δ10.23(s,1H),8.75(d,J＝5.2Hz,1H),8.45(d,J＝2.4Hz,1H),8.08-7.97(m,2H),7.88-7.81(m ,1H),7.78-7.66(m,2H),7.54-7.42(m,2H),7.34(td,J=7.6,1.2Hz,1H),7.08(d,J=5.2Hz,1H),6.73( d, J=15.6Hz, 1H), 3.99-3.84(m, 4H), 3.68(s, 3H), 3.29-3.19(m, 4H), 2.77(s, 3H), 2.38(s, 3H); ESI - MS (m/z): 604.0 [M+H] + .
实施例26-32参考实施例25的制备方法，以相应的原料，制得了以下实施例中的化合物。


Examples 26-32 Referring to the preparation method of Example 25, the compounds in the following examples were prepared with corresponding raw materials.


实施例33Example 33
(E)-2，6-二氟-N-(5-(3-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2,6-difluoro-N-(5-(3-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline-6- The preparation of -2-methoxypyridin-3-yl)benzenesulfonamide
步骤a)：N-(5-(4-氯-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺的制备Step a): Preparation of N-(5-(4-chloro-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide
将6-溴-4-氯-3-氟喹啉(60mg,0.231mmol)、2,6-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(108mg,0.254mmol)、Pd(dppf)Cl2(17mg,0.023mmol)和碳酸铯(225mg,0.693mmol)加入二氧六环/水混合溶剂(5mL，v/v＝4:1)中，加毕，氮气保护下升温至85℃搅拌5h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得N-(5-(4-氯-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺，产率90.1％；ESI-MS(m/z)：480.0[M+H]+。6-Bromo-4-chloro-3-fluoroquinoline (60mg, 0.231mmol), 2,6-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (108mg, 0.254mmol), Pd(dppf)Cl 2 (17mg, 0.023mmol) and carbonic acid Cesium (225mg, 0.693mmol) was added into dioxane/water mixed solvent (5mL, v/v=4:1). After the addition was completed, the temperature was raised to 85°C under nitrogen protection and stirred for 5h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain N-(5-(4-chloro-3-fluoroquinolin-6-yl)- 2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide, yield 90.1%; ESI-MS (m/z): 480.0 [M+H] + .
步骤b)：4-(6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl) Preparation of tert-butyl piperazine-1-carboxylate
将N-(5-(4-氯-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺(100mg,0.208mmol)、哌嗪-1-甲酸叔丁酯(47mg,0.250mmol)、Pd2(dba)3(38mg,0.042mmol)、RuPhos(29mg,0.029mmol)和碳酸铯(205mg,0.624mmol)加入甲苯(8mL)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率45.8％；ESI-MS(m/z):630.0[M+H]+。N-(5-(4-chloro-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide (100mg, 0.208mmol), tert-butyl piperazine-1-carboxylate (47mg, 0.250mmol), Pd2 (dba) 3 (38mg, 0.042mmol), RuPhos (29mg, 0.029mmol) and cesium carbonate (205mg, 0.624mmol) were added toluene (8mL) After the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product Purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to give 4-(6-(5-((2,6-difluorophenyl)sulfonamide) -6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 45.8%; ESI-MS (m/z): 630.0 [M +H] + .
步骤c)：2,6-二氟-N-(5-(3-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,6-difluoro-N-(5-(3-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl) Preparation of Benzenesulfonamide Trifluoroacetate
将4-(6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯(60mg,0.096mmol)溶于二氯甲烷(4mL)中，在冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入甲基叔丁基醚(5mL)，搅拌析出固体，过滤，得2,6-二氟-N-(5-(3-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：530.0[M+H]+。4-(6-(5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl)piperazine- 1-Tert-butyl carboxylate (60mg, 0.096mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether (5 mL) to the crude product, stir and precipitate the solid, filter to obtain 2,6-difluoro-N-(5-(3-fluoro-4-(piper Oxyzin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 530.0[M+H] + .
步骤d)：(E)-2,6-二氟-N-(5-(3-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,6-difluoro-N-(5-(3-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinone Preparation of phen-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
将2,6-二氟-N-(5-(3-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐(60mg,0.096mmol)溶于四氢呋喃(3mL)中，将反应体系降温-78℃，依次加入DIPEA(62mg,0.480mmol)、(E)-4-氧代戊-2-烯酸(16mg,0.144mmol)和T3P乙酸乙酯溶液(122mg,0.192mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,6-二氟-N-(5-(3-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺，产率35.3％；1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),8.82(d,J＝4.4Hz,1H),8.49(s,1H),8.28(d,J＝2.0Hz,1H),8.20-8.04(m,2H),8.03-7.92(m,1H),7.76-7.63(m,1H),7.51(d,J＝16.0Hz,1H),7.26(t,J＝9.2Hz,2H),6.72(d,J＝16.0Hz,1H),4.10-3.74(m,4H),3.68(s,3H),3.47-3.35(m,4H),2.38(s,3H)；ESI-MS(m/z)：626.0[M+H]+。2,6-Difluoro-N-(5-(3-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide Dissolve trifluoroacetate (60mg, 0.096mmol) in tetrahydrofuran (3mL), cool the reaction system to -78°C, add DIPEA (62mg, 0.480mmol), (E)-4-oxopent-2-ene in sequence Acid (16mg, 0.144mmol) and T 3 P ethyl acetate solution (122mg, 0.192mmol, 50%wt) were added and stirred at -78°C for 1h. After the reaction, quench the reaction with saturated ammonium chloride solution (50mL) at -78°C, extract with dichloromethane (100mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), and anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure, the resulting crude product was purified by Prep-HPLC (method 2) to obtain (E)-2,6-difluoro-N-(5-(3-fluoro-4-(4-(4 -Oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 35.3%; 1 H NMR (400MHz ,DMSO-d 6 )δ10.65(s,1H),8.82(d,J=4.4Hz,1H),8.49(s,1H),8.28(d,J=2.0Hz,1H),8.20-8.04( m, 2H), 8.03-7.92(m, 1H), 7.76-7.63(m, 1H), 7.51(d, J=16.0Hz, 1H), 7.26(t, J=9.2Hz, 2H), 6.72(d , J=16.0Hz, 1H), 4.10-3.74(m, 4H), 3.68(s, 3H), 3.47-3.35(m, 4H), 2.38(s, 3H); ESI-MS(m/z): 626.0[M+H] + .
实施例34-39参考实施例33的制备方法，以相应的原料，制得了以下实施例中的化合物。

Examples 34-39 Referring to the preparation method of Example 33, the compounds in the following examples were prepared with corresponding raw materials.

实施例40Example 40
(E)-2，4-二氟-N-(5-(3-氟-4-(1-(4-氧代戊-2-烯酰基)-1，2，3，6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(5-(3-fluoro-4-(1-(4-oxopent-2-enoyl)-1,2,3,6-tetrahydropyridine Preparation of -4-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
步骤a)：N-(5-(4-氯-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step a): Preparation of N-(5-(4-chloro-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
将6-溴-4-氯-3-氟喹啉(380mg,1.459mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(684mg,1.605mmol)、Pd(dppf)Cl2(107mg,0.146mmol)、碳酸铯(1.43g,4.377mmol)和1,4-二氧六环/水混合溶剂(20mL，v/v＝10/1)加入反应瓶中，加毕，氮气保护下升温至100℃反应2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到20/1)，得N-(5-(4-氯-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率58.6％；ESI-MS(m/z)：480.0[M+H]+。6-Bromo-4-chloro-3-fluoroquinoline (380mg, 1.459mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (684mg, 1.605mmol), Pd(dppf)Cl 2 (107mg, 0.146mmol), carbonic acid Cesium (1.43g, 4.377mmol) and 1,4-dioxane/water mixed solvent (20mL, v/v=10/1) were added into the reaction flask, after the addition was completed, the temperature was raised to 100°C under nitrogen protection for 2h reaction. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 20/1) to obtain N-(5-(4-chloro-3-fluoroquinolin-6-yl)- 2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 58.6%; ESI-MS (m/z): 480.0 [M+H] + .
步骤b)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl) Preparation of tert-butyl-3,6-dihydropyridine-1(2H)-carboxylate
将N-(5-(4-氯-3-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(350mg,0.729mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(248mg,0.802mmol)、Pd(dppf)Cl2(53mg,0.073mmol)、碳酸铯(713mg,2.187mmol)和1,4-二氧六环/水混合溶剂(20mL，v/v＝10/1)加入反应瓶中，加毕，氮气保护下升温至100℃反应2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL次)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/20到2/1)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯，产率61.4％；ESI-MS(m/z)：627.2[M+H]+。N-(5-(4-chloro-3-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (350mg, 0.729mmol), 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl Ester (248mg, 0.802mmol), Pd(dppf)Cl 2 (53mg, 0.073mmol), cesium carbonate (713mg, 2.187mmol) and 1,4-dioxane/water mixed solvent (20mL, v/v=10 /1) Add it into the reaction flask, after the addition is complete, raise the temperature to 100° C. for 2 hours under the protection of nitrogen. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL times), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20 to 2/1) to obtain 4-(6-(5-((2,4-difluorophenyl) Sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, yield 61.4% ; ESI-MS (m/z): 627.2 [M+H] + .
步骤c)：2,4-二氟-N-(5-(3-氟-4-(1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-Difluoro-N-(5-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2- Preparation of methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-3-氟喹啉-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(80mg,0.128mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得2,4-二氟-N-(5-(3-氟-4-(1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：527.2[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-3-fluoroquinolin-4-yl)-3, 6-Dihydropyridine-1(2H)-tert-butyl carboxylate (80mg, 0.128mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(5-(3-fluoro-4-(1,2 ,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 527.2[M+H] + .
步骤d)：(E)-2,4-二氟-N-(5-(3-氟-4-(1-(4-氧代戊-2-烯酰基)-1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-difluoro-N-(5-(3-fluoro-4-(1-(4-oxopent-2-enoyl)-1,2,3,6 Preparation of -tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
将2,4-二氟-N-(5-(3-氟-4-(1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐(60mg,0.094mmol)溶于四氢呋喃(2mL)中，将反应体系降温至-78℃，依次加入DIPEA(73mg,0.564mmol)、(E)-4-氧代戊-2-烯酸(11mg,0.094mmol)和T3P乙酸乙酯溶液(120mg,0.188mmol,50％wt)，加毕，在-78℃反应1h。反应结束后，加入乙腈(1mL)稀释反应液，将反应液经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(5-(3-氟-4-(1-(4-氧代戊-2-烯酰基)-1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺，产率25.3％；1H NMR(400MHz,Chloroform-d)δ8.84(s,1H),8.40(d,J＝8.8Hz,1H),8.22-8.14(m,1H),8.13-8.05(m,1H),8.00(s,1H),7.93-7.80(m,2H),7.35-7.27(m,1H),7.16-7.04(m,1H),7.00-6.88(m,2H),6.02(d,J＝23.2Hz,1H),4.47(d,J＝14.0Hz,2H),4.13-4.02(m,1H),3.97(s,3H),3.95-3.89(m,1H),2.68-2.57(m,2H),2.39(s,3H)；ESI-MS(m/z)：623.0[M+H]+。2,4-Difluoro-N-(5-(3-fluoro-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxy Pyridin-3-yl)benzenesulfonamide trifluoroacetate (60mg, 0.094mmol) was dissolved in tetrahydrofuran (2mL), the reaction system was cooled to -78°C, and DIPEA (73mg, 0.564mmol), (E) -4-Oxopent-2-enoic acid (11 mg, 0.094 mmol) and T 3 P ethyl acetate solution (120 mg, 0.188 mmol, 50% wt) were added, and reacted at -78°C for 1 h. After the reaction was completed, acetonitrile (1 mL) was added to dilute the reaction solution, and the reaction solution was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(5-(3-fluoro-4- (1-(4-oxopent-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxypyridin-3-yl ) benzenesulfonamide, yield 25.3%; 1 H NMR (400MHz, Chloroform-d) δ8.84(s, 1H), 8.40(d, J=8.8Hz, 1H), 8.22-8.14(m, 1H), 8.13-8.05(m,1H),8.00(s,1H),7.93-7.80(m,2H),7.35-7.27(m,1H),7.16-7.04(m,1H),7.00-6.88(m,2H ),6.02(d,J=23.2Hz,1H),4.47(d,J=14.0Hz,2H),4.13-4.02(m,1H),3.97(s,3H),3.95-3.89(m,1H) , 2.68-2.57 (m, 2H), 2.39 (s, 3H); ESI-MS (m/z): 623.0 [M+H] + .
实施例41-42参考实施例40的制备方法，以相应的原料，制得了以下实施例中的化合物。

Examples 41-42 Referring to the preparation method of Example 40, the compounds in the following examples were prepared with corresponding raw materials.

实施例43Example 43
(E)-2，4-二氟-N-(5-(8-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(5-(8-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline-6- The preparation of -2-methoxypyridin-3-yl)benzenesulfonamide
步骤a)：N-(5-(4-氯-8-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step a): Preparation of N-(5-(4-chloro-8-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
将6-溴-4-氯-8-氟喹啉(210.0mg,0.806mmol)，2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(379.8mg，0.887mmol)，Pd(dppf)Cl2(59.3mg，0.081mmol)，碳酸铯(527.8mg，1.612mmol)，水(0.4mL)和1,4-二氧六环(2mL)加入反应瓶中，氮气置换3次，在氮气保护下升温至85℃反应1h。将反应液冷却至室温，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/5)，得N-(5-(4-氯-8-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率56.6％；ESI-MS(m/z)：480.3[M+H]+。6-bromo-4-chloro-8-fluoroquinoline (210.0mg, 0.806mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (379.8mg, 0.887mmol), Pd(dppf) Cl2 (59.3mg, 0.081mmol ), cesium carbonate (527.8mg, 1.612mmol), water (0.4mL) and 1,4-dioxane (2mL) were added into the reaction flask, replaced with nitrogen three times, and heated to 85°C under nitrogen protection for 1h reaction. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/5) to obtain N-(5-(4-chloro-8-fluoro Quinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 56.6%; ESI-MS (m/z): 480.3[M+H] + .
步骤b)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-8-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-8-fluoroquinolin-4-yl) Preparation of tert-butyl piperazine-1-carboxylate
将N-(5-(4-氯-8-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(220.0mg,0.458mmol)，哌嗪-1-甲酸叔丁酯(128.5mg，0.687mmol)，2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯(42.9mg，0.092mmol)，三(二亚苄基丙酮)二钯(26.5mg，0.046mmol)，碳酸铯(299.8mg，0.916mmol)和甲苯(2mL)加入反应瓶中，氮气保护下升温至110℃搅拌16h。反应结束后，将反应液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-8-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率58.7％；ESI-MS(m/z)：630.1[M+H]+。N-(5-(4-chloro-8-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (220.0mg, 0.458mmol) , tert-butyl piperazine-1-carboxylate (128.5mg, 0.687mmol), 2-dicyclohexylphosphonium-2',6'-diisopropoxy-1,1'-biphenyl (42.9mg, 0.092mmol ), tris(dibenzylideneacetone)dipalladium (26.5mg, 0.046mmol), cesium carbonate (299.8mg, 0.916mmol) and toluene (2mL) were added into the reaction flask, heated to 110°C under nitrogen protection and stirred for 16h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 4-(6-(5-((2,4-difluorophenyl)sulfonyl Amino)-6-methoxypyridin-3-yl)-8-fluoroquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 58.7%; ESI-MS (m/z): 630.1[M+H] + .
步骤c)：2,4-二氟-N-(5-(8-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-Difluoro-N-(5-(8-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl) Preparation of Benzenesulfonamide Trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-8-氟喹啉-4-基)哌嗪-1-甲酸叔丁酯(90.0mg,0.143mmol)和二氯甲烷(1mL)加入反应瓶中，室温搅拌溶解，再加入三氟乙酸(1mL)，室温搅拌1h，将反应液减压浓缩，残余物加甲基叔丁基醚(5mL)室温搅拌30min，过滤，滤饼干燥，得2,4-二氟-N-(5-(8-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐，收率90.2％；ESI-MS(m/z)：530.1[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-8-fluoroquinolin-4-yl)piperazine- 1-tert-butyl formate (90.0mg, 0.143mmol) and dichloromethane (1mL) were added to the reaction flask, stirred at room temperature to dissolve, then added trifluoroacetic acid (1mL), stirred at room temperature for 1h, the reaction solution was concentrated under reduced pressure, and the residue Add methyl tert-butyl ether (5mL) and stir at room temperature for 30min, filter, and dry the filter cake to give 2,4-difluoro-N-(5-(8-fluoro-4-(piperazin-1-yl)quinone Phenyl-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate, yield 90.2%; ESI-MS (m/z): 530.1 [M+H] + .
步骤d)：(E)-2,4-二氟-N-(5-(8-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-difluoro-N-(5-(8-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinone Preparation of phen-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
将2,4-二氟-N-(5-(8-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐(110.0mg,0.171mmol)， (E)-4-氧代戊-2-烯酸(19.5mg，0.171mmol)，DIPEA(84.0mg，0.631mmol)和四氢呋喃(2mL)加入反应瓶中，在-78℃搅拌条件下，缓慢加入50％的1-丙基磷酸酐乙酸乙酯溶液(160mg，0.252mmol)，加毕，维持-78℃反应30min。反应结束后，向反应液中加入水(2mL)和乙酸乙酯(5mL)，自然升温至室温搅拌10min，分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(5-(8-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺，收率25.8％；1H NMR(400MHz,CDCl3)δ10.26(s,1H),8.75(d,J＝4.8Hz,1H),8.41(s,1H),8.01(s,1H),7.97(s,1H),7.88(d,J＝12.0Hz,1H),7.81-7.75(m,1H),7.53-7.47(m,2H),7.21-7.16(m,1H),7.14(d,J＝5.2Hz,1H),6.73(d,J＝16.0Hz,1H),3.95-3.87(m,4H),3.71(s,3H),3.30-3.26(m,4H),2.37(s,3H)；ESI-MS(m/z)：626.0[M+H]+。2,4-Difluoro-N-(5-(8-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide Trifluoroacetate (110.0mg, 0.171mmol), (E)-4-Oxopent-2-enoic acid (19.5mg, 0.171mmol), DIPEA (84.0mg, 0.631mmol) and tetrahydrofuran (2mL) were added to the reaction flask, and slowly added under stirring at -78°C 50% 1-propylphosphoric anhydride ethyl acetate solution (160mg, 0.252mmol) was added, and the reaction was maintained at -78°C for 30min. After the reaction was completed, water (2 mL) and ethyl acetate (5 mL) were added to the reaction liquid, and the temperature was naturally raised to room temperature and stirred for 10 min, separated, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with Purification by Prep-HPLC (Method 2) to give (E)-2,4-difluoro-N-(5-(8-fluoro-4-(4-(4-oxopent-2-enoyl)piperazine) -1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 25.8%; 1 H NMR (400MHz, CDCl 3 ) δ10.26 (s, 1H) ,8.75(d,J=4.8Hz,1H),8.41(s,1H),8.01(s,1H),7.97(s,1H),7.88(d,J=12.0Hz,1H),7.81-7.75( m,1H),7.53-7.47(m,2H),7.21-7.16(m,1H),7.14(d,J=5.2Hz,1H),6.73(d,J=16.0Hz,1H),3.95-3.87 (m, 4H), 3.71 (s, 3H), 3.30-3.26 (m, 4H), 2.37 (s, 3H); ESI-MS (m/z): 626.0 [M+H] + .
实施例44Example 44
(E)-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)-2，4-二甲基噻唑-5-磺酰胺的制备
(E)-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridine-3 Preparation of -yl)-2,4-dimethylthiazole-5-sulfonamide
步骤a)：4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): 4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine- Preparation of tert-butyl 1-formate
将4-(6-溴喹啉-4-基)哌嗪-1-甲酸叔丁酯(900mg,2.294mmol)、双联频哪醇硼酸酯(870mg,3.426mmol)、Pd(dppf)Cl2(340mg,0.465mmol)、乙酸钾(900mg,9.170mmol)和二氧六环(20mL)加入反应瓶中，加毕，氮气保护下升温至100℃搅拌反应3h。反应结束后，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/3到1/1)，得4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率92.8％；ESI-MS(m/z)：440.2[M+H]+。4-(6-Bromoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (900mg, 2.294mmol), double pinacol borate (870mg, 3.426mmol), Pd(dppf)Cl 2 (340mg, 0.465mmol), potassium acetate (900mg, 9.170mmol) and dioxane (20mL) were added into the reaction flask, after the addition was completed, the temperature was raised to 100°C under nitrogen protection and the reaction was stirred for 3h. After the reaction was completed, filter and concentrate the filtrate under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/3 to 1/1) to obtain 4-(6-(4,4 , tert-butyl 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine-1-carboxylate, yield 92.8%; ESI - MS (m/z): 440.2 [M+H] + .
步骤b)：4-(6-(5-((2,4-二甲基噻唑)-5-磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,4-dimethylthiazole)-5-sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piper Preparation of tert-butyl oxazine-1-carboxylate
将4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(170mg,0.387mmol)、N-(5-溴-2-甲氧基吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺(147mg,0.389mmol)、Pd(dppf)Cl2(57mg,0.078mmol)、碳酸铯(250mg,0.767mmol)和二氧六环/水混合溶剂(4.4mL，v/v＝10:1)加入反应瓶中，加毕，氮气保护下升温至100℃搅拌反应3h。反应结束后，过滤，加水(3mL)淬灭反应，用二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到10/1)，得4-(6-(5-((2,4-二甲基噻唑)-5-磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率65.4％；ESI-MS(m/z)：611.6[M+H]+。4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester (170mg, 0.387mmol), N-(5-bromo-2-methoxypyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide (147mg, 0.389mmol), Pd (dppf)Cl 2 (57mg, 0.078mmol), cesium carbonate (250mg, 0.767mmol) and dioxane/water mixed solvent (4.4mL, v/v=10:1) were added to the reaction flask, after addition, nitrogen Under protection, the temperature was raised to 100°C and the reaction was stirred for 3h. After the reaction, filter, add water (3mL) to quench the reaction, extract with dichloromethane (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, the obtained crude product is purified by silica gel column chromatography (Eluant: dichloromethane/methanol = 1/0 to 10/1), to give 4-(6-(5-((2,4-dimethylthiazole)-5-sulfonamido)-6- Methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 65.4%; ESI-MS (m/z): 611.6 [M+H] + .
步骤c)：N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺三氟乙酸盐的制备Step c): N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)-2,4-dimethylthiazole-5 - Preparation of sulfonamide trifluoroacetate
将4-(6-(5-((2,4-二甲基噻唑)-5-磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(240mg,0.393mmol)溶于二氯甲烷(4mL)中，在冰浴下缓慢滴加三氟乙酸(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向残余物加入甲基叔丁基醚(5mL)，室温搅拌30min，过滤，滤饼减压干燥，得N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺三氟乙酸盐；ESI-MS(m/z)：511.2[M+H]+。4-(6-(5-((2,4-dimethylthiazole)-5-sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1 - Dissolve tert-butyl formate (240mg, 0.393mmol) in dichloromethane (4mL), slowly add trifluoroacetic acid (2mL) dropwise under ice-cooling, after the addition is complete, stir at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, methyl tert-butyl ether (5 mL) was added to the residue, stirred at room temperature for 30 min, filtered, and the filter cake was dried under reduced pressure to obtain N-(2-methoxy-5-(4-( Piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide trifluoroacetate; ESI-MS (m/z): 511.2 [M+H] + .
步骤d)：(E)-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺的制备Step d): (E)-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl )pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide preparation
将N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺三氟乙酸盐(240mg,0.384mmol)加入四氢呋喃(4mL)中，降温至-78℃，依次加入(E)-4-氧代戊-2-烯酸(44mg，0.384mmol)、DIPEA(298mg，2.304mmol)、T3P的乙酸乙酯溶液(244mg，0.384mmol，50％w)，加毕，在-78℃下反应30min。反应结束后，减压浓缩，加入乙腈(2mL)稀释，经Prep-HPLC(方法2)纯化得(E)-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)-2,4-二甲基噻唑-5-磺酰胺，产率14.6％；1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.74(d,J＝8.0Hz,1H),8.52(s,1H),8.19(d,J＝4.0Hz,1H),8.09-8.06(m,2H),8.02-7.99(m,1H),7.50(d,J＝16.0Hz,1H),7.08(d,J＝4.0Hz,1H),6.74(d,J＝12.0Hz,1H),4.96-3.90(m,4H),3.76(s,3H),3.31-3.26(m,4H),2.59(s,3H),2.40-2.38(m,6H)；ESI-MS(m/z)：607.0[M+H]+。N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide Add trifluoroacetate (240mg, 0.384mmol) into tetrahydrofuran (4mL), cool down to -78°C, add (E)-4-oxopent-2-enoic acid (44mg, 0.384mmol), DIPEA (298mg , 2.304mmol), T 3 P in ethyl acetate solution (244mg, 0.384mmol, 50%w), the addition was completed, and the reaction was carried out at -78°C for 30min. After the reaction was completed, it was concentrated under reduced pressure, diluted with acetonitrile (2 mL), and purified by Prep-HPLC (method 2) to obtain (E)-N-(2-methoxy-5-(4-(4-(4-oxo Substituent-2-enoyl)piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)-2,4-dimethylthiazole-5-sulfonamide, yield 14.6%; 1 H NMR(400MHz,DMSO-d 6 )δ10.43(s,1H),8.74(d,J＝8.0Hz,1H),8.52(s,1H),8.19(d,J＝4.0Hz,1H),8.09 -8.06(m,2H),8.02-7.99(m,1H),7.50(d,J=16.0Hz,1H),7.08(d,J=4.0Hz,1H),6.74(d,J=12.0Hz, 1H), 4.96-3.90(m, 4H), 3.76(s, 3H), 3.31-3.26(m, 4H), 2.59(s, 3H), 2.40-2.38(m, 6H); ESI-MS(m/ z): 607.0 [M+H] + .
实施例45-47参考实施例44的制备方法，以相应的原料，制得了以下实施例中的化合物。

Examples 45-47 Referring to the preparation method of Example 44, the compounds in the following examples were prepared with corresponding raw materials.

