WO2022268209A1 - Derivative having pyrimidine-fused cyclic structure, and use thereof - Google Patents

Derivative having pyrimidine-fused cyclic structure, and use thereof Download PDF

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WO2022268209A1
WO2022268209A1 PCT/CN2022/101219 CN2022101219W WO2022268209A1 WO 2022268209 A1 WO2022268209 A1 WO 2022268209A1 CN 2022101219 W CN2022101219 W CN 2022101219W WO 2022268209 A1 WO2022268209 A1 WO 2022268209A1
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alkyl
independently selected
occurrence
heteroaryl
amino
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PCT/CN2022/101219
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French (fr)
Chinese (zh)
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陈寿军
强晓明
宁德争
丁兆
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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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Priority to CN202280044402.4A priority Critical patent/CN117580836A/en
Publication of WO2022268209A1 publication Critical patent/WO2022268209A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to the technical field of medicine, in particular to a compound used as an SOS1 protein inhibitor and its application.
  • SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells, as a kind of guanine nucleotide exchange factor of Ras or Rac1 protein, it plays a role in intracellular Ras or Rac1 signal transduction pathway Important regulatory roles (Baltanás, FC; Zarich, N.; Rojas- JM; Santos, E. Biochim. Biophys. Acta. Rev. Cancer. 2020, 1874, 188445).
  • the role of SOS1 protein in the Ras signal transduction pathway is to promote the release of GDP from Ras, bind to GTP, and change the Ras protein from an inactive state to an active state.
  • the currently known RAS family has three genes: KRAS, NRAS and HRAS. Mutations in RAS enzymes are closely related to tumorigenesis, and mutations are detected in about 25% of all tumors (de Castro J.; Belda-Iniesta C.; Transl Lung Cancer Res. 2013, 2(2), 142-51.), in different types of tumors, the types of RAS mutations are also different. RAS mutations (KRAS, NRAS, HRAS) are present in 90% of pancreatic cancers, 45% of colon cancers and 35% of lung cancers. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases (Jemal, B.; et al, CA Cancer J. Clin.
  • Ras proto-oncogene is the most common in NSCLC Mutated genes (Prior, L. et al, Cancer Res. 2012, 72(10), 2457-2467; Li, L. et al, J Exp Clin Cancer Res. 2018, 37(1), 178), where, v -Ki-ras2Kirsten
  • the rat sarcoma virus oncogene (Kras) accounts for 90% of RAS mutations in lung adenocarcinomas (Hunter, JC; et al, Mol. Cancer Res. 2015, 13(9), 1325-35).
  • SOS1 plays an important regulatory role in many signal transduction pathways in cells. Studies have shown that inhibition of SOS1 activity has a potent inhibitory effect on cancer cell proliferation based on all major Kras gene mutations (Kessler, D.; Gerlach, D.; Kraut, N., McConnell, D.B. Curr. Opin. Chem. Biol .2021, 62, 109-118). In addition, a clinical study in 62 patients with ovarian cancer showed that the expressions of RAS mutation and SOS1 mutation were significantly increased in ovarian cancer tissues, and both were associated with shortened PFS in terms of prognosis, suggesting that RAS and SOS1 targeted therapy is effective in ovarian cancer.
  • SOS1 gene mutations are also found in many other cancer cells, such as embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and cutaneous granulosa cell tumor (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3): 242-52) and lung adenocarcinoma (Cancer Genome AtIas Research Network., Nature 2014, 511(7511), 543-50).
  • SOS1 gene is involved in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49(4), 317-20) and prostate cancer (Timofeeva et al., Int.J.Oncol., 2009, 35(4 ):751-60) were highly expressed.
  • BCR-ABL activates GRB2 through phosphorylation and recruits SOS1, thereby continuously activating the Ras/MAPK signaling pathway, leading to the malignant proliferation of hematopoietic stem cells. Therefore, SOS1 protein is also a potential new target for the treatment of chronic myelogenous leukemia.
  • hereditary SOS1 gene mutations are also closely related to some pathogenic rash diseases such as Noonan syndrome (NS), heart-facial skin syndrome (CFC) and type I hereditary gingival fibromatosis (Pierre et al. al., Biochem. Pharmacol., 2011, 82(9): 1049-56).
  • NS Noonan syndrome
  • CFC heart-facial skin syndrome
  • type I hereditary gingival fibromatosis Pierre et al. al., Biochem. Pharmacol., 2011, 82(9): 1049-56.
  • SOS1 inhibition is mechanistically similar to SHP2 inhibition (Nichols, RJ; et al. Nat Cell Biol. 2018, 20(9), 1064-1073), suggesting that SOS1 inhibition can also enhance the efficacy of KRAS G12C and MEK inhibitors .
  • Preliminary data show a significant synergy between SOS1 and MEK inhibition in multiple PDX models with G12 and G13 KRAS mutations (Hofmann, MH; et al; Cancer Discov. 2020, 10.1158/2159-8290. CD-20 -0142.).
  • the technical problem mainly solved by the present invention is to provide a pyrimidocyclic derivative which has a strong and selective inhibitory effect on SOS1.
  • the present invention provides a compound having the structure shown in formula I or its tautomers, mesoforms, racemates, enantiomers, diastereoisomers or its mixture form, pharmaceutically acceptable hydrate, solvate or salt, or,
  • a 1 is selected from CH, CH 2 or N, NR 28 , O, S
  • a 2 is selected from C or N
  • a 3 is selected from CH, CH 2 , N, NR 28 , O, S
  • a 4 is selected from CH, CH 2 or a bond; preferably, A 4 is selected from CH, CH 2 or a single bond;
  • Y is selected from bond, CR 6 R 7 , O, NR 5 , S, S(O); when A 1 , A 3 , A 4 are CH and A 2 is C (that is, when ring A is a benzene ring structure) , Y is not a key;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are independently selected from H and alkyl; preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 28 are independently selected from H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl;
  • Ar is selected from aryl, heteroaryl, and heterocyclic aliphatic, and when ring A does not have aromaticity, the heteroaryl is not pyridyl, wherein the aryl, heteroaryl, heterocyclic aliphatic optionally substituted by one or more R 8 ;
  • Each occurrence of R is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 10 , -C(O)NR b R c , -C(O)OR a , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more R 11 are substituted;
  • Each occurrence of R 11 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by one or multiple R 13 substitutions;
  • Each occurrence of R 13 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR a , -NR b R c , -SR d , -C(O)R 14 , -C (O)NR b R c , -C(O)OR a ;
  • R 1 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, -OR e , -NR f R g , -SR h , -C(O)R 15 , -C (O)NR f R g , -C(O)OR e , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 16 ;
  • Each occurrence of R 16 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR e , -NR f R g , -SR h , -C(O)R 17 , -C (O)NR f R g , -C(O)OR e ;
  • Ring E is selected from cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, wherein cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl is optionally substituted by one or more R 18 ;
  • Each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR i , -NR j R k , -SR m , -C( O)R 19 , -C(O)NR j R k , -C(O)OR i , or two adjacent R 18 and the ring atoms on the ring E to which they are connected together form a cycloalkyl group or an aliphatic heterocyclic group , aryl, heteroaryl, wherein the alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 25 ;
  • each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , or two adjacent R 18 and the atoms connected to them together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally substituted by one or more R 25 ;
  • Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, -NR j R k substituted alkyl, cycloalkyl, aliphatic heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C(O)NR j R k , -C(O)OR i ;
  • Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, cycloalkyl, heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C (O)NR j R k , -C(O)OR i ;
  • R a , R b , R c , R d , Re , R f , R g , Rh , R i , R j , R k , R m is independently selected from H, alkyl, cycloalkyl , aliphatic heterocyclic group, -C(O)R 20 , or R b , R c and the N atoms connected to them together form an aliphatic heterocyclic group, wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally Substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic;
  • R 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each independently selected from H, alkyl, cycloalkyl, and aliphatic heterocyclic group, and the alkyl, Cycloalkyl, heteroalicyclic are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, heteroalicyclic.
  • the present invention provides the structure shown in formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable hydrate, solvate or salt, or,
  • a 1 is selected from CH, CH 2 or N, NR 28 , O, S
  • a 2 is selected from C or N
  • a 3 is selected from CH, CH 2 , N, NR 28 , O, S
  • a 4 is selected from CH, CH 2 or a bond; preferably, A 4 is selected from CH, CH 2 or a single bond;
  • Y is selected from bond, CR 6 R 7 , O, NR 5 , S, S(O); when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond;
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are independently selected from H and alkyl; preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 28 are independently selected from H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl;
  • Ar is selected from aryl or heteroaryl, and when ring A does not possess aromaticity, said heteroaryl is not pyridyl, wherein said aryl or heteroaryl is optionally replaced by one or more R 8 replace;
  • Each occurrence of R is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 10 , -C(O)NR b R c , -C(O)OR a , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more R 11 are substituted;
  • Each occurrence of R 11 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by one or multiple R 13 substitutions;
  • Each occurrence of R 13 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR a , -NR b R c , -SR d , -C(O)R 14 , -C (O)NR b R c , -C(O)OR a ;
  • R 1 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, -OR e , -NR f R g , -SR h , -C(O)R 15 , -C (O)NR f R g , -C(O)OR e , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 16 ;
  • Each occurrence of R 16 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR e , -NR f R g , -SR h , -C(O)R 17 , -C (O)NR f R g , -C(O)OR e ;
  • Ring E is selected from cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, wherein cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl is optionally substituted by one or more R 18 ;
  • Each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 19 , -C (O)NR j R k , -C(O)OR i , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 25 ;
  • Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, cycloalkyl, heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C (O)NR j R k , -C(O)OR i ;
  • R a , R b , R c , R d , Re , R f , R g , Rh , R i , R j , R k , R m is independently selected from H, alkyl, cycloalkyl , aliphatic heterocyclic group, -C(O)R 20 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino , alkyl, cycloalkyl, aliphatic heterocyclic;
  • R 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each independently selected from H, alkyl, cycloalkyl, and aliphatic heterocyclic group, and the alkyl, Cycloalkyl, heteroalicyclic are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, heteroalicyclic.
  • each occurrence of R a , R b , R c , and R d is independently selected from H, alkyl, -C(O)R 20 , wherein the alkyl is optionally substituted by one or more of the following Base substitution: halogen, cyano, hydroxyl, amino, alkyl;
  • each occurrence of R a , R b , R c , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R a , R b , R c , and R d 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 , R c , and R d is independently selected from H and methyl, preferably, R b , R c are methyl.
  • each occurrence of R i , R j , R k , and R d is independently selected from H, alkyl, -C(O)R 20 , wherein the alkyl is optionally substituted by one or more of the following Base substitution: halogen, cyano, hydroxyl, amino, alkyl;
  • each occurrence of R i , R j , R k , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R i , R j , R k , and R d 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;
  • R i , R j , R k , R d are each independently selected from H, methyl, difluoromethyl, preferably H, methyl, preferably H at each occurrence.
  • the heteroaryl is not pyridyl
  • the heteroaryl is not only unsubstituted pyridyl, nor is it any structure in the art Substituent substituted pyridyl.
  • R 8 is independently selected from each occurrence means that when the number of R 8 is greater than 1, different R 8 can be selected from the same or different groups. For example, when the number of R 8 is 2, one R 8 can be selected from an alkyl group, and the other R 8 can be selected from a halogen group; or, both R 8 can be selected from an alkyl group; the rest of the similar situations are the same. Further, A 1 is selected from CH, CH 2 or N. Preferably it is CH.
  • A2 is selected from C or N, preferably C.
  • a 3 is selected from CH, CH 2 , N, NR 28 , O, S, wherein R 28 is selected from H, alkyl, preferably H, C1-C6 alkyl, more preferably H, C1-C3 alkyl , more preferably H, methyl; further, A 3 is selected from CH or N.
  • a 4 is selected from CH, CH 2 or a bond, more preferably CH, CH 2 or a single bond, more preferably CH.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are each independently selected from H, C1-C6 alkyl, preferably H, C1-C3 alkyl, More preferably H, methyl.
  • R 5 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group.
  • the compound of the present invention has the structure shown in formula II or its isomers, tautomers, mesomers, racemates, enantiomers, diastereoisomers or mixtures thereof , a pharmaceutically acceptable hydrate, solvate or salt, or,
  • Ring E is selected from C3-C6 cycloalkyl, 4-7 membered aliphatic heterocyclic group, phenyl, 5-6 membered heteroaryl group, preferably 5-7 membered aliphatic heterocyclic group, phenyl group, more preferably N-containing 6 Aliphatic heterocyclic group, phenyl, more preferably phenyl; wherein, cycloalkyl, aliphatic heterocyclic group, phenyl, heteroaryl are optionally substituted by one or more R 18 , R 18 as defined above stated;
  • n 1 is an integer selected from 0-5, preferably an integer of 1-3, preferably 1, 2, more preferably 2.
  • ring E is selected from phenyl, 5-6 membered N-heteroaryl, 5-6 membered thioaryl, more preferably phenyl, 6-membered N-heteroaryl, 5-membered thiaryl, more preferably benzene Base, pyridyl or thienyl; wherein, the phenyl, 5-6 membered N heteroaryl, 5-6 membered thiaaryl, 6-membered N heteroaryl, 5-membered thiaryl, pyridyl, Thienyl is optionally substituted with one or more R 18 , R 18 being as previously defined.
  • ring E is selected from phenyl, 5-6 membered N heteroaryl, preferably phenyl, 6 membered N heteroaryl, more preferably phenyl or pyridyl; wherein, phenyl, pyridyl, N heteroaryl Optionally substituted with one or more R 18 , R 18 as defined above.