实施例48Example 48
(E)-N-(5-(3-氰基-4-(1-(4-氧代戊-2-烯酰基)-1，2，3，6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2，6-二氟苯磺酰胺制备
(E)-N-(5-(3-cyano-4-(1-(4-oxopent-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)quinone Preparation of phen-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide
步骤a)：N-(5-(4-氯-3-氰基喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺的制备Step a): Preparation of N-(5-(4-chloro-3-cyanoquinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide
将6-溴-4-氯喹啉-3-氰基(200mg,0.748mmol)、2,6-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(319mg,0.748mmol)、Pd(dppf)Cl2(109mg,0.150mmol)和碳酸氢钠(189mg,2.244mmol)加入二氧六环/水混合溶剂中(5.5mL，v/v＝10:1)中，加毕，氮气保护室温反应24h。反应结束后，加水(5mL)淬灭反应，以二氯甲烷(10mL×2)萃取，合并有机相，用水(10mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1到1/1)，得N-(5-(4-氯-3-氰基喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺，产率5.3％；ESI-MS(m/z)：486.9[M+H]+。6-bromo-4-chloroquinoline-3-cyano (200mg, 0.748mmol), 2,6-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl Base-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (319mg, 0.748mmol), Pd(dppf)Cl 2 (109mg, 0.150mmol) and carbonic acid Sodium hydrogen (189mg, 2.244mmol) was added to dioxane/water mixed solvent (5.5mL, v/v=10:1). After the addition was complete, the mixture was reacted at room temperature under nitrogen protection for 24h. After the reaction was completed, add water (5 mL) to quench the reaction, extract with dichloromethane (10 mL×2), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by column chromatography (eluent: petroleum ether/ethyl acetate = 5/1 to 1/1) to obtain N-(5-(4-chloro-3-cyanoquinolin-6-yl)-2- Methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide, yield 5.3%; ESI-MS (m/z): 486.9 [M+H] + .
步骤b)：4-(3-氰基-6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯的制备 Step b): 4-(3-cyano-6-(5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl )-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester
将N-(5-(4-氯-3-氰基喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺(25mg,0.051mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(16mg,0.051mmol)、Pd(dppf)Cl2(8mg,0.010mmol)和碳酸铯(33mg,0.102mmol)加入二氧六环/水混合溶剂中(2.2mL，v/v＝10:1)中，加毕，氮气保护升温至100℃反应2h。反应结束后，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到20/1)，得4-(3-氰基-6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯，产率54.3％；ESI-MS(m/z)：634.1[M+H]+。N-(5-(4-chloro-3-cyanoquinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide (25mg, 0.051mmol) , 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert Butyl ester (16mg, 0.051mmol), Pd(dppf)Cl 2 (8mg, 0.010mmol) and cesium carbonate (33mg, 0.102mmol) were added to dioxane/water mixed solvent (2.2mL, v/v=10: In 1), after the addition is completed, the temperature is raised to 100° C. for 2 hours under nitrogen protection. After the reaction, filter and concentrate the filtrate under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: dichloromethane/methanol=1/0 to 20/1) to obtain 4-(3-cyano-6- (5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)-3,6-dihydropyridine-1(2H) - tert-butyl formate, yield 54.3%; ESI-MS (m/z): 634.1 [M+H] + .
步骤c)：N-(5-(3-氰基-4-(1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺三氟乙酸盐的制备Step c): N-(5-(3-cyano-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxypyridine-3 Preparation of -yl)-2,6-difluorobenzenesulfonamide trifluoroacetate
将4-(3-氰基-6-(5-((2,6-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯(20mg,0.032mmol)溶于二氯甲烷(2mL)中，冰浴下缓慢滴加三氟乙酸(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，得N-(5-(3-氰基-4-(1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：534.2[M+H]+。4-(3-cyano-6-(5-((2,6-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)-3 , 6-dihydropyridine-1(2H)-tert-butyl carboxylate (20mg, 0.032mmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (1mL) was slowly added dropwise under ice-cooling, and stirred at room temperature 1h. After the reaction, concentrate under reduced pressure to obtain N-(5-(3-cyano-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methyl Oxypyridin-3-yl)-2,6-difluorobenzenesulfonamide trifluoroacetate; ESI-MS (m/z): 534.2 [M+H] + .
步骤d)：(E)-N-(5-(3-氰基-4-(1-(4-氧代戊-2-烯酰基)-1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺的制备Step d): (E)-N-(5-(3-cyano-4-(1-(4-oxopent-2-enoyl)-1,2,3,6-tetrahydropyridine-4 Preparation of -yl)quinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluorobenzenesulfonamide
将N-(5-(3-氰基-4-(1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺三氟乙酸盐(20mg,0.031mmol)加入四氢呋喃(1mL)中，降温至-78℃，依次加入(E)-4-氧代戊-2-烯酸(4mg，0.031mmol)，DIPEA(24mg，0.186mmol)，50％的T3P乙酸乙酯溶液(20mg，0.031mmol)，加毕，在-78℃下反应30min。反应结束后，减压浓缩，加入乙腈(2mL)稀释，经Prep-HPLC(方法2)纯化得(E)-N-(5-(3-氰基-4-(1-(4-氧代戊-2-烯酰基)-1,2,3,6-四氢吡啶-4-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,6-二氟苯磺酰胺，产率25.0％；1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),9.18(s,1H),8.50(s,1H),8.25(s,2H),8.16-8.15(m,1H),8.08-8.07(m,1H),7.74-7.67(m,1H),7.51(dd,J＝34.0Hz,15.6Hz,1H),7.29-7.24(m,2H),6.74(dd,J＝15.6Hz,3.6Hz,1H),6.16-6.14(m,1H),4.51(s,1H),4.35(s,1H),4.04-3.90(m,2H),3.67(s,3H),2.66(s,1H),2.58(s,1H),2.38(d,J＝4.4Hz,3H)；ESI-MS(m/z)：630.0[M+H]+。N-(5-(3-cyano-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxypyridin-3-yl) Add -2,6-difluorobenzenesulfonamide trifluoroacetate (20mg, 0.031mmol) into tetrahydrofuran (1mL), cool down to -78°C, add (E)-4-oxopent-2-enoic acid in turn (4mg, 0.031mmol), DIPEA (24mg, 0.186mmol), 50% T 3 P ethyl acetate solution (20mg, 0.031mmol), after adding, react at -78°C for 30min. After the reaction was completed, it was concentrated under reduced pressure, diluted with acetonitrile (2 mL), and purified by Prep-HPLC (method 2) to obtain (E)-N-(5-(3-cyano-4-(1-(4-oxo Pent-2-enoyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)-2,6-difluoro Benzenesulfonamide, yield 25.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ10.64(s,1H),9.18(s,1H),8.50(s,1H),8.25(s,2H), 8.16-8.15(m,1H),8.08-8.07(m,1H),7.74-7.67(m,1H),7.51(dd,J=34.0Hz,15.6Hz,1H),7.29-7.24(m,2H) ,6.74(dd,J=15.6Hz,3.6Hz,1H),6.16-6.14(m,1H),4.51(s,1H),4.35(s,1H),4.04-3.90(m,2H),3.67( s, 3H), 2.66 (s, 1H), 2.58 (s, 1H), 2.38 (d, J=4.4Hz, 3H); ESI-MS (m/z): 630.0 [M+H] + .
实施例49-50参考实施例48的制备方法，以相应的原料，制得了以下实施例中的化合物。
Examples 49-50 Referring to the preparation method of Example 48, the compounds in the following examples were prepared with corresponding raw materials.
实施例51Example 51
(E)-2，4，6-三氟-N-(2-氧代-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-1，2-二氢吡啶-3-基)苯磺酰胺的制备
(E)-2,4,6-trifluoro-N-(2-oxo-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline Preparation of -6-yl)-1,2-dihydropyridin-3-yl)benzenesulfonamide
将(E)-2,4,6-三氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺(100mg,0.160mmol)、乙腈(10mL)和水(10mL)加入反应瓶中，加入浓盐酸(2mL)，冻干24h，将冻干物经Prep-HPLC(方法2)纯化，得(E)-2,4,6-三氟-N-(2-氧代-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-1,2-二氢吡啶-3-基)苯磺酰胺，产率9.8％；1H NMR(400MHz,DMSO-d6)δ9.05(brs,1H),8.69-8.65(m,1H),8.23(d,J＝52.8Hz,1H), 8.03-8.00(m,1H),7.94(d,J＝8.8Hz,1H),7.83-7.81(m,1H),7.54-7.42(m,2H),7.26(s,1H),7.13-7.00(m,3H),6.75-6.67(m,1H),3.97-3.88(m,4H),3.26-3.15(m,4H),2.37-2.35(m,3H)；ESI-MS(m/z)：612.0[M+H]+。(E)-2,4,6-trifluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl) Quinolin-6-yl)pyridin-3-yl)benzenesulfonamide (100mg, 0.160mmol), acetonitrile (10mL) and water (10mL) were added to the reaction flask, concentrated hydrochloric acid (2mL) was added, lyophilized for 24h, and the lyophilized The dry matter was purified by Prep-HPLC (method 2) to give (E)-2,4,6-trifluoro-N-(2-oxo-5-(4-(4-(4-oxopent-2 -enoyl)piperazin-1-yl)quinolin-6-yl)-1,2-dihydropyridin-3-yl)benzenesulfonamide, yield 9.8%; 1 H NMR (400MHz, DMSO-d 6 )δ9.05(brs,1H),8.69-8.65(m,1H),8.23(d,J＝52.8Hz,1H), 8.03-8.00(m,1H),7.94(d,J＝8.8Hz,1H),7.83-7.81(m,1H),7.54-7.42(m,2H),7.26(s,1H),7.13-7.00( m,3H),6.75-6.67(m,1H),3.97-3.88(m,4H),3.26-3.15(m,4H),2.37-2.35(m,3H); ESI-MS(m/z): 612.0[M+H] + .
实施例52Example 52
(E)-2-氟-N-(5-(5-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2-fluoro-N-(5-(5-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)- Preparation of 2-methoxypyridin-3-yl)benzenesulfonamide
步骤a)：N-(5-(4-氯-5-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2-氟苯磺酰胺的制备6-溴-4-氯-5-氟喹啉(300mg,1.152mmol)、2-氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(563mg,1.382mmol)、Pd(dppf)Cl2(84mg,0.115mmol)和碳酸铯(1.1g,3.456mmol)、二氧六环/水混合溶剂(10mL，v/v＝4:1)加入反应瓶中，加毕，氮气保护下升温至80℃搅拌4h。反应结束后，加水(50mL)淬灭反应，用二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到10/1)，得N-(5-(4-氯-5-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2-氟苯磺酰胺的混合物，产率65.8％；ESI-MS(m/z)：462.0[M+H]+。Step a): Preparation of N-(5-(4-chloro-5-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2-fluorobenzenesulfonamide 6-bromo-4 -Chloro-5-fluoroquinoline (300mg, 1.152mmol), 2-fluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (563 mg, 1.382 mmol), Pd(dppf)Cl 2 (84 mg, 0.115 mmol) and cesium carbonate (1.1 g, 3.456 mmol), Dioxane/water mixed solvent (10 mL, v/v=4:1) was added into the reaction flask, after the addition was completed, the temperature was raised to 80° C. and stirred for 4 h under the protection of nitrogen. After the reaction was finished, add water (50 mL) to quench the reaction, extract with dichloromethane (10 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (washing Removal agent: dichloromethane/methanol=1/0 to 10/1), to get N-(5-(4-chloro-5-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl )-2-Fluorobenzenesulfonamide mixture, yield 65.8%; ESI-MS (m/z): 462.0 [M+H] + .
步骤b)：4-(5-氟-6-(5-((2-氟苯基)磺胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(5-fluoro-6-(5-((2-fluorophenyl)sulfonyl)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1 -Preparation of tert-butyl formate
将N-(5-(4-氯-5-氟喹啉-6-基)-2-甲氧基吡啶-3-基)-2-氟苯磺酰胺(350mg，0.758mmol)、哌嗪-1-甲酸叔丁酯(212mg，1.137mmol)、Pd2(dba)3(139mg，0.152mmol)、RuPhos(106mg，0.227mmol)和碳酸铯(741mg，2.274mmol)、甲苯(10mL)加入反应瓶中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，以乙酸乙酯(100mL×2)萃取，合并有机相，用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯＝2/1到1/2)，得4-(5-氟-6-(5-((2-氟苯基)磺胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率53.9％；ESI-MS(m/z)：612.3[M+H]+。N-(5-(4-chloro-5-fluoroquinolin-6-yl)-2-methoxypyridin-3-yl)-2-fluorobenzenesulfonamide (350mg, 0.758mmol), piperazine- tert-Butyl 1-carboxylate (212 mg, 1.137 mmol), Pd 2 (dba) 3 (139 mg, 0.152 mmol), RuPhos (106 mg, 0.227 mmol) and cesium carbonate (741 mg, 2.274 mmol), toluene (10 mL) were added to the reaction flask After the addition was completed, the temperature was raised to 110° C. and stirred for 2 h under the protection of nitrogen. After the reaction was completed, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=2/1 to 1/2) to obtain 4-(5-fluoro-6-(5-((2-fluorophenyl) Sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 53.9%; ESI-MS (m/z): 612.3 [M+ H] + .
步骤c)：2-氟-N-(5-(5-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2-fluoro-N-(5-(5-fluoro-4-(piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide Preparation of trifluoroacetate
将4-(5-氟-6-(5-((2-氟苯基)磺胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的混合物(250mg,0.409mmol)、二氯甲烷(4mL)加入反应瓶中，冰浴下缓慢滴加三氟乙酸(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩,，残余物加入甲基叔丁基醚(10mL)打浆0.5h，过滤，滤饼干燥，得2-氟-N-(5-(5-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：512.0[M+H]+。4-(5-fluoro-6-(5-((2-fluorophenyl)sulfonyl)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert A mixture of butyl esters (250mg, 0.409mmol) and dichloromethane (4mL) were added to the reaction flask, and trifluoroacetic acid (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, it was concentrated under reduced pressure, and the residue was slurried by adding methyl tert-butyl ether (10mL) for 0.5h, filtered, and the filter cake was dried to obtain 2-fluoro-N-(5-(5-fluoro-4-(piper Oxyzin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 512.0[M+H] + .
步骤d)：(E)-2-氟-N-(5-(5-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备将2-氟-N-(5-(5-氟-4-(哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐(75mg,0.120mmol)、(E)-4-氧代戊-2-烯酸(15mg,0.135mmol)、DIPEA(80mg,0.615mmol)溶于四氢呋喃(5mL)中，-78℃温度下缓慢加入T3P的乙酸乙酯溶液(156mg,0.246mmol,50％w)，加毕，在-78℃搅拌1h。反应结束后加饱和氯化铵(40mL)淬灭反应，用二氯甲烷(40mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2-氟-N-(5-(5-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺，产率16.1％；1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.73(d,J＝4.8Hz,1H),8.14-8.00(m,2H),7.84-7.76(m,2H),7.76-7.69(m,1H),7.63-7.54(m,1H),7.47(d,J＝16.0Hz,1H),7.35(d,J＝9.6Hz,1H),7.27(t,J＝7.6Hz,1H),7.03(d,J＝5.2Hz,1H),6.72(d,J＝15.6Hz,1H),3.96-3.79(m,4H),3.74(s,3H),3.28-3.20(m,4H),2.37(s,3H)；ESI-MS(m/z)：608.0[M+H]+。Step d): (E)-2-fluoro-N-(5-(5-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline-6 -yl)-2-methoxypyridin-3-yl)benzenesulfonamide preparation 2-fluoro-N-(5-(5-fluoro-4-(piperazin-1-yl)quinoline-6- Base)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate (75mg, 0.120mmol), (E)-4-oxopent-2-enoic acid (15mg, 0.135mmol), DIPEA (80mg, 0.615mmol) was dissolved in tetrahydrofuran (5mL), slowly added T 3 P ethyl acetate solution (156mg, 0.246mmol, 50%w) at -78°C, after addition, stirred at -78°C for 1h . After the reaction was completed, add saturated ammonium chloride (40mL) to quench the reaction, extract with dichloromethane (40mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was subjected to Prep-HPLC ( Method 2) purification to obtain (E)-2-fluoro-N-(5-(5-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinoline -6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 16.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.92(s,1H), 8.73(d, J=4.8Hz,1H),8.14-8.00(m,2H),7.84-7.76(m,2H),7.76-7.69(m,1H),7.63-7.54(m,1H),7.47(d,J= 16.0Hz, 1H), 7.35(d, J=9.6Hz, 1H), 7.27(t, J=7.6Hz, 1H), 7.03(d, J=5.2Hz, 1H), 6.72(d, J=15.6Hz ,1H),3.96-3.79(m,4H),3.74(s,3H),3.28-3.20(m,4H),2.37(s,3H); ESI-MS(m/z): 608.0[M+H ] + .
实施例53Example 53
(E)-2-氟-N-(5-(7-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2-fluoro-N-(5-(7-fluoro-4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)quinolin-6-yl)- Preparation of 2-methoxypyridin-3-yl)benzenesulfonamide
制备方法参考实施例52，经prep-HPLC(方法2)纯化，得(E)-2-氟-N-(5-(7-氟-4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)苯磺酰胺，产率1.4％；1H NMR(400MHz,DMSO-d6)δ8.64(d,J＝4.8Hz,1H),7.84-7.71(m,2H),7.60-7.50(m,2H),7.49-7.40(m,2H),7.39-7.28(m,1H),7.20-7.08(m,2H),6.99(d,J＝5.2Hz,1H),6.72(d,J＝15.6Hz,1H),3.80(s,3H),3.12-2.90(m,8H),2.37(s,3H)；ESI-MS(m/z)：608.0[M+H]+。The preparation method refers to Example 52 and is purified by prep-HPLC (method 2) to obtain (E)-2-fluoro-N-(5-(7-fluoro-4-(4-(4-oxopentyl-2- Enyl)piperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 1.4%; 1 H NMR (400MHz, DMSO-d 6 )δ8 .64(d,J＝4.8Hz,1H),7.84-7.71(m,2H),7.60-7.50(m,2H),7.49-7.40(m,2H),7.39-7.28(m,1H),7.20 -7.08(m,2H),6.99(d,J=5.2Hz,1H),6.72(d,J=15.6Hz,1H),3.80(s,3H),3.12-2.90(m,8H),2.37( s, 3H); ESI-MS (m/z): 608.0 [M+H] + .
实施例54Example 54
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinoline Preparation of -6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：6-溴-4-氯异喹啉的制备Step a): Preparation of 6-bromo-4-chloroisoquinoline
将6-溴异喹啉(2g,9.613mmol)和磺酰氯(5mL)加入到反应瓶中，升温至60℃搅拌5min，再加入磺酰氯(5mL)，继续反应30min。反应结束后，冰水浴下用饱和碳酸钠溶液调至pH＝8，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10到1/1)，得6-溴-4-氯异喹啉，产率46.6％；ESI-MS(m/z)：243.9[M+H]+。Add 6-bromoisoquinoline (2g, 9.613mmol) and sulfonyl chloride (5mL) into the reaction flask, heat up to 60°C and stir for 5min, then add sulfonyl chloride (5mL) and continue the reaction for 30min. After the reaction, adjust the pH to 8 with saturated sodium carbonate solution in an ice-water bath, extract with ethyl acetate (200mL×2), combine the organic phases, wash the organic phases with saturated brine (50mL), dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10 to 1/1) to obtain 6-bromo-4-chloroisoquinoline with a yield of 46.6 %; ESI-MS (m/z): 243.9 [M+H] + .
步骤b)：N-(5-(4-氯异喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step b): Preparation of N-(5-(4-chloroisoquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide
将6-溴-4-氯异喹啉(800mg,3.299mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(1.42g,3.299mmol)、Pd(dppf)Cl2(241mg,0.330mmol)和碳酸铯(3.22g,9.897mmol)加入二氧六环/水混合溶剂中(30mL，v/v＝10:1)中，加毕，氮气保护下升温至100℃搅拌3h。反应结束后，加水(50mL)淬灭反应，用乙酸乙酯(150mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/50)，得N-(5-(4-氯异喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率51.2％；ESI-MS(m/z)：462.0[M+H]+。6-Bromo-4-chloroisoquinoline (800mg, 3.299mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (1.42g, 3.299mmol), Pd(dppf)Cl 2 (241mg, 0.330mmol) and cesium carbonate ( 3.22g, 9.897mmol) was added into dioxane/water mixed solvent (30mL, v/v=10:1), after the addition was completed, the temperature was raised to 100°C under nitrogen protection and stirred for 3h. After the reaction, add water (50mL) to quench the reaction, extract with ethyl acetate (150mL×2), combine the organic phases, wash the organic phase with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/50) to obtain N-(5-(4-chloroisoquinolin-6-yl)-2- Methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 51.2%; ESI-MS (m/z): 462.0 [M+H] + .
步骤c)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备将Step c): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-4-yl)piperazine- The preparation of tert-butyl 1-formate will
N-(5-(4-氯异喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(250mg,0.541mmol)、哌嗪-1-甲酸叔丁酯(101mg,0.541mmol)、Pd2(dba)3(99mg,0.108mmol)、RuPhos(76mg,0.162mmol)和叔丁醇钠(156mg,1.623mmol)加入二氧六环(10mL)中，加毕，氮气保护下升温至110℃搅拌过夜。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/30)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率42.3％；ESI-MS(m/z)：612.2[M+H]+。N-(5-(4-chloroisoquinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (250mg, 0.541mmol), piperazine-1 - Dioxane ( 10mL ), after the addition was completed, the temperature was raised to 110° C. and stirred overnight under the protection of nitrogen. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/30) to obtain 4-(6-(5-((2,4-difluorophenyl)sulfonamide Base)-6-methoxypyridin-3-yl)isoquinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 42.3%; ESI-MS (m/z): 612.2 [M+ H] + .
步骤d)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)异喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step d): 2,4-Difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)isoquinolin-6-yl)pyridin-3-yl)benzenesulfonamide Preparation of trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-4-基)哌嗪-1-甲酸叔丁酯(100mg,0.163mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加三氟乙酸(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)异喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐，产率78.8％；ESI-MS(m/z)：512.2[M+H]+。 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-4-yl)piperazine-1-carboxylic acid Tert-butyl ester (100mg, 0.163mmol) was dissolved in dichloromethane (4mL), and trifluoroacetic acid (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5 mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piper Oxyzin-1-yl)isoquinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate, yield 78.8%; ESI-MS (m/z): 512.2[M+H] + .
步骤e)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-6-基)吡啶-3-基)苯磺酰胺的制备Step e): (E)-2,4-Difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) isoquinolin-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)异喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(60mg,0.096mmol)和四氢呋喃(2mL)加入反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(74mg,0.576mmol)、(E)-4-氧代戊-2-烯酸(11mg,0.096mmol)和T3P乙酸乙酯溶液(122mg,0.192mmol,50％wt)，加毕，在-78℃反应1h。反应结束后，加入乙腈(1mL)稀释反应液，反应液经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-6-基)吡啶-3-基)苯磺酰胺，产率21.7％；1H NMR(400MHz,DMSO-d6)δ10.39(brs,1H),9.08(s,1H),8.52(d,J＝2.4Hz,1H),8.25-8.20(m,3H),8.07(d,J＝2.4Hz,1H),7.98(d,J＝8.4Hz,1H),7.82-7.76(m,1H),7.63-7.53(m,1H),7.50(d,J＝16.0Hz,1H),7.27-7.17(m,1H),6.73(d,J＝16.0Hz,1H),4.00-3.80(m,4H),3.71(s,3H),3.26-3.11(m,4H),2.38(s,3H)；ESI-MS(m/z)：608.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)isoquinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroethyl Acid salt (60mg, 0.096mmol) and tetrahydrofuran (2mL) were added to the reaction flask, the reaction system was cooled to -78°C, and DIPEA (74mg, 0.576mmol) and (E)-4-oxopent-2-ene were added successively Acid (11mg, 0.096mmol) and T 3 P ethyl acetate solution (122mg, 0.192mmol, 50%wt) were added and reacted at -78°C for 1h. After the reaction was completed, acetonitrile (1 mL) was added to dilute the reaction solution, and the reaction solution was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(4 -(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinolin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 21.7%; 1 H NMR ( 400MHz,DMSO-d 6 )δ10.39(brs,1H),9.08(s,1H),8.52(d,J＝2.4Hz,1H),8.25-8.20(m,3H),8.07(d,J＝ 2.4Hz, 1H), 7.98(d, J=8.4Hz, 1H), 7.82-7.76(m, 1H), 7.63-7.53(m, 1H), 7.50(d, J=16.0Hz, 1H), 7.27- 7.17(m,1H),6.73(d,J＝16.0Hz,1H),4.00-3.80(m,4H),3.71(s,3H),3.26-3.11(m,4H),2.38(s,3H) ; ESI-MS (m/z): 608.0 [M+H] + .
实施例55Example 55
(E)-2，4-二氟-N-(5-(4-氟-1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(5-(4-fluoro-1-(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinoline-7 Preparation of -yl)-2-methoxypyridin-3-yl)benzenesulfonamide
步骤a)：7-溴-4-氟异喹啉-1-醇的制备Step a): Preparation of 7-bromo-4-fluoroisoquinolin-1-ol
将7-溴异喹啉-1-醇(2g,8.927mmol)、1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(3.16g,8.927mmol)加入乙腈(20mL)中，氮气保护下回流反应过夜。反应结束后，加水(100mL)淬灭反应，用乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10到1/1)，得7-溴-4-氟异喹啉-1-醇，产率40.1％；ESI-MS(m/z)：242.0[M+H]+。7-bromoisoquinolin-1-ol (2g, 8.927mmol), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (3.16g, 8.927mmol) was added into acetonitrile (20mL), and the reaction was refluxed overnight under the protection of nitrogen. After the reaction, add water (100mL) to quench the reaction, extract with ethyl acetate (200mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10 to 1/1) to obtain 7-bromo-4-fluoroisoquinolin-1-ol with a yield of 40.1% ; ESI-MS (m/z): 242.0 [M+H] + .
步骤b)：2,4-二氟-N-(5-(4-氟-1-羟基异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备Step b): Preparation of 2,4-difluoro-N-(5-(4-fluoro-1-hydroxyisoquinolin-7-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
将7-溴-4-氟异喹啉-1-醇(380mg,1.570mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(669mg,1.570mmol)、Pd(dppf)Cl2(115mg,0.157mmol)和碳酸铯(1.53g,4.710mmol)加入二氧六环/水混合溶剂中(10mL，v/v＝10:1)中，加毕，氮气保护升温至100℃搅拌3h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/10)，得2,4-二氟-N-(5-(4-氟-1-羟基异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺，产率50.3％；ESI-MS(m/z)：462.0[M+H]+。7-bromo-4-fluoroisoquinolin-1-ol (380mg, 1.570mmol), 2,4-difluoro-N-(2-methoxy-5-(4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (669mg, 1.570mmol), Pd(dppf)Cl 2 (115mg, 0.157mmol) and Cesium carbonate (1.53g, 4.710mmol) was added to dioxane/water mixed solvent (10mL, v/v=10:1). After the addition was completed, the temperature was raised to 100°C under nitrogen protection and stirred for 3h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/10) to obtain 2,4-difluoro-N-(5-(4-fluoro-1-hydroxyiso Quinolin-7-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 50.3%; ESI-MS (m/z): 462.0 [M+H] + .
步骤c)：7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-4-氟异喹啉-1-基三氟甲磺酸酯的制备Step c): 7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-fluoroisoquinolin-1-yltrifluoromethane Preparation of sulfonate
将2,4-二氟-N-(5-(4-氟-1-羟基异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺(280mg,0.607mmol)和二氯甲烷(10mL)加入反应瓶中，冰水浴下向反应液中加入三乙胺(120mg,1.214mmol)、三氟甲磺酸酐(171mg,0.607mmol)，加毕，升至室温反应1h。反应结束后，加水(50mL)淬灭反应，二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10到1/1)，得7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-4-氟异喹啉-1-基三氟甲磺酸酯，产率52.8％；ESI-MS(m/z)：594.0[M+H]+。2,4-Difluoro-N-(5-(4-fluoro-1-hydroxyisoquinolin-7-yl)-2-methoxypyridin-3-yl)benzenesulfonamide (280mg, 0.607mmol) Add dichloromethane (10mL) into the reaction flask, add triethylamine (120mg, 1.214mmol) and trifluoromethanesulfonic anhydride (171mg, 0.607mmol) to the reaction solution under an ice-water bath, after the addition is complete, rise to room temperature and react for 1h . After the reaction was completed, add water (50 mL) to quench the reaction, extract with dichloromethane (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10 to 1/1) to obtain 7-(5-((2,4-difluorophenyl)sulfonamide) -6-methoxypyridin-3-yl)-4-fluoroisoquinolin-1-yl trifluoromethanesulfonate, yield 52.8%; ESI-MS (m/z): 594.0[M+H] + .
步骤d)：4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-4-氟异喹啉-1-基)哌嗪-1-甲酸叔丁酯的制备Step d): 4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-fluoroisoquinolin-1-yl ) Preparation of piperazine-1-formic acid tert-butyl ester
将7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-4-氟异喹啉-1-基三氟甲磺酸酯(100mg,0.169mmol)、哌嗪-1-甲酸叔丁酯(35mg,0.186mmol)加入二甲基亚砜(3mL)中，再向反应液中加入三乙胺(51mg,0.507mmol)， 加毕，升至60℃反应过夜。反应结束后，加水(30mL)淬灭反应，二氯甲烷(50mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/100到1/30)，得4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-4-氟异喹啉-1-基)哌嗪-1-甲酸叔丁酯，产率88.5％；ESI-MS(m/z)：630.2[M+H]+。7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-fluoroisoquinolin-1-yl trifluoromethanesulfonate (100mg, 0.169mmol), tert-butyl piperazine-1-carboxylate (35mg, 0.186mmol) were added to dimethyl sulfoxide (3mL), and then triethylamine (51mg, 0.507mmol) was added to the reaction solution, After the addition was completed, the temperature was raised to 60° C. to react overnight. After the reaction, add water (30 mL) to quench the reaction, extract with dichloromethane (50 mL×2), combine the organic phases, wash the organic phase with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/100 to 1/30) to obtain 4-(7-(5-((2,4-difluorophenyl)sulfonamide yl)-6-methoxypyridin-3-yl)-4-fluoroisoquinolin-1-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 88.5%; ESI-MS (m/z): 630.2[M+H] + .
步骤e)：2,4-二氟-N-(5-(4-氟-1-(哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step e): 2,4-Difluoro-N-(5-(4-fluoro-1-(piperazin-1-yl)isoquinolin-7-yl)-2-methoxypyridin-3-yl ) Preparation of benzenesulfonamide trifluoroacetate
将4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-4-氟异喹啉-1-基)哌嗪-1-甲酸叔丁酯(80mg,0.127mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得2,4-二氟-N-(5-(4-氟-1-(哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐，产率81.3％；ESI-MS(m/z)：530.2[M+H]+。4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-4-fluoroisoquinolin-1-yl)piperazine - tert-Butyl 1-carboxylate (80mg, 0.127mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, stir at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5 mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(5-(4-fluoro-1-(piperazine- 1-yl) isoquinolin-7-yl)-2-methoxypyridin-3-yl)benzenesulfonamide trifluoroacetate, yield 81.3%; ESI-MS (m/z): 530.2 [M +H] + .
步骤f)：(E)-2,4-二氟-N-(5-(4-氟-1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺的制备Step f): (E)-2,4-difluoro-N-(5-(4-fluoro-1-(4-(4-oxopent-2-enoyl)piperazin-1-yl)iso Preparation of quinoline-7-yl)-2-methoxypyridin-3-yl)benzenesulfonamide
将2,4-二氟-N-(5-(4-氟-1-(哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺三氟乙酸盐(50mg,0.078mmol)和四氢呋喃(2mL)加入反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(60mg,0.468mmol)、(E)-4-氧代戊-2-烯酸(9mg,0.078mmol)和T3P乙酸乙酯溶液(99mg,0.156mmol,50％wt)，加毕，在-78℃反应1h。反应结束后，加入乙腈(1mL)稀释反应液，反应液经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(5-(4-氟-1-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-7-基)-2-甲氧基吡啶-3-基)苯磺酰胺，产率26.9％；1H NMR(400MHz,DMSO-d6+D2O)δ8.53-8.43(m,1H),8.30(s,1H),8.23-8.14(m,3H),8.05(d,J＝2.4Hz,1H),7.90-7.79(m,1H),7.59-7.52(m,1H),7.50(d,J＝16.0Hz,1H),7.30-7.21(m,1H),6.76(d,J＝16.0Hz,1H),3.99-3.86(m,4H),3.76(s,3H),3.43-3.35(m,4H),2.41(s,3H)；ESI-MS(m/z)：626.0[M+H]+。2,4-difluoro-N-(5-(4-fluoro-1-(piperazin-1-yl)isoquinolin-7-yl)-2-methoxypyridin-3-yl)benzenesulfonate Add amide trifluoroacetate (50mg, 0.078mmol) and tetrahydrofuran (2mL) into the reaction flask, cool the reaction system to -78°C, add DIPEA (60mg, 0.468mmol), (E)-4-oxopentyl -2-enoic acid (9mg, 0.078mmol) and T 3 P ethyl acetate solution (99mg, 0.156mmol, 50%wt) were added and reacted at -78°C for 1h. After the reaction was completed, acetonitrile (1 mL) was added to dilute the reaction solution, and the reaction solution was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(5-(4-fluoro-1-( 4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinolin-7-yl)-2-methoxypyridin-3-yl)benzenesulfonamide, yield 26.9%; 1 H NMR(400MHz,DMSO-d 6 +D2O)δ8.53-8.43(m,1H),8.30(s,1H),8.23-8.14(m,3H),8.05(d,J＝2.4Hz,1H ),7.90-7.79(m,1H),7.59-7.52(m,1H),7.50(d,J=16.0Hz,1H),7.30-7.21(m,1H),6.76(d,J=16.0Hz, 1H), 3.99-3.86(m, 4H), 3.76(s, 3H), 3.43-3.35(m, 4H), 2.41(s, 3H); ESI-MS(m/z): 626.0[M+H] + .
实施例56Example 56
(E)-2，4-二氟-N-(2-甲氧基-5-(5-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-3-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(5-(4-(4-oxopent-2-enoyl)piperazin-1-yl)isoquinoline Preparation of -3-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(3-氯异喹啉-5-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(3-chloroisoquinolin-5-yl)piperazine-1-carboxylate
将5-溴-3-氯异喹啉(200mg,0.825mmol)、哌嗪-1-甲酸叔丁酯(419mg,0.988mmol)、Pd2(dba)3(73mg,0.082mmol)、BINAP(56mg,0.082mmol)和碳酸铯(391mg,2.469mmol)加入甲苯(8mL)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(3-氯异喹啉-5-基)哌嗪-1-甲酸叔丁酯，产率69.9％；ESI-MS(m/z)：348.3[M+H]+。5-Bromo-3-chloroisoquinoline (200mg, 0.825mmol), piperazine-1-carboxylic acid tert-butyl ester (419mg, 0.988mmol), Pd 2 (dba) 3 (73mg, 0.082mmol), BINAP (56mg , 0.082mmol) and cesium carbonate (391mg, 2.469mmol) were added into toluene (8mL). After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain tert-4-(3-chloroisoquinolin-5-yl)piperazine-1-carboxylate Butyl ester, yield 69.9%; ESI-MS (m/z): 348.3 [M+H] + .
步骤b)：4-(3-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-5-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(3-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-5-yl)piperazine- Preparation of tert-butyl 1-formate
将4-(3-氯异喹啉-5-基)哌嗪-1-甲酸叔丁酯(200mg,0.575mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(294mg,0.690mmol)、Pd(dppf)Cl2(84.1mg,0.115mmol)和碳酸铯(374.7mg,1.150mmol)加入二氧六环和水的混合溶剂(10mL，V1/V2＝4:1)中，加毕，氮气保护下升温至110℃搅拌2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/乙酸乙酯＝100/1到10/1)，得4-(3-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-5-基)哌嗪-1-甲酸叔丁酯，产率62.5％；ESI-MS(m/z)：612.6[M+H]+。4-(3-Chloroisoquinolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.575mmol), 2,4-difluoro-N-(2-methoxy-5-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (294mg, 0.690mmol), Pd(dppf) Cl 2 (84.1mg, 0.115mmol) and cesium carbonate (374.7mg, 1.150mmol) were added into a mixed solvent of dioxane and water (10mL, V1/V2=4:1), after the addition was complete, the temperature was raised to Stir at 110°C for 2h. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (200 mL×2), combine the organic phases, wash the organic phase with saturated brine (100 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate=100/1 to 10/1) to obtain 4-(3-(5-((2,4-difluorophenyl) Sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-5-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 62.5%; ESI-MS (m/z): 612.6[ M+H] + .
步骤c)：2,4-二氟-N-(2-甲氧基-5-(5-(哌嗪-1-基)异喹啉-3-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-Difluoro-N-(2-methoxy-5-(5-(piperazin-1-yl)isoquinolin-3-yl)pyridin-3-yl)benzenesulfonamide Preparation of trifluoroacetate
将4-(3-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)异喹啉-5-基)哌嗪-1-甲酸叔丁酯(220mg,0.359mmol)溶于二氯甲烷(6mL)中，在冰浴下缓慢滴加TFA(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入适量甲基叔丁基醚打浆，析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(5-(哌嗪-1-基)异喹啉-3-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：512.1[M+H]+。4-(3-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)isoquinolin-5-yl)piperazine-1-carboxylic acid Tert-butyl ester (220mg, 0.359mmol) was dissolved in dichloromethane (6mL), and TFA (2mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and an appropriate amount of methyl tert-butyl ether was added to the crude product to make a slurry, and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(2-methoxy-5-(5-(piper Azin-1-yl)isoquinolin-3-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 512.1 [M+H] + .
步骤d)：(E)-2,4-二氟-N-(2-甲氧基-5-(5-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-3-基)吡啶-3-基)苯磺酰胺的制 备Step d): (E)-2,4-Difluoro-N-(2-methoxy-5-(5-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) isoquinolin-3-yl) pyridin-3-yl) benzenesulfonamide preparation prepare
将2,4-二氟-N-(2-甲氧基-5-(5-(哌嗪-1-基)异喹啉-3-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(200mg,0.320mmol)和四氢呋喃(6mL)加入到反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(213mg,1.640mmol)、(E)-4-氧代戊-2-烯酸(56mg,0.493mmol)和50％的T3P乙酸乙酯溶液(417mg,0.656mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃用饱和氯化铵溶液(50mL)淬灭反应，二氯甲烷(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(5-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)异喹啉-3-基)吡啶-3-基)苯磺酰胺，产率24.3％；1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.39(s,1H),8.77(s,1H),8.38(d,J＝2.4Hz,1H),8.33(s,1H),7.85(d,J＝8.0Hz,1H),7.82-7.73(m,1H),7.65-7.55(m,2H),7.50(d,J＝16.0Hz,1H),7.40(d,J＝7.6Hz,1H),7.26-7.16(m,1H),6.74(d,J＝16.0Hz,1H),3.99-3.84(m,4H),3.72(s,3H),3.18-3.02(m,4H),2.38(s,3H)；ESI-MS(m/z)：608.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(5-(piperazin-1-yl)isoquinolin-3-yl)pyridin-3-yl)benzenesulfonamide trifluoroethyl Acid salt (200mg, 0.320mmol) and tetrahydrofuran (6mL) were added to the reaction flask, the reaction system was cooled to -78°C, and DIPEA (213mg, 1.640mmol) and (E)-4-oxopent-2- Acenoic acid (56mg, 0.493mmol) and 50% T 3 P ethyl acetate solution (417mg, 0.656mmol, 50%wt) were added, and stirred at -78°C for 1h. After the reaction, quench the reaction with saturated ammonium chloride solution (50mL) at -78°C, extract with dichloromethane (100mL×2), combine the organic phases, wash the organic phase with saturated brine (100mL), and anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure, and the resulting crude product is purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(5-(4- (4-oxopent-2-enoyl)piperazin-1-yl)isoquinolin-3-yl)pyridin-3-yl)benzenesulfonamide, yield 24.3%; 1H NMR (400MHz, DMSO-d 6 ) δ10.31(s,1H),9.39(s,1H),8.77(s,1H),8.38(d,J＝2.4Hz,1H),8.33(s,1H),7.85(d,J＝ 8.0Hz, 1H), 7.82-7.73(m, 1H), 7.65-7.55(m, 2H), 7.50(d, J=16.0Hz, 1H), 7.40(d, J=7.6Hz, 1H), 7.26- 7.16(m,1H),6.74(d,J＝16.0Hz,1H),3.99-3.84(m,4H),3.72(s,3H),3.18-3.02(m,4H),2.38(s,3H) ; ESI-MS (m/z): 608.0 [M+H] + .
实施例57Example 57
(E)-2，4-二氟-N-(2-甲氧基-5-(5-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-1，8-萘啶-3-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(5-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-1, Preparation of 8-naphthyridin-3-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：3-溴-5-氯-1,8-萘啶的制备Step a): Preparation of 3-bromo-5-chloro-1,8-naphthyridine