  • ring E is phenyl, piperidinyl, wherein, phenyl, piperidinyl is optionally substituted by one or more R 18 , and said R 18 is as defined above.
  • R 18 is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted by 1-3 alkyl groups, halogens, hydroxyl groups, amino groups, and cyano groups.
  • R 18 is C1-C3 alkyl that is unsubstituted or substituted by hydroxyl.
  • Ring E is piperidinyl, it has the following structure: The following structure is preferred:
  • n 2 is an integer selected from 1 to 3, preferably 2.
  • ring E is selected from phenyl, 5-6 membered N-heteroaryl, preferably phenyl, 6-membered N-heteroaryl, more preferably phenyl or pyridyl; among them, phenyl, pyridyl, N-heteroaryl Optionally substituted by one or more R 18 ;
  • the compound of the present invention has the structure shown in formula III or its isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof , a pharmaceutically acceptable hydrate, solvate or salt, or,
  • R 23 is selected from C1 ⁇ C3 alkyl, C1 ⁇ C3 alkyl substituted by halogen and/or hydroxyl, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C( OH) CH 3 CH 3 , more preferably trifluoromethyl;
  • the compound of the present invention has the structure shown in formula III' or its isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof form, a pharmaceutically acceptable hydrate, solvate or salt, or,
  • each occurrence of R 18 is independently selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR i , -NR j R k , -C(O)R 19 , -C (O)NR j R k , -C(O)OR i , or two adjacent R 18 and the ring atoms on the ring E to which they are connected together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, or a heteroaryl group , wherein the cycloalkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 25 ;
  • each occurrence of R 18 is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, phenyl, -NR j R k , or both
  • Two adjacent R 18 and the ring atoms on the ring E connected together form a C5-C10 cycloalkyl group, a 5-10-membered aliphatic heterocyclic group, a C5-C10 aryl group, and a 5-10-membered heteroaryl group, wherein the Alkyl, alkoxy, phenyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally substituted by 1 to 4 R 25 , R j and R k are independently selected from H at each occurrence , C1 ⁇ C6 alkyl.
  • each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR j R k , or two adjacent R 18 and the ring atoms on the ring E to which it is connected together form a C5-C6 cycloalkyl group, a 5-6-membered aliphatic heterocyclic group, and a 5-6-membered heteroaryl group, wherein the alkyl, alkoxy, phenyl , cycloalkyl, aliphatic heterocyclic group, and heteroaryl are optionally substituted by 1 to 3 R 25 , and R j and R k are independently selected from H, C1 to C3 alkyl at each occurrence;
  • each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR j R k , or both
  • Two adjacent R 18 and the ring atoms on the ring E connected together form cyclopentyl, tetrahydrofuranyl, pyrrolyl, wherein the C1 ⁇ C3 alkyl, C1 ⁇ C3 alkoxy, phenyl, cyclopentane Base, tetrahydrofuryl, pyrrolyl are optionally substituted by 1 to 3 R 25 , R j , R k are both H;
  • each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , or two adjacent R 18 and the atoms connected to it together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, and aliphatic heterocyclic group , aryl, heteroaryl are optionally substituted by one or more R 25 ;
  • each occurrence of R 18 is independently selected from halogen, cyano, C1 ⁇ C6 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to them together form a C5 ⁇ C10 cycloalkyl, 5-10 membered aliphatic heterocyclic group, C5-C10 aryl group, 5-10 membered heteroaryl group, wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by 1- 4 R 25 substitutions, each occurrence of R j and R k are independently selected from H, C1-C6 alkyl;
  • each occurrence of R 18 is independently selected from halogen, cyano, C1 ⁇ C3 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to them together form a C5 ⁇ C6 cycloalkyl, 5-6 membered aliphatic heterocyclic group, 5-6 membered heteroaryl group, wherein the alkyl, cycloalkyl, aliphatic heterocyclic group, and heteroaryl group are optionally substituted by 1 to 3 R 25 , R j ,
  • Each occurrence of R k is independently selected from H, C1-C3 alkyl;
  • each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to form cyclopentyl, tetrahydrofuryl , pyrrolyl, wherein the C1-C3 alkyl, cyclopentyl, tetrahydrofuranyl, and pyrrolyl are optionally substituted by 1-3 R 25 , and both R j and R k are H.
  • each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , wherein the alkyl group is optionally substituted by one or more R 25 ;
  • each occurrence of R 18 is independently selected from halogen, cyano, C1-C6 alkyl, -OR i , -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 ;
  • each occurrence of R 18 is independently selected from halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 .
  • each occurrence of R 18 is independently selected from halogen, cyano, hydroxy, amino, methyl, CF 3 , -CF 2 CH 3 , -CF 2 H, -CF 2 CH 2 OH, -C (CH 3 ) 2 OH, -OCF 2 H, -CH 2 NHCH 3 substituted phenyl or pyridyl, or, two adjacent R 18 and the ring atoms on the ring E connected to form a cyclopentyl group, Tetrahydrofuryl, pyrrolyl, wherein the cyclopentyl, tetrahydrofuryl, pyrrolyl is optionally substituted by one or more F atoms.
  • each occurrence of R 25 is independently selected from halogen, C1-C6 alkyl, -OR i , -CH 2 NR j R k , -NR j R k ;
  • each occurrence of R 25 is independently selected from halogen, C1 ⁇ C6 alkyl, -OR i , -NR j R k , preferably halogen, C1 ⁇ C3 alkyl, -OR i , more preferably halogen or -OR i , more preferably halogen, wherein, R i , R j , R k are as defined above, preferably, R i , R j , R k are independently selected from H, alkyl, more preferably, R i , R j , R k is H; further, each occurrence of R is independently selected from F, Cl, methyl, ethyl, propyl, hydroxyl, preferably F, methyl, hydroxyl, more preferably F, hydroxyl.
  • each occurrence of R 18 is independently selected from F, CN, -NH 2 , -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, -C(OH) CH 3 CH 3 , or two adjacent R 18 together form the atoms to which they are attached
  • each occurrence of R 18 is independently selected from -F, -CN, -NH 2 , -OH, -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, -OCF 2 H, Or two adjacent R 18 together with the atoms they are connected to form
  • each occurrence of R 18 is independently selected from F, CN, -NH 2 , -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, or two adjacent R 18 together with the atoms to which it is attached
  • R 22 , R 23 , and R 24 are independently selected from H, halogen, cyano, C1 ⁇ C6 alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , wherein the alkyl group is optionally substituted by one or more R 25 ;
  • R 22 , R 23 , and R 24 are each independently selected from H, halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 .
  • R 22 is selected from H or halogen, preferably H or F, more preferably H;
  • R 23 is selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxyl, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C(OH)CH 3 CH 3 , more preferably trifluoromethyl;
  • R 24 is selected from H, NH 2 , preferably NH 2 .
  • ring E is selected from the following structures:
  • ring E is selected from the following structures:
  • ring E is selected from the following structures:
  • Y is selected from bond, CR 6 R 7 , O, NR 5 , when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond.
  • Y is selected from a bond, O, and NR 5 , and when A 1 , A 3 , and A 4 are CH and A 2 is C, Y is not a bond.
  • R 5 , R 6 , and R 7 are independently selected from H and alkyl groups, preferably H, C1-C6 alkyl groups, more preferably H, C1-C3 alkyl groups, more preferably H, and methyl groups;
  • connection position of R 18 in is not fixed, which means that R 18 can be any substitutable position on the benzene ring, and the same applies to other similar situations.
  • Y is selected from bond, CR 6 R 7 , O, NR 5 , when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond.
  • Y is selected from a bond, O, and NR 5 , and when A 1 , A 3 , and A 4 are CH and A 2 is C, Y is not a bond.
  • R 5 is selected from H, alkyl, preferably H, C1 ⁇ C6 alkyl, more preferably H, C1 ⁇ C3 alkyl, more preferably H, methyl; or, R 5 is C1 ⁇ C6 alkyl, preferably C1 ⁇ C3 alkyl, more preferably methyl;
  • Y is selected from O, NR 5 ; wherein, R 5 is selected from H, alkyl, preferably H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl; or, R 5 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group.
  • Ar is selected from C6-C10 aryl, 5-10 membered heteroaryl, and 3-10 membered aliphatic heterocyclic groups, wherein the aryl, heteroaryl, and aliphatic heterocyclic groups are optionally replaced by one or Multiple R 8 substitutions;
  • Ar is selected from phenyl, 6-9 membered heteroaryl, and 5-6 membered aliphatic heterocyclic groups, wherein the phenyl, heteroaryl, and aliphatic heterocyclic groups are optionally replaced by one or more R 8 replaced;
  • Ar is selected from phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, and N-heterocyclohexadienone, wherein the phenyl, 6-membered N-heteroaryl, 9-membered N-hetero Aryl, N heterocyclohexadienone are optionally substituted by one or more R 8 ;
  • Ar is selected from phenyl, 6-membered N heteroaryl, N heterocyclohexadienone, wherein, the phenyl, 6-member N heteroaryl, N heterocyclohexadienone optionally Replaced by one or more R 8 ;
  • Ar is selected from phenyl, pyridyl, Among them, the phenyl, pyridyl, optionally substituted by one or more R 8 ;
  • Ar is selected from phenyl, pyridyl, Among them, the phenyl, pyridyl, optionally substituted with one or more R 8 .
  • Ar is selected from phenyl or 5-10 membered heteroaryl, preferably phenyl or 6-9 membered heteroaryl, more preferably phenyl or N hetero6-9 membered heteroaryl, more preferably phenyl, pyridine Base, 9-membered N heteroaryl, wherein, the phenyl, pyridyl, and heteroaryl are optionally substituted by one or more R 8 , and the R 8 is as defined above.
  • Ar is optionally substituted by 1-3 R 8 ; further, Ar is optionally substituted by 1-2 R 8 .
  • each occurrence of R 8 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 membered cycloalkyl, 3-6 membered aliphatic heterocyclic group, -OR a , -NR b R c , wherein, the alkyl group, cycloalkyl group, and aliphatic heterocyclic group are optionally substituted by one or more R 11 , and the R a , R b , R c , and R 11 are as defined above.
  • each occurrence of R 8 is independently selected from C1 ⁇ C3 alkyl, -OR a , -NR b R c , wherein the alkyl group is optionally substituted by one or more R 11 , said R a , R b , R c , R 11 are as defined above.
  • each occurrence of R 8 is independently selected from C1 ⁇ C3 alkyl, -OR a , -NR b R c , wherein R a is selected from H and alkyl, and R b and R c are independently selected from H, Alkyl, or R b , R c and the N atoms connected to them together form an aliphatic heterocyclic group, and the alkyl and aliphatic heterocyclic groups are optionally substituted by one or more R 11 ;
  • each occurrence of R 8 is independently selected from methyl, ethyl, propyl, -OR a , -NR b R c , wherein R a is selected from H, C1-C6 alkyl, R b , R c are independently selected from C1-C6 alkyl groups, or R b , R c and the N atoms connected to them together form a 5-membered aliphatic heterocyclic group, and the methyl, ethyl, propyl, alkyl, and aliphatic heterocyclic groups are optionally is substituted by one or more R 11 ;
  • each occurrence of R 8 is independently selected from methyl, ethyl, -OR a , -NR b R c , wherein R a is selected from H, C1 ⁇ C3 alkyl, R b and R c are independently selected from From C1 ⁇ C3 alkyl, or R b , R c and N atom together The methyl, ethyl, alkyl, optionally substituted with one or more R 11 .
  • each occurrence of R 8 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , -NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CN,
  • each occurrence of R 8 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O) N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CN,
  • each occurrence of R 8 is independently selected from -OCH 3 , -OH, -CH 2 C(O)N(CH 3 ) 2 , -CH2CH2N ( CH3 ) 2 , -CH2CN , -CH3 ;
  • each occurrence of R 8 is independently selected from -OCH 3 , -OH, -CH 2 C(O)N(CH 3 ) 2 , -CH2CH2N ( CH3 )2 , -CH2CN .
  • each occurrence of R 11 is independently selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 12 , -C (O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, heteroaryl are optionally substituted by one or more R 13 ;
  • each occurrence of R 11 is independently selected from halogen, cyano, C1-C6 alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -OR a , -NR b R c , -C (O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally substituted by one or more R 13 ;
  • each occurrence of R 11 is independently selected from halogen, cyano, C1-C6 alkyl, 5-6 membered heteroaryl, -OR a , -NR b R c , -C(O)R 12 , - C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally substituted by 1 to 3 R 13 ;
  • each occurrence of R 11 is independently selected from cyano, C1-C3 alkyl, 5-membered heteroaryl, -NR b R c , -C(O)NR b R c , wherein the alkyl, Aryl and heteroaryl are optionally substituted by 1 to 3 R 13 ;
  • the 5-membered heteroaryl group in R 11 is selected from thiazolyl and imidazolyl, wherein the thiazolyl and imidazolyl are optionally substituted by 1 to 2 R 13 ;
  • each occurrence of R is independently selected from cyano, methyl, ethyl, propyl, -N(CH 3 ) 2 , -C(O)N(CH 3 ) 2 ,
  • each occurrence of R 11 is independently selected from alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -C(O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, aryl group, and heteroaryl group are optionally substituted by one or more R 13 , and the R a , R b , R c , R 12 , R 13 as defined above.
  • each occurrence of R 11 is independently selected from 5-6 membered heteroaryl, -C(O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein, the Heteroaryl is optionally substituted by one or more R 13 , wherein R a , R b , R c , R 12 , R 13 are as defined above.