将6-溴-1,8-萘啶-4-醇(50mg,0.222mmol)溶于三氯氧磷(5mL)中，加毕，氮气保护下升温至110℃搅拌3h。反应结束后，将反应液减压浓缩，向浓缩物中加水(3mL)淬灭反应，用乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，得3-溴-5-氯-1,8-萘啶，产率72.4％；ESI-MS(m/z)：242.9[M+H]+。6-Bromo-1,8-naphthyridin-4-ol (50mg, 0.222mmol) was dissolved in phosphorus oxychloride (5mL). After the addition was completed, the temperature was raised to 110°C under nitrogen protection and stirred for 3h. After the reaction, the reaction solution was concentrated under reduced pressure, and water (3 mL) was added to the concentrate to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , to obtain 3-bromo-5-chloro-1,8-naphthyridine with a yield of 72.4%; ESI-MS (m/z): 242.9 [M+H] + .
步骤b)：4-(6-溴-1,8-萘啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): Preparation of tert-butyl 4-(6-bromo-1,8-naphthyridin-4-yl)piperazine-1-carboxylate
将3-溴-5-氯-1,8-萘啶(50mg,0.205mmol)、哌嗪-1-甲酸叔丁酯(76mg,0.410mmol)溶于DMF(5mL)中，最后加入DIPEA(79mg,0.615mmol)加毕，氮气保护下升温至110℃搅拌24h。反应结束后，向反应液加水(3mL)淬灭反应，用乙酸乙酯(10mL×3)萃取，合并有机相，用水(5mL×3)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/1到0/1)，得4-(6-溴-1,8-萘啶-4-基)哌嗪-1-甲酸叔丁酯,产率28.2％；ESI-MS(m/z)：395.0[M+H]+。Dissolve 3-bromo-5-chloro-1,8-naphthyridine (50mg, 0.205mmol), piperazine-1-carboxylic acid tert-butyl ester (76mg, 0.410mmol) in DMF (5mL), and finally add DIPEA (79mg , 0.615mmol) was added, heated to 110°C under nitrogen protection and stirred for 24h. After the reaction, add water (3 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with water (5 mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2/1 to 0/1) to obtain 4-(6-bromo-1,8-naphthyridin-4-yl)piper tert-butyloxine-1-carboxylate, yield 28.2%; ESI-MS (m/z): 395.0[M+H] + .
步骤c)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-1,8-萘啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step c): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-1,8-naphthyridin-4-yl ) Preparation of piperazine-1-formic acid tert-butyl ester
将4-(6-溴-1,8-萘啶-4-基)哌嗪-1-甲酸叔丁酯(50mg,0.127mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(54mg,0.127mmol)、Pd(dppf)Cl2(19mg,0.025mmol)和碳酸铯(83mg,0.254mmol)溶于二氧六环/水混合溶剂(3.3mL，v/v＝10:1)中，加毕，氮气保护下升温至100℃搅拌3h。反应结束后，加水(3mL)淬灭反应，用二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到10/1)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-1,8-萘啶-4-基)哌嗪-1-甲酸叔丁酯,产率52.4％；ESI-MS(m/z)：613.6[M+H]+。4-(6-bromo-1,8-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (50mg, 0.127mmol), 2,4-difluoro-N-(2-methoxy -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (54mg, 0.127mmol), Pd(dppf)Cl 2 (19mg, 0.025mmol) and cesium carbonate (83mg, 0.254mmol) were dissolved in dioxane/water mixed solvent (3.3mL, v/v=10:1), after addition, nitrogen protection The temperature was raised to 100°C and stirred for 3h. After the reaction, add water (3mL) to quench the reaction, extract with dichloromethane (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (washing Removal agent: dichloromethane/methanol=1/0 to 10/1), to get 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridine- 3-yl)-1,8-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 52.4%; ESI-MS (m/z): 613.6[M+H] + .
步骤d)：2,4-二氟-N-(2-甲氧基-5-(5-(哌嗪-1-基)-1,8-萘啶-3-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step d): 2,4-difluoro-N-(2-methoxy-5-(5-(piperazin-1-yl)-1,8-naphthyridin-3-yl)pyridin-3-yl ) Preparation of benzenesulfonamide trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-1,8-萘啶-4-基)哌嗪-1-甲酸叔丁酯(50mg,0.082mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加三氟乙酸(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，得2,4-二氟-N-(2-甲氧基-5-(5-(哌嗪-1-基)-1,8-萘啶-3-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：513.1[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-1,8-naphthyridin-4-yl)piperazine - tert-Butyl 1-carboxylate (50mg, 0.082mmol) was dissolved in dichloromethane (4mL), and trifluoroacetic acid (2mL) was slowly added dropwise under ice-cooling. After the addition was complete, stir at room temperature for 1h. After the reaction, concentrate under reduced pressure to obtain 2,4-difluoro-N-(2-methoxy-5-(5-(piperazin-1-yl)-1,8-naphthyridin-3-yl) Pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 513.1 [M+H] + .
步骤e)：(E)-2,4-二氟-N-(2-甲氧基-5-(5-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-1,8-萘啶-3-基)吡啶-3-基)苯磺酰胺的制备Step e): (E)-2,4-difluoro-N-(2-methoxy-5-(5-(4-(4-oxopent-2-enoyl)piperazin-1-yl )-1,8-naphthyridin-3-yl)pyridin-3-yl)benzenesulfonamide preparation
将2,4-二氟-N-(2-甲氧基-5-(5-(哌嗪-1-基)-1,8-萘啶-3-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(50mg,0.080mmol)、(E)-4-氧代戊-2-烯酸(9mg,0.080mmol)和四氢呋喃(2mL)加入到反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(62mg,0.480mmol)和50％的T3P乙酸乙酯溶液(51mg,0.080mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃加水(1mL)淬灭反应，体系于室温下减压浓缩，向浓缩物中加入乙腈(2mL)稀释，经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(5-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-1,8-萘啶-3-基)吡啶-3-基)苯磺酰胺，产率26.7％；1H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.30(d,J＝2.4Hz,1H),8.87(d,J＝5.2Hz,1H),8.55(s,2H),8.11(d,J＝2.4Hz,1H),7.82-7.76(m,1H),7.60-7.54(m,1H),7.49(d,J＝15.6Hz,1H),7.24-7.19(m,1H),7.13(d,J＝5.2Hz,1H),6.73(d,J＝15.6Hz,1H),3.95-3.87(m,4H),3.70(s,3H),3.38-3.32(m,4H),2.37(s,3H)；ESI- MS(m/z)：609.0[M+H]+。2,4-Difluoro-N-(2-methoxy-5-(5-(piperazin-1-yl)-1,8-naphthyridin-3-yl)pyridin-3-yl)benzenesulfonate Amide trifluoroacetate (50mg, 0.080mmol), (E)-4-oxopent-2-enoic acid (9mg, 0.080mmol) and tetrahydrofuran (2mL) were added to the reaction flask, and the reaction system was cooled to - At 78°C, DIPEA (62mg, 0.480mmol) and 50% T 3 P ethyl acetate solution (51mg, 0.080mmol, 50%wt) were added sequentially, and the mixture was stirred at -78°C for 1h. After the reaction, add water (1 mL) at -78°C to quench the reaction, concentrate the system under reduced pressure at room temperature, add acetonitrile (2 mL) to the concentrate for dilution, and purify by Prep-HPLC (method 2) to obtain (E)- 2,4-Difluoro-N-(2-methoxy-5-(5-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-1,8-naphthyridine -3-yl)pyridin-3-yl)benzenesulfonamide, yield 26.7%; 1 H NMR (400MHz, DMSO-d 6 )δ10.39(s, 1H), 9.30(d, J=2.4Hz, 1H ),8.87(d,J=5.2Hz,1H),8.55(s,2H),8.11(d,J=2.4Hz,1H),7.82-7.76(m,1H),7.60-7.54(m,1H) ,7.49(d,J=15.6Hz,1H),7.24-7.19(m,1H),7.13(d,J=5.2Hz,1H),6.73(d,J=15.6Hz,1H),3.95-3.87( m,4H),3.70(s,3H),3.38-3.32(m,4H),2.37(s,3H);ESI- MS (m/z): 609.0 [M+H] + .
实施例58Example 58
(E)-2，4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-1，5-萘啶-2-基)吡啶-3-基)苯磺酰胺制备
(E)-2,4-difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-1, Preparation of 5-naphthyridin-2-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：2,8-二氯-1,5-萘啶的制备Step a): Preparation of 2,8-dichloro-1,5-naphthyridine
将6-氯-1,5-萘啶-4-醇(50mg,0.277mmol)溶于三氯氧磷(3mL)中，加毕，升温110℃搅拌3h。反应结束后，将反应液减压浓缩，向浓缩物中加入饱和碳酸氢钠(10mL)调pH＝7～8，水相用乙酸乙酯(5mL×3)萃取，有机相水(5mL)洗，有机相无水硫酸钠干燥，过滤、滤液减压浓缩，得2,8-二氯-1,5-萘啶，产率84.1％；ESI-MS(m/z)：199.1[M+H]+。6-Chloro-1,5-naphthyridin-4-ol (50mg, 0.277mmol) was dissolved in phosphorus oxychloride (3mL). After the addition was completed, the temperature was raised to 110°C and stirred for 3h. After the reaction, the reaction solution was concentrated under reduced pressure, and saturated sodium bicarbonate (10 mL) was added to the concentrate to adjust the pH to 7-8. The aqueous phase was extracted with ethyl acetate (5 mL×3), and the organic phase was washed with water (5 mL). , the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2,8-dichloro-1,5-naphthyridine with a yield of 84.1%; ESI-MS (m/z): 199.1 [M+H ] + .
步骤b)：4-(6-氯-1,5-萘啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): Preparation of tert-butyl 4-(6-chloro-1,5-naphthyridin-4-yl)piperazine-1-carboxylate
将2,8-二氯-1,5-萘啶(60mg,0.301mmol)溶于DMF(3mL)中，依次加入哌嗪-1-甲酸叔丁酯(56mg,0.301mmol)和DIPEA(78mg,0.602mmol)加毕，升温至50℃搅拌12h。反应结束后，加水(3mL)淬灭反应，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相水(5mL×3)洗，有机相无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1到1/1)，得4-(6-氯-1,5-萘啶-4-基)哌嗪-1-甲酸叔丁酯,产率69.5％；ESI-MS(m/z)：349.1[M+H]+。Dissolve 2,8-dichloro-1,5-naphthyridine (60mg, 0.301mmol) in DMF (3mL), add piperazine-1-carboxylic acid tert-butyl ester (56mg, 0.301mmol) and DIPEA (78mg, 0.602mmol) was added, heated to 50°C and stirred for 12h. After the reaction, add water (3mL) to quench the reaction, extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phase with water (5mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate, and the obtained crude product is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 1/1) to obtain 4-(6-chloro-1,5-naphthyridin-4-yl) Piperazine-1-carboxylic acid tert-butyl ester, yield 69.5%; ESI-MS (m/z): 349.1[M+H] + .
步骤c)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-1,5-萘啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step c): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-1,5-naphthyridin-4-yl ) Preparation of piperazine-1-formic acid tert-butyl ester
将4-(6-氯-1,5-萘啶-4-基)哌嗪-1-甲酸叔丁酯(80mg,0.229mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(98mg,0.229mmol)、Pd(dppf)Cl2(34mg,0.046mmol)和碳酸铯(149mg,0.458mmol)溶于二氧六环/水混合溶剂(3.3mL，v/v＝10:1)中，加毕，氮气保护下升温至100℃搅拌3h。反应结束后，加水(3mL)淬灭反应，用二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝1/0到10/1)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-1,5-萘啶-4-基)哌嗪-1-甲酸叔丁酯,产率57.6％；ESI-MS(m/z)：613.5[M+H]+。4-(6-Chloro-1,5-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (80mg, 0.229mmol), 2,4-difluoro-N-(2-methoxy -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (98mg, 0.229mmol), Pd(dppf)Cl 2 (34mg, 0.046mmol) and cesium carbonate (149mg, 0.458mmol) were dissolved in dioxane/water mixed solvent (3.3mL, v/v=10:1), after addition, nitrogen protection The temperature was raised to 100°C and stirred for 3h. After the reaction, add water (3mL) to quench the reaction, extract with dichloromethane (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (washing Removal agent: dichloromethane/methanol=1/0 to 10/1), to get 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridine- 3-yl)-1,5-naphthyridin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 57.6%; ESI-MS (m/z): 613.5[M+H] + .
步骤d)：2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)-1,5-萘啶-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step d): 2,4-difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-3-yl ) Preparation of benzenesulfonamide trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-1,5-萘啶-4-基)哌嗪-1-甲酸叔丁酯(120mg,0.196mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加三氟乙酸(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入甲基叔丁基醚(5mL)，室温搅拌30min，过滤，滤饼减压干燥，得2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)-1,5-萘啶-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐，产率49.9％；ESI-MS(m/z)：513.1[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-1,5-naphthyridin-4-yl)piperazine - tert-Butyl 1-carboxylate (120mg, 0.196mmol) was dissolved in dichloromethane (4mL), and trifluoroacetic acid (2mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether (5 mL) to the crude product, stir at room temperature for 30 min, filter, and dry the filter cake under reduced pressure to obtain 2,4-difluoro-N-(2-methoxy -5-(8-(piperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate, yield 49.9%; ESI-MS ( m/z): 513.1 [M+H] + .
步骤e)：(E)-2,4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-1,5-萘啶-2-基)吡啶-3-基)苯磺酰胺的制备Step e): (E)-2,4-difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl )-1,5-naphthyridin-2-yl)pyridin-3-yl)benzenesulfonamide preparation
将2,4-二氟-N-(2-甲氧基-5-(8-(哌嗪-1-基)-1,5-萘啶-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(80mg,0.128mmol)、(E)-4-氧代戊-2-烯酸(15mg,0.128mmol)和四氢呋喃(2mL)加入到反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(83mg,0.640mmol)和50％的T3P乙酸乙酯溶液(81mg,0.128mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃加水(1mL)淬灭反应，体系于室温下减压浓缩，向浓缩物中加入乙腈(2mL)稀释，经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(8-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-1,5-萘啶-2-基)吡啶-3-基)苯磺酰胺，产率31.9％；1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.62(d,J＝4.4Hz,1H),8.26-8.11(m,3H),7.79-7.73(m,1H),7.56-7.43(m,4H),7.17-7.13(m,1H),6.70(d,J＝16.0Hz,1H),3.77-3.69(m,9H),3.29(s,2H),2.36(s,3H)；ESI-MS(m/z)：609.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(8-(piperazin-1-yl)-1,5-naphthyridin-2-yl)pyridin-3-yl)benzenesulfonate Amide trifluoroacetate (80mg, 0.128mmol), (E)-4-oxopent-2-enoic acid (15mg, 0.128mmol) and tetrahydrofuran (2mL) were added to the reaction flask, and the reaction system was cooled to - At 78°C, DIPEA (83mg, 0.640mmol) and 50% T 3 P ethyl acetate solution (81mg, 0.128mmol, 50%wt) were added sequentially, and the mixture was stirred at -78°C for 1h. After the reaction, add water (1 mL) at -78°C to quench the reaction, concentrate the system under reduced pressure at room temperature, add acetonitrile (2 mL) to the concentrate for dilution, and purify by Prep-HPLC (method 2) to obtain (E)- 2,4-Difluoro-N-(2-methoxy-5-(8-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-1,5-naphthyridine -2-yl)pyridin-3-yl)benzenesulfonamide, yield 31.9%; 1 H NMR (400MHz, DMSO-d 6 )δ10.19(s, 1H), 8.62(d, J=4.4Hz, 1H ),8.26-8.11(m,3H),7.79-7.73(m,1H),7.56-7.43(m,4H),7.17-7.13(m,1H),6.70(d,J＝16.0Hz,1H), 3.77-3.69 (m, 9H), 3.29 (s, 2H), 2.36 (s, 3H); ESI-MS (m/z): 609.0 [M+H] + .
实施例59Example 59
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-2H-吡唑并[3，4-d]嘧啶-2-基)吡啶-3-基)苯磺酰胺制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-2H- Preparation of pyrazolo[3,4-d]pyrimidin-2-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：5-(2-(二苯基亚甲基)肼基)-2-甲氧基-3-硝基吡啶的制备Step a): Preparation of 5-(2-(diphenylmethylene)hydrazino)-2-methoxy-3-nitropyridine
将5-溴-2-甲氧基-3-硝基吡啶(10.0g,42.915mmol)、(二苯基亚甲基)肼(12.6g,64.372mmol)、醋酸钯(963mg,4.292mmol)、BINAP(5.3g,8.583mmol)和碳酸铯(21.8g,85.830mmol)加入甲苯(150mL)中，加毕，氮气保护升温110℃反应24h。反应结束后，过滤、滤液减压浓缩，向浓缩物中加水(100mL)，以乙酸乙酯(200mL×2)萃取，合并有机相，有机相水(100mL×2)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝20/1到10/1)，得5-(2-(二苯基亚甲基)肼基)-2-甲氧基-3-硝基吡啶，产率53.5％；ESI-MS(m/z)：349.3[M+H]+。5-bromo-2-methoxy-3-nitropyridine (10.0g, 42.915mmol), (diphenylmethylene)hydrazine (12.6g, 64.372mmol), palladium acetate (963mg, 4.292mmol), BINAP (5.3g, 8.583mmol) and cesium carbonate (21.8g, 85.830mmol) were added into toluene (150mL). After the addition was completed, the temperature was raised to 110°C under nitrogen protection for 24h. After the reaction, filter and concentrate the filtrate under reduced pressure, add water (100mL) to the concentrate, extract with ethyl acetate (200mL×2), combine the organic phases, wash the organic phase with water (100mL×2), and dry over anhydrous sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=20/1 to 10/1) to obtain 5-(2-(diphenylmethylene )hydrazino)-2-methoxy-3-nitropyridine, yield 53.5%; ESI-MS (m/z): 349.3[M+H] + .
步骤b)：5-肼基-2-甲氧基-3-硝基吡啶的制备Step b): Preparation of 5-hydrazino-2-methoxy-3-nitropyridine
将5-(2-(二苯基亚甲基)肼基)-2-甲氧基-3-硝基吡啶(2.0g,5.741mmol)溶于乙酸乙酯(10mL)中，加入6M稀盐酸(10mL)，加毕，升温60℃反应12h。反应结束后，向反应液加入水(10mL)淬灭反应，反应液乙酸乙酯(20mL)萃取、分液、收集水相，水相用饱和碳酸氢钠调至pH＝7～8，水相用乙酸乙酯(20mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得5-肼基-2-甲氧基-3-硝基吡啶，产率6.1％；ESI-MS(m/z)：185.1[M+H]+。Dissolve 5-(2-(diphenylmethylene)hydrazino)-2-methoxy-3-nitropyridine (2.0g, 5.741mmol) in ethyl acetate (10mL), add 6M dilute hydrochloric acid (10 mL), after the addition was completed, the temperature was raised to 60° C. for 12 h. After the reaction finishes, add water (10mL) to the reaction solution to quench the reaction, the reaction solution is extracted with ethyl acetate (20mL), separated, and the water phase is collected. The water phase is adjusted to pH=7～8 with saturated sodium bicarbonate, and the water phase is Extract with ethyl acetate (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 5-hydrazino-2-methoxy-3-nitropyridine with a yield of 6.1% ; ESI-MS (m/z): 185.1 [M+H] + .
步骤c)：3-氨基-1-(6-甲氧基-5-硝基吡啶-3-基)-1H-吡唑-4-甲酸乙酯的制备Step c): Preparation of ethyl 3-amino-1-(6-methoxy-5-nitropyridin-3-yl)-1H-pyrazole-4-carboxylate
将5-肼基-2-甲氧基-3-硝基吡啶(110mg,0.597mmol)、(E)-2-氰基-3-乙氧基丙烯酸乙酯(101mg,0.597mmol)和乙酸钠(99mg,1.194mmol)加入乙酸(3mL)和水(0.5mL)中，加毕，氮气保护升温至回流反应2h。反应结束后，减压浓缩，浓缩物用饱和碳酸氢钠调至pH＝7～8，用乙酸乙酯(10mL)萃取，合并有机相，用水(10mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得3-氨基-1-(6-甲氧基-5-硝基吡啶-3-基)-1H-吡唑-4-甲酸乙酯，产率52.6％；ESI-MS(m/z)：308.0[M+H]+。5-hydrazino-2-methoxy-3-nitropyridine (110mg, 0.597mmol), (E)-2-cyano-3-ethoxy ethyl acrylate (101mg, 0.597mmol) and sodium acetate (99mg, 1.194mmol) was added to acetic acid (3mL) and water (0.5mL). After the addition was complete, the temperature was raised to reflux under nitrogen protection for 2h. After the reaction, concentrate under reduced pressure, adjust the concentrate to pH=7-8 with saturated sodium bicarbonate, extract with ethyl acetate (10 mL), combine the organic phases, wash with water (10 mL), dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure to obtain ethyl 3-amino-1-(6-methoxy-5-nitropyridin-3-yl)-1H-pyrazole-4-carboxylate with a yield of 52.6%; ESI-MS ( m/z): 308.0 [M+H] + .
步骤d)：2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-醇的制备Step d): Preparation of 2-(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-ol
将3-氨基-1-(6-甲氧基-5-硝基吡啶-3-基)-1H-吡唑-4-甲酸乙酯(110mg,0.358mmol)溶于甲酰胺(4mL)中，升温150℃反应10h。反应结束后，向反应液加入水(10mL)淬灭反应，乙酸乙酯(20mL)萃取，分液，有机相水(5mL)洗，无水硫酸钠干燥，过滤、滤液减压浓缩，得2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-醇，产率14.4％；ESI-MS(m/z)：289.2[M+H]+。Ethyl 3-amino-1-(6-methoxy-5-nitropyridin-3-yl)-1H-pyrazole-4-carboxylate (110 mg, 0.358 mmol) was dissolved in formamide (4 mL), The temperature was raised to 150°C for 10 hours. After the reaction, add water (10 mL) to the reaction solution to quench the reaction, extract with ethyl acetate (20 mL), separate the layers, wash the organic phase with water (5 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2 -(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-ol, yield 14.4%; ESI-MS(m/z) : 289.2[M+H] + .
步骤e)：4-氯-2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶的制备Step e): Preparation of 4-chloro-2-(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidine
将2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-醇(29mg,0.101mmol)溶于三氯氧磷(3mL)中，加入DIPEA(26mg,0.201mmol)加毕，升温110℃反应3h。反应结束后，将反应液减压浓缩，向浓缩物加入水(3mL)淬灭反应，饱和碳酸氢钠调至pH＝7～8，用乙酸乙酯(10mL)萃取，合并有机相，用水(5mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得4-氯-2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶，产率96.9％；ESI-MS(m/z)：307.0[M+H]+。Dissolve 2-(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-ol (29mg, 0.101mmol) in phosphorus oxychloride (3mL), DIPEA (26mg, 0.201mmol) was added to complete the addition, and the temperature was raised to 110°C for 3h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and water (3 mL) was added to the concentrate to quench the reaction, adjusted to pH=7-8 with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL), combined organic phases, and water ( 5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-chloro-2-(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3, 4-d] pyrimidine, yield 96.9%; ESI-MS (m/z): 307.0 [M+H] + .
步骤f)：4-(2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step f): 4-(2-(6-Methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1- Preparation of tert-butyl formate
将4-氯-2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶(30mg,0.098mmol)溶于DMF(3mL)中，依次加入DIPEA(25mg,0.196mmol)和哌嗪-1-甲酸叔丁酯(18mg,0.098mmol)加毕，升温60℃反应2h。反应结束后，向反应液加入水(3mL)淬灭反应，用乙酸乙酯(3mL×2)萃取，合并有机相，用水(2mL×3)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1到1/1),得4-(2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯，产率31.8％；ESI-MS(m/z)：457.1[M+H]+。4-Chloro-2-(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidine (30 mg, 0.098 mmol) was dissolved in DMF (3 mL) Add DIPEA (25mg, 0.196mmol) and tert-butyl piperazine-1-carboxylate (18mg, 0.098mmol) successively, and then heat up to 60°C for 2h. After the reaction, add water (3mL) to the reaction solution to quench the reaction, extract with ethyl acetate (3mL×2), combine the organic phases, wash with water (2mL×3), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentration, the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 3/1 to 1/1), to obtain 4-(2-(6-methoxy-5-nitropyridine- 3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 31.8%; ESI-MS (m/z): 457.1 [M +H] + .
步骤g)：4-(2-(5-氨基-6-甲氧基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备 Step g): 4-(2-(5-Amino-6-methoxypyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid Preparation of tert-butyl ester
将4-(2-(6-甲氧基-5-硝基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(20mg,0.044mmol)溶于乙醇(3mL)和水(1mL)中，依次加入铁粉(12mg,0.219mmol)和氯化铵(1mg,0.009mmol)加毕，升温至回流反应3h。反应结束后，将反应液过滤，滤液减压浓缩，向浓缩物加入二氯甲烷(5mL)，有机相用水(2mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得4-(2-(5-氨基-6-甲氧基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯，产率50.8％；ESI-MS(m/z)：427.0[M+H]+。4-(2-(6-methoxy-5-nitropyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl The ester (20mg, 0.044mmol) was dissolved in ethanol (3mL) and water (1mL), iron powder (12mg, 0.219mmol) and ammonium chloride (1mg, 0.009mmol) were added in turn, and the temperature was raised to reflux for 3h. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, dichloromethane (5 mL) was added to the concentrate, the organic phase was washed with water (2 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4-( 2-(5-Amino-6-methoxypyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 50.8 %; ESI-MS (m/z): 427.0 [M+H] + .
步骤h)：4-(2-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step h): 4-(2-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-2H-pyrazolo[3,4- d] Preparation of pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester
将4-(2-(5-氨基-6-甲氧基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(30mg,0.070mmol)和2,4-二氟苯磺酰氯(45mg,0.211mmol)溶于吡啶(3mL)中，升温70℃反应2h。反应结束后，将反应液减压浓缩，向浓缩物加入水(3mL)淬灭反应，用二氯甲烷(10mL)萃取，合并有机相，用水(5mL×2)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到20/1)，得4-(2-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯，产率34.4％；ESI-MS(m/z)：603.2[M+H]+。tert-butyl 4-(2-(5-amino-6-methoxypyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylate (30mg, 0.070mmol) and 2,4-difluorobenzenesulfonyl chloride (45mg, 0.211mmol) were dissolved in pyridine (3mL), heated at 70°C for 2h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and water (3 mL) was added to the concentrate to quench the reaction, extracted with dichloromethane (10 mL), and the organic phases were combined, washed with water (5 mL×2), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure, the resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol = 100/1 to 20/1) to obtain 4-(2-(5-((2,4- Difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, Yield 34.4%; ESI-MS (m/z): 603.2 [M+H] + .
步骤i)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)-2H-吡唑并[3,4-d]嘧啶-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step i): 2,4-Difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)-2H-pyrazolo[3,4-d]pyrimidine-2- Base) pyridin-3-yl) preparation of benzenesulfonamide trifluoroacetate
将4-(2-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-2H-吡唑并[3,4-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(20mg,0.033mmol)溶于二氯甲烷(2mL)中，冰浴下缓慢滴加三氟乙酸(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)-2H-吡唑并[3,4-d]嘧啶-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：503.2[M+H]+。4-(2-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-2H-pyrazolo[3,4-d]pyrimidine -4-yl)piperazine-1-carboxylic acid tert-butyl ester (20mg, 0.033mmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (1mL) was slowly added dropwise under ice-cooling, after the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)-2H-pyrazolo[3,4-d ]pyrimidin-2-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 503.2 [M+H] + .
步骤j)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-2H-吡唑[3,4-d]嘧啶-2-基)吡啶-3-基)苯磺酰胺制备Step j): (E)-2,4-Difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl )-2H-pyrazol[3,4-d]pyrimidin-2-yl)pyridin-3-yl)benzenesulfonamide preparation
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)-2H-吡唑[3,4-d]嘧啶-2-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(20mg,0.032mmol)、(E)-4-氧代戊-2-烯酸(4mg,0.032mmol)和四氢呋喃(2mL)加入到反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(21mg,0.160mmol)和50％的T3P乙酸乙酯溶液(20mg,0.032mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃加水(1mL)淬灭反应，体系于室温下减压浓缩，向浓缩物中加入乙腈(2mL)稀释，经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-2H-吡唑[3,4-d]嘧啶-2-基)吡啶-3-基)苯磺酰胺，产率23.8％；1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.33(s,1H),7.93(d,J＝2.4Hz,1H),7.84-7.78(m,2H),7.44(d,J＝15.6Hz,1H),7.18-7.13(m,1H),7.06-7.01(m,1H),6.74(d,J＝15.6Hz,1H),4.08-4.03(m,4H),3.87-3.76(m,7H),2.38(s,3H)；ESI-MS(m/z)：599.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)-2H-pyrazol[3,4-d]pyrimidin-2-yl)pyridine- 3-yl)benzenesulfonamide trifluoroacetate (20mg, 0.032mmol), (E)-4-oxopent-2-enoic acid (4mg, 0.032mmol) and tetrahydrofuran (2mL) were added to the reaction flask, The reaction system was cooled to -78°C, DIPEA (21mg, 0.160mmol) and 50% T 3 P ethyl acetate solution (20mg, 0.032mmol, 50%wt) were added sequentially, and the mixture was stirred at -78°C for 1h. After the reaction, add water (1 mL) at -78°C to quench the reaction, concentrate the system under reduced pressure at room temperature, add acetonitrile (2 mL) to the concentrate for dilution, and purify by Prep-HPLC (method 2) to obtain (E)- 2,4-Difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-2H-pyrazol[3 ,4-d]pyrimidin-2-yl)pyridin-3-yl)benzenesulfonamide, yield 23.8%; 1 H NMR (400MHz, DMSO-d 6 )δ8.46(s,1H),8.33(s, 1H), 7.93(d, J=2.4Hz, 1H), 7.84-7.78(m, 2H), 7.44(d, J=15.6Hz, 1H), 7.18-7.13(m, 1H), 7.06-7.01(m , 1H), 6.74(d, J=15.6Hz, 1H), 4.08-4.03(m, 4H), 3.87-3.76(m, 7H), 2.38(s, 3H); ESI-MS(m/z): 599.0[M+H] + .
实施例60Example 60
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)噻吩并[2，3-d]嘧啶-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)thieno[ Preparation of 2,3-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：4-(6-溴噻吩并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step a): Preparation of tert-butyl 4-(6-bromothieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate
将6-溴-4-氯噻吩并[2,3-d]嘧啶(320mg,1.283mmol)、哌嗪-1-甲酸叔丁酯(263mg,1.411mmol)、DIPEA(663mg,5.132mmol)和乙腈(5mL)加入反应瓶中，升温至80℃反应1.5h。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1到3/1)，得4-(6-溴噻吩并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯，产率 93.8％；ESI-MS(m/z)：401.0[M+H]+。6-Bromo-4-chlorothieno[2,3-d]pyrimidine (320mg, 1.283mmol), tert-butyl piperazine-1-carboxylate (263mg, 1.411mmol), DIPEA (663mg, 5.132mmol) and acetonitrile (5 mL) was added into the reaction flask, and the temperature was raised to 80° C. for 1.5 h. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (50mL×2), combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate = 10/1 to 3/1) to give 4-(6-bromothieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 93.8%; ESI-MS (m/z): 401.0 [M+H] + .
步骤b)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)噻吩并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯的制备Step b): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)thieno[2,3-d]pyrimidine- Preparation of tert-butyl 4-yl)piperazine-1-carboxylate
将4-(6-溴噻吩并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(200mg,0.501mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(235mg,0.551mmol)、Pd(dppf)Cl2(37mg,0.050mmol)和碳酸铯(490mg,1.503mmol)、二氧六环/水混合溶剂(4.8mL，v/v＝5:1)加入反应瓶中，加毕，氮气保护下升温至100℃搅拌1.5h。反应结束后，加水(30mL)淬灭反应，乙酸乙酯(60mL×2)萃取，合并有机相，无水硫酸钠干燥、过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)噻吩并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯，产率80.7％；ESI-MS(m/z)：619.2[M+H]+。4-(6-Bromothieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.501mmol), 2,4-difluoro-N-(2- Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (235mg, 0.551 mmol), Pd(dppf)Cl 2 (37mg, 0.050mmol), cesium carbonate (490mg, 1.503mmol), and dioxane/water mixed solvent (4.8mL, v/v=5:1) were added to the reaction flask, After the addition was complete, the temperature was raised to 100° C. and stirred for 1.5 h under the protection of nitrogen. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (60mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (elution Agent: dichloromethane/methanol=100/1 to 10/1), get 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridine-3 -yl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 80.7%; ESI-MS (m/z): 619.2[M+H] + .
步骤c)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step c): 2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)thieno[2,3-d]pyrimidin-6-yl)pyridine- Preparation of 3-yl)benzenesulfonamide trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)噻吩并[2,3-d]嘧啶-4-基)哌嗪-1-甲酸叔丁酯(250mg,0.404mmol)、二氯甲烷(3mL)加入反应瓶中，冰浴下缓慢滴加三氟乙酸(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向粗品中加入适量甲基叔丁基醚，搅拌析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：519.0[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)thieno[2,3-d]pyrimidin-4-yl ) tert-butyl piperazine-1-carboxylate (250mg, 0.404mmol) and dichloromethane (3mL) were added into the reaction flask, and trifluoroacetic acid (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add an appropriate amount of methyl tert-butyl ether to the crude product, stir to precipitate a solid, filter to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piper Azin-1-yl)thieno[2,3-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS(m/z):519.0[M+H ] + .
步骤d)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)苯磺酰胺的制备Step d): (E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) Thieno[2,3-d] pyrimidin-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(100mg,0.158mmol)、(E)-4-氧代戊-2-烯酸(20mg,0.174mmol)和四氢呋喃(3mL)加入反应瓶中，将反应体系冷却至-78℃，依次加入50％的T3P乙酸乙酯溶液(151mg,0.237mmol)和DIPEA(163mg,1.264mmol)，加毕，在-78℃搅拌0.5h。反应结束后，在-78℃用饱和氯化铵溶液(30mL)淬灭反应，二氯甲烷(50mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)噻吩并[2,3-d]嘧啶-6-基)吡啶-3-基)苯磺酰胺，产率46.2％；1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.48-8.46(m,1H),8.44(s,1H),8.06-8.03(m,1H),7.95(s,1H),7.80-7.72(m,1H),7.62-7.54(m,1H),7.45(d,J＝15.6Hz,1H),7.25-7.19(m,1H),6.75(d,J＝15.6Hz,1H),4.06-3.99(m,4H),3.90-3.84(m,2H),3.81-3.75(m,2H),3.63(s,3H),2.38(s,3H)；ESI-MS(m/z)：615.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)thieno[2,3-d]pyrimidin-6-yl)pyridin-3-yl ) benzenesulfonamide trifluoroacetate (100mg, 0.158mmol), (E)-4-oxopent-2-enoic acid (20mg, 0.174mmol) and tetrahydrofuran (3mL) were added in the reaction flask, and the reaction system was cooled To -78°C, 50% T 3 P ethyl acetate solution (151mg, 0.237mmol) and DIPEA (163mg, 1.264mmol) were added successively, and the mixture was stirred at -78°C for 0.5h. After the reaction, quench the reaction with saturated ammonium chloride solution (30mL) at -78°C, extract with dichloromethane (50mL×2), combine the organic phases, wash the organic phase with saturated brine (30mL), and anhydrous sodium sulfate Drying, filtration, and concentration of the filtrate under reduced pressure, the obtained crude product was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(4-(4- (4-oxopent-2-enoyl)piperazin-1-yl)thieno[2,3-d]pyrimidin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 46.2%; 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),8.48-8.46(m,1H),8.44(s,1H),8.06-8.03(m,1H),7.95(s,1H) ,7.80-7.72(m,1H),7.62-7.54(m,1H),7.45(d,J=15.6Hz,1H),7.25-7.19(m,1H),6.75(d,J=15.6Hz,1H ),4.06-3.99(m,4H),3.90-3.84(m,2H),3.81-3.75(m,2H),3.63(s,3H),2.38(s,3H); ESI-MS(m/z ): 615.0[M+H] + .
实施例61Example 61
(E)-2，4-二氟-N-(2-甲氧基-5-(9-甲基-6-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-9H-嘌呤-8-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(9-methyl-6-(4-(4-oxopent-2-enoyl)piperazine-1- Base)-9H-purin-8-yl)pyridin-3-yl)benzenesulfonamide preparation
步骤a)：6-氯-9-甲基-9H-嘌呤的制备Step a): Preparation of 6-chloro-9-methyl-9H-purine
将氢化钠(780mg,19.410mmol)和DMF(10mL)加入反应瓶中，冷却至0℃，滴加6-氯-9H-嘌呤(2.0g,12.940mmol)的DMF(10mL)溶液，加毕，维持0℃搅拌30min，滴加碘甲烷(2.2g,15.528mmol)，加毕，室温搅拌2h。反应结束后，加水(30mL)淬灭反应，乙酸乙酯(20mL×2)萃取，合并有机相，有机相水(10mL×3)洗，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1到1/2)，得6-氯-9-甲基-9H-嘌呤，产率24.4％；ESI-MS(m/z)：169.0[M+H]+。Sodium hydride (780mg, 19.410mmol) and DMF (10mL) were added to the reaction flask, cooled to 0°C, a solution of 6-chloro-9H-purine (2.0g, 12.940mmol) in DMF (10mL) was added dropwise, and the addition was completed. Stir at 0°C for 30 min, add iodomethane (2.2 g, 15.528 mmol) dropwise, and stir at room temperature for 2 h after the addition is complete. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (20mL×2), combine the organic phases, wash the organic phase with water (10mL×3), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the obtained crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 to 1/2) to obtain 6-chloro-9-methyl-9H-purine with a yield of 24.4%; ESI - MS (m/z): 169.0 [M+H] + .
步骤b)：8-溴-6-氯-9-甲基-9H-嘌呤的制备Step b): Preparation of 8-bromo-6-chloro-9-methyl-9H-purine
将6-氯-9-甲基-9H-嘌呤(457mg,2.711mmol)和四氢呋喃(6mL)加入反应瓶中，加毕，氮气保护下冷却至-70℃，滴加二异丙基氨基锂的四氢呋喃溶液(3mL,5.964mmol)，加毕，维持-70℃搅拌1h，继续滴加1,2-二溴四氟乙烷(1.620g,6.235mmol)，加毕，维持-70℃反应1h。反应结束后，加水(10mL)淬灭反应，乙酸乙酯(10mL×2)萃取，合并有机相，有机相水(5mL×2)洗，有机相无水硫酸钠干燥，过滤、滤液减压浓缩，得6- 氯-9-甲基-9H-嘌呤，产率41.15％；ESI-MS(m/z)：249.0[M+H]+。Add 6-chloro-9-methyl-9H-purine (457mg, 2.711mmol) and tetrahydrofuran (6mL) into the reaction flask, after the addition is complete, cool to -70°C under the protection of nitrogen, and dropwise add diisopropylamide lithium Tetrahydrofuran solution (3mL, 5.964mmol) was added, and stirred at -70°C for 1h, and 1,2-dibromotetrafluoroethane (1.620g, 6.235mmol) was added dropwise. After the addition was completed, the reaction was maintained at -70°C for 1h. After the reaction, add water (10mL) to quench the reaction, extract with ethyl acetate (10mL×2), combine the organic phases, wash the organic phase with water (5mL×2), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , get 6- Chloro-9-methyl-9H-purine, yield 41.15%; ESI-MS (m/z): 249.0 [M+H] + .
步骤c)：4-(8-溴-9-甲基-9H-嘌呤-6-基)哌嗪-1-甲酸叔丁酯的制备Step c): Preparation of tert-butyl 4-(8-bromo-9-methyl-9H-purin-6-yl)piperazine-1-carboxylate
依次将6-氯-9-甲基-9H-嘌呤(200mg,0.808mmol)、哌嗪-1-甲酸叔丁酯(226mg,1.212mmol)和DIPEA(209mg,1.616mmol)、DMF(4mL)加入反应瓶中，加毕，氮气保护下升温至50℃搅拌3h。反应结束后，加水(10mL)淬灭反应，乙酸乙酯(10mL×3)萃取，合并有机相，有机相水(10mL×3)洗，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1到1/1)，得4-(8-溴-9-甲基-9H-嘌呤-6-基)哌嗪-1-甲酸叔丁酯，产率33.4％；ESI-MS(m/z)：399.0[M+H]+。6-Chloro-9-methyl-9H-purine (200mg, 0.808mmol), tert-butyl piperazine-1-carboxylate (226mg, 1.212mmol) and DIPEA (209mg, 1.616mmol), DMF (4mL) were added in sequence In the reaction flask, after the addition was completed, the temperature was raised to 50° C. and stirred for 3 h under the protection of nitrogen. After the reaction, add water (10mL) to quench the reaction, extract with ethyl acetate (10mL×3), combine the organic phases, wash the organic phase with water (10mL×3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1 to 1/1) to obtain 4-(8-bromo-9-methyl-9H-purin-6-yl)piper tert-butyloxine-1-carboxylate, yield 33.4%; ESI-MS (m/z): 399.0 [M+H] + .
步骤d)：4-(8-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-9-甲基-9H-嘌呤-6-基)哌嗪-1-甲酸叔丁酯的制备Step d): 4-(8-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-9-methyl-9H-purine-6 Preparation of -yl)piperazine-1-carboxylic acid tert-butyl ester
依次将4-(8-溴-9-甲基-9H-嘌呤-6-基)哌嗪-1-甲酸叔丁酯(160mg,0.403mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(172mg,0.403mmol)、Pd(dppf)Cl2(59mg,0.081mmol)和碳酸铯(262mg,0.805mmol)、二氧六环/水混合溶剂(6.6mL，v/v＝10:1)加入反应瓶中，加毕，氮气保护下升温至100℃搅拌2h。反应结束后，加水(6mL)淬灭反应，二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得4-(8-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-9-甲基-9H-嘌呤-6-基)哌嗪-1-甲酸叔丁酯，产率96.0％；ESI-MS(m/z)：617.2[M+H]+。4-(8-bromo-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid tert-butyl ester (160mg, 0.403mmol), 2,4-difluoro-N-(2- Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (172mg, 0.403 mmol), Pd(dppf)Cl 2 (59mg, 0.081mmol), cesium carbonate (262mg, 0.805mmol), and dioxane/water mixed solvent (6.6mL, v/v=10:1) were added to the reaction flask, After the addition was complete, the temperature was raised to 100° C. and stirred for 2 h under the protection of nitrogen. After the reaction, add water (6mL) to quench the reaction, extract with dichloromethane (10mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product is purified by silica gel column chromatography (elution Agent: dichloromethane/methanol=100/1 to 10/1), get 4-(8-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridine-3 -yl)-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 96.0%; ESI-MS (m/z): 617.2 [M+H] + .
步骤e)：2,4-二氟-N-(2-甲氧基-5-(9-甲基-6-(哌嗪-1-基)-9H-嘌呤-8-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step e): 2,4-Difluoro-N-(2-methoxy-5-(9-methyl-6-(piperazin-1-yl)-9H-purin-8-yl)pyridine-3 Preparation of -yl)benzenesulfonamide trifluoroacetate
将4-(8-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)-9-甲基-9H-嘌呤-6-基)哌嗪-1-甲酸叔丁酯(200mg,0.324mmol)、二氯甲烷(4mL)加入反应瓶中，冰浴下缓慢滴加三氟乙酸(2mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，向浓缩物中加入甲基叔丁基醚(5mL)，打浆，过滤，滤饼减压真空干燥，得2,4-二氟-N-(2-甲氧基-5-(9-甲基-6-(哌嗪-1-基)-9H-嘌呤-8-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：516.9[M+H]+。4-(8-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)-9-methyl-9H-purin-6-yl) Piperazine-1-carboxylic acid tert-butyl ester (200mg, 0.324mmol) and dichloromethane (4mL) were added to the reaction flask, and trifluoroacetic acid (2mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction, concentrate under reduced pressure, add methyl tert-butyl ether (5 mL) to the concentrate, make a slurry, filter, and dry the filter cake under reduced pressure to obtain 2,4-difluoro-N-(2-methoxy -5-(9-Methyl-6-(piperazin-1-yl)-9H-purin-8-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z ): 516.9[M+H] + .
步骤f)：(E)-2,4-二氟-N-(2-甲氧基-5-(9-甲基-6-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-9H-嘌呤-8-基)吡啶-3-基)苯磺酰胺的制备Step f): (E)-2,4-difluoro-N-(2-methoxy-5-(9-methyl-6-(4-(4-oxopent-2-enoyl)piper Preparation of oxazin-1-yl)-9H-purin-8-yl)pyridin-3-yl)benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(9-甲基-6-(哌嗪-1-基)-9H-嘌呤-8-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(200mg,0.317mmol)、(E)-4-氧代戊-2-烯酸(36mg,0.317mmol)和四氢呋喃(2mL)加入到反应瓶中，将反应体系降温至-78℃，依次加入DIPEA(246mg,1.902mmol)和50％的T3P乙酸乙酯溶液(202mg,0.317mmol,50％wt)，加毕，在-78℃搅拌1h。反应结束后，在-78℃加水(1mL)淬灭反应，体系于室温下减压浓缩，向浓缩物中加入乙腈(2mL)稀释，经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(9-甲基-6-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)-9H-嘌呤-8-基)吡啶-3-基)苯磺酰胺，产率33.4％；1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.49(s,1H),8.33(s,1H),8.04(s,1H),7.84-7.80(m,1H),7.60-7.55(m,1H),7.49(d,J＝16.0Hz,1H),7.26-7.22(m,1H),6.71(d,J＝16.0Hz,1H),4.36-4.26(m,4H),3.83-3.79(m,5H),3.73-3.71(m,5H),2.38(s,3H)；ESI-MS(m/z)：613.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(9-methyl-6-(piperazin-1-yl)-9H-purin-8-yl)pyridin-3-yl) Benzenesulfonamide trifluoroacetate (200mg, 0.317mmol), (E)-4-oxopent-2-enoic acid (36mg, 0.317mmol) and tetrahydrofuran (2mL) were added to the reaction flask, and the reaction system was cooled To -78°C, DIPEA (246mg, 1.902mmol) and 50% T 3 P ethyl acetate solution (202mg, 0.317mmol, 50%wt) were added sequentially, and the mixture was stirred at -78°C for 1h. After the reaction, add water (1 mL) at -78°C to quench the reaction, concentrate the system under reduced pressure at room temperature, add acetonitrile (2 mL) to the concentrate for dilution, and purify by Prep-HPLC (method 2) to obtain (E)- 2,4-Difluoro-N-(2-methoxy-5-(9-methyl-6-(4-(4-oxopent-2-enoyl)piperazin-1-yl)-9H -Purin-8-yl)pyridin-3-yl)benzenesulfonamide, yield 33.4%; 1 H NMR (400MHz, DMSO-d 6 )δ10.47(s,1H),8.49(s,1H),8.33 (s,1H),8.04(s,1H),7.84-7.80(m,1H),7.60-7.55(m,1H),7.49(d,J＝16.0Hz,1H),7.26-7.22(m,1H ), 6.71(d, J=16.0Hz, 1H), 4.36-4.26(m, 4H), 3.83-3.79(m, 5H), 3.73-3.71(m, 5H), 2.38(s, 3H); ESI- MS (m/z): 613.0 [M+H] + .
实施例62Example 62
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)酞嗪-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)phthalazine- Preparation of 6-yl)pyridin-3-yl)benzenesulfonamide
步骤a)：3,6-二溴异苯并呋喃-1(3H)-酮的制备Step a): Preparation of 3,6-dibromoisobenzofuran-1(3H)-one
将6-溴异苯并呋喃-1(3H)-酮(1.0g,4.694mmol)、2,2'-偶氮二(2-甲基丙腈)(77mg,0.469mmol)、N-溴代丁二酰亚胺(961mg,5.398mmol)加入三氯甲烷(10mL)中，加毕，升温至回流反应2h。反应结束后，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/20到1/5)，得3,6-二溴异苯并呋喃-1(3H)-酮，产率67.7％；1H NMR(400MHz,DMSO-d6)δ8.02-7.96(m,2H),7.64(d,J＝8.0Hz,1H),6.66(s,1H)。6-Bromoisobenzofuran-1(3H)-one (1.0g, 4.694mmol), 2,2'-azobis(2-methylpropionitrile) (77mg, 0.469mmol), N-bromo Succinimide (961mg, 5.398mmol) was added into chloroform (10mL), after the addition was completed, the temperature was raised to reflux for 2h. After the reaction, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/20 to 1/5) to obtain 3,6-dibromoisobenzofuran-1 (3H)-ketone, yield 67.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.02-7.96(m, 2H), 7.64(d, J=8.0Hz, 1H), 6.66(s, 1H ).
步骤b)：7-溴酞-1-醇的制备Step b): Preparation of 7-bromophthalein-1-ol
将3,6-二溴异苯并呋喃-1(3H)-酮(790mg,2.706mmol)、水合肼(542mg,13.530mmol,80％wt)加入无水乙醇(15mL)中，加毕，90℃反应2h。反应结束后，向反应液加水(50mL)，析出固体，过滤，滤饼经水洗涤(5mL×3)，60℃真空干燥6h，得7-溴酞-1-醇，产率30.6％；ESI-MS(m/z)：224.9[M+H]+。Add 3,6-dibromoisobenzofuran-1(3H)-one (790mg, 2.706mmol) and hydrazine hydrate (542mg, 13.530mmol, 80%wt) into absolute ethanol (15mL), after adding, 90 ℃ reaction 2h. After the reaction, add water (50mL) to the reaction solution to precipitate a solid, filter, wash the filter cake with water (5mL×3), and dry under vacuum at 60°C for 6h to obtain 7-bromophthal-1-ol with a yield of 30.6%; ESI - MS (m/z): 224.9 [M+H] + .
步骤c)：1,7-二氯酞嗪的制备Step c): Preparation of 1,7-dichlorophthalazine
将7-溴酞-1-醇(200mg,0.889mmol)加入三氯氧磷(10mL)中，加毕，100℃反应3h。反应结束后，减压浓缩，冰浴下向残余物中缓慢加水(30mL)淬灭反应，用饱和碳酸氢钠溶液调至pH＝7～8，用二氯甲烷(50mL×2)萃取，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得1,7-二氯酞嗪，产率79.2％；ESI-MS(m/z)：199.0[M+H]+。Add 7-bromophthalein-1-ol (200mg, 0.889mmol) into phosphorus oxychloride (10mL), after the addition is complete, react at 100°C for 3h. After the reaction was completed, concentrate under reduced pressure, slowly add water (30 mL) to the residue in an ice bath to quench the reaction, adjust the pH to 7-8 with saturated sodium bicarbonate solution, extract with dichloromethane (50 mL×2), and combine The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1,7-dichlorophthalazine with a yield of 79.2%; ESI-MS (m/z): 199.0[ M+H] + .
步骤d)：4-(7-氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯的制备Step d): Preparation of tert-butyl 4-(7-chlorophthalazin-1-yl)piperazine-1-carboxylate
将1,7-二氯酞嗪(50mg,0.251mmol)、哌嗪-1-甲酸叔丁酯(47mg,0.251mmol)、DIPEA(97mg,0.753mmol)加入DMF(2mL)中，加毕，120℃反应16h。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯(50mL×2)萃取，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10到1/0)，得4-(7-氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯，产率66.6％；ESI-MS(m/z)：349.2[M+H]+。Add 1,7-dichlorophthalazine (50mg, 0.251mmol), piperazine-1-carboxylic acid tert-butyl ester (47mg, 0.251mmol), DIPEA (97mg, 0.753mmol) into DMF (2mL), add, 120 ℃ reaction 16h. After the reaction was completed, add water (30 mL) to quench the reaction, extract with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product Purify by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/10 to 1/0) to obtain tert-butyl 4-(7-chlorophthalazin-1-yl)piperazine-1-carboxylate , yield 66.6%; ESI-MS (m/z): 349.2 [M+H] + .
步骤e)：4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯的制备Step e): 4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)phthalazin-1-yl)piperazine-1 -Preparation of tert-butyl formate
将4-(7-氯酞嗪-1-基)哌嗪-1-甲酸叔丁酯(60mg,0.172mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(81mg,0.189mmol)、Pd(dppf)Cl2(12mg,0.017mmol)、碳酸铯(168mg,0.516mmol)、1,4-二氧六环和水的混合溶剂(5mL，v/v＝10/1)加入反应瓶中，加毕，氮气保护下升温至100℃反应2h。反应结束后，加水(50mL)淬灭反应，乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到20/1)，得4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯，产率70.1％；ESI-MS(m/z)：613.2[M+H]+。4-(7-chlorophthalazin-1-yl)piperazine-1-carboxylic acid tert-butyl ester (60mg, 0.172mmol), 2,4-difluoro-N-(2-methoxy-5-(4 ,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (81mg, 0.189mmol), Pd(dppf)Cl 2 (12mg, 0.017mmol), cesium carbonate (168mg, 0.516mmol), a mixed solvent of 1,4-dioxane and water (5mL, v/v=10/1) was added to the reaction flask, after the addition was complete, nitrogen Under protection, the temperature was raised to 100°C for 2 hours. After the reaction, add water (50 mL) to quench the reaction, extract with ethyl acetate (100 mL×2), combine the organic phases, wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 20/1) to obtain 4-(7-(5-((2,4-difluorophenyl)sulfonamide yl)-6-methoxypyridin-3-yl)phthalazin-1-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 70.1%; ESI-MS (m/z): 613.2 [M+H ] + .
步骤f)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)酞嗪-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step f): 2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)phthalazin-6-yl)pyridin-3-yl)benzenesulfonamide tris Preparation of fluoroacetate
将4-(7-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)酞嗪-1-基)哌嗪-1-甲酸叔丁酯(50mg,0.082mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)酞嗪-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：513.2[M+H]+。4-(7-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)phthalazin-1-yl)piperazine-1-carboxylic acid Butyl ester (50mg, 0.082mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5 mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piper oxazin-1-yl)phthalazin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 513.2 [M+H] + .
步骤g)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)酞嗪-6-基)吡啶-3-基)苯磺酰胺的制备Step g): (E)-2,4-Difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) phthalazin-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)酞嗪-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(40mg,0.064mmol)和四氢呋喃(2mL)加入反应瓶中，将反应体系降温至-78℃，依次加入N,N-二异丙基乙胺(50mg,0.384mmol)、(E)-4-氧代戊-2-烯酸(7mg,0.064mmol)和T3P乙酸乙酯溶液(81mg,0.128mmol,50％wt)，加毕，在-78℃反应1h。反应结束后，加入乙腈(1mL)稀释反应液，反应液经Prep-HPLC(方法2)纯化，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)酞嗪-6-基)吡啶-3-基)苯磺酰胺，产率20.8％；1H NMR(400MHz,DMSO-d6)δ10.38(br s,1H),9.35(s,1H),8.52(s,1H),8.28-8.15(m,3H),8.07(d,J＝2.4Hz,1H),7.82-7.73(m,1H),7.61-7.53(m,1H),7.50(d,J＝16.0Hz,1H),7.24-7.17(m,1H),6.73(d,J＝15.6Hz,1H),3.99-3.82(m,4H),3.70(s,3H),3.60-3.46(m,4H),2.38(s,3H).；ESI-MS(m/z)：609.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)phthalazin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetic acid Salt (40mg, 0.064mmol) and tetrahydrofuran (2mL) were added to the reaction flask, the reaction system was cooled to -78°C, and N,N-diisopropylethylamine (50mg, 0.384mmol), (E)-4 -Oxopent-2-enoic acid (7mg, 0.064mmol) and T 3 P ethyl acetate solution (81mg, 0.128mmol, 50%wt) were added and reacted at -78°C for 1h. After the reaction was completed, acetonitrile (1 mL) was added to dilute the reaction solution, and the reaction solution was purified by Prep-HPLC (method 2) to obtain (E)-2,4-difluoro-N-(2-methoxy-5-(4 -(4-(4-oxopent-2-enoyl)piperazin-1-yl)phthalazin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 20.8%; 1 H NMR (400MHz ,DMSO-d 6 )δ10.38(br s,1H),9.35(s,1H),8.52(s,1H),8.28-8.15(m,3H),8.07(d,J＝2.4Hz,1H) ,7.82-7.73(m,1H),7.61-7.53(m,1H),7.50(d,J=16.0Hz,1H),7.24-7.17(m,1H),6.73(d,J=15.6Hz,1H ),3.99-3.82(m,4H),3.70(s,3H),3.60-3.46(m,4H),2.38(s,3H).; ESI-MS(m/z):609.0[M+H] + .
实施例63Example 63
(E)-2，4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)吡咯[1，2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺的制备
(E)-2,4-difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)pyrrole[1 , 2-b] pyridazin-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
步骤a)：1-氨基-4-溴-1H-吡咯-2-甲酸甲酯的制备Step a): Preparation of 1-amino-4-bromo-1H-pyrrole-2-carboxylic acid methyl ester
将叔丁醇钾(8.25g,73.523mmol)加入DMF(30mL)中，冰浴下滴加4-溴-1H-吡咯-2-甲酸甲酯(5.0g,24.507mmol)的DMF(30mL)溶液，加毕，室温反应1h。将反应液冷却至0℃，将O-对硝基苯甲酰基羟胺(8.93g,49.014mmol)溶于DMF(30mL)中后滴加入反应液，加毕，室温反应过夜。反应结束后，加水(100mL)淬灭反应，用稀盐酸(2M)调至pH为中性，用乙酸乙酯(200mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL次)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/30到1/1)，得1-氨基-4-溴-1H-吡咯-2-甲酸甲酯，产率22.1％；ESI-MS(m/z)：219.1[M+H]+。Potassium tert-butoxide (8.25g, 73.523mmol) was added in DMF (30mL), and a solution of 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (5.0g, 24.507mmol) in DMF (30mL) was added dropwise under ice-cooling , After addition, react at room temperature for 1h. The reaction liquid was cooled to 0°C, O-p-nitrobenzoyl hydroxylamine (8.93 g, 49.014 mmol) was dissolved in DMF (30 mL) and added dropwise to the reaction liquid. After the addition was complete, the reaction was carried out overnight at room temperature. After the reaction, add water (100mL) to quench the reaction, adjust the pH to neutral with dilute hydrochloric acid (2M), extract with ethyl acetate (200mL×2), combine the organic phase, and use saturated brine (100mL times) for the organic phase Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/30 to 1/1) to obtain 1-amino-4 -Bromo-1H-pyrrole-2-carboxylic acid methyl ester, yield 22.1%; ESI-MS (m/z): 219.1 [M+H] + .
步骤b)：4-溴-1-((3-甲氧基-3-氧代丙-1-烯-1-基)氨基)-1H-吡咯-2-甲酸甲酯的制备Step b): Preparation of methyl 4-bromo-1-((3-methoxy-3-oxoprop-1-en-1-yl)amino)-1H-pyrrole-2-carboxylate
将1-氨基-4-溴-1H-吡咯-2-甲酸甲酯(1.10g,5.022mmol)、2-炔丙酸甲酯(4.22g,50.220mmol)加入甲醇(10mL)中，加毕，80℃反应过夜。反应结束后，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/10到1/3)，得4-溴-1-((3-甲氧基-3-氧代丙-1-烯-1-基)氨基)-1H-吡咯-2-甲酸甲酯，产率83.4％；ESI-MS(m/z)：303.1[M+H]+。Add methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (1.10g, 5.022mmol) and methyl 2-propargyl (4.22g, 50.220mmol) into methanol (10mL), and the addition is complete. React overnight at 80°C. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10 to 1/3) to obtain 4-bromo-1-((3-methoxy Methyl-3-oxoprop-1-en-1-yl)amino)-1H-pyrrole-2-carboxylic acid methyl ester, yield 83.4%; ESI-MS (m/z): 303.1[M+H] + .
步骤c)：6-溴-4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-3-甲酸乙酯的制备Step c): Preparation of ethyl 6-bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate
将4-溴-1-((3-甲氧基-3-氧代丙-1-烯-1-基)氨基)-1H-吡咯-2-甲酸甲酯(1.18g,3.893mmol)、叔丁醇钾(874mg,7.786mmol)加入无水乙醇(15mL)中，加毕，85℃反应2h。反应结束后，冰浴下加水(100mL)淬灭反应，用乙酸乙酯(100mL×2)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得6-溴-4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-3-甲酸乙酯，产率86.4％；ESI-MS(m/z)：285.1[M+H]+。4-Bromo-1-((3-methoxy-3-oxoprop-1-en-1-yl)amino)-1H-pyrrole-2-carboxylic acid methyl ester (1.18g, 3.893mmol), tert Potassium butoxide (874mg, 7.786mmol) was added into absolute ethanol (15mL). After the addition was complete, the reaction was carried out at 85°C for 2h. After the reaction was over, add water (100mL) under ice bath to quench the reaction, extract with ethyl acetate (100mL×2), combine the organic phases, wash the organic phases with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and filtrate Concentration under reduced pressure gave ethyl 6-bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate with a yield of 86.4%; ESI-MS (m/z ): 285.1 [M+H] + .
步骤d)：6-溴-4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-3-甲酸的制备Step d): Preparation of 6-bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid
将6-溴-4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-3-甲酸乙酯(800mg,2.806mmol)、加入无水乙醇(20mL)中，再加入氢氧化钠溶液(20mL,2M),加毕，85℃反应过夜。反应结束后，减压浓缩，残余物于冰浴下用稀盐酸(2M)调至pH＝3，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得6-溴-4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-3-甲酸，产率88.7％；ESI-MS(m/z)：257.0[M+H]+。Add ethyl 6-bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylate (800mg, 2.806mmol) into absolute ethanol (20mL), and then Sodium hydroxide solution (20mL, 2M) was added, the addition was completed, and the reaction was carried out overnight at 85°C. After the reaction was completed, it was concentrated under reduced pressure, and the residue was adjusted to pH=3 with dilute hydrochloric acid (2M) under an ice bath, extracted with ethyl acetate (50mL×2), and the organic phases were combined, and the organic phase was washed with saturated brine (50mL) Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 6-bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid, yield 88.7 %; ESI-MS (m/z): 257.0 [M+H] + .
步骤e)：6-溴吡咯并[1,2-b]哒嗪-4(1H)-酮的制备Step e): Preparation of 6-bromopyrrolo[1,2-b]pyridazin-4(1H)-one
将6-溴-4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-3-甲酸(700mg,2.723mmol)加入苯醚-联苯共晶(10mL)中，260℃反应1h。反应结束后，将反应液经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/100到1/10)，得6-溴吡咯并[1,2-b]哒嗪-4(1H)-酮，产率48.0％；ESI-MS(m/z)：213.0[M+H]+。6-Bromo-4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazine-3-carboxylic acid (700 mg, 2.723 mmol) was added to phenylene ether-biphenyl cocrystal (10 mL), Reaction at 260°C for 1h. After the reaction, the reaction solution was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether = 1/100 to 1/10) to obtain 6-bromopyrrolo[1,2-b]pyridazine- 4(1H)-ketone, yield 48.0%; ESI-MS (m/z): 213.0 [M+H] + .
步骤f)：2,4-二氟-N-(2-甲氧基-5-(4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺的制备 Step f): 2,4-Difluoro-N-(2-methoxy-5-(4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazin-6-yl) Preparation of pyridin-3-yl)benzenesulfonamide
将6-溴吡咯并[1,2-b]哒嗪-4(1H)-酮(135mg,0.634mmol)、2,4-二氟-N-(2-甲氧基-5-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)吡啶-3-基)苯磺酰胺(297mg,0.697mmol)、Pd(dppf)Cl2(46mg,0.063mmol)和碳酸铯(620g,1.902mmol)加入1,4-二氧六环/水混合溶剂(10mL，v/v＝10/1)中，加毕，氮气保护下升温至100℃反应2h。反应结束后，加水(30mL)淬灭反应，乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL次)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到10/1)，得2,4-二氟-N-(2-甲氧基-5-(4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺，产率68.7％；ESI-MS(m/z)：433.1[M+H]+。6-bromopyrrolo[1,2-b]pyridazin-4(1H)-one (135mg, 0.634mmol), 2,4-difluoro-N-(2-methoxy-5-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)benzenesulfonamide (297mg, 0.697mmol), Pd(dppf)Cl 2 (46mg, 0.063mmol) and cesium carbonate (620g, 1.902mmol) were added into 1,4-dioxane/water mixed solvent (10mL, v/v=10/1), after addition, the temperature was raised to 100 ℃ reaction 2h. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (50mL×2), combine the organic phases, wash the organic phase with saturated brine (30mL times), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the obtained crude product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1 to 10/1) to obtain 2,4-difluoro-N-(2-methoxy-5-(4 -Oxo-1,4-dihydropyrrolo[1,2-b]pyridazin-6-yl)pyridin-3-yl)benzenesulfonamide, yield 68.7%; ESI-MS (m/z): 433.1[M+H] + .
步骤g)：6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)吡咯并[1,2-b]哒嗪-4-基三氟甲磺酸盐的制备Step g): 6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-4- Preparation of Trifluoromethanesulfonate
将2,4-二氟-N-(2-甲氧基-5-(4-氧代-1,4-二氢吡咯并[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺(80mg，0.185mmol)、三乙胺(28mg，0.278mmol)加入二氯甲烷(10mL)中，冰浴下将三氟甲磺酸酐(63mg，0.222mmol)缓慢滴入反应液，加毕，保持冰浴反应1h。反应结束后，加水(30mL)淬灭反应，用饱和碳酸氢钠溶液调至pH为中性，用乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL次)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，得6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)吡咯并[1,2-b]哒嗪-4-基三氟甲磺酸盐，产率77.7％；ESI-MS(m/z)：565.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-oxo-1,4-dihydropyrrolo[1,2-b]pyridazin-6-yl)pyridine-3 -yl) benzenesulfonamide (80mg, 0.185mmol), triethylamine (28mg, 0.278mmol) were added in dichloromethane (10mL), and trifluoromethanesulfonic anhydride (63mg, 0.222mmol) was slowly dropped into the reaction under ice-cooling After the addition, keep the reaction in ice bath for 1h. After the reaction is over, add water (30mL) to quench the reaction, adjust the pH to neutral with saturated sodium bicarbonate solution, extract with ethyl acetate (50mL×2), combine the organic phase, and use saturated brine (30mL times) for the organic phase Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)pyrrolo [1,2-b]pyridazin-4-yl trifluoromethanesulfonate, yield 77.7%; ESI-MS (m/z): 565.0 [M+H] + .
步骤h)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)吡咯并[1,2-b]哒嗪-4-基)哌嗪-1-甲酸叔丁酯的制备Step h): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine Preparation of -4-yl)piperazine-1-carboxylic acid tert-butyl ester
将6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)吡咯并[1,2-b]哒嗪-4-基三氟甲磺酸盐(70mg，0.124mmol)、哌嗪-1-甲酸叔丁酯(46mg，0.248mmol)、DIPEA(48mg，0.372mmol)加入DMF(2mL)中，加毕，50℃反应4h。反应结束后，加水(30mL)淬灭反应，乙酸乙酯(50mL×2)萃取，合并有机相，有机相用饱和食盐水(30mL次)洗涤，无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝11/10到1/0)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)吡咯并[1,2-b]哒嗪-4-基)哌嗪-1-甲酸叔丁酯，产率87.2％；ESI-MS(m/z)：601.2[M+H]+。6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yltrifluoro Methanesulfonate (70mg, 0.124mmol), tert-butyl piperazine-1-carboxylate (46mg, 0.248mmol), DIPEA (48mg, 0.372mmol) were added to DMF (2mL), after the addition was complete, the reaction was carried out at 50°C for 4h. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (50mL×2), combine the organic phases, wash the organic phase with saturated brine (30mL times), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=11/10 to 1/0) to obtain 4-(6-(5-((2,4-difluorophenyl) Sulfonamido)-6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 87.2%; ESI-MS (m/z): 601.2 [M+H] + .
步骤i)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)吡咯并[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step i): 2,4-Difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)pyridine Preparation of -3-yl)benzenesulfonamide trifluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)吡咯并[1,2-b]哒嗪-4-基)哌嗪-1-甲酸叔丁酯(50mg,0.083mmol)溶于二氯甲烷(4mL)中，冰浴下缓慢滴加TFA(1mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆,析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)吡咯并[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：501.2[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-4- Base) tert-butyl piperazine-1-carboxylate (50mg, 0.083mmol) was dissolved in dichloromethane (4mL), and TFA (1mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piper Azin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 501.2 [M+ H] + .
步骤j)：(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)吡咯[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺的制备Step j): (E)-2,4-Difluoro-N-(2-methoxy-5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl ) pyrrole [1,2-b] pyridazin-6-yl) pyridin-3-yl) preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)吡咯并[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(40mg,0.065mmol)溶于四氢呋喃(2mL)中，将反应体系降温至-78℃，依次加入N,N-二异丙基乙胺(50mg,0.390mmol)、(E)-4-氧代戊-2-烯酸(7mg,0.065mmol)和50％的T3P乙酸乙酯溶液(82mg,0.130mmol,50％wt)，加毕，在-78℃反应1h。反应结束后，加入乙腈(1mL)稀释反应液，将反应液经Prep-HPLC(方法2)纯化，冻干，得(E)-2,4-二氟-N-(2-甲氧基-5-(4-(4-(4-氧代戊-2-烯酰基)哌嗪-1-基)吡咯[1,2-b]哒嗪-6-基)吡啶-3-基)苯磺酰胺，产率29.4％；1H NMR(400MHz,Chloroform-d)δ8.15(d,J＝2.4Hz,1H),7.98(d,J＝2.4Hz,1H),7.91-7.81(m,2H),7.22(d,J＝13.2Hz,1H),7.10(d,J＝15.6Hz,2H),7.00-6.84(m,3H),6.60(d,J＝2.0Hz,1H),5.89(d,J＝5.2Hz,1H),3.97(d,J＝4.4Hz,2H),3.92(s,3H),3.86(s,2H),3.60-3.44(m,4H),2.38(s,3H).；ESI-MS(m/z)：597.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)pyrrolo[1,2-b]pyridazin-6-yl)pyridine-3- Base) benzenesulfonamide trifluoroacetate (40mg, 0.065mmol) was dissolved in tetrahydrofuran (2mL), the reaction system was cooled to -78°C, and N,N-diisopropylethylamine (50mg, 0.390mmol ), (E)-4-oxopent-2-enoic acid (7mg, 0.065mmol) and 50% T 3 P ethyl acetate solution (82mg, 0.130mmol, 50%wt), after addition, at -78 ℃ reaction 1h. After the reaction, acetonitrile (1 mL) was added to dilute the reaction solution, the reaction solution was purified by Prep-HPLC (method 2), and lyophilized to obtain (E)-2,4-difluoro-N-(2-methoxy- 5-(4-(4-(4-oxopent-2-enoyl)piperazin-1-yl)pyrrole[1,2-b]pyridazin-6-yl)pyridin-3-yl)benzenesulfonate Amide, yield 29.4%; 1H NMR (400MHz, Chloroform-d) δ8.15(d, J=2.4Hz, 1H), 7.98(d, J=2.4Hz, 1H), 7.91-7.81(m, 2H) ,7.22(d,J=13.2Hz,1H),7.10(d,J=15.6Hz,2H),7.00-6.84(m,3H),6.60(d,J=2.0Hz,1H),5.89(d, J＝5.2Hz, 1H), 3.97(d, J＝4.4Hz, 2H), 3.92(s, 3H), 3.86(s, 2H), 3.60-3.44(m, 4H), 2.38(s, 3H). ; ESI-MS (m/z): 597.0 [M+H] + .
对照实施例Comparative example
N-(5-(4-(4-丙烯酰哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2，4-二氟苯磺酰胺的制备
N-(5-(4-(4-acryloylpiperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide preparation
步骤a)：4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯的制备 Step a): 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1 -Preparation of tert-butyl formate
将N-(5-溴-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺(400mg,1.055mmol)、4-(6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(510mg,1.161mmol)、Pd(dppf)Cl2(78mg,0.106mmol)和碳酸铯(1.03g,3.165mmol)溶于二氧六环/水混合溶剂(6mL，v/v＝5:1)中，加毕，氮气保护下升温至100℃搅拌2h。反应结束后，加水(30mL)淬灭反应，乙酸乙酯(60mL×2)萃取，合并有机相，有机相用无水硫酸钠干燥，过滤、滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝100/1到30/1)，得4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯，产率84.1％；ESI-MS(m/z)：612.6[M+H]+。N-(5-bromo-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide (400mg, 1.055mmol), 4-(6-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (510mg, 1.161mmol), Pd(dppf)Cl 2 (78mg, 0.106mmol) and cesium carbonate (1.03g, 3.165mmol) were dissolved in dioxane/water mixed solvent (6mL, v/v=5:1), after addition, the temperature was raised to 100°C under nitrogen protection Stir for 2h. After the reaction, add water (30mL) to quench the reaction, extract with ethyl acetate (60mL×2), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (Eluent: dichloromethane/methanol=100/1 to 30/1), 4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxy Pyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, yield 84.1%; ESI-MS (m/z): 612.6[M+H] + .
步骤b)：2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐的制备Step b): 2,4-Difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide tris Preparation of fluoroacetate
将4-(6-(5-((2,4-二氟苯基)磺酰胺基)-6-甲氧基吡啶-3-基)喹啉-4-基)哌嗪-1-甲酸叔丁酯(300mg,0.490mmol)溶于二氯甲烷(2mL)中，冰浴下缓慢滴加三氟乙酸(0.7mL)，加毕，室温搅拌1h。反应结束后，减压浓缩，粗品用甲基叔丁基醚(5mL)打浆，析出固体，过滤，得2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐；ESI-MS(m/z)：512.1[M+H]+。4-(6-(5-((2,4-difluorophenyl)sulfonamido)-6-methoxypyridin-3-yl)quinolin-4-yl)piperazine-1-carboxylic acid tert Butyl ester (300mg, 0.490mmol) was dissolved in dichloromethane (2mL), and trifluoroacetic acid (0.7mL) was slowly added dropwise under ice-cooling. After the addition was complete, it was stirred at room temperature for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (5 mL), and the solid was precipitated and filtered to obtain 2,4-difluoro-N-(2-methoxy-5-(4-(piper Azin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetate; ESI-MS (m/z): 512.1 [M+H] + .
步骤c)：N-(5-(4-(4-丙烯酰哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺的制备Step c): N-(5-(4-(4-acryloylpiperazin-1-yl)quinolin-6-yl)-2-methoxypyridin-3-yl)-2,4-difluoro Preparation of benzenesulfonamide
将2,4-二氟-N-(2-甲氧基-5-(4-(哌嗪-1-基)喹啉-6-基)吡啶-3-基)苯磺酰胺三氟乙酸盐(250mg,0.400mmol)和四氢呋喃(3mL)加入反应瓶中，将反应体系冷却至-78℃，依次加入DIPEA(258mg,2.000mmol)、丙烯酸(26mg,0.360mmol)和50％的T3P乙酸乙酯溶液(509mg,0.800mmol)，加毕，在-78℃搅拌10min。反应结束后，反应液用乙腈(1mL)稀释，经Prep-HPLC(方法2)纯化，得N-(5-(4-(4-丙烯酰哌嗪-1-基)喹啉-6-基)-2-甲氧基吡啶-3-基)-2,4-二氟苯磺酰胺，产率15.1％；1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.73-8.70(m,1H),8.46-8.42(m,1H),8.18-8.15(m,1H),8.07-8.03(m,1H),8.02-7.95(m,2H),7.82-7.75(m,1H),7.58-7.50(m,1H),7.24-7.17(m,1H),7.05(d,J＝5.2Hz,1H),6.87(dd,J1＝16.4Hz,J2＝10.4Hz,1H),6.20-6.13(m,1H),5.76-5.71(m,1H),3.92-3.82(m,4H),3.71(s,3H),3.27-3.20(m,4H)；ESI-MS(m/z)：566.0[M+H]+。2,4-difluoro-N-(2-methoxy-5-(4-(piperazin-1-yl)quinolin-6-yl)pyridin-3-yl)benzenesulfonamide trifluoroacetic acid Salt (250mg, 0.400mmol) and tetrahydrofuran (3mL) were added to the reaction flask, the reaction system was cooled to -78°C, DIPEA (258mg, 2.000mmol), acrylic acid (26mg, 0.360mmol) and 50% T 3 P were added successively Ethyl acetate solution (509 mg, 0.800 mmol) was added and stirred at -78°C for 10 min. After the reaction, the reaction solution was diluted with acetonitrile (1 mL) and purified by Prep-HPLC (method 2) to obtain N-(5-(4-(4-acryloylpiperazin-1-yl)quinolin-6-yl )-2-methoxypyridin-3-yl)-2,4-difluorobenzenesulfonamide, yield 15.1%; 1 H NMR (400MHz, DMSO-d 6 )δ10.36(s,1H), 8.73 -8.70(m,1H),8.46-8.42(m,1H),8.18-8.15(m,1H),8.07-8.03(m,1H),8.02-7.95(m,2H),7.82-7.75(m, 1H),7.58-7.50(m,1H),7.24-7.17(m,1H),7.05(d,J=5.2Hz,1H),6.87(dd,J1=16.4Hz,J2=10.4Hz,1H), 6.20-6.13(m,1H),5.76-5.71(m,1H),3.92-3.82(m,4H),3.71(s,3H),3.27-3.20(m,4H); ESI-MS(m/z ): 566.0[M+H] + .
生物活性测试Biological activity test
本发明所用的PI3Kα抑制剂阳性参照化合物为Alpelisib(NVP-BYL-719)，结构如下：
The positive reference compound of PI3Kα inhibitor used in the present invention is Alpelisib (NVP-BYL-719), and the structure is as follows:
本发明所用的PI3Kδ抑制剂阳性参照化合物为Parsaclisib(IBI-376)，结构如下：
The positive reference compound of PI3Kδ inhibitor used in the present invention is Parsaclisib (IBI-376), the structure is as follows:
本发明所用的KRAS G12C抑制剂阳性参照化合物为Sotorasib(AMG 510)，结构如下：
The KRAS G12C inhibitor positive reference compound used in the present invention is Sotorasib (AMG 510), and the structure is as follows:
测试例1:PI3Kα抑制活性测定Test Example 1: Determination of PI3Kα inhibitory activity
通过ADP-Glo技术检测筛测化合物对PI3Kα亚型酶活的影响，从而评估其对PI3K蛋白酶活的抑制水平。所用蛋白和检测试剂采用ADP-GloTM Kinase Assay Kit(Promage)，首先将2mM受试化合物母液(溶于DMSO中)用DMSO逐次进行5倍浓度梯度稀释，得到化合物工作液1(200倍)共8个浓度。再依次对8个浓度的工作液1进行20倍浓度梯度稀释，即吸取5μL工作液1加入到95μL ddH2O中，漩涡混合器上充分震荡混匀，得到筛测化合物工作液2(10倍)共8个浓度。在384孔浅孔白板中，每孔依次加入2μL 2.5×PI3Kα激酶溶液和1μL化合物工 作液2(10倍)，混匀，室温孵育15min；每孔依次加入2μL 2.5×PI底物和ATP混合溶液，混匀，室温孵育60min；每孔依次加入5μL ADP-Glo(含10mM MgCl2)试剂，混匀，室温孵育40min；每孔依次加入10μL Kinase Detection Reagent试剂，混匀，室温孵育40min；将384孔板置于多功能酶标仪上读值，选择luminescence通道，记录luminescence值，通过下面公式计算抑制率：The effect of the screening compounds on the PI3Kα subtype enzyme activity was detected by ADP-Glo technology, so as to evaluate its inhibition level on PI3K protease activity. The protein and detection reagents used were ADP-Glo ™ Kinase Assay Kit (Promage). First, the 2mM test compound mother solution (dissolved in DMSO) was diluted with DMSO successively by 5-fold concentration to obtain the compound working solution 1 (200-fold). 8 concentrations. Then, 20-fold concentration gradient dilutions were performed on 8 concentrations of working solution 1 in turn, that is, 5 μL of working solution 1 was added to 95 μL of ddH 2 O, and the vortex mixer was fully shaken to obtain the screening compound working solution 2 (10 times ) with a total of 8 concentrations. In a 384-well shallow-well white plate, add 2 μL 2.5×PI3Kα kinase solution and 1 μL compound engineering solution to each well As solution 2 (10 times), mix well, and incubate at room temperature for 15 min; add 2 μL of 2.5×PI substrate and ATP mixed solution to each well, mix well, and incubate at room temperature for 60 min; add 5 μL ADP-Glo (containing 10 mM MgCl 2 ) reagent, mix well, and incubate at room temperature for 40 minutes; add 10 μL of Kinase Detection Reagent to each well in turn, mix well, and incubate at room temperature for 40 minutes; place the 384-well plate on a multi-functional microplate reader to read the value, select the luminescence channel, and record the luminescence value, The inhibition rate was calculated by the following formula:
％抑制率＝[(阴性-受试化合物)/(阴性-Blank)]*100% inhibition rate=[(negative-test compound)/(negative-Blank)]*100
IC50通过抑制率由GraphPad Prism软件，选择log(inhibitor)vs.response—Variable Slope(four parameters)进行拟合计算(注：阴性为不加抑制剂组；Blank为不加酶组)。实施例化合物测试数据如表1～表2所示。IC 50 was calculated by fitting the inhibition rate with GraphPad Prism software and selecting log(inhibitor)vs.response—Variable Slope(four parameters) (Note: Negative means no inhibitor group; Blank means no enzyme group). The test data of the compounds of the examples are shown in Table 1-Table 2.
测试例2:PI3Kδ酶抑制活性测定Test Example 2: Determination of PI3Kδ Enzyme Inhibitory Activity
通过ADP-Glo技术检测筛测化合物对PI3Kδ亚型酶活的影响，从而评估其对PI3K蛋白酶活的抑制水平。所用蛋白和检测试剂采用ADP-GloTM Kinase Assay Kit(Promage)，首先将2mM受试化合物母液(溶于DMSO中)用DMSO逐次进行5倍浓度梯度稀释，得到化合物工作液1(200倍)共8个浓度。再依次对8个浓度的工作液1进行20倍浓度梯度稀释，即吸取5μL工作液1加入到95μL ddH2O中，漩涡混合器上充分震荡混匀，得到化合物工作液2(10倍)共8个浓度。在384孔浅孔白板中，每孔依次加入2μL 2.5×PI3Kδ激酶溶液和1μL筛测化合物工作液2(10倍)，混匀，室温孵育15min；每孔依次加入2μL 2.5×PI底物和ATP混合溶液，混匀，室温孵育60min；每孔依次加入5μL ADP-Glo(含10mM MgCl2)试剂，混匀，室温孵育40min；每孔依次加入10μL Kinase Detection Reagent试剂，混匀，室温孵育40min；将384孔板置于多功能酶标仪上读值，选择luminescence通道，记录luminescence值，通过下面公式计算抑制率：The effect of the screening compound on the enzyme activity of PI3Kδ subtype was detected by ADP-Glo technology, so as to evaluate its inhibition level on PI3K protease activity. The protein and detection reagents used were ADP-Glo ™ Kinase Assay Kit (Promage). First, the 2mM test compound mother solution (dissolved in DMSO) was diluted with DMSO successively by 5-fold concentration to obtain the compound working solution 1 (200-fold). 8 concentrations. Then, 20-fold concentration gradient dilutions were performed on 8 concentrations of working solution 1 in turn, that is, 5 μL of working solution 1 was added to 95 μL ddH 2 O, and the vortex mixer was fully shaken to obtain compound working solution 2 (10 times). 8 concentrations. In a 384-well shallow-well white plate, add 2 μL 2.5×PI3Kδ kinase solution and 1 μL screening compound working solution 2 (10 times) to each well, mix well, and incubate at room temperature for 15 minutes; add 2 μL 2.5×PI substrate and ATP to each well in turn Mix the solution, mix well, and incubate at room temperature for 60 min; add 5 μL of ADP-Glo (containing 10 mM MgCl 2 ) reagent to each well, mix well, and incubate at room temperature for 40 min; add 10 μL Kinase Detection Reagent reagent to each well, mix well, and incubate at room temperature for 40 min; Place the 384-well plate on a multi-functional microplate reader to read the value, select the luminescence channel, record the luminescence value, and calculate the inhibition rate by the following formula:
％抑制率＝[(阴性-受试化合物)/(阴性-Blank)]*100% inhibition rate=[(negative-test compound)/(negative-Blank)]*100
IC50通过抑制率由GraphPad Prism软件，选择log(inhibitor)vs.response—Variable Slope(four parameters)进行拟合计算(注：阴性为不加抑制剂组；Blank为不加酶组)。实施例化合物测试数据如表1～表2所示。IC 50 was calculated by fitting the inhibition rate with GraphPad Prism software and selecting log(inhibitor)vs.response—Variable Slope(four parameters) (Note: Negative means no inhibitor group; Blank means no enzyme group). The test data of the compounds of the examples are shown in Table 1-Table 2.
表1 测定第一批次化合物对PI3Kα和PI3Kδ抑制活性
Table 1 Determination of the inhibitory activity of the first batch of compounds on PI3Kα and PI3Kδ
表2 测定第二批次化合物对PI3Kα和PI3Kδ抑制活性