  • each occurrence of R 11 is independently selected from 5-membered heteroaryl, -C(O)NR b R c , preferably -C(O)NR b R c , wherein the heteroaryl is optionally One or more R 13 are substituted, and the R b , R c , R 13 are as defined above.
  • each occurrence of R 11 is independently selected from thiazolyl, imidazolyl, -C(O)NR b R c , wherein, said thiazolyl and imidazolyl are optionally replaced by one or more R 13 is substituted, and the R b , R c , and R 13 are as defined above.
  • each occurrence of R 13 is independently selected from halogen, C1 ⁇ C6 alkyl, -OR a , -NR b R c , -C(O)R 14 , -C(O)NR b R c , -C (O) OR a , said R a , R b , R c , and R 14 are as defined above.
  • each occurrence of R 13 is independently selected from halogen, C1-C6 alkyl, preferably C1-C3 alkyl, preferably methyl.
  • each occurrence of R a , R b , R c , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
  • each occurrence of R a , R b , R c , and R d 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 , R c , and R d is independently selected from H and methyl, preferably, R b , R c are methyl.
  • Ar is selected from the following groups:
  • Ar is selected from the following groups:
  • Ar is selected from the following groups:
  • Ar is selected from the following groups:
  • Ar is selected from the following groups:
  • the compound of the present invention has the structure shown in formula IV or formula V or formula VI or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or its Mixture form, pharmaceutically acceptable hydrate, solvate or salt, or,
  • a 5 and A 6 are independently selected from CR 27 or N, wherein R 27 is selected from H, C1-C3 alkyl, preferably H;
  • R 21 is selected from H, C1 ⁇ C6 alkyl, -OR a , -NR b R c , preferably C1 ⁇ C3 alkyl, -OR a , -NR b R c , preferably methyl, ethyl, -OR a , -NR b R c , more preferably -OR a .
  • formula IV is further formula IV':
  • formula IV' and formula V' mean that in the original formula IV, A 1 , A 3 , and A 4 are CH, and A 2 is C, so it should be understood that when A 1 , A 3 , and A 4 are CH and A When 2 is C, Y is not a limiting condition for a bond.
  • Y is NR 5 ; in formula VI, Y is selected from a bond, O, and NR 5 .
  • each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , wherein the alkyl group is optionally substituted by one or more R 25 , and the R i , R j , R k , R 19 , R 25 are as defined above.
  • each occurrence of R 18 is independently selected from halogen, cyano, C1 ⁇ C6 alkyl, -OR i , -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 ,
  • the R i , R j , R k and R 25 are as defined above.
  • each occurrence of R 18 is independently selected from halogen, C1 ⁇ C3 alkyl, -NR j R k , wherein said alkyl is optionally substituted by one or more R 25 , said R j , R k , R 25 are as defined above.
  • R 22 , R 23 , and R 24 are independently selected from H, halogen, cyano, C1 ⁇ C6 alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , wherein the alkyl group is optionally substituted by one or more R 25 , and the R i , R j , R k , R 19 , and R 25 are as defined above.
  • R 22 , R 23 , and R 24 are independently selected from H, halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 , the R j , R k , R 25 are as defined above.
  • R 25 is independently selected from halogen, C1 ⁇ C6 alkyl, -OR i , -NR j R k each occurrence, preferably halogen, C1 ⁇ C3 alkyl, -OR i , more Halogen is preferred; R i , R j , R k are as defined above.
  • each occurrence of R i , R j , R k , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1 ⁇ C6 alkyl;
  • each occurrence of R i , R j , R k , and R d 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 i , R j , R k , R d is independently selected from H, methyl, preferably H.
  • R 22 is selected from H or halogen, preferably H or F, more preferably H;
  • R 23 is selected from C1 ⁇ C3 alkyl, C1 ⁇ C3 alkane substituted by halogen and/or hydroxyl group, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C(OH)CH 3 CH 3 , more preferably trifluoromethyl;
  • R 24 is selected from H, NH 2 , preferably to NH 2 .
  • the compound of the present invention has the structure shown in formula VII or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, pharmaceutically available Accepted hydrates, solvates or salts, or,
  • R 1 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, 6-10 membered aryl, -OR e , -NR f R g , -C(O)R 15 , -C(O) NR f R g , -C(O)OR e , wherein the alkyl group is optionally substituted by one or more R 16 , and the R e , R f , R g , R 15 , and R 16 are as defined above;
  • R 1 is selected from hydrogen, halogen, cyano, C1 ⁇ C3 alkyl, -OR e , -NR f R g , wherein the alkyl group is optionally substituted by one or more R 16 , said R e , R f , R g , R 16 are as defined above;
  • R 1 is selected from halogen, C1-C3 alkyl.
  • R 1 is selected from hydrogen, halogen, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 16 .
  • each occurrence of R 16 is independently selected from halogen, cyano, C1 ⁇ C6 alkyl, -OR e , -NR f R g , -C(O)R 17 , -C(O)NR f R g , -C(O)OR e .
  • each occurrence of R 16 is independently selected from halogen, C1-C3 alkyl, -OR e , -NR f R g .
  • R 16 is -OR e .
  • each occurrence of R e , R f , R g , and Rh is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
  • each occurrence of R e , R f , R g , and Rh 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 Re , Rf , Rg , Rh is independently selected from H, methyl, ethyl.
  • R e is H.
  • R 1 is selected from H, Cl, Br, I, hydroxyl, cyano, methyl, difluoromethyl, ethyl, -CH 2 OH, -CH 2 NH 2 , -NHCH 3 , -OCH 2 CH 3 , preferably methyl or Cl. further, is configured as
  • R 1 is selected from H, Cl, Br, I, hydroxyl, cyano, methyl, difluoromethyl, ethyl, -CH 2 OH, -CH 2 NH 2 , -NHCH 3 , - OCH 2 CH 3 , more preferably H, Cl, methyl, ethyl, -CH 2 CH 2 OH; more preferably methyl or Cl;
  • R 1 is selected from Cl, methyl, -CH 2 CH 2 OH, -CH 2 CH 3 , cyclopropanyl;
  • each occurrence of R 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 is independently selected from H, C1-C6 alkyl, and the alkyl is optionally replaced by Substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
  • each occurrence of R 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 is independently selected from H, C1-C3 alkyl, and the alkyl is optionally replaced by Substituted by one or more of the following substituents: halogen, hydroxyl, amino, C1-C3 alkyl.
  • the compound structure is selected from one of the following:
  • Another aspect of the present invention provides a kind of preparation method of above-mentioned compound, described preparation method comprises the step that is selected from following synthetic scheme:
  • the compound of formula 1-1 is reacted with the compound of formula 1-2 to obtain the compound of formula 1-3, and the compound of formula 1-3 is reacted with POX 3 to obtain the compound of formula 1-4;
  • X represents halogen, preferably selected from chlorine or bromine; the definitions of A, A 1 , A 2 , A 3 , and A 4 are the same as those of the compound of formula (I);
  • Route A the compound of formula 2-1 is first substituted with the compound of formula 2-2 to obtain the compound of formula 2-3, and the compound of formula 2-3 is then substituted with the compound of formula 2-4 to obtain the compound of formula (I'); or,
  • Route B the compound of formula 2-1 is first substituted with the compound of formula 2-4 to obtain the compound of formula 2-3, and the compound of formula 2-3 is then substituted with the compound of formula 2-4 to obtain the compound of formula (I');
  • X represents halogen, preferably selected from chlorine or bromine; the definitions of R 1 , R 2 , R 3 , R 4 , A, A 1 , A 2 , A 3 , A 4 , and Y are the same as the compounds of formula (I) ; M and M' are selected from X or Y, provided that M and M' are not X or Y at the same time;
  • E', R1', Ar' each define the same as E, R1, Ar in the compound of formula (I), with the proviso that when the substituents in the three in the compound of formula (I) include a hydroxyl group, the hydroxyl group is optionally is replaced by OTBS;
  • step A and step B also include the step of removing TBS in the compound of formula (I');
  • substituents among the three in (I) compound include amino
  • said amino is optionally substituted by -NO 2 or -C(O)OCH 2 CH 3 ; optionally, after step A and step B, also Including the step of reducing -NH 2 in the compound of formula (I') to -NO 2 or removing the -C(O)OCH 2 CH 3 protecting group;
  • step A and step B also include in the compound of formula (I') revert to or ethyl steps;
  • the compound of formula 3-2 undergoes a cyclization reaction in the presence of Cs 2 CO 3 and 18-crown ether-6 to obtain the compound of formula 3-2;
  • R 1 , R 2 , R 3 , R 4 , A, A 1 , A 2 , A 3 , A 4 , Y, Ar is the same as that of the compound of formula (I);
  • R 1 , R 2 , R 3 , R 4 , A, A 1 , A 2 , A 3 , A 4 , E ring, and Y is the same as that of the compound of formula (I);
  • N ring is selected from phenyl or pyridyl .
  • the present invention also provides a pharmaceutical composition, the active ingredient of which is selected from one of the above-mentioned compounds or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or co-crystals or A combination of two or more.
  • the present invention also provides the above compounds or their tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions used in the preparation of SOS1 inhibitors use.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions used for the treatment of SOS1 Use in medicines for mediated diseases.
  • the disease is selected from: cancer, pathogenic rash 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, and breast cancer .
  • the pathogenic rash disease is selected from the group consisting of Noonan syndrome, cardiofacial skin syndrome, and type I hereditary gingival fibromatosis.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions in the preparation and treatment of excessive SOS1 protein Use in medicines for expressed diseases.
  • the present invention also provides the above-mentioned compounds or their tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions for the preparation of SOS1 protein overexpression Use in medicines for disease-causing diseases.
  • compositions containing the compound of the present invention or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals may contain pharmaceutically acceptable excipients .
  • 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.
  • the "isotopic label” in the present invention means that one or more atoms in a molecule are replaced by atoms with different atomic mass or mass number.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine such as, but not limited to, 2H, 3H , 11C , 13C , 14C , respectively , 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I and 125 I.
  • Certain isotopically labeled compounds of the present invention are useful in drug and/or substrate tissue distribution studies, and the radioisotopes tritium, i.e. 3 H and carbon-14, i.e. 14 C, are particularly useful for this purpose due to their ease of incorporation and convenient means of detection,
  • a compound of the invention may be 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or 99% enriched for a given isotope.
  • substitution of the compounds of the invention with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages.
  • the “pharmaceutically acceptable salt” in the present invention refers to the salt formed by the compound of the present invention and acid or base which is suitable for use as 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 "pharmaceutically acceptable salt” of the present invention is preferably hydrochloride and format
  • 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.
  • “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.
  • Binders include syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.) , gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone, etc.; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, phosphoric acid Calcium hydrogen, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowder silica gel, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and Its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pre
  • 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 method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • Liquid dosage forms may contain, in addition to the active compound, inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • 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 compound.
  • 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. Delivery to the route of administration may contribute to stability.
  • 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.
  • 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.
  • Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.
  • the "key” mentioned in the present invention means that there is only one connecting key, and it can also be understood as “none”.
  • Y is a bond in formula I, it means that Ar is directly connected to ring A.
  • 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 the substituent indicates the minimum value and the number of carbon atoms in the substituent Maximum, for example, "C1-C6 alkyl” refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms.
  • Heteroalkyl refers to an alkyl group containing heteroatoms.
  • Cycloalkyl refers to a saturated cyclic hydrocarbon substituent.
  • Heteroalicyclic group refers to a substituent group formed by a compound containing at least one heteroatom in the ring skeleton and having no aromaticity.
  • 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:
  • Ar can be a tautomer of heteroaryl, such as tautomers
  • N heterocyclohexadienone group refers to a substituent containing at least one N atom on the ring skeleton of cyclohexadienone, for example
  • Halogen or "halo" means fluorine, chlorine, bromine or iodine.
  • Amino refers to -NH2 .
  • the present invention provides a series of compounds with obvious inhibitory effect on SOS1 protein, which provides a new solution for the treatment of diseases such as cancer and pathogenic rash diseases with SOS1 as the target of treatment, which can be used It is used in the preparation of drugs for the treatment of related diseases and has broad application prospects.
  • 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) Sun Fire Prep C18 OBDTM 5 ⁇ m, 30x 150mm Column, 0.06% formic acid in water/acetonitrile; (Method 3) Xbridge Prep C18 OBDTM 5 ⁇ m, 30 x 150mm Column, 10 mM NH 4 HCO 3 in water/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
  • LiHMDS lithium bis(trimethylsilyl)amide
  • TBS tert-butyldimethylsilyl
  • 6-Bromo-4-chloro-2-methylquinazoline (2.2g, 8.594mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane- 1-Amine hydrochloride (2.6g, 9.453mmol), DIPEA (3.3g, 25.581mmol), and DMSO (20mL) were successively added into the reaction flask, and the temperature was raised to 80°C under nitrogen protection, and the reaction was stirred for 2h.
  • reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (5mL ⁇ 3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5mL ⁇ 1), the organic phases were combined, and saturated with Wash with sodium chloride aqueous solution (10mL ⁇ 1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.
  • 6-Bromo-2,4-dichloroquinazoline (618mg, 2.222mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine salt
  • Acetyl chloride 500mg, 1.852mmol
  • DIPEA 717mg, 5.556mmol
  • DMSO 10mL
  • 6-Bromo-4-chloro-2-methylquinazoline 200mg, 0.733mmol
  • (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1- Amine hydrochloride 165 mg, 0.733 mmol
  • DIPEA 283 mg, 2.198 mmol
  • 6-bromo-4-chloro-2-methylquinazoline 200mg, 0.777mmol
  • (S)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1- Amine hydrochloride (175mg, 0.777mmol) and DIPEA (301mg, 2.331mmol) were dissolved in DMSO (5mL), and the reaction was heated to 80°C and stirred for 1h. After the reaction was completed, the reaction solution was cooled to room temperature, and water (50mL) was added.
  • Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)benzoate (570mg, 1.727mmol), 2-(4-amino-2-methoxyphenyl)-N,N-dimethyl Acetamide (490 mg, 1.900 mmol), Pd 2 (dba) 3 (158 mg, 0.173 mmol), Cs 2 CO 3 (1.1 g, 3.545 mmol), toluene (5 mL) and X-Phos (165 mg, 0.346 mmol) were added sequentially Into the reaction flask, replaced with nitrogen three times, heated to 110°C and stirred for 3h.
  • Methyl 2-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl)(methyl)amino)benzoate (340mg, 0.913mmol ) and urea (2.0 g, 33.333 mmol) were mixed and added into the reaction flask, and the reaction temperature was raised to 160° C. for 3 h.
  • 6-Methoxy-N-methyl-5-nitropyridin-2-amine (4.8g, 26.229mmol) was dissolved in tetrahydrofuran (60mL) and DMF (10mL), and sodium hydride (2.3g , 57.703mmol, 60%), stirred for 15min, benzyl chloroformate (5.4g, 31.475mmol) was added dropwise, after the addition was complete, it was raised to room temperature and stirred for 30min.
  • Benzyl (6-methoxy-5-nitropyridin-2-yl)(methyl)carbamate (2.5 g, 7.886 mmol) was dissolved in methanol (20 mL) and water (10 mL), and iron powder ( 2.2g, 39.432mmol) and ammonium chloride (2.1g, 39.433mmol), heated to reflux and stirred for 2h.
  • Benzyl (5-bromo-6-methoxypyridin-2-yl)(methyl)carbamate (900 mg, 2.571 mmol), (2-(dimethylamino)-2-oxoethyl)magnesium bromide Tetrahydrofuran solution (5.2mL, 5.141mmol, 1M), Pd(dba) 2 (148mg, 0.257mmol), X-phos (244mg, 0.514mmol) and tetrahydrofuran (15mL) were added in the reaction flask, replaced with nitrogen three times, and the temperature was raised To 80 ° C, stirring the reaction for 2h. After the reaction, cool to room temperature, filter, and concentrate the filtrate under reduced pressure.
  • Benzyl (5-(2-(dimethylamino)-2-oxoethyl)-6-methoxypyridin-2-yl)(methyl)carbamate (900 mg, 2.549 mmol) was dissolved in methanol ( 15 mL), add palladium carbon (270.0 mg, 0.255 mmol), replace with hydrogen three times, and stir at room temperature for 3 h. Filtration, and the filtrate was concentrated under reduced pressure to give 2-(2-methoxy-6-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide with a yield of 93.2%; ESI-MS (m /z): 224.1[M+H] + .
  • the preparation method refers to Example 38 to obtain (R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methano ylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 43.8%;
  • Methyl 2-amino-5-bromobenzoate (5.0 g, 0.022 mol), ethyl cyanoacetate (2.7 g, 0.024 mol) and hydrogen chloride dioxane solution (4M, 50 mL) were added to a constant volume reactor , 100°C for 16h.
  • reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5mL ⁇ 3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5mL), the organic phases were combined, and washed with saturated brine ( 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Ethanol (8 mL), water (8 mL), 1-(5-amino-2-methoxypyridin-3-yl)-3-methylimidazolidin-2-one (800 mg, 3.172 mmol), iron powder ( 710mg, 12.687mmol), anhydrous ammonium chloride (679mg, 12.687mmol) were sequentially added into the reaction flask, and the reaction was maintained at 80°C for 2h with stirring.
  • the preparation method refers to Example 48 to obtain (R)-1-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl ylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-3-methylimidazolidin-2-one, yield 61.6%;
  • the preparation method refers to Example 35, and is purified by Pre-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 14.0 %;
  • the preparation method refers to Example 35 and is purified by Pre-HPLC (Method 3) to obtain (R)-2-(5-((4-((1-(5-(difluoromethyl)pyridin-2-yl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 15.0 %;
  • Ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate (6.46g, 21.746mmol), tributyl(1-ethoxyvinyl)stannane (10.207g, 28.276mmol), Pd(PPh 3 )Cl 2 (763mg, 1.087mmol), triethylamine (4.39g, 43.492mmol), 1,4-dioxane (100mL) were added to the reaction flask, and nitrogen replacement was performed 3 times , heated to 100°C for overnight reaction.
  • 6-Bromo-4-chloro-2-methylquinazoline (577mg, 2.240mmol), (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2 - Ethyl difluoroacetate hydrochloride (800mg, 2.680mmol), DIPEA (870mg, 6.720mmol) and DMSO (10mL) were added to the reaction flask, and the reaction solution was heated to 80°C and stirred for 1h.
  • reaction solution was Cool to room temperature, add water (50 mL) to quench, extract with ethyl acetate (50 mL ⁇ 3), 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

Abstract

Disclosed are a derivative having a pyrimidine-fused cyclic structure, and the use thereof. The compound has a significant inhibitory effect on SOS1 protein activity; can be used as an SOS1 protein inhibitor; has excellent druggability; can be used to prepare drugs for treating diseases mediated by the SOS1 protein, such as cancer and pathogenic rashes; and has broad application prospects.

Description

一种嘧啶并环结构衍生物及其用途A kind of pyrimido ring structure derivative and its application 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SOS1蛋白抑制剂的化合物及其用途。The invention relates to the technical field of medicine, in particular to a compound used as an SOS1 protein inhibitor and its application.
背景技术Background technique
SOS1(son of sevenless homolog 1)蛋白是一种在细胞中广泛表达的调控蛋白，作为Ras或Rac1蛋白的一类鸟嘌呤核苷酸交换因子，在细胞内Ras或Rac1信号转导通路中起着重要的调控作用(Baltanás，F.C.；Zarich，N.；Rojas-
Figure PCTCN2022101219-appb-000001
J.M.；Santos，E.Biochim.Biophys.Acta.Rev.Cancer.2020，1874，188445)。SOS1蛋白在Ras信号转导途径中的作用是促进Ras释放GDP，结合GTP，使Ras蛋白由非活性状态转变为活性状态。 SOS1 (son of sevenless homolog 1) protein is a regulatory protein widely expressed in cells, as a kind of guanine nucleotide exchange factor of Ras or Rac1 protein, it plays a role in intracellular Ras or Rac1 signal transduction pathway Important regulatory roles (Baltanás, FC; Zarich, N.; Rojas-
Figure PCTCN2022101219-appb-000001
JM; Santos, E. Biochim. Biophys. Acta. Rev. Cancer. 2020, 1874, 188445). The role of SOS1 protein in the Ras signal transduction pathway is to promote the release of GDP from Ras, bind to GTP, and change the Ras protein from an inactive state to an active state.
目前已知的RAS家族共有三个基因：KRAS，NRAS和HRAS。RAS酶的突变与肿瘤发生密切相关，在所有肿瘤中约25％检测到突变(de Castro
Figure PCTCN2022101219-appb-000002
J.；Belda-Iniesta C.；Transl Lung Cancer Res.2013，2(2)，142-51.)，在不同类型的肿瘤中，RAS突变类型也不同。RAS突变(KRAS，NRAS，HRAS)存在于90％的胰腺癌，45％的结肠癌和35％的肺癌中。非小细胞肺癌(NSCLC)占所有肺癌病例的80％(Jemal，B.；et al，CA CancerJ.Clin.2011，61(2)，69-90)，Ras原癌基因是NSCLC中最常见的突变基因(Prior，L.et al，Cancer Res.2012，72(10)，2457-2467；Li，L.et al，J Exp Clin Cancer Res.2018，37(1)，178)，其中，v-Ki-ras2Kirsten大鼠肉瘤病毒致癌基因(Kras)占肺腺癌RAS突变的90％(Hunter，J.C.；et al，Mol.Cancer Res.2015，13(9)，1325-35)。 The currently known RAS family has three genes: KRAS, NRAS and HRAS. Mutations in RAS enzymes are closely related to tumorigenesis, and mutations are detected in about 25% of all tumors (de Castro
Figure PCTCN2022101219-appb-000002
J.; Belda-Iniesta C.; Transl Lung Cancer Res. 2013, 2(2), 142-51.), in different types of tumors, the types of RAS mutations are also different. RAS mutations (KRAS, NRAS, HRAS) are present in 90% of pancreatic cancers, 45% of colon cancers and 35% of lung cancers. Non-small cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases (Jemal, B.; et al, CA Cancer J. Clin. 2011, 61(2), 69-90), and the Ras proto-oncogene is the most common in NSCLC Mutated genes (Prior, L. et al, Cancer Res. 2012, 72(10), 2457-2467; Li, L. et al, J Exp Clin Cancer Res. 2018, 37(1), 178), where, v -Ki-ras2Kirsten The rat sarcoma virus oncogene (Kras) accounts for 90% of RAS mutations in lung adenocarcinomas (Hunter, JC; et al, Mol. Cancer Res. 2015, 13(9), 1325-35).
作为Kras的“心脏起搏器”，SOS1在细胞内许多信号转导通路中起着重要的调控作用。研究表明，抑制SOS1活性对于基于所有主要Kras基因突变所导致的癌细胞增殖具有有效的抑制作用(Kessler，D.；Gerlach，D.；Kraut，N.，McConnell，D.B.Curr.Opin.Chem.Biol.2021，62，109-118)。另外，一项在62例卵巢癌患者中的临床研究显示，RAS突变和SOS1突变在卵巢癌组织中表达显著上升，且预后上均与患者PFS缩短相关，提示RAS和SOS1靶向治疗在卵巢癌患者中有潜在价值。同时，SOS1基因突变也在其他很多癌细胞中发现例如胚胎横纹肌肉瘤、塞尔托利细胞睾丸肿瘤、皮肤颗粒细胞瘤(Denayer etal.，Genes Chromosomes Cancer，2010，49(3)：242-52)和肺腺癌(Cancer Genome AtIas Research Network.，Nature 2014，511(7511)，543-50)。另外，研究发现SOS1基因在膀胱癌(Watanabe etal.，IUBMB Life.，2000，49(4)，317-20)及前列腺癌(Timofeeva et al.，Int.J.Oncol.，2009，35(4)：751-60)中均有高表达。在慢性粒细胞白血病的发生发展过程中，BCR-ABL通过磷酸化活化GRB2、募集SOS1，从而持续性激活Ras/MAPK信号通路，导致造血干细胞的恶性增殖。因此，SOS1蛋白也是慢性粒细胞白血病治疗潜在的新靶标。除了癌症外，研究表明遗传性SOS1基因突变也与一些病原性皮疹病如努南综合症(NS)，心面皮肤综合症(CFC)及I型遗传性牙龈纤维瘤病也密切相关(Pierre et al.，Biochem.Pharmacol.，2011，82(9)：1049-56)。As the "pacemaker" of Kras, SOS1 plays an important regulatory role in many signal transduction pathways in cells. Studies have shown that inhibition of SOS1 activity has a potent inhibitory effect on cancer cell proliferation based on all major Kras gene mutations (Kessler, D.; Gerlach, D.; Kraut, N., McConnell, D.B. Curr. Opin. Chem. Biol .2021, 62, 109-118). In addition, a clinical study in 62 patients with ovarian cancer showed that the expressions of RAS mutation and SOS1 mutation were significantly increased in ovarian cancer tissues, and both were associated with shortened PFS in terms of prognosis, suggesting that RAS and SOS1 targeted therapy is effective in ovarian cancer. Potential value in patients. At the same time, SOS1 gene mutations are also found in many other cancer cells, such as embryonal rhabdomyosarcoma, Sertoli cell testicular tumor, and cutaneous granulosa cell tumor (Denayer et al., Genes Chromosomes Cancer, 2010, 49(3): 242-52) and lung adenocarcinoma (Cancer Genome AtIas Research Network., Nature 2014, 511(7511), 543-50). In addition, studies have found that the SOS1 gene is involved in bladder cancer (Watanabe et al., IUBMB Life., 2000, 49(4), 317-20) and prostate cancer (Timofeeva et al., Int.J.Oncol., 2009, 35(4 ):751-60) were highly expressed. During the development of chronic myelogenous leukemia, BCR-ABL activates GRB2 through phosphorylation and recruits SOS1, thereby continuously activating the Ras/MAPK signaling pathway, leading to the malignant proliferation of hematopoietic stem cells. Therefore, SOS1 protein is also a potential new target for the treatment of chronic myelogenous leukemia. In addition to cancer, studies have shown that hereditary SOS1 gene mutations are also closely related to some pathogenic rash diseases such as Noonan syndrome (NS), heart-facial skin syndrome (CFC) and type I hereditary gingival fibromatosis (Pierre et al. al., Biochem. Pharmacol., 2011, 82(9): 1049-56).