Table 2 Determination of the inhibitory activity of the second batch of compounds on PI3Kα and PI3Kδ

注：N.T.-not testedNote: N.T.-not tested
Alpelisib、Parsaclisib分别是目前已知的PI3Kα抑制剂、PI3Kδ抑制剂，从表1～表2中数据可以看出，本发明化合物对PI3Kα、PI3Kδ具有明显的抑制作用，部分化合物的活性与阳性化合物相比更具优势，可用作PI3K抑制剂，在由PI3K蛋白介导的癌症等疾病领域具有广阔的应用前景。Alpelisib and Parsaclisib are currently known PI3Kα inhibitors and PI3Kδ inhibitors respectively. From the data in Table 1 to Table 2, it can be seen that the compounds of the present invention have obvious inhibitory effects on PI3Kα and PI3Kδ, and the activity of some compounds is comparable to that of positive compounds. Compared with the invention, it has more advantages, can be used as a PI3K inhibitor, and has broad application prospects in the fields of cancer and other diseases mediated by PI3K protein.
测试例3 KRAS-G12C/SOS1结合抑制活性测定Test Example 3 Determination of KRAS-G12C/SOS1 binding inhibitory activity
通过HTRF技术检测KRAS-G12C抑制剂对KRAS-G12C与SOS1蛋白之间相互作用的影响，从而评估其对KRAS-G12C蛋白的抑制活性。所用蛋白和检测试剂采用KRAS G12C/SOS1 binding assay kits(Cisbio)，首先将2mM受试化合物母液(溶于DMSO中)用DMSO逐次进行5倍浓度梯度稀释，得到化合物工作液1(200倍)共8个浓度。再依次对8个浓度的工作液1进行20倍浓度梯度稀释，即吸取5μL工作液1加入到95μL Diluent稀释缓冲液中，漩涡混合器上充分震荡混匀，得到筛测化合物工作液2(10倍)共8个浓度。在384孔浅孔白板中，每孔依次加入4μL Tag2-KRASG12C溶液、2μL化合物工作液2(10倍)和4μL Tag1-SOS1溶液，混匀，室温孵育15min；每孔依次加入Anti-tag1-Tb3+工作液和Anti-tag2-XL665工作液各5μL，混匀，于4℃孵育3h。将384孔板置于配置HTRF功能的酶标仪上，设置激发光波长为337nm，记录620nm和665nm的读值。数据结果以每孔665nm信号值与620nm信号值的比值呈现，即：Ratio＝104×665nm信号值/620nm信号值。通过下面公式计算抑制率：The effect of KRAS-G12C inhibitor on the interaction between KRAS-G12C and SOS1 protein was detected by HTRF technology, so as to evaluate its inhibitory activity on KRAS-G12C protein. The protein and detection reagents used were KRAS G12C/SOS1 binding assay kits (Cisbio). Firstly, the 2mM test compound mother solution (dissolved in DMSO) was diluted with DMSO successively by 5-fold concentration to obtain the compound working solution 1 (200-fold). 8 concentrations. Then, 20-fold concentration gradient dilutions were performed on 8 concentrations of working solution 1 in sequence, that is, 5 μL of working solution 1 was added to 95 μL of Diluent dilution buffer, and the vortex mixer was fully shaken to obtain the screening compound working solution 2 (10 times) a total of 8 concentrations. In a 384-well shallow-well white plate, add 4 μL Tag2-KRASG12C solution, 2 μL compound working solution 2 (10 times) and 4 μL Tag1-SOS1 solution to each well, mix well, and incubate at room temperature for 15 minutes; add Anti-tag1-Tb3+ to each well in turn 5 μL each of working solution and Anti-tag2-XL665 working solution, mix well, and incubate at 4°C for 3 hours. Place the 384-well plate on a microplate reader configured with HTRF function, set the excitation light wavelength to 337nm, and record the readings at 620nm and 665nm. The data results are presented as the ratio of the 665nm signal value to the 620nm signal value of each well, ie: Ratio=10 4 ×665nm signal value/620nm signal value. The inhibition rate was calculated by the following formula:
％抑制率＝[(Rati阴性-Rati化合物)/(Rati阴性-RatioBlank)]×100% inhibition rate=[(Rati Negative -Rati Compound )/(Rati Negative -Ratio Blank )]×100
注：阴性为不加抑制剂组；Blank为不加酶组。Note: Negative means no inhibitor group; Blank means no enzyme group.
IC50通过抑制率由GraphPad Prism软件,选择log(inhibitor)vs.response工作液riable Slope(four parameters)进行拟合计算。实施例化合物测试数据如表3、表4所示。IC 50 was calculated by fitting and calculating the inhibition rate by GraphPad Prism software, selecting log (inhibitor) vs. response working solution ribable Slope (four parameters). The test data of the compounds of the examples are shown in Table 3 and Table 4.
表3 测定第一批次化合物对KRAS-G12C/SOS1结合的抑制活性