SOS1抑制在机理上与SHP2抑制颇为相似(Nichols，R.J.；et al.Nat Cell Biol.2018，20(9)，1064-1073)，这表明SOS1抑制同样可以增强KRAS G12C和MEK抑制剂的功效。初步数据显示，在多个G12和G13 KRAS突变的PDX模型中，SOS1和MEK抑制之间存在显著的协同作用(Hofmann，M.H.；et al；Cancer Discov.2020，10.1158/2159-8290.CD-20-0142.)。除了抑制Kras wt的反馈激活外，由于KRAS G12C变构抑制剂只能与KRAS GDP结合，抑制SOS1具有通过增加突变体KRAS G12C的数量来直接提高KRAS G12C抑制剂的疗效的潜在优势(Hillig，R.C.，et al，Proc Natl Acad Sci U S A.2019，116(7)，2551-2560)。虽然还有待进一步的研究，作为一种联合疗法的策略，抑制SOS1在临床上具有很大的应用潜力。 SOS1 inhibition is mechanistically similar to SHP2 inhibition (Nichols, RJ; et al. Nat Cell Biol. 2018, 20(9), 1064-1073), suggesting that SOS1 inhibition can also enhance the efficacy of KRAS G12C and MEK inhibitors . Preliminary data show a significant synergy between SOS1 and MEK inhibition in multiple PDX models with G12 and G13 KRAS mutations (Hofmann, MH; et al; Cancer Discov. 2020, 10.1158/2159-8290. CD-20 -0142.). In addition to inhibiting feedback activation of Kras wt , since KRAS G12C allosteric inhibitors can only bind KRAS GDP , inhibition of SOS1 has the potential advantage of directly enhancing the efficacy of KRAS G12C inhibitors by increasing the amount of mutant KRAS G12C (Hillig, RC , et al, Proc Natl Acad Sci U S A. 2019, 116(7), 2551-2560). Although further research is warranted, inhibition of SOS1 has great clinical potential as a combination therapy strategy.
目前，全球范围内仍无针对SOS1靶点的药物上市，在研化合物均处于早期临床或临床前研究阶段。虽然有少数几个药研公司或研究机构对SOS1抑制剂均有相应研究并有相关专利公布，例如勃林格殷格翰公司公开了一类苄胺取代的喹唑啉衍生物用作SOS1抑制剂(US20190358230A1)以及拜耳制药公开了一类2-甲基-氮杂喹唑啉类化合物用作SOS1抑制剂(WO2019201848A1)，但现阶段已开发的SOS1抑制剂远未达到临床满足需求，开发新的SOS1抑制剂仍具有非常广阔的临床应用前景。At present, there is still no drug targeting SOS1 on the market worldwide, and the compounds under research are all in the early clinical or preclinical research stage. Although a few pharmaceutical research companies or research institutions have corresponding research on SOS1 inhibitors and published related patents, for example, Boehringer Ingelheim has disclosed a class of benzylamine-substituted quinazoline derivatives as SOS1 inhibitors ( US20190358230A1) and Bayer Pharmaceuticals disclosed a class of 2-methyl-azaquinazoline compounds as SOS1 inhibitors (WO2019201848A1), but the SOS1 inhibitors developed at this stage are far from meeting the clinical needs, and the development of new SOS1 Inhibitors still have very broad prospects for clinical application.
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嘧啶并环衍生物，对SOS1具有强效的选择性抑制作用。The technical problem mainly solved by the present invention is to provide a pyrimidocyclic derivative which has a strong and selective inhibitory effect on SOS1.
为解决上述技术问题，本发明提供一种化合物，具有式I所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，In order to solve the above technical problems, the present invention provides a compound having the structure shown in formula I or its tautomers, mesoforms, racemates, enantiomers, diastereoisomers or its mixture form, pharmaceutically acceptable hydrate, solvate or salt, or,
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、同位素标记物、药学上可接受的盐或共晶：Has the structure shown in formula I or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals:
Figure PCTCN2022101219-appb-000003
Figure PCTCN2022101219-appb-000003
其中：in:
A 1选自CH、CH 2或N、NR 28、O、S，A 2选自C或N，A 3选自CH、CH 2、N、NR 28、O、S，A 4选自CH、CH 2或键；优选地，A 4选自CH、CH 2或单键； A 1 is selected from CH, CH 2 or N, NR 28 , O, S, A 2 is selected from C or N, A 3 is selected from CH, CH 2 , N, NR 28 , O, S, A 4 is selected from CH, CH 2 or a bond; preferably, A 4 is selected from CH, CH 2 or a single bond;
Y选自键、CR 6R 7、O、NR 5、S、S(O)；当A 1、A 3、A 4为CH且A 2为C时(即当环A为苯环结构时)，Y不为键； Y is selected from bond, CR 6 R 7 , O, NR 5 , S, S(O); when A 1 , A 3 , A 4 are CH and A 2 is C (that is, when ring A is a benzene ring structure) , Y is not a key;
R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、烷基；优选地，R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、C1～C6烷基，进一步优选H、C1～C3烷基，更优选H、甲基； R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are independently selected from H and alkyl; preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 28 are independently selected from H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl;
Ar选自芳基、杂芳基、脂杂环基，且当环A不具备芳香性时，所述杂芳基不为吡啶基，其中，所述芳基、杂芳基、脂杂环基任选地被一个或多个R 8取代； Ar is selected from aryl, heteroaryl, and heterocyclic aliphatic, and when ring A does not have aromaticity, the heteroaryl is not pyridyl, wherein the aryl, heteroaryl, heterocyclic aliphatic optionally substituted by one or more R 8 ;
R 8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、-OR a、-NR bR c、-SR d、-C(O)R 10、-C(O)NR bR c、-C(O)OR a，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R 11取代； Each occurrence of R is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 10 , -C(O)NR b R c , -C(O)OR a , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more R 11 are substituted;
R 11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、-OR a、-NR bR c、-SR d、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，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R 13取代； Each occurrence of R 11 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by one or multiple R 13 substitutions;
R 13每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR a、-NR bR c、-SR d、-C(O)R 14、-C(O)NR bR c、-C(O)OR a； Each occurrence of R 13 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR a , -NR b R c , -SR d , -C(O)R 14 , -C (O)NR b R c , -C(O)OR a ;
R 1选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、-OR e、-NR fR g、-SR h、-C(O)R 15、-C(O)NR fR g、-C(O)OR e，其中，烷基、环烷基、脂杂环基任选地被一个或多个R 16取代； R 1 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, -OR e , -NR f R g , -SR h , -C(O)R 15 , -C (O)NR f R g , -C(O)OR e , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 16 ;
R 16每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR e、-NR fR g、-SR h、-C(O)R 17、-C(O)NR fR g、-C(O)OR e； Each occurrence of R 16 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR e , -NR f R g , -SR h , -C(O)R 17 , -C (O)NR f R g , -C(O)OR e ;
环E选自环烷基、脂杂环基、芳基、杂芳基，其中，环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R 18取代； Ring E is selected from cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, wherein cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl is optionally substituted by one or more R 18 ;
R 18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、-OR i、-NR jR k、-SR m、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的环E上的环原子共同组成环烷基、脂杂环基、芳基、杂芳基，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R 25取代； Each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR i , -NR j R k , -SR m , -C( O)R 19 , -C(O)NR j R k , -C(O)OR i , or two adjacent R 18 and the ring atoms on the ring E to which they are connected together form a cycloalkyl group or an aliphatic heterocyclic group , aryl, heteroaryl, wherein the alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 25 ;
优选地，R 18每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的原子共同组成环烷基、脂杂环基、芳基、杂芳基，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R 25取代； Preferably, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , or two adjacent R 18 and the atoms connected to them together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally substituted by one or more R 25 ;
R 25每次出现时独立选自卤素、氰基、烷基、-NR jR k取代的烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 26、-C(O)NR jR k、-C(O)OR i； Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, -NR j R k substituted alkyl, cycloalkyl, aliphatic heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C(O)NR j R k , -C(O)OR i ;
R 25每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 26、-C(O)NR jR k、-C(O)OR i； Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, cycloalkyl, heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C (O)NR j R k , -C(O)OR i ;
R a、R b、R c、R d、R e、R f、R g、R h、R i、R j、R k、R m每次出现时独立选自H、烷基、环烷基、脂杂环 基、-C(O)R 20，或R b、R c与其相连的N原子共同组成脂杂环基，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； Each occurrence of R a , R b , R c , R d , Re , R f , R g , Rh , R i , R j , R k , R m is independently selected from H, alkyl, cycloalkyl , aliphatic heterocyclic group, -C(O)R 20 , or R b , R c and the N atoms connected to them together form an aliphatic heterocyclic group, wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally Substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic;
R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自H、烷基、环烷基、脂杂环基，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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each independently selected from H, alkyl, cycloalkyl, and aliphatic heterocyclic group, and the alkyl, Cycloalkyl, heteroalicyclic are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, heteroalicyclic.
在一实施方式中，本发明提供具有式I所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，In one embodiment, the present invention provides the structure shown in formula I or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable hydrate, solvate or salt, or,
在一实施方式中，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、同位素标记物、药学上可接受的盐或共晶，其中，In one embodiment, the structure represented by formula I or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals, wherein,
A 1选自CH、CH 2或N、NR 28、O、S，A 2选自C或N，A 3选自CH、CH 2、N、NR 28、O、S，A 4选自CH、CH 2或键；优选地，A 4选自CH、CH 2或单键； A 1 is selected from CH, CH 2 or N, NR 28 , O, S, A 2 is selected from C or N, A 3 is selected from CH, CH 2 , N, NR 28 , O, S, A 4 is selected from CH, CH 2 or a bond; preferably, A 4 is selected from CH, CH 2 or a single bond;
Y选自键、CR 6R 7、O、NR 5、S、S(O)；当A 1、A 3、A 4为CH且A 2为C时，Y不为键； Y is selected from bond, CR 6 R 7 , O, NR 5 , S, S(O); when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond;
R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、烷基；优选地，R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、C1～C6烷基，进一步优选H、C1～C3烷基，更优选H、甲基； R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are independently selected from H and alkyl; preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 28 are independently selected from H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl;
Ar选自芳基或杂芳基，且当环A不具备芳香性时，所述杂芳基不为吡啶基，其中，所述芳基或杂芳基任选地被一个或多个R 8取代； Ar is selected from aryl or heteroaryl, and when ring A does not possess aromaticity, said heteroaryl is not pyridyl, wherein said aryl or heteroaryl is optionally replaced by one or more R 8 replace;
R 8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、-OR a、-NR bR c、-SR d、-C(O)R 10、-C(O)NR bR c、-C(O)OR a，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R 11取代； Each occurrence of R is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 10 , -C(O)NR b R c , -C(O)OR a , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more R 11 are substituted;
R 11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、-OR a、-NR bR c、-SR d、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，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R 13取代； Each occurrence of R 11 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by one or multiple R 13 substitutions;
R 13每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR a、-NR bR c、-SR d、-C(O)R 14、-C(O)NR bR c、-C(O)OR a； Each occurrence of R 13 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR a , -NR b R c , -SR d , -C(O)R 14 , -C (O)NR b R c , -C(O)OR a ;
R 1选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、-OR e、-NR fR g、-SR h、-C(O)R 15、-C(O)NR fR g、-C(O)OR e，其中，烷基、环烷基、脂杂环基任选地被一个或多个R 16取代； R 1 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, -OR e , -NR f R g , -SR h , -C(O)R 15 , -C (O)NR f R g , -C(O)OR e , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 16 ;
R 16每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR e、-NR fR g、-SR h、-C(O)R 17、-C(O)NR fR g、-C(O)OR e； Each occurrence of R 16 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR e , -NR f R g , -SR h , -C(O)R 17 , -C (O)NR f R g , -C(O)OR e ;
环E选自环烷基、脂杂环基、芳基、杂芳基，其中，环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R 18取代； Ring E is selected from cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, wherein cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl is optionally substituted by one or more R 18 ;
R 18每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基、环烷基、脂杂环基任选地被一个或多个R 25取代； Each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 19 , -C (O)NR j R k , -C(O)OR i , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 25 ;
R 25每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 26、-C(O)NR jR k、-C(O)OR i； Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, cycloalkyl, heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C (O)NR j R k , -C(O)OR i ;
R a、R b、R c、R d、R e、R f、R g、R h、R i、R j、R k、R m每次出现时独立选自H、烷基、环烷基、脂杂环基、-C(O)R 20，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； Each occurrence of R a , R b , R c , R d , Re , R f , R g , Rh , R i , R j , R k , R m is independently selected from H, alkyl, cycloalkyl , aliphatic heterocyclic group, -C(O)R 20 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino , alkyl, cycloalkyl, aliphatic heterocyclic;
R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自H、烷基、环烷基、脂杂环基，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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each independently selected from H, alkyl, cycloalkyl, and aliphatic heterocyclic group, and the alkyl, Cycloalkyl, heteroalicyclic are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, heteroalicyclic.
进一步地，R a、R b、R c、R d每次出现时独立选自H、烷基、-C(O)R 20，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、烷基； Further, each occurrence of R a , R b , R c , and R d is independently selected from H, alkyl, -C(O)R 20 , wherein the alkyl is optionally substituted by one or more of the following Base substitution: halogen, cyano, hydroxyl, amino, alkyl;
进一步地，R a、R b、R c、R d每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 , R c , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
进一步地，R a、R b、R c、R d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 , R c , and R d 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，R a、R b、R c、R d每次出现时独立选自H、甲基，优选地，R b、R c为甲基。 Furthermore, each occurrence of R a , R b , R c , and R d is independently selected from H and methyl, preferably, R b , R c are methyl.