Table 3 Determination of the inhibitory activity of the first batch of compounds on KRAS-G12C/SOS1 binding

表4 测定第二批次化合物对KRAS-G12C/SOS1结合的抑制活性
Table 4 Determination of the inhibitory activity of the second batch of compounds on KRAS-G12C/SOS1 binding
从表3、表4中的数据可以看出，对照实施例不具有KRAS-G12C/SOS1结合抑制活性，而本发明的化合物能有效阻断KRAS-G12C/SOS1结合，可用作KRAS G12C抑制剂，在由KRAS G12C蛋白介导的癌症等疾病及多靶点治疗领域具有广阔的应用前景。As can be seen from the data in Table 3 and Table 4, the comparative examples do not have KRAS-G12C/SOS1 binding inhibitory activity, while the compounds of the present invention can effectively block the KRAS-G12C/SOS1 binding and can be used as KRAS G12C inhibitors , which has broad application prospects in the field of cancer and other diseases mediated by KRAS G12C protein and multi-target therapy.
测试例4 KRAS G12C突变细胞株NCI-H358细胞、MIA Paca-2细胞增殖活性抑制作用的测定Test Example 4 Determination of KRAS G12C Mutant Cell Line NCI-H358 Cells and MIA Paca-2 Cell Proliferation Inhibition
1、通过试剂检测活细胞数量，从而评估化合物对细胞增殖的抑制作用。收集处于对数生长期的NCI-H358细胞，接种到透明底96孔板，每孔80μL，密度4×103个/孔，37℃、5％CO2培养过夜；化合物用DMSO逐次进行5倍稀释，得到8个浓度的梯度稀释液，然后分别用RPMI-640(10％FBS)细胞培养基稀释得到化合物工作液(5倍)，按每孔20μL加入细胞上清中，37℃、5％CO2条件下继续培养3天。取出孔板，在室温下(25℃)使孔板及混合试剂保持平衡约10-30分钟；小心吸弃50μL培养基，然后加入50μL试剂。用微孔振荡器使细胞与混合试剂充分混合2min，室温下孵化10min。将96孔板置于多功能酶标仪上记录发光值(RLU)。1. Pass The reagent detects the number of viable cells to evaluate the inhibitory effect of the compound on cell proliferation. Collect NCI-H358 cells in the logarithmic growth phase, inoculate into a transparent bottom 96-well plate, 80 μL per well, density 4×10 3 cells/well, culture overnight at 37°C, 5% CO 2 ; Dilute to obtain 8 concentrations of gradient dilutions, then dilute with RPMI-640 (10% FBS) cell culture medium to obtain compound working solution (5 times), add 20 μL per well to the cell supernatant, 37 ° C, 5% The culture was continued for 3 days under CO 2 conditions. Take out the orifice plate, and let the orifice plate and Mix the reagents and keep equilibrating for about 10-30 minutes; carefully aspirate 50 μL of medium, then add 50 μL reagent. Cells were mixed with the microwell shaker The mixed reagents were mixed thoroughly for 2 minutes, and incubated at room temperature for 10 minutes. The 96-well plate was placed on a multifunctional microplate reader to record the luminescence value (RLU).
通过下面公式计算抑制率：
The inhibition rate was calculated by the following formula:
IC50通过抑制率由GraphPad Prism软件进行计算(注：阴性对照为不加抑制剂组，Blank为不加细胞组)。实施例化合物测试数据如表5～表7所示。IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 5-Table 7.
2、通过试剂检测活细胞数量，从而评估化合物对细胞增殖的抑制作用。收集处于对数生长期的 MIA PaCa-2细胞，接种到透明底384孔板，每孔15μL，密度600个/孔，37℃、5％CO2培养过夜；化合物用DMSO逐次进行4倍稀释，得到9个浓度的梯度稀释液，然后分别用DMEM(10％FBS+2.5％马血清+1％P/S)细胞培养基稀释得到化合物工作液(2倍终浓度)，按每孔15μL加入细胞上清中，37℃、5％CO2条件下继续培养3天。取出孔板，在室温下(25℃)使孔板及混合试剂平衡30min；加入25μL试剂。用微孔振荡器使细胞与混合试剂充分混合2min，室温下孵化至少30min。将384孔板置于多功能酶标仪上记录发光值(RLU)。2. Pass The reagent detects the number of viable cells to evaluate the inhibitory effect of the compound on cell proliferation. collected in the logarithmic growth phase MIA PaCa-2 cells were inoculated into a transparent bottom 384-well plate, 15 μL per well, at a density of 600 cells/well, and cultured overnight at 37°C, 5% CO 2 ; the compound was diluted 4-fold with DMSO to obtain 9 concentrations of serial dilutions solution, and then diluted with DMEM (10% FBS + 2.5% horse serum + 1% P/S) cell culture medium to obtain the compound working solution (2 times final concentration), add 15 μL per well to the cell supernatant, 37 ° C, Culture was continued for 3 days under 5% CO 2 condition. Take out the orifice plate, and let the orifice plate and Mix the reagents and equilibrate for 30min; add 25μL reagent. Cells were mixed with the microwell shaker The mixed reagents were mixed thoroughly for 2 minutes and incubated at room temperature for at least 30 minutes. The 384-well plate was placed on a multifunctional microplate reader to record the luminescence value (RLU).
通过下面公式计算抑制率：
The inhibition rate was calculated by the following formula:
IC50通过抑制率由GraphPad Prism软件进行计算(注：阴性对照为不加抑制剂组，Blank为不加细胞组)。实施例化合物测试数据如表5、表6所示。IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 5 and Table 6.
表5 测定第一批次化合物对NCI-H358细胞(G12C突变)抑制活性
Table 5 Determination of the inhibitory activity of the first batch of compounds on NCI-H358 cells (G12C mutation)
表6 测定第二批次化合物对NCI-H358细胞和MIA Paca-2细胞抑制活性