进一步地，R i、R j、R k、R d每次出现时独立选自H、烷基、-C(O)R 20，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、烷基； Further, each occurrence of R i , R j , R k , and R d is independently selected from H, alkyl, -C(O)R 20 , wherein the alkyl is optionally substituted by one or more of the following Base substitution: halogen, cyano, hydroxyl, amino, alkyl;
进一步地，R i、R j、R k、R d每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 i , R j , R k , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
进一步地，R i、R j、R k、R d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 i , R j , R k , and R d 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，R i、R j、R k、R d每次出现时独立选自H、甲基、二氟甲基，优选H、甲基，优选H。 Further, R i , R j , R k , R d are each independently selected from H, methyl, difluoromethyl, preferably H, methyl, preferably H at each occurrence.
所述“当环A不具备芳香性时，所述杂芳基不为吡啶基”，应当理解为，此时杂芳基不仅不为未取代的吡啶基，也不为被本领域任意结构的取代基取代的吡啶基。The said "when ring A does not have aromaticity, the heteroaryl is not pyridyl", it should be understood that, at this time, the heteroaryl is not only unsubstituted pyridyl, nor is it any structure in the art Substituent substituted pyridyl.
“R 8每次出现时独立选自”，是指当R 8的数量大于1时，不同的R 8可以选自相同或不同的基团。例如，R 8的数量为2时，一个R 8可以选自烷基，另一个R 8可以选自卤素；或者，两个R 8可以均选自烷基；其余类似情况同理。进一步地，A 1选自CH、CH 2或N。优选为CH。 "R 8 is independently selected from each occurrence" means that when the number of R 8 is greater than 1, different R 8 can be selected from the same or different groups. For example, when the number of R 8 is 2, one R 8 can be selected from an alkyl group, and the other R 8 can be selected from a halogen group; or, both R 8 can be selected from an alkyl group; the rest of the similar situations are the same. Further, A 1 is selected from CH, CH 2 or N. Preferably it is CH.
进一步地，A 2选自C或N，优选为C。 Further, A2 is selected from C or N, preferably C.
进一步地，A 3选自CH、CH 2、N、NR 28、O、S，其中，R 28选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基；进一步地，A 3选自CH或N。 Further, A 3 is selected from CH, CH 2 , N, NR 28 , O, S, wherein R 28 is selected from H, alkyl, preferably H, C1-C6 alkyl, more preferably H, C1-C3 alkyl , more preferably H, methyl; further, A 3 is selected from CH or N.
进一步地，A 4选自CH、CH 2或键，更优选为CH、CH 2或单键，更优选为CH。 Further, A 4 is selected from CH, CH 2 or a bond, more preferably CH, CH 2 or a single bond, more preferably CH.
进一步地，
Figure PCTCN2022101219-appb-000004
选自如下基团： further,
Figure PCTCN2022101219-appb-000004
selected from the following groups:
Figure PCTCN2022101219-appb-000005
Figure PCTCN2022101219-appb-000005
优选自如下基团：It is preferably selected from the following groups:
Figure PCTCN2022101219-appb-000006
Figure PCTCN2022101219-appb-000006
更优选
Figure PCTCN2022101219-appb-000007
更优选
Figure PCTCN2022101219-appb-000008
more preferred
Figure PCTCN2022101219-appb-000007
more preferred
Figure PCTCN2022101219-appb-000008
在本发明的具体实施方式中，R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、C1～C6烷基，优选H、C1～C3烷基，更优选H、甲基。 In a specific embodiment of the present invention, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are each independently selected from H, C1-C6 alkyl, preferably H, C1-C3 alkyl, More preferably H, methyl.
进一步地，R 5为C1～C6烷基，优选C1～C3烷基，更优选甲基。 Further, R 5 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group.
进一步地，本发明化合物具有式II所示结构或其异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，Further, the compound of the present invention has the structure shown in formula II or its isomers, tautomers, mesomers, racemates, enantiomers, diastereoisomers or mixtures thereof , a pharmaceutically acceptable hydrate, solvate or salt, or,
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、同位素标记物、药学上可接受的盐、共晶：Has the structure shown in formula II or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts, co-crystals:
Figure PCTCN2022101219-appb-000009
Figure PCTCN2022101219-appb-000009
环E选自C3～C6环烷基、4～7元脂杂环基、苯基、5～6元杂芳基，优选5～7元脂杂环基、苯基，进一步优选含N的6元脂杂环基、苯基，更优选苯基；其中，环烷基、脂杂环基、苯基、杂芳基任选地被一个或多个R 18取代，R 18的定义如前文所述； Ring E is selected from C3-C6 cycloalkyl, 4-7 membered aliphatic heterocyclic group, phenyl, 5-6 membered heteroaryl group, preferably 5-7 membered aliphatic heterocyclic group, phenyl group, more preferably N-containing 6 Aliphatic heterocyclic group, phenyl, more preferably phenyl; wherein, cycloalkyl, aliphatic heterocyclic group, phenyl, heteroaryl are optionally substituted by one or more R 18 , R 18 as defined above stated;
n 1选自0～5的整数，优选1～3的整数，优选1、2，更优选2。 n 1 is an integer selected from 0-5, preferably an integer of 1-3, preferably 1, 2, more preferably 2.
优选地，环E选自苯基、5～6元N杂芳基、5～6元硫杂芳基，更优选苯基、6元N杂芳基、5元硫杂芳基，更优选苯基、吡啶基或噻吩基；其中，所述苯基、5～6元N杂芳基、5～6元硫杂芳基、6元N杂芳基、5元硫杂芳基、吡啶基、噻吩基任选地被一个或多个R 18取代，R 18如前文所定义。 Preferably, ring E is selected from phenyl, 5-6 membered N-heteroaryl, 5-6 membered thioaryl, more preferably phenyl, 6-membered N-heteroaryl, 5-membered thiaryl, more preferably benzene Base, pyridyl or thienyl; wherein, the phenyl, 5-6 membered N heteroaryl, 5-6 membered thiaaryl, 6-membered N heteroaryl, 5-membered thiaryl, pyridyl, Thienyl is optionally substituted with one or more R 18 , R 18 being as previously defined.
优选地，环E选自苯基、5～6元N杂芳基，优选苯基、6元N杂芳基，更优选苯基或吡啶基；其中，苯基、吡啶基、N杂芳基任选地被一个或多个R 18取代，R 18如前文所定义。 Preferably, ring E is selected from phenyl, 5-6 membered N heteroaryl, preferably phenyl, 6 membered N heteroaryl, more preferably phenyl or pyridyl; wherein, phenyl, pyridyl, N heteroaryl Optionally substituted with one or more R 18 , R 18 as defined above.
在本发明的具体实施方式中，环E为苯基、哌啶基，其中，苯基、哌啶基任选地被一个或多个R 18取代，所述R 18如前文所定义。 In a specific embodiment of the present invention, ring E is phenyl, piperidinyl, wherein, phenyl, piperidinyl is optionally substituted by one or more R 18 , and said R 18 is as defined above.
进一步地，当环E为哌啶基时，R 18为C1～C6烷基，其中，所述烷基任选地被1～3个烷基、卤素、羟基、氨基、氰基取代。 Further, when the ring E is piperidinyl, R 18 is a C1-C6 alkyl group, wherein the alkyl group is optionally substituted by 1-3 alkyl groups, halogens, hydroxyl groups, amino groups, and cyano groups.
在本发明的具体实施方式中，当环E为哌啶基时，R 18为非取代或被羟基取代的C1～C3烷基。 In a specific embodiment of the present invention, when ring E is piperidinyl, R 18 is C1-C3 alkyl that is unsubstituted or substituted by hydroxyl.
进一步地，环E为哌啶基时，为如下结构：
Figure PCTCN2022101219-appb-000010
优选如下结构： Further, when Ring E is piperidinyl, it has the following structure:
Figure PCTCN2022101219-appb-000010
The following structure is preferred:
Figure PCTCN2022101219-appb-000011
n 2选自1～3的整数，优选2。
Figure PCTCN2022101219-appb-000011
n 2 is an integer selected from 1 to 3, preferably 2.
进一步地，环E选自苯基、5～6元N杂芳基，优选苯基、6元N杂芳基，更优选苯基或吡啶基；其中，苯基、吡啶基、N杂芳基任选地被一个或多个R 18取代；n 1选自0～5的整数，优选1～3的整数，优选1、2，更优选2。 Further, ring E is selected from phenyl, 5-6 membered N-heteroaryl, preferably phenyl, 6-membered N-heteroaryl, more preferably phenyl or pyridyl; among them, phenyl, pyridyl, N-heteroaryl Optionally substituted by one or more R 18 ;
进一步地，本发明化合物具有式III所示结构或其异构体、互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，Further, the compound of the present invention has the structure shown in formula III or its isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof , a pharmaceutically acceptable hydrate, solvate or salt, or,
具有式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、同位素标记物、药学上可接受的盐或共晶：Has the structure shown in formula III or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals:
Figure PCTCN2022101219-appb-000012
Figure PCTCN2022101219-appb-000012
进一步地，R 23选自C1～C3烷基、被卤素和/或羟基取代的C1～C3烷基，优选为甲基、二氟甲基、三氟甲基、CF 2CH 2OH、C(OH)CH 3CH 3，更优选为三氟甲基； Further, R 23 is selected from C1～C3 alkyl, C1～C3 alkyl substituted by halogen and/or hydroxyl, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C( OH) CH 3 CH 3 , more preferably trifluoromethyl;
进一步地，本发明化合物具有式III’所示结构或其异构体、互变异构体、内消旋体、外消旋体、对映 异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，Further, the compound of the present invention has the structure shown in formula III' or its isomers, tautomers, mesoforms, racemates, enantiomers, diastereoisomers or mixtures thereof form, a pharmaceutically acceptable hydrate, solvate or salt, or,
具有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、同位素标记物、药学上可接受的盐或共晶：Has the structure shown in III' or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals:
Figure PCTCN2022101219-appb-000013
Figure PCTCN2022101219-appb-000013
在一实施方式中，R 18每次出现时独立选自卤素、氰基、烷基、芳基、杂芳基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的环E上的环原子共同组成环烷基、脂杂环基、芳基、杂芳基，其中所述环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R 25取代； In one embodiment, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR i , -NR j R k , -C(O)R 19 , -C (O)NR j R k , -C(O)OR i , or two adjacent R 18 and the ring atoms on the ring E to which they are connected together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, or a heteroaryl group , wherein the cycloalkyl, heteroalicyclic, aryl, heteroaryl are optionally substituted by one or more R 25 ;
在一实施方式中，进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、C1～C6烷氧基、-OH、苯基、-NR jR k，或两个相邻的R 18与其相连的环E上的环原子共同组成C5～C10环烷基、5～10元脂杂环基、C5～C10芳基、5～10元杂芳基，其中所述烷基、烷氧基、苯基、环烷基、脂杂环基、芳基、杂芳基任选地被1～4个R 25取代，R j、R k每次出现时独立选自H、C1～C6烷基。 In one embodiment, further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, phenyl, -NR j R k , or both Two adjacent R 18 and the ring atoms on the ring E connected together form a C5-C10 cycloalkyl group, a 5-10-membered aliphatic heterocyclic group, a C5-C10 aryl group, and a 5-10-membered heteroaryl group, wherein the Alkyl, alkoxy, phenyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally substituted by 1 to 4 R 25 , R j and R k are independently selected from H at each occurrence , C1 ~ C6 alkyl.
在一实施方式中，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、C1～C3烷氧基、-OH、苯基、-NR jR k，或两个相邻的R 18与其相连的环E上的环原子共同组成C5～C6环烷基、5～6元脂杂环基、5～6元杂芳基，其中所述烷基、烷氧基、苯基、环烷基、脂杂环基、杂芳基任选地被1～3个R 25取代，R j、R k每次出现时独立选自H、C1～C3烷基； In one embodiment, each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR j R k , or two adjacent R 18 and the ring atoms on the ring E to which it is connected together form a C5-C6 cycloalkyl group, a 5-6-membered aliphatic heterocyclic group, and a 5-6-membered heteroaryl group, wherein the alkyl, alkoxy, phenyl , cycloalkyl, aliphatic heterocyclic group, and heteroaryl are optionally substituted by 1 to 3 R 25 , and R j and R k are independently selected from H, C1 to C3 alkyl at each occurrence;
在一实施方式中，进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、C1～C3烷氧基、-OH、苯基、-NR jR k，或两个相邻的R 18与其相连的环E上的环原子共同组成环戊烷基、四氢呋喃基、吡咯基，其中所述C1～C3烷基、C1～C3烷氧基、苯基、环戊烷基、四氢呋喃基、吡咯基任选地被1～3个R 25取代，R j、R k均为H； In one embodiment, further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR j R k , or both Two adjacent R 18 and the ring atoms on the ring E connected together form cyclopentyl, tetrahydrofuranyl, pyrrolyl, wherein the C1～C3 alkyl, C1～C3 alkoxy, phenyl, cyclopentane Base, tetrahydrofuryl, pyrrolyl are optionally substituted by 1 to 3 R 25 , R j , R k are both H;
进一步地，R 18每次出现时独立选自卤素、氰基、烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的原子共同组成环烷基、脂杂环基、芳基、杂芳基，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R 25取代； Further, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , or two adjacent R 18 and the atoms connected to it together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, and aliphatic heterocyclic group , aryl, heteroaryl are optionally substituted by one or more R 25 ;
进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、-NR jR k，或两个相邻的R 18与其相连的原子共同组成C5～C10环烷基、5～10元脂杂环基、C5～C10芳基、5～10元杂芳基，其中所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被1～4个R 25取代，R j、R k每次出现时独立选自H、C1～C6烷基； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1~C6 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to them together form a C5~C10 cycloalkyl, 5-10 membered aliphatic heterocyclic group, C5-C10 aryl group, 5-10 membered heteroaryl group, wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by 1- 4 R 25 substitutions, each occurrence of R j and R k are independently selected from H, C1-C6 alkyl;
进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、-NR jR k，或两个相邻的R 18与其相连的原子共同组成C5～C6环烷基、5～6元脂杂环基、5～6元杂芳基，其中所述烷基、环烷基、脂杂环基、杂芳基任选地被1～3个R 25取代，R j、R k每次出现时独立选自H、C1～C3烷基； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1~C3 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to them together form a C5~C6 cycloalkyl, 5-6 membered aliphatic heterocyclic group, 5-6 membered heteroaryl group, wherein the alkyl, cycloalkyl, aliphatic heterocyclic group, and heteroaryl group are optionally substituted by 1 to 3 R 25 , R j , Each occurrence of R k is independently selected from H, C1-C3 alkyl;
进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、-NR jR k，或两个相邻的R 18与其相连的原子共同组成环戊烷基、四氢呋喃基、吡咯基，其中所述C1～C3烷基、环戊烷基、四氢呋喃基、吡咯基任选地被1～3个R 25取代，R j、R k均为H。 Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to form cyclopentyl, tetrahydrofuryl , pyrrolyl, wherein the C1-C3 alkyl, cyclopentyl, tetrahydrofuranyl, and pyrrolyl are optionally substituted by 1-3 R 25 , and both R j and R k are H.