Table 6 Determination of the inhibitory activity of the second batch of compounds on NCI-H358 cells and MIA Paca-2 cells

注：N.T.-not testedNote: N.T.-not tested
从表5～表6中的数据可以看出，本发明的化合物对KRAS G12C突变的肿瘤有很强的抗细胞增殖活性。It can be seen from the data in Tables 5 to 6 that the compounds of the present invention have strong anti-cell proliferation activity against KRAS G12C mutated tumors.
测试例5 NCI-H358-AMGR耐药细胞株构建方法Test example 5 NCI-H358-AMGR drug-resistant cell line construction method
将NCI-H358细胞接种到六孔板中，RPMI-640(10％FBS)培养基，37℃、5％CO2条件下培养至融合度为50-70％时开始添加AMG 510进行诱导。共设三个起始浓度组别：1nM、10nM、50nM组，每3天更换含相同浓度AMG 510的培养基一次。当细胞达到100％融合时传代，每传2代后增加AMG 510浓度，以3倍递增，如此反复直至AMG 510浓度到达1μM为止。比较AMG 510对耐药细胞株及亲代细胞株的抑制率，当最大给药浓度(10μM)的抑制率<50％时表明NCI-H358-AMGR耐药细胞株构建成功。NCI-H358 cells were inoculated into six-well plates, cultured in RPMI-640 (10% FBS) medium at 37°C and 5% CO 2 until the confluence was 50-70%, and AMG 510 was added for induction. Three initial concentration groups were established: 1nM, 10nM, and 50nM groups, and the culture medium containing the same concentration of AMG 510 was replaced every 3 days. When the cells reached 100% fusion, the AMG 510 concentration was increased by 3 times after every 2 passages, and so on until the AMG 510 concentration reached 1 μM. Comparing the inhibition rate of AMG 510 on the drug-resistant cell line and the parental cell line, when the inhibition rate of the maximum administration concentration (10 μM) was less than 50%, it indicated that the NCI-H358-AMGR drug-resistant cell line was successfully constructed.
收集对数生长期的NCI-H358-AMGR细胞，接种到透明底96孔板，每孔80μL，密度4×103个/孔，37℃、5％CO2培养过夜；化合物用DMSO逐次进行5倍稀释，得到8个浓度的梯度稀释液，然后分别用RPMI-640(10％FBS)细胞培养基稀释得到化合物工作液(5倍)，按每孔20μL加入细胞上清中，继续培养3天。取出孔板，在室温下(25℃)使孔板及混合试剂保持平衡约10-30min；小心吸弃50μL培养基，然后加入50μL 试剂。用微孔振荡器使细胞与混合试剂充分混合2min，室温下孵化10min。将96孔板置于多功能酶标仪上记录发光值(RLU)。Collect NCI-H358-AMGR cells in the logarithmic growth phase, inoculate into transparent bottom 96-well plate, 80 μL per well, density 4×10 3 cells/well, culture overnight at 37°C, 5% CO 2 ; 1-fold dilution to obtain 8 concentrations of gradient dilutions, and then diluted with RPMI-640 (10% FBS) cell culture medium to obtain compound working solution (5 times), add 20 μL per well to the cell supernatant, and continue to culture for 3 days . Take out the orifice plate, and let the orifice plate and Keep the mixed reagent equilibrated for about 10-30min; carefully aspirate 50μL of medium, then add 50μL reagent. Cells were mixed with the microwell shaker The mixed reagents were mixed thoroughly for 2 minutes, and incubated at room temperature for 10 minutes. The 96-well plate was placed on a multifunctional microplate reader to record the luminescence value (RLU).
通过下面公式计算抑制率：
The inhibition rate was calculated by the following formula:
IC50通过抑制率由GraphPad Prism软件进行计算(注：阴性对照为不加抑制剂组，Blank为不加细胞组)。实施例化合物测试数据如表7、表8所示。IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 7 and Table 8.
表7 测试第一批次化合物对NCI-H358-AMGR耐药细胞增殖抑制活性

Table 7 Test the inhibitory activity of the first batch of compounds on NCI-H358-AMGR drug-resistant cell proliferation

表8 测试第二批次化合物对NCI-H358-AMGR耐药细胞增殖抑制活性
Table 8 Test the second batch of compounds on NCI-H358-AMGR drug-resistant cell proliferation inhibitory activity
测试例6 MIA PaCa-2-AMGR耐药细胞株构建方法Test example 6 MIA PaCa-2-AMGR drug-resistant cell line construction method
将MIA PaCa-2细胞接种到六孔板中，DMEM(10％FBS+2.5％马血清)培养基，37℃、5％CO2条件下培养至融合度为50-70％时开始添加AMG 510进行诱导。共设三个起始浓度组别：1nM、10nM、50nM组，每3天更换含相同浓度AMG 510的培养基一次。当细胞达到100％融合时传代，每传2代后增加AMG 510浓度，以3倍递增，如此反复直至AMG 510浓度到达1μM为止。比较AMG510对耐药细胞株及亲代细胞株的抑制率，当最大给药浓度(10μM)的抑制率<50％时表明MIA PaCa-2-AMGR耐药细胞株构建成功。MIA PaCa-2 cells were inoculated into six-well plates in DMEM (10% FBS+2.5% horse serum) medium, and cultured at 37°C and 5% CO2 until the confluence was 50-70%, and AMG 510 was added. To induce. Three initial concentration groups were established: 1nM, 10nM, and 50nM groups, and the culture medium containing the same concentration of AMG 510 was replaced every 3 days. When the cells reached 100% fusion, the AMG 510 concentration was increased by 3 times after every 2 passages, and so on until the AMG 510 concentration reached 1 μM. Comparing the inhibition rate of AMG510 on the drug-resistant cell line and the parental cell line, when the inhibition rate of the maximum administration concentration (10 μM) was less than 50%, it indicated that the MIA PaCa-2-AMGR drug-resistant cell line was successfully constructed.
收集对数生长期的MIA PaCa-2-AMGR细胞，接种到透明底96孔板，每孔80μL，密度4×103个/孔，37℃、5％CO2培养过夜；化合物用DMSO逐次进行5倍稀释，得到8个浓度的梯度稀释液，然后分别用DMEM(10％FBS+2.5％马血清)细胞培养基稀释得到化合物工作液(5倍)，按每孔20μL加入细胞上清中，继续培养3天。取出孔板，在室温下(25℃)使孔板及混合试剂保持平衡约10-30min；小心吸弃50μL培养基，然后加入50μL试剂。用微孔振荡器使细胞与混合试剂充分混合2min，室温下孵化10min。将96孔板置于多功能酶标仪上记录发光值(RLU)。Collect MIA PaCa-2-AMGR cells in the logarithmic growth phase, inoculate them into a transparent bottom 96-well plate, 80 μL per well, at a density of 4× 10 cells/well, and culture overnight at 37°C, 5% CO 2 ; Diluted 5 times to obtain 8 concentrations of gradient dilutions, then diluted with DMEM (10% FBS+2.5% horse serum) cell culture medium to obtain compound working solution (5 times), and added 20 μL per well to the cell supernatant, Culture was continued for 3 days. Take out the orifice plate, and let the orifice plate and Keep the mixed reagent equilibrated for about 10-30min; carefully aspirate 50μL of medium, then add 50μL reagent. Cells were mixed with the microwell shaker The mixed reagents were mixed thoroughly for 2 minutes, and incubated at room temperature for 10 minutes. The 96-well plate was placed on a multifunctional microplate reader to record the luminescence value (RLU).
通过下面公式计算抑制率：
The inhibition rate was calculated by the following formula:
IC50通过抑制率由GraphPad Prism软件进行计算(注：阴性对照为不加抑制剂组，Blank为不加细胞组)。实施例化合物测试数据如表9、表10所示。IC 50 was calculated by GraphPad Prism software based on inhibition rate (Note: Negative control is no inhibitor group, Blank is no cell group). The test data of the compounds of the examples are shown in Table 9 and Table 10.
表9 测试第一批次化合物对MIA PaCa2-AMGR耐药细胞增殖抑制活性

Table 9 Test the first batch of compounds for MIA PaCa2-AMGR drug-resistant cell proliferation inhibitory activity

表10 测试第二批次化合物对MIA PaCa2-AMGR耐药细胞增殖抑制活性
Table 10 Test the second batch of compounds on MIA PaCa2-AMGR drug-resistant cell proliferation inhibitory activity
从表7～表10数据可以看出，本发明化合物对于KRAS-G12C抑制剂如AMG 510耐药癌细胞具有极强的抑制作用，可用于克服由单纯KRAS-G12C抑制剂所产生的耐药问题。From the data in Table 7 to Table 10, it can be seen that the compound of the present invention has a strong inhibitory effect on KRAS-G12C inhibitors such as AMG 510 drug-resistant cancer cells, and can be used to overcome the problem of drug resistance caused by simple KRAS-G12C inhibitors .
尽管已经示出和描述了本发明的实施例，对于本领域的普通技术人员而言，可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由所附权利要求及其等同物限定。 Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.

Claims (21)