进一步地，R 18每次出现时独立选自卤素、氰基、烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基任选地被一个或多个R 25取代； Further, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , wherein the alkyl group is optionally substituted by one or more R 25 ;
进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、-OR i、-NR jR k，其中所述烷基任选地被一个或多个R 25取代； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C6 alkyl, -OR i , -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 ;
进一步地，R 18每次出现时独立选自卤素、C1～C3烷基、-NR jR k，其中所述烷基任选地被一个或多个R 25取代。 Further, each occurrence of R 18 is independently selected from halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 .
在一实施方式中，R 18每次出现时独立选自卤素、氰基、羟基、氨基、甲基、CF 3、-CF 2CH 3、-CF 2H、-CF 2CH 2OH、-C(CH 3) 2OH、-OCF 2H、-CH 2NHCH 3取代的苯基或吡啶基，或者，两个相邻的R 18与其相连的环E上的环原子共同组成环戊烷基、四氢呋喃基、吡咯基，其中所述环戊烷基、四氢呋喃基、吡咯基任选地被一个或多个F原子取代。 In one embodiment, each occurrence of R 18 is independently selected from halogen, cyano, hydroxy, amino, methyl, CF 3 , -CF 2 CH 3 , -CF 2 H, -CF 2 CH 2 OH, -C (CH 3 ) 2 OH, -OCF 2 H, -CH 2 NHCH 3 substituted phenyl or pyridyl, or, two adjacent R 18 and the ring atoms on the ring E connected to form a cyclopentyl group, Tetrahydrofuryl, pyrrolyl, wherein the cyclopentyl, tetrahydrofuryl, pyrrolyl is optionally substituted by one or more F atoms.
在一实施方式中，R 25每次出现时独立选自卤素、C1～C6烷基、-OR i、-CH 2NR jR k、-NR jR k； In one embodiment, each occurrence of R 25 is independently selected from halogen, C1-C6 alkyl, -OR i , -CH 2 NR j R k , -NR j R k ;
进一步地，R 25每次出现时独立选自卤素、C1～C6烷基、-OR i、-NR jR k，优选卤素、C1～C3烷基、-OR i，更优选卤素或-OR i，更优选卤素，其中，R i、R j、R k如前文所定义，优选地，R i、R j、R k独立选自H、烷基，更优选地，R i、R j、R k为H；进一步地，R 25每次出现时独立选自F、Cl、甲基、乙基、丙基、羟基，优选F、甲基、羟基，更优选F、羟基。 Further, each occurrence of R 25 is independently selected from halogen, C1～C6 alkyl, -OR i , -NR j R k , preferably halogen, C1～C3 alkyl, -OR i , more preferably halogen or -OR i , more preferably halogen, wherein, R i , R j , R k are as defined above, preferably, R i , R j , R k are independently selected from H, alkyl, more preferably, R i , R j , R k is H; further, each occurrence of R is independently selected from F, Cl, methyl, ethyl, propyl, hydroxyl, preferably F, methyl, hydroxyl, more preferably F, hydroxyl.
进一步地，R 18每次出现时独立选自F、CN、-NH 2、-CH 3、-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH、-C(OH)CH 3CH 3，或两个相邻的R 18与其相连的原子共同组成
Figure PCTCN2022101219-appb-000014
Further, each occurrence of R 18 is independently selected from F, CN, -NH 2 , -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, -C(OH) CH 3 CH 3 , or two adjacent R 18 together form the atoms to which they are attached
Figure PCTCN2022101219-appb-000014
在一实施方式中，R 18每次出现时独立选自-F、-CN、-NH 2、-OH、-CH 3、-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH、-OCF 2H、
Figure PCTCN2022101219-appb-000015
或两个相邻的R 18与其相连的原子共同组成
Figure PCTCN2022101219-appb-000016
In one embodiment, each occurrence of R 18 is independently selected from -F, -CN, -NH 2 , -OH, -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, -OCF 2 H,
Figure PCTCN2022101219-appb-000015
Or two adjacent R 18 together with the atoms they are connected to form
Figure PCTCN2022101219-appb-000016
进一步地，R 18每次出现时独立选自F、CN、-NH 2、-CH 3、-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH，或两个相邻的R 18与其相连的原子共同组成
Figure PCTCN2022101219-appb-000017
Further, each occurrence of R 18 is independently selected from F, CN, -NH 2 , -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, or two adjacent R 18 together with the atoms to which it is attached
Figure PCTCN2022101219-appb-000017
进一步地，所述的化合物其结构中
Figure PCTCN2022101219-appb-000018
为
Figure PCTCN2022101219-appb-000019
其中R 22、R 23、R 24分别独立选自H、卤素、氰基、C1～C6烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基任选地被一个或多个R 25取代； Further, in the structure of the compound
Figure PCTCN2022101219-appb-000018
for
Figure PCTCN2022101219-appb-000019
Wherein R 22 , R 23 , and R 24 are independently selected from H, halogen, cyano, C1~C6 alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , wherein the alkyl group is optionally substituted by one or more R 25 ;
进一步地，R 22、R 23、R 24分别独立选自H、卤素、C1～C3烷基、-NR jR k，其中所述烷基任选地被一个或多个R 25取代。 Further, R 22 , R 23 , and R 24 are each independently selected from H, halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 .
进一步地，R 22选自H或卤素，优选为H或F，更优选为H； Further, R 22 is selected from H or halogen, preferably H or F, more preferably H;
R 23选自C1～C3烷基、被卤素和/或羟基取代的C1～C3烷基，优选为甲基、二氟甲基、三氟甲基、CF 2CH 2OH、C(OH)CH 3CH 3，更优选为三氟甲基； R 23 is selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxyl, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C(OH)CH 3 CH 3 , more preferably trifluoromethyl;
R 24选自H、NH 2，优选为NH 2。 R 24 is selected from H, NH 2 , preferably NH 2 .
在一实施方式中，环E选自如下结构：In one embodiment, ring E is selected from the following structures:
Figure PCTCN2022101219-appb-000020
Figure PCTCN2022101219-appb-000020
进一步地，环E选自如下结构：Further, ring E is selected from the following structures:
Figure PCTCN2022101219-appb-000021
Figure PCTCN2022101219-appb-000021
Figure PCTCN2022101219-appb-000022
Figure PCTCN2022101219-appb-000022
进一步地，环E选自如下结构：Further, ring E is selected from the following structures:
Figure PCTCN2022101219-appb-000023
Figure PCTCN2022101219-appb-000023
Y选自键、CR 6R 7、O、NR 5，当A 1、A 3、A 4为CH且A 2为C时，Y不为键。 Y is selected from bond, CR 6 R 7 , O, NR 5 , when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond.
在本发明的具体实施方式中，Y选自键、O、NR 5，当A 1、A 3、A 4为CH且A 2为C时，Y不为键。其中，R 5、R 6、R 7分别独立选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基； In a specific embodiment of the present invention, Y is selected from a bond, O, and NR 5 , and when A 1 , A 3 , and A 4 are CH and A 2 is C, Y is not a bond. Wherein, R 5 , R 6 , and R 7 are independently selected from H and alkyl groups, preferably H, C1-C6 alkyl groups, more preferably H, C1-C3 alkyl groups, more preferably H, and methyl groups;
进一步地
Figure PCTCN2022101219-appb-000024
中R 18的连接位点不固定，是指R 18可以是在苯环上的任意可取代位点，其余类似情况同理。 further
Figure PCTCN2022101219-appb-000024
The connection position of R 18 in is not fixed, which means that R 18 can be any substitutable position on the benzene ring, and the same applies to other similar situations.
进一步地，Y选自键、CR 6R 7、O、NR 5，当A 1、A 3、A 4为CH且A 2为C时，Y不为键。 Further, Y is selected from bond, CR 6 R 7 , O, NR 5 , when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond.
在本发明的具体实施方式中，Y选自键、O、NR 5，当A 1、A 3、A 4为CH且A 2为C时，Y不为键。其中，R 5选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基；或者，R 5为C1～C6烷基，优选C1～C3烷基，更优选甲基； In a specific embodiment of the present invention, Y is selected from a bond, O, and NR 5 , and when A 1 , A 3 , and A 4 are CH and A 2 is C, Y is not a bond. Wherein, R 5 is selected from H, alkyl, preferably H, C1～C6 alkyl, more preferably H, C1～C3 alkyl, more preferably H, methyl; or, R 5 is C1～C6 alkyl, preferably C1 ~C3 alkyl, more preferably methyl;
进一步地，Y选自O、NR 5；其中，R 5选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基；或者，R 5为C1～C6烷基，优选C1～C3烷基，更优选甲基。 Further, Y is selected from O, NR 5 ; wherein, R 5 is selected from H, alkyl, preferably H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl; or, R 5 is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, more preferably a methyl group.
进一步地，Ar选自C6～C10芳基、5～10元杂芳基、3～10元脂杂环基，其中，所述芳基、杂芳基、脂杂环基任选地被一个或多个R 8取代； Further, Ar is selected from C6-C10 aryl, 5-10 membered heteroaryl, and 3-10 membered aliphatic heterocyclic groups, wherein the aryl, heteroaryl, and aliphatic heterocyclic groups are optionally replaced by one or Multiple R 8 substitutions;
进一步地，Ar选自苯基、6～9元杂芳基、5～6元脂杂环基，其中，所述苯基、杂芳基、脂杂环基任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, 6-9 membered heteroaryl, and 5-6 membered aliphatic heterocyclic groups, wherein the phenyl, heteroaryl, and aliphatic heterocyclic groups are optionally replaced by one or more R 8 replaced;
进一步地，Ar选自苯基、6元N杂芳基、9元N杂芳基、N杂环己二烯酮基，其中，所述苯基、6元N杂芳基、9元N杂芳基、N杂环己二烯酮基任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, and N-heterocyclohexadienone, wherein the phenyl, 6-membered N-heteroaryl, 9-membered N-hetero Aryl, N heterocyclohexadienone are optionally substituted by one or more R 8 ;
进一步地，Ar选自苯基、6元N杂芳基、N杂环己二烯酮基，其中，所述苯基、6元N杂芳基、N杂环己二烯酮基任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, 6-membered N heteroaryl, N heterocyclohexadienone, wherein, the phenyl, 6-member N heteroaryl, N heterocyclohexadienone optionally Replaced by one or more R 8 ;
进一步地，Ar选自苯基、吡啶基、
Figure PCTCN2022101219-appb-000025
其中，所述苯基、吡啶基、
Figure PCTCN2022101219-appb-000026
任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, pyridyl,
Figure PCTCN2022101219-appb-000025
Among them, the phenyl, pyridyl,
Figure PCTCN2022101219-appb-000026
optionally substituted by one or more R 8 ;
进一步地，Ar选自苯基、吡啶基、
Figure PCTCN2022101219-appb-000027
其中，所述苯基、吡啶基、
Figure PCTCN2022101219-appb-000028
Figure PCTCN2022101219-appb-000029
任选地被一个或多个R 8取代。 Further, Ar is selected from phenyl, pyridyl,
Figure PCTCN2022101219-appb-000027
Among them, the phenyl, pyridyl,
Figure PCTCN2022101219-appb-000028
Figure PCTCN2022101219-appb-000029
optionally substituted with one or more R 8 .
进一步地，Ar选自苯基或5～10元杂芳基，优选苯基或6～9元杂芳基，更优选苯基或N杂6～9元杂芳基，更优选苯基、吡啶基、9元N杂芳基，其中，所述苯基、吡啶基、杂芳基任选地被一个或多个R 8取代，所述R 8如前文所定义。 Further, Ar is selected from phenyl or 5-10 membered heteroaryl, preferably phenyl or 6-9 membered heteroaryl, more preferably phenyl or N hetero6-9 membered heteroaryl, more preferably phenyl, pyridine Base, 9-membered N heteroaryl, wherein, the phenyl, pyridyl, and heteroaryl are optionally substituted by one or more R 8 , and the R 8 is as defined above.
根据前文中的“当环A不具备芳香性时，所述杂芳基不为吡啶基”限定，则当Ar为吡啶基时，应当理解为环A具备芳香性。According to the limitation of "when ring A does not have aromaticity, the heteroaryl group is not pyridyl", when Ar is pyridyl, it should be understood that ring A has aromaticity.