  1. 一种化合物，其特征在于，具有式I所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
    A compound, characterized in that it has the structure shown in formula I or its tautomers, stereoisomers, solvates, metabolites, pharmaceutically acceptable salts, co-crystals:
    其中：in:
    T选自S(O)2、C＝O、CH2或NHS(O)2；T is selected from S(O) 2 , C=O, CH 2 or NHS(O) 2 ;
    A1选自CR10、CR11R12或N，A2选自CR13、CR14R15或N，A3选自CR16、CR17R18或N，A4选自CR19、CR20R21或N，A5选自C、CR41、N或S，A6选自CR9、CR42R43、N或A6不存在，A7选自CR8、CR44R45、N、NR8或S，A8选自C、CR46或N，其中，当A1和A3同时为N时，A6不存在；A 1 is selected from CR 10 , CR 11 R 12 or N, A 2 is selected from CR 13 , CR 14 R 15 or N, A 3 is selected from CR 16 , CR 17 R 18 or N, A 4 is selected from CR 19 , CR 20 R 21 or N, A 5 is selected from C, CR 41 , N or S, A 6 is selected from CR 9 , CR 42 R 43 , N or A 6 is absent, A 7 is selected from CR 8 , CR 44 R 45 , N, NR 8 or S, A 8 is selected from C, CR 46 or N, wherein, when A 1 and A 3 are N at the same time, A 6 does not exist;
    环C、环D、环E中的表示此处为一单键或无，且环C中任意两个相邻的不同时为单键；Ring C, Ring D, Ring E Indicates that there is a single bond or nothing here, and any two adjacent ring C Not single key at the same time;
    B为B1、B2所在的环为5～10元氮杂环烷基、5～10元氮杂环烯基，且B1、B2所在的环为单环、螺环或桥环，B1选自C、CR22或N，B2选自C、CR23或N，且B1、B2中至少有一个为N；B for The rings of B 1 and B 2 are 5-10 membered azacycloalkyl groups, 5-10 membered azacycloalkenyl groups, and the rings of B 1 and B 2 are monocyclic, spiro or bridged rings, B 1 selected from C, CR 22 or N, B 2 selected from C, CR 23 or N, and at least one of B 1 and B 2 is N;
    R7每次出现时分别独立选自卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORn、-NRoRp、-C(O)R24、-C(O)NRoRp、-C(O)ORn，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个卤素、氰基、烷基、环烷基、脂杂环基、-ORn、-NRoRp、-C(O)R24、-C(O)NRoRp、-C(O)ORn取代；Each occurrence of R 7 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR n , -NR o R p , -C(O)R 24. -C(O)NR o R p , -C(O)OR n , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more halogen, Cyano, Alkyl, Cycloalkyl, Heteroalicyclic, -OR n , -NR o R p , -C(O)R 24 , -C(O)NR o R p , -C(O)OR n replace;
    n1选自0、1、2、3、4；n 1 is selected from 0, 1, 2, 3, 4;
    R5、R6各自独立选自氢、卤素、氰基、烷基、脂杂环基、芳基、杂芳基、-ORa、-NRbRc、-C(O)R25、-S(O)R26、-S(O)2R26、-P(O)R26R27、-C(O)NRbRc、-C(O)ORa，且R5和R6不同时为氢；可选的，当R6选自-C(O)R25时，R25可与B环上任意一个R7相连共同组成4～12元脂杂环基；其中，所述烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R28取代；R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, alkyl, aliphatic heterocyclic group, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 25 , - S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27 , -C(O)NR b R c , -C(O)OR a , and R 5 and R 6 not be hydrogen at the same time; optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 on the B ring to form a 4-12-membered aliphatic heterocyclic group; wherein, the Alkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 28 ;
    R28每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORa、-NRbRc、-C(O)R25、-C(O)NRbRc、-C(O)ORa；Each occurrence of R 28 is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, -OR a , -NR b R c , -C(O)R 25 , -C(O)NR b R c , -C(O)OR a ;
    R1、R2分别独立选自氢、烷基、环烷基、脂杂环基、-C(O)R29，其中，所述烷基、环烷基、脂杂环基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基；当环E中的为一键时，R2为无；R 1 and R 2 are independently selected from hydrogen, alkyl, cycloalkyl, aliphatic heterocyclic group, and -C(O)R 29 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally replaced by One or more of the following substituents are substituted: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic ring; when ring E When it is a key, R 2 is none;
    R3选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORg、-NRhRi、-C(O)R30、-C(O)RhRi、-C(O)ORg，当环E中的为无时，R3还可以是与其连接的碳原子共同组成羰基，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R31取代；R 3 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR g , -NR h R i , -C(O)R 30 , -C (O)R h R i , -C(O)OR g , when ring E When it is none, R3 can also be carbon atoms connected to it to form a carbonyl group, wherein, alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by one or more R31 ;
    R31每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORg、-NRhRi、-C(O)R32、-C(O)NRhRi、-C(O)ORg；Each occurrence of R 31 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR g , -NR h R i , -C(O)R 32 , -C(O)NR h R i , -C(O)OR g ;
    R4选自烷基、环烷基、脂杂环基、芳基、杂芳基，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R33取代； R is selected from alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl, wherein, alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally replaced by one or more R 33 replacement;
    R33每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORj、-NRkRm、-C(O)R34、-C(O)NRkRm、-C(O)ORj，其中，所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR j , -NR k R m , -C(O)R 34 , -C(O)NR k R m , -C(O)OR j , wherein, the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, heteroaryl group are optionally replaced by one or more R 35 replaced;
    R35每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORj、-NRkRm、-C(O)R36、-C(O)NRkRm、-C(O)ORj；Each occurrence of R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR j , -NR k R m , -C(O)R 36 , -C(O)NR k R m , -C(O)OR j ;
    R8、R9、R10、R16、R19、R11、R12、R17、R18、R20、R21、R22、R23、R41、R42、R43、R44、R45、R46分别独立选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、杂芳基、-ORq、-NRrRs、-C(O)R37、-C(O)NRrRs、-C(O)ORq或无，其中，烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R38取代；R 8 , R 9 , R 10 , R 16 , R 19 , R 11 , R 12 , R 17 , R 18 , R 20 , R 21 , R 22 , R 23 , R 41 , R 42 , R 43 , R 44 , R 45 , R 46 are independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, -OR q , -NR r R s , -C(O )R 37 , -C(O)NR r R s , -C(O)OR q or none, wherein the alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or Multiple R 38 substitutions;
    R38每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-ORq、-NRrRs、-C(O)R39、-C(O)NRrRs、-C(O)ORq；Each occurrence of R 38 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR q , -NR r R s , -C(O)R 39 , -C(O)NR r R s , -C(O)OR q ;
    R13、R14、R15分别独立选自氢、甲基； R 13 , R 14 , and R 15 are independently selected from hydrogen and methyl;
    Ra、Rb、Rc、Rg、Rh、Ri、Rj、Rk、Rm、Rn、Ro、Rp、Rq、Rr、Rs每次出现时独立选自H、烷基、环烷基、脂杂环基、-C(O)R40，其中，所述烷基、环烷基、脂杂环基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基；R a , R b , R c , R g , R h , R i , R j , R k , R m , R n , R o , R p , R q , R r , R s are selected independently for each occurrence. from H, alkyl, cycloalkyl, aliphatic heterocyclic group, -C(O)R 40 , wherein the alkyl, cycloalkyl, aliphatic heterocyclic group is optionally substituted by one or more of the following substituents : Halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic heterocyclic;
    R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时分别独立选自氢、卤素、氰基、烷基、环烷基、脂杂环基，所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、烷基、环烷基、脂杂环基。R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , R 40 are each independently selected from hydrogen, halogen, cyano, Alkyl, cycloalkyl, aliphatic heterocyclic group, said alkyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, alkyl, cycloalkyl, alicyclic.
  2. 根据权利要求1所述化合物，其特征在于，选自如下基团： 优选地，具有芳香性。According to the described compound of claim 1, it is characterized in that, selected from the following groups: Preferably, Aromatic.
  3. 根据权利要求2所述化合物，其特征在于，According to the described compound of claim 2, it is characterized in that,
    选自如下基团：
    优选更优选     selected from the following groups:
    preferred more preferred
    或者，为其中，A1选自CR10、N，A2选自CR13、N，A3选自CR16、N，A4选自CR19、N，且A1和A3不同时为N； or, for Wherein, A 1 is selected from CR 10 and N, A 2 is selected from CR 13 and N, A 3 is selected from CR 16 and N, A 4 is selected from CR 19 and N, and A 1 and A 3 are not N at the same time;
    进一步地，选自如下基团： 优选 优选 更优选 further, selected from the following groups: preferred preferred more preferred
  4. 根据权利要求1～3任一项所述化合物，其特征在于，B为B1、B2所在的环为6～9元氮杂环烷基、6～9元氮杂环烯基，且B1、B2所在的环为单环、螺环或桥环，B1选自C、CR22或N，B2选自CR23或N，且B1、B2中至少有一个为N；或，The compound according to any one of claims 1 to 3, wherein B is The rings of B 1 and B 2 are 6-9 membered azacycloalkyl, 6-9 membered azacycloalkenyl, and the rings of B 1 and B 2 are monocyclic, spiro or bridged rings, B 1 selected from C, CR 22 or N, B 2 selected from CR 23 or N, and at least one of B 1 and B 2 is N; or,
    B为B1、B2所在的环为6～9元氮杂环烷基且为单环或螺环； B for The rings where B 1 and B 2 are located are 6-9 membered azacycloalkyl groups and are monocyclic or spiro rings;
    进一步地，B为B1、B2所在的环为6元氮杂单环烷基或8～9元氮杂螺环烷基；Further, B is The rings where B 1 and B 2 are located are 6-membered azamonocycloalkyl or 8-9 membered azaspirocycloalkyl;
    进一步地，选自如下基团：
    further, selected from the following groups:
    R22选自氢、卤素、C1～C6烷基，优选氢、卤素、C1～C3烷基，更优选氢；R 22 is selected from hydrogen, halogen, C1～C6 alkyl, preferably hydrogen, halogen, C1～C3 alkyl, more preferably hydrogen;
    R23选自氢、卤素、C1～C6烷基，优选氢、卤素、C1～C3烷基，或R23与R6及其相连的链段共同组成4～6元环烯基，优选R23与R6及其相连的链段共同组成5元环烯基；R 23 is selected from hydrogen, halogen, C1-C6 alkyl, preferably hydrogen, halogen, C1-C3 alkyl, or R 23 and R 6 and their connected segments together form a 4-6 membered cycloalkenyl, preferably R 23 Together with R6 and the chain segment connected to it, it forms a 5-membered cycloalkenyl group;
    进一步地，选自优选 further, selected from preferred
    或者，B为B1、B2所在的环为6～9元氮杂桥环烷基，优选为7～8元氮杂桥环烷基，更优选为8元氮杂桥环烷基；Alternatively, B is The rings of B 1 and B 2 are 6-9 membered azabridged cycloalkyl groups, preferably 7-8 membered azabridged cycloalkyl groups, more preferably 8-membered azabridged cycloalkyl groups;
    进一步地，B1、B2均为N；Further, both B 1 and B 2 are N;
    进一步地，为 further, for
    或者，B为B1、B2所在的环为6～9元氮杂环烯基，且B1、B2所在的环为单环、螺环或桥环，B1选自C、CR22或N，B2选自CR23或N，且B1、B2中至少有一个为N；Alternatively, B is The rings where B 1 and B 2 are located are 6-9 membered azacycloalkenyl groups, and the rings where B 1 and B 2 are located are monocyclic, spiro or bridged rings, and B 1 is selected from C, CR 22 or N, B 2 is selected from CR 23 or N, and at least one of B 1 and B 2 is N;
    优选地，B1、B2所在的环为6元氮杂环烯基，且B1、B2所在的环为单环，B1为C，B2为N；Preferably, the rings where B 1 and B 2 are located are 6-membered azacycloalkenyl groups, and the rings where B 1 and B 2 are located are monocyclic, B 1 is C, and B 2 is N;
    优选地，为 Preferably, for
    进一步地，n1选自0、1、2、3，优选0、1、2，更优选0或1。Further, n 1 is selected from 0, 1, 2, 3, preferably 0, 1, 2, more preferably 0 or 1.
  5. 根据权利要求1～4任一项所述化合物，其特征在于，T选自S(O)2或C＝O，优选S(O)2；The compound according to any one of claims 1-4, characterized in that T is selected from S(O) 2 or C=O, preferably S(O) 2 ;
    进一步地，R1、R2分别独立选自氢、卤素、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基、C3～C6环烷基、3～6元脂杂环基；当环E中的为一键时，R2为无；Further, R 1 and R 2 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, wherein the alkyl and cycloalkyl are optionally replaced by one or more of the following substituents Substitution: halogen, cyano, hydroxyl, amino, C1~C6 alkyl, C3~C6 cycloalkyl, 3~6 membered aliphatic heterocyclic group; when ring E When it is a key, R 2 is none;
    进一步地，R1、R2分别独立选自氢、卤素、C1～C3烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C3烷基、C3～C6环烷基；当环E中的为一键时，R2为无； Further, R 1 and R 2 are independently selected from hydrogen, halogen, C1-C3 alkyl, wherein the alkyl and cycloalkyl are optionally substituted by one or more of the following substituents: halogen, cyano, Hydroxy, amino, C1~C3 alkyl, C3~C6 cycloalkyl; when ring E When it is a key, R 2 is none;
    R1、R2分别独立选自氢或甲基；当环E中的为一键时，R2为无；R 1 and R 2 are independently selected from hydrogen or methyl; when ring E in When it is a key, R 2 is none;
    更进一步地，R1为氢；Further, R 1 is hydrogen;
    更进一步地，环E中的为一单键且R2为无，或者，环E中的为无且R2为氢；Further, the ring E in the is a single bond and R 2 is none, or, in ring E is None and R is hydrogen;
    更进一步地，环E中的为一键且R2为无。Further, the ring E in the is a bond and R2 is None.
  6. 根据权利要求1～5任一项所述化合物，其特征在于，R5、R6分别独立选自氢、卤素、C1～C6烷基、C3～C6环烷基、3～6元脂杂环基、6～10元芳基、5～10元杂芳基、-C(O)R25、-S(O)R26、-S(O)2R26、-P(O)R26R27、-C(O)NRbRc、-C(O)ORa，且R5和R6不同时为氢，其中，所述烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R28取代；The compound according to any one of claims 1-5, characterized in that R 5 and R 6 are independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclic radical, 6-10 membered aryl group, 5-10 membered heteroaryl group, -C(O)R 25 , -S(O)R 26 , -S(O) 2 R 26 , -P(O)R 26 R 27. -C(O)NR b R c , -C(O)OR a , and R 5 and R 6 are not hydrogen at the same time, wherein the alkyl, aliphatic heterocyclic group, aryl group, and heteroaryl group are any optionally replaced by one or more R 28 ;
    R28每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORa、-NRbRc；Each occurrence of R 28 is independently selected from halogen, cyano, C1～C6 alkyl, C3～C6 cycloalkyl, -OR a , -NR b R c ;
    可选地，当R6选自-C(O)R25时，R25可与任意一个R7相连共同组成n2选自0、1、2、3、4；Optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 to form n 2 is selected from 0, 1, 2, 3, 4;
    进一步地，R5、R6分别独立选自氢、卤素、C1～C3烷基、5～6元杂芳基、-C(O)R25、-S(O)2R16、-P(O)R16R17，且R5和R6不同时为氢，其中，所述烷基、杂芳基任选地被一个或多个R28取代；Further, R 5 and R 6 are independently selected from hydrogen, halogen, C1-C3 alkyl, 5-6 membered heteroaryl, -C(O)R 25 , -S(O) 2 R 16 , -P( O) R 16 R 17 , and R 5 and R 6 are not hydrogen at the same time, wherein the alkyl and heteroaryl are optionally substituted by one or more R 28 ;
    R28每次出现时独立选自卤素、C1～C3烷基、-ORa、-NRbRc；Each occurrence of R 28 is independently selected from halogen, C1～C3 alkyl, -OR a , -NR b R c ;
    可选地，当R6选自-C(O)R25时，R25可与任意一个R7相连共同组成n2选自1、2；Optionally, when R 6 is selected from -C(O)R 25 , R 25 can be connected with any R 7 to form n 2 is selected from 1, 2;
    进一步地，R5、R6分别独立选自H、F、C1～C3烷基、-C(O)CH3、-C(O)CH2CH2CH3、-CH2N(CH3)2、-CH2F、-S(O)2CH3、-P(O)(CH3)2，且R5和R6不同时为氢；Further, R 5 and R 6 are independently selected from H, F, C1-C3 alkyl, -C(O)CH 3 , -C(O)CH 2 CH 2 CH 3 , -CH 2 N(CH 3 ) 2. -CH 2 F, -S(O) 2 CH 3 , -P(O)(CH 3 ) 2 , and R 5 and R 6 are not hydrogen at the same time;
    可选地，当R6选自-C(O)CH2CH2CH3时，R25可与任意一个R7相连共同组成 Optionally, when R 6 is selected from -C(O)CH 2 CH 2 CH 3 , R 25 can be connected with any R 7 to form
    进一步地，R5为H；Further, R 5 is H;
    R6为-C(O)CH3，或者R6为-C(O)CH2CH2CH3且与任意一个R7相连共同组成优选地，R6为-C(O)CH3；R 6 is -C(O)CH 3 , or R 6 is -C(O)CH 2 CH 2 CH 3 and is combined with any R 7 Preferably, R 6 is -C(O)CH 3 ;
    进一步地，的构型为 further, is configured as
  7. 根据权利要求1～6任一项所述化合物，其特征在于，R7每次出现时分别独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORn、-NRoRp，其中，烷基、环烷基任选地被一个或多个选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORn、-NRoRp的取代基取代；The compound according to any one of claims 1 to 6, wherein each occurrence of R 7 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -OR n , - NR o R p , wherein, alkyl and cycloalkyl are optionally replaced by one or more selected from halogen, cyano, C1~C6 alkyl, C3~C6 cycloalkyl, -OR n , -NR o R p Substituent substitution;
    进一步地，R7选自C1～C3烷基、-ORn、-NRoRp，其中，烷基任选地被一个或多个卤素、氰基、C1～C3烷基、-ORn、-NRoRp取代；Further, R 7 is selected from C1～C3 alkyl, -OR n , -NR o R p , wherein the alkyl is optionally replaced by one or more halogen, cyano, C1～C3 alkyl, -OR n , -NR o R p substitution;
    进一步地，R7选自C1～C3烷基，优选甲基。Further, R 7 is selected from C1-C3 alkyl, preferably methyl.
  8. 根据权利要求1～7任一项所述化合物，其特征在于，R3选自氢、卤素、氰基、C1～C6烷基、C3～C6环烷基、3～6元脂杂环基、-ORg、-NRhRi，当环E中的为无时，R3还可以是与其连接的碳原子共同组成羰基，其中，烷基、环烷基、脂杂环基任选地被一个或多个R31取代，所述R31每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORg、-NRhRi；The compound according to any one of claims 1-7, wherein R is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 3-6 membered aliphatic heterocyclic groups, -OR g , -NR h R i , when ring E When it is None, R3 can also be a carbonyl group formed by the carbon atoms connected to it, wherein the alkyl group, cycloalkyl group, and aliphatic heterocyclic group are optionally substituted by one or more R31 , and each occurrence of R31 When independently selected from halogen, cyano, C1～C6 alkyl, C3～C6 cycloalkyl, -OR g , -NR h R i ;
    进一步地，R3选自氢、卤素、C1～C3烷基、-ORg、-NRhRi，当环E中的为无时，R3与其连接的碳原子共同组成羰基，其中，烷基任选地被一个或多个R31取代，R31每次出现时独立选自卤素、氰基、C1～C3烷基、-ORg、-NRhRi；Further, R 3 is selected from hydrogen, halogen, C1～C3 alkyl, -OR g , -NR h R i , when ring E When it is None, R3 and the carbon atom to which it is connected together form a carbonyl group, wherein the alkyl group is optionally substituted by one or more R31 , and each occurrence of R31 is independently selected from halogen, cyano, C1～C3 alkyl , -OR g , -NR h R i ;
    进一步地，R3选自氢、F、Cl、Br、甲基、-ORg、-NRhRi，当环E中的为无时，R3与其连接的碳原子共同组成羰基；Further, R 3 is selected from hydrogen, F, Cl, Br, methyl, -OR g , -NR h R i , when ring E When none, R 3 and the carbon atom connected to it together form a carbonyl group;
    进一步地，R3选自氢、C1～3烷基、-ORg，其中，所述烷基任选地被一个或多个卤素取代；Further, R 3 is selected from hydrogen, C1~3 alkyl, -OR g , wherein the alkyl is optionally substituted by one or more halogens;
    进一步地，R3为-ORg；优选为甲氧基、二氟甲氧基、三氟甲氧基，更优选为甲氧基。Further, R 3 is -OR g ; preferably methoxy, difluoromethoxy, trifluoromethoxy, more preferably methoxy.
  9. 根据权利要求1～8任一项所述化合物，其特征在于，Rg、Rh、Ri每次出现时独立选自H、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基；The compound according to any one of claims 1-8, characterized in that R g , Rh , and R i are independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl each time they appear, wherein, The alkyl and cycloalkyl are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1-C6 alkyl;
    进一步地，Rg、Rh、Ri每次出现时独立选自H、C1～C3烷基、环丙基、环戊基，其中，所述烷基、环丙基任选 地被一个或多个如下取代基取代：卤素、C1～C3烷基；Further, each occurrence of R g , Rh , and R i is independently selected from H, C1-C3 alkyl, cyclopropyl, and cyclopentyl, wherein the alkyl and cyclopropyl are optionally is substituted by one or more of the following substituents: halogen, C1-C3 alkyl;
    更进一步地，Rg、Rh、Ri每次出现时独立选自H、甲基、环丙基、环戊基，其中，所述甲基任选地被一个或多个卤素取代。Further, each occurrence of R g , Rh , R i is independently selected from H, methyl, cyclopropyl, cyclopentyl, wherein said methyl is optionally substituted by one or more halogens.
  10. 根据权利要求1～9任一项所述化合物，其特征在于，R8、R9、R10、R16、R19、R11、R12、R17、R18、R20、R21、R22、R23分别独立选自氢、卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORq、-NRrRs或无，其中，烷基、环烷基任选地被一个或多个R38取代；The compound according to any one of claims 1-9, characterized in that, R 8 , R 9 , R 10 , R 16 , R 19 , R 11 , R 12 , R 17 , R 18 , R 20 , R 21 , R 22 and R 23 are independently selected from hydrogen, halogen, cyano, C1~C6 alkyl, C3~C6 cycloalkyl, -OR q , -NR r R s or none, wherein alkyl and cycloalkyl are any optionally replaced by one or more R38 ;
    R38每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORq、-NRrRs、-C(O)R39、-C(O)NRrRs、-C(O)ORq；Each occurrence of R 38 is independently selected from halogen, cyano, C1～C6 alkyl, C3～C6 cycloalkyl, -OR q , -NR r R s , -C(O)R 39 , -C(O) NR r R s , -C(O)OR q ;
    进一步地，R8、R9、R10、R16、R19分别独立选自氢、卤素、氰基、C1～C6烷基、-ORq、-NRrRs，Rq、Rr、Rs每次出现时独立选自H、C1～C6烷基，其中，烷基任选地被一个或多个R38取代，R38每次出现时独立选自卤素；R13选自氢、甲基；Further, R 8 , R 9 , R 10 , R 16 , and R 19 are independently selected from hydrogen, halogen, cyano, C1-C6 alkyl, -OR q , -NR r R s , R q , R r , Each occurrence of R s is independently selected from H, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 38 , each occurrence of R 38 is independently selected from halogen; R 13 is selected from hydrogen, methyl;
    优选地，R8、R9、R10、R16、R19分别独立选自氢、氟、氯、溴、氰基、甲基、二氟甲基、三氟甲基、羟基、甲氧基、二氟甲氧基、三氟甲氧基、氨基、甲氨基；R13选自氢、甲基；Preferably, R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, trifluoromethyl, hydroxyl, and methoxy , difluoromethoxy, trifluoromethoxy, amino, methylamino; R 13 is selected from hydrogen, methyl;
    进一步地，R8、R9、R10、R16、R19分别独立选自氢、卤素、氰基、C1～C6烷基；R13选自氢、甲基；Further, R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, halogen, cyano, and C1-C6 alkyl; R 13 is selected from hydrogen and methyl;
    优选地，R8、R9、R10、R16、R19分别独立选自氢、氟、氰基、甲基；R13选自氢、甲基；Preferably, R 8 , R 9 , R 10 , R 16 , and R 19 are each independently selected from hydrogen, fluorine, cyano, and methyl; R 13 is selected from hydrogen, methyl;
    更优选地，R8选自氢、氟、甲基；R9选自氢、氟；R10选自氢、氟、氰基；R16选自氢、氟；R19选自氢、氟；R13为氢。More preferably, R 8 is selected from hydrogen, fluorine, methyl; R 9 is selected from hydrogen, fluorine; R 10 is selected from hydrogen, fluorine, cyano; R 16 is selected from hydrogen, fluorine; R 19 is selected from hydrogen, fluorine; R 13 is hydrogen.
  11. 根据权利要求1～10任一项所述化合物，其特征在于，Rq、Rr、Rs每次出现时独立选自H、C1～C6烷基、C3～C6环烷基，其中，所述烷基、环烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基。The compound according to any one of claims 1-10, wherein R q , R r , and R s are independently selected from H, C1-C6 alkyl, and C3-C6 cycloalkyl at each occurrence, wherein, The above-mentioned alkyl and cycloalkyl are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
  12. 根据权利要求1～11任一项所述化合物，其特征在于，R4选自C1～C6烷基、C3～C9环烷基、3～6元杂环烷基、6～10元芳基、5～10元杂芳基，其中，烷基、环烷基、杂环烷基、芳基、杂芳基任选地被一个或多个R33取代；The compound according to any one of claims 1 to 11, wherein R is selected from C1 to C6 alkyl, C3 to C9 cycloalkyl, 3 to 6 membered heterocycloalkyl, 6 to 10 membered aryl, 5-10 membered heteroaryl, wherein, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by one or more R33 ;
    R33每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6环烷基、-ORj、-NRkRm、-C(O)R27、-C(O)NRkRm、-C(O)ORj，其中，所述烷基、环烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, -OR j , -NR k R m , -C(O)R 27 , -C(O) NR k R m , -C(O)OR j , wherein the alkyl and cycloalkyl are optionally substituted by one or more R 35 ;
    R35每次出现时独立选自卤素、氰基、烷基、环烷基、-ORj、-NRkRm；Each occurrence of R 35 is independently selected from halogen, cyano, alkyl, cycloalkyl, -OR j , -NR k R m ;
    进一步地，R4选自C1～C3烷基、C3～C6环烷基、苯基、5～6元氮杂芳基、5～6元硫杂芳基，其中，烷基、环烷基、芳基、氮杂芳基、硫杂芳基任选地被1～3个R33取代；Further, R 4 is selected from C1～C3 alkyl, C3～C6 cycloalkyl, phenyl, 5～6 membered azaaryl, 5～6 membered thiaaryl, wherein, alkyl, cycloalkyl, Aryl, azaaryl, and thiaaryl are optionally substituted by 1 to 3 R33 ;
    R33每次出现时独立选自卤素、氰基、C1～C3烷基、C3～C6环烷基、-ORj、-NRkRm，其中，所述烷基、环烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1～C3 alkyl, C3～C6 cycloalkyl, -OR j , -NR k R m , wherein the alkyl and cycloalkyl are optionally replaced by one or more R35 ;
    进一步地，R4选自C1～C3烷基、环己基、苯基、吡啶基、噻吩基，其中，烷基、环己基、苯基、吡啶基、噻吩基任选地被1～3个R33取代；Further, R 4 is selected from C1～C3 alkyl, cyclohexyl, phenyl, pyridyl, thienyl, wherein, alkyl, cyclohexyl, phenyl, pyridyl, thienyl are optionally replaced by 1 to 3 R 33 replaced;
    R33每次出现时独立选自F、Cl、Br、C1～C3烷基、-ORj，优选F、Cl、甲基、甲氧基；Each occurrence of R 33 is independently selected from F, Cl, Br, C1-C3 alkyl, -OR j , preferably F, Cl, methyl, methoxy;
    进一步地，R4选自6～10元芳基、5～10元杂芳基，其中，芳基、杂芳基任选地被一个或多个R33取代；Further, R 4 is selected from 6-10 membered aryl groups and 5-10 membered heteroaryl groups, wherein the aryl and heteroaryl groups are optionally substituted by one or more R 33 ;
    R33每次出现时独立选自卤素、氰基、C1～C6烷基、-ORj，其中，所述烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C6 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
    R35每次出现时独立选自卤素；each occurrence of R is independently selected from halogen;
    进一步地，R4选自苯基、5～6元杂芳基，所述杂芳基含有1～2个选自N、S的杂原子，其中，苯基、杂芳基任选地被1～3个R33取代；Further, R 4 is selected from phenyl, 5-6 membered heteroaryl, and said heteroaryl contains 1-2 heteroatoms selected from N and S, wherein, phenyl and heteroaryl are optionally replaced by 1 ~3 R33 substitutions;
    R33每次出现时独立选自卤素、氰基、C1～C3烷基、-ORj，其中，所述烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C3 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
    R35每次出现时独立选自卤素；each occurrence of R is independently selected from halogen;
    进一步地，R4选自苯基、吡啶基、噻唑基，上述基团任选地被1～3个R33取代；Further, R 4 is selected from phenyl, pyridyl, thiazolyl, and the above groups are optionally substituted by 1 to 3 R 33 ;
    R33每次出现时独立选自卤素、氰基、C1～C3烷基、-ORj，其中，所述烷基任选地被一个或多个R35取代；Each occurrence of R 33 is independently selected from halogen, cyano, C1-C3 alkyl, -OR j , wherein the alkyl is optionally substituted by one or more R 35 ;
    R35每次出现时独立选自卤素；each occurrence of R is independently selected from halogen;
    进一步地，R35为F；Further, R 35 is F;
    进一步地，R33每次出现时独立选自F、Cl、氰基、甲基、三氟甲基、甲氧基；Further, each occurrence of R is independently selected from F, Cl, cyano, methyl, trifluoromethyl, methoxy;
    进一步地，R4选自苯基、吡啶基，其中，苯基、吡啶基任选地被1～3个R33取代；Further, R 4 is selected from phenyl and pyridyl, wherein, phenyl and pyridyl are optionally substituted by 1 to 3 R 33 ;
    R33每次出现时独立选自F、甲基；R 33 is independently selected from F, methyl each time it occurs;
    进一步地，R4选自甲基、环己基、苯基、 Further, R 4 is selected from methyl, cyclohexyl, phenyl,
    进一步地，R4选自 Further, R 4 is selected from
  13. 根据权利要求1～12任意一项所述化合物，其特征在于，R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时独立选自H、C1～C6烷基，所述烷基任选地被一个或多个如下取代基取代：卤素、氰基、羟基、氨基、C1～C6烷基；The compound according to any one of claims 1-12, characterized in that, R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , Each occurrence of R 40 is independently selected from H, C1～C6 alkyl, said alkyl is optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1～C6 alkyl;
    进一步地，R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时独立选自H、C1～C3烷基，所述烷基任选地被一个或多个如下取代基取代：卤素、羟基、氨基、C1～C3烷基；Further, each occurrence of R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 is independently selected from H, C1-C3 Alkyl, said alkyl is optionally substituted by one or more of the following substituents: halogen, hydroxyl, amino, C1～C3 alkyl;
    进一步地，R24、R25、R26、R27、R29、R30、R32、R34、R36、R37、R39、R40每次出现时独立选自C1～C3烷基，优选甲基、丙基。Further, R 24 , R 25 , R 26 , R 27 , R 29 , R 30 , R 32 , R 34 , R 36 , R 37 , R 39 , and R 40 are each independently selected from C1-C3 alkyl groups. , preferably methyl, propyl.
  14. 根据权利要求1～13任一项所述化合物，其特征在于，具有式II、式III、式IV或V所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶：
    According to any one of claims 1 to 13, the compound is characterized in that it has the structure shown in formula II, formula III, formula IV or V or its tautomers, stereoisomers, solvates, metabolites, Pharmaceutically acceptable salts, co-crystals:
    其中，式II中B、A1、A2、A3、A4、R1、R2、R3、R4、R5、R6、R8、R9、R25各基团定义如前述式I化合物所定义； Among them, the definitions of B, A 1 , A 2 , A 3 , A 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , and R 25 in formula II are as follows: As defined by the aforementioned compound of formula I;
    式III中B1、B2、A1、A2、A3、A4、R1、R3、R4、R5、R7、R8、R25各基团定义如前述式I化合物所定义；The definitions of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 25 in formula III are as defined above for the compound of formula I defined by
    式IV中A1、A2、A3、A4、R1、R3、R4、R5各基团定义如前述式I化合物所定义；The definitions of A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , and R 5 in formula IV are as defined for the aforementioned compound of formula I;
    式V中B1、B2、A1、A2、A3、A4、R1、R3、R4、R7、R8各基团定义如前述式I化合物所定义。The definitions of B 1 , B 2 , A 1 , A 2 , A 3 , A 4 , R 1 , R 3 , R 4 , R 7 , and R 8 in formula V are as defined for the aforementioned compound of formula I.
  15. 根据权利要求1～14任一项所述的化合物，其特征在于，所述化合物结构选自如下之一：





    The compound according to any one of claims 1-14, wherein the compound structure is selected from one of the following:





    。.
  16. 一种药用组合物，其特征在于，该药用组合物的活性成份选自权利要求1～15任一项所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶中的一种或两种以上的组合。A pharmaceutical composition, characterized in that the active ingredient of the pharmaceutical composition is selected from the compound or its tautomers, stereoisomers, solvates, and metabolites described in any one of claims 1 to 15 , pharmaceutically acceptable salts, co-crystals or a combination of two or more.
  17. 权利要求1～15任一项所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或包含所述化合物的药物组合物在制备KRAS抑制剂和/或PI3K抑制剂中的用途；The compound according to any one of claims 1 to 15 or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pharmaceutical composition comprising the compound is being prepared Use in KRAS inhibitors and/or PI3K inhibitors;
    进一步地，所述KRAS抑制剂选自KRAS G12C抑制剂、KRAS G12V抑制剂、KRAS G12D抑制剂、KRAS G12S抑制剂，优选KRAS G12C抑制剂；Further, the KRAS inhibitor is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
    所述PI3K抑制剂为PI3Kα抑制剂和/或PI3Kδ抑制剂。The PI3K inhibitor is a PI3Kα inhibitor and/or a PI3Kδ inhibitor.
  18. 权利要求1～15任意一项所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或包含所述化合物的药物组合物在制备用于治疗由KRAS和/或PI3K介导的疾病的药物中的用途；The compound according to any one of claims 1 to 15 or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pharmaceutical composition comprising the compound is being prepared Use in a medicament for the treatment of diseases mediated by KRAS and/or PI3K;
    进一步地，所述用途是在制备用于治疗由KRAS G12C、PI3Kα、PI3Kδ中的一种或多种介导的疾病的药物中的用途；Further, the use is in the preparation of medicines for treating diseases mediated by one or more of KRAS G12C, PI3Kα, and PI3Kδ;
    进一步地，所述疾病为癌症或自身免疫性疾病；Further, the disease is cancer or autoimmune disease;
    进一步地，所述癌症选自：非小细胞肺癌、肺癌、胰腺癌、卵巢癌、膀胱癌、***癌、慢性粒细胞白血病、结直肠癌、脑癌、肝癌、肾癌、胃癌、乳腺癌、三阴性乳腺癌、皮肤癌、黑色素癌、头颈癌、骨癌、***、盆腔癌、***癌、口腔癌、淋巴癌、血癌、食管癌、尿道癌、鼻腔癌。Further, the cancer is selected from: non-small cell lung cancer, lung cancer, pancreatic cancer, ovarian cancer, bladder cancer, prostate cancer, chronic myelogenous leukemia, colorectal cancer, brain cancer, liver cancer, kidney cancer, gastric cancer, breast cancer, Triple negative breast cancer, skin cancer, melanoma, head and neck cancer, bone cancer, cervical cancer, pelvic cancer, vaginal cancer, oral cancer, lymphatic cancer, blood cancer, esophageal cancer, urinary tract cancer, nasal cavity cancer.
  19. 权利要求1～15任一项所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或包含所述化合物的药物组合物在制备用于治疗对抗癌剂产生耐药的疾病的药物中的用途；The compound according to any one of claims 1 to 15 or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pharmaceutical composition comprising the compound is being prepared Use in a medicament for the treatment of diseases resistant to anticancer agents;
    进一步地，所述抗癌剂选自KRAS G12C抑制剂、KRAS G12V抑制剂、KRAS G12D抑制剂、KRAS G12S抑制剂，优选KRAS G12C抑制剂；Further, the anticancer agent is selected from KRAS G12C inhibitors, KRAS G12V inhibitors, KRAS G12D inhibitors, KRAS G12S inhibitors, preferably KRAS G12C inhibitors;
    进一步地，所述抗癌剂选自AMG-510、MRTX-849，优选AMG-510。Further, the anticancer agent is selected from AMG-510, MRTX-849, preferably AMG-510.
  20. 权利要求1～15任一项所述化合物或互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或包含所述化合物的药物组合物在制备治疗致使PI3K蛋白和/或KRAS G12C蛋白过度表达的疾病的药物中的用途。The compound or tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pharmaceutical composition comprising the compound described in any one of claims 1 to 15 is used in the preparation of therapeutic Use in medicine for diseases that cause overexpression of PI3K protein and/or KRAS G12C protein.
  21. 权利要求1～15任一项所述化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、药学上可接受的盐、共晶或包含所述化合物的药物组合物在制备治疗PI3K蛋白和/或KRAS G12C蛋白过度表达所致疾病的药物中的用途。 The compound according to any one of claims 1 to 15 or its tautomer, stereoisomer, solvate, metabolite, pharmaceutically acceptable salt, co-crystal or pharmaceutical composition comprising the compound is being prepared Use in drugs for treating diseases caused by overexpression of PI3K protein and/or KRAS G12C protein.
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