进一步地，Ar任选地被1～3个R 8取代；进一步地，Ar任选地被1～2个R 8取代。 Further, Ar is optionally substituted by 1-3 R 8 ; further, Ar is optionally substituted by 1-2 R 8 .
进一步地，R 8每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6元环烷基、3～6元脂杂环基、-OR a、-NR bR c，其中，烷基、环烷基、脂杂环基任选地被一个或多个R 11取代，所述R a、R b、R c、R 11如前文所定义。 Further, each occurrence of R 8 is independently selected from halogen, cyano, C1-C6 alkyl, C3-C6 membered cycloalkyl, 3-6 membered aliphatic heterocyclic group, -OR a , -NR b R c , Wherein, the alkyl group, cycloalkyl group, and aliphatic heterocyclic group are optionally substituted by one or more R 11 , and the R a , R b , R c , and R 11 are as defined above.
进一步地，R 8每次出现时独立选自C1～C3烷基、-OR a、-NR bR c，其中，烷基任选地被一个或多个R 11取代，所述R a、R b、R c、R 11如前文所定义。 Further, each occurrence of R 8 is independently selected from C1～C3 alkyl, -OR a , -NR b R c , wherein the alkyl group is optionally substituted by one or more R 11 , said R a , R b , R c , R 11 are as defined above.
进一步地，R 8每次出现时独立选自C1～C3烷基、-OR a、-NR bR c，其中，R a选自H、烷基，R b、R c分别独立选自H、烷基，或R b、R c与其相连的N原子共同组成脂杂环基，所述烷基、脂杂环基任选地被一个或多个R 11取代； Further, each occurrence of R 8 is independently selected from C1～C3 alkyl, -OR a , -NR b R c , wherein R a is selected from H and alkyl, and R b and R c are independently selected from H, Alkyl, or R b , R c and the N atoms connected to them together form an aliphatic heterocyclic group, and the alkyl and aliphatic heterocyclic groups are optionally substituted by one or more R 11 ;
进一步地，R 8每次出现时独立选自甲基、乙基、丙基、-OR a、-NR bR c，其中，R a选自H、C1～C6烷基，R b、R c分别独立选自C1～C6烷基，或R b、R c与其相连的N原子共同组成5元脂杂环基，所述甲基、乙基、丙基、烷基、脂杂环基任选地被一个或多个R 11取代； Further, each occurrence of R 8 is independently selected from methyl, ethyl, propyl, -OR a , -NR b R c , wherein R a is selected from H, C1-C6 alkyl, R b , R c are independently selected from C1-C6 alkyl groups, or R b , R c and the N atoms connected to them together form a 5-membered aliphatic heterocyclic group, and the methyl, ethyl, propyl, alkyl, and aliphatic heterocyclic groups are optionally is substituted by one or more R 11 ;
进一步地，R 8每次出现时独立选自甲基、乙基、-OR a、-NR bR c，其中，R a选自H、C1～C3烷基，R b、R c分别独立选自C1～C3烷基，或R b、R c与N原子共同组成
Figure PCTCN2022101219-appb-000030
所述甲基、乙基、烷基、
Figure PCTCN2022101219-appb-000031
任选地被一个或多个R 11取代。 Further, each occurrence of R 8 is independently selected from methyl, ethyl, -OR a , -NR b R c , wherein R a is selected from H, C1～C3 alkyl, R b and R c are independently selected from From C1～C3 alkyl, or R b , R c and N atom together
Figure PCTCN2022101219-appb-000030
The methyl, ethyl, alkyl,
Figure PCTCN2022101219-appb-000031
optionally substituted with one or more R 11 .
进一步地，R 8每次出现时独立选自-OH、-OCH 3、-N(CH 3) 2、-NHCH 3、-CH 2C(O)N(CH 3) 2、-CH 2CH 2C(O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、-CH 2CN、
Figure PCTCN2022101219-appb-000032
Further, each occurrence of R 8 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , -NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CN,
Figure PCTCN2022101219-appb-000032
进一步地，R 8每次出现时独立选自-OH、-OCH 3、-N(CH 3) 2、-CH 2C(O)N(CH 3) 2、-CH 2CH 2C(O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、-CH 2CN、
Figure PCTCN2022101219-appb-000033
Further, each occurrence of R 8 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O) N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CN,
Figure PCTCN2022101219-appb-000033
进一步地，R 8每次出现时独立选自-OCH 3、-OH、
Figure PCTCN2022101219-appb-000034
-CH 2C(O)N(CH 3) 2、
Figure PCTCN2022101219-appb-000035
-CH 2CH 2N(CH 3) 2、-CH 2CN、-CH 3； Further, each occurrence of R 8 is independently selected from -OCH 3 , -OH,
Figure PCTCN2022101219-appb-000034
-CH 2 C(O)N(CH 3 ) 2 ,
Figure PCTCN2022101219-appb-000035
-CH2CH2N ( CH3 ) 2 , -CH2CN , -CH3 ;
进一步地，R 8每次出现时独立选自-OCH 3、-OH、
Figure PCTCN2022101219-appb-000036
-CH 2C(O)N(CH 3) 2、
Figure PCTCN2022101219-appb-000037
-CH 2CH 2N(CH 3) 2、-CH 2CN。 Further, each occurrence of R 8 is independently selected from -OCH 3 , -OH,
Figure PCTCN2022101219-appb-000036
-CH 2 C(O)N(CH 3 ) 2 ,
Figure PCTCN2022101219-appb-000037
-CH2CH2N ( CH3 )2 , -CH2CN .
在一实施方式中，R 11每次出现时独立选自卤素、氰基、烷基、芳基、杂芳基、-OR a、-NR bR c、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被一个或多个R 13取代； In one embodiment, each occurrence of R 11 is independently selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR a , -NR b R c , -C(O)R 12 , -C (O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, heteroaryl are optionally substituted by one or more R 13 ;
进一步地，R 11每次出现时独立选自卤素、氰基、C1～C6烷基、6～10元芳基、5～9元杂芳基、-OR a、-NR bR c、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被一个或多个R 13取代； Further, each occurrence of R 11 is independently selected from halogen, cyano, C1-C6 alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -OR a , -NR b R c , -C (O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally substituted by one or more R 13 ;
进一步地，R 11每次出现时独立选自卤素、氰基、C1～C6烷基、5～6元杂芳基、-OR a、-NR bR c、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被1～3个R 13取代； Further, each occurrence of R 11 is independently selected from halogen, cyano, C1-C6 alkyl, 5-6 membered heteroaryl, -OR a , -NR b R c , -C(O)R 12 , - C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally substituted by 1 to 3 R 13 ;
进一步地，R 11每次出现时独立选自氰基、C1～C3烷基、5元杂芳基、-NR bR c、-C(O)NR bR c，其中，所述烷基、芳基、杂芳基任选地被1～3个R 13取代； Further, each occurrence of R 11 is independently selected from cyano, C1-C3 alkyl, 5-membered heteroaryl, -NR b R c , -C(O)NR b R c , wherein the alkyl, Aryl and heteroaryl are optionally substituted by 1 to 3 R 13 ;
进一步地，R 11中的5元杂芳基选自噻唑基、咪唑基，其中，所述噻唑基、咪唑基任选地被1～2个R 13取代； Further, the 5-membered heteroaryl group in R 11 is selected from thiazolyl and imidazolyl, wherein the thiazolyl and imidazolyl are optionally substituted by 1 to 2 R 13 ;
进一步地，R 11每次出现时独立选自氰基、甲基、乙基、丙基、
Figure PCTCN2022101219-appb-000038
-N(CH 3) 2、-C(O)N(CH 3) 2、
Figure PCTCN2022101219-appb-000039
 Further , each occurrence of R is independently selected from cyano, methyl, ethyl, propyl,
Figure PCTCN2022101219-appb-000038
-N(CH 3 ) 2 , -C(O)N(CH 3 ) 2 ,
Figure PCTCN2022101219-appb-000039
在一实施方式中，R 11每次出现时独立选自烷基、6～10元芳基、5～9元杂芳基、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被一个或多个R 13取代，所述R a、R b、R c、R 12、R 13如前文所定义。 In one embodiment, each occurrence of R 11 is independently selected from alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -C(O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, aryl group, and heteroaryl group are optionally substituted by one or more R 13 , and the R a , R b , R c , R 12 , R 13 as defined above.
进一步地，R 11每次出现时独立选自5～6元杂芳基、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述杂芳基任选地被一个或多个R 13取代，所述R a、R b、R c、R 12、R 13如前文所定义。 Further, each occurrence of R 11 is independently selected from 5-6 membered heteroaryl, -C(O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein, the Heteroaryl is optionally substituted by one or more R 13 , wherein R a , R b , R c , R 12 , R 13 are as defined above.
进一步地，R 11每次出现时独立选自5元杂芳基、-C(O)NR bR c，优选-C(O)NR bR c，其中，所述杂芳基任选地被一个或多个R 13取代，所述R b、R c、R 13如前文所定义。 Further, each occurrence of R 11 is independently selected from 5-membered heteroaryl, -C(O)NR b R c , preferably -C(O)NR b R c , wherein the heteroaryl is optionally One or more R 13 are substituted, and the R b , R c , R 13 are as defined above.
在本发明的具体实施方式中，R 11每次出现时独立选自噻唑基、咪唑基、-C(O)NR bR c，其中，所述噻唑基、咪唑基任选地被一个或多个R 13取代，所述R b、R c、R 13如前文所定义。 In a specific embodiment of the present invention, each occurrence of R 11 is independently selected from thiazolyl, imidazolyl, -C(O)NR b R c , wherein, said thiazolyl and imidazolyl are optionally replaced by one or more R 13 is substituted, and the R b , R c , and R 13 are as defined above.
进一步地，R 11中可选的噻唑基、咪唑基为如下结构：
Figure PCTCN2022101219-appb-000040
Further, the optional thiazolyl and imidazolyl groups in R11 have the following structures:
Figure PCTCN2022101219-appb-000040
进一步地，R 13每次出现时独立选自卤素、C1～C6烷基、-OR a、-NR bR c、-C(O)R 14、-C(O)NR bR c、-C(O)OR a，所述R a、R b、R c、R 14如前文所定义。 Further, each occurrence of R 13 is independently selected from halogen, C1～C6 alkyl, -OR a , -NR b R c , -C(O)R 14 , -C(O)NR b R c , -C (O) OR a , said R a , R b , R c , and R 14 are as defined above.
在本发明的具体实施方式中，R 13每次出现时独立选自卤素、C1～C6烷基，优选C1～C3烷基，优选甲基。 In a specific embodiment of the present invention, each occurrence of R 13 is independently selected from halogen, C1-C6 alkyl, preferably C1-C3 alkyl, preferably methyl.
进一步地，R a、R b、R c、R d每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 , R c , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
进一步地，R a、R b、R c、R d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 , R c , and R d 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，在本发明的具体实施方式中，R a、R b、R c、R d每次出现时独立选自H、甲基，优选地，R b、R c为甲基。 Furthermore, in a specific embodiment of the present invention, each occurrence of R a , R b , R c , and R d is independently selected from H and methyl, preferably, R b , R c are methyl.
在一实施方式中，Ar选自如下基团：In one embodiment, Ar is selected from the following groups:
Figure PCTCN2022101219-appb-000041
Figure PCTCN2022101219-appb-000041
Figure PCTCN2022101219-appb-000042
Figure PCTCN2022101219-appb-000042
进一步地，Ar选自如下基团：Further, Ar is selected from the following groups:
Figure PCTCN2022101219-appb-000043
Figure PCTCN2022101219-appb-000043
Ar选自如下基团：Ar is selected from the following groups:
Figure PCTCN2022101219-appb-000044
Figure PCTCN2022101219-appb-000044
进一步地，Ar选自如下基团：Further, Ar is selected from the following groups:
Figure PCTCN2022101219-appb-000045
Figure PCTCN2022101219-appb-000045
进一步地，Ar选自如下基团：Further, Ar is selected from the following groups:
Figure PCTCN2022101219-appb-000046
Figure PCTCN2022101219-appb-000046
进一步地，本发明化合物具有式IV或式V或式VI所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，Further, the compound of the present invention has the structure shown in formula IV or formula V or formula VI or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or its Mixture form, pharmaceutically acceptable hydrate, solvate or salt, or,
具有式IV或式V或式VI所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、同位素标记物、药学上可接受的盐或共晶：Has the structure shown in Formula IV or Formula V or Formula VI or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals:
Figure PCTCN2022101219-appb-000047
Figure PCTCN2022101219-appb-000047
A 5、A 6分别独立选自CR 27或N，其中R 27选自H、C1～C3烷基，优选H； A 5 and A 6 are independently selected from CR 27 or N, wherein R 27 is selected from H, C1-C3 alkyl, preferably H;
R 21选自H、C1～C6烷基、-OR a、-NR bR c，优选C1～C3烷基、-OR a、-NR bR c，优选甲基、乙基、-OR a、-NR bR c，更优选-OR a。 R 21 is selected from H, C1～C6 alkyl, -OR a , -NR b R c , preferably C1～C3 alkyl, -OR a , -NR b R c , preferably methyl, ethyl, -OR a , -NR b R c , more preferably -OR a .
在本发明的具体实施方式中，式IV的结构进一步为式IV’：In a specific embodiment of the present invention, the structure of formula IV is further formula IV':
Figure PCTCN2022101219-appb-000048
Figure PCTCN2022101219-appb-000048
式V的结构进一步为式V’：The structure of formula V is further formula V':
Figure PCTCN2022101219-appb-000049
Figure PCTCN2022101219-appb-000049
式IV’、式V’的结构表示原式IV中A 1、A 3、A 4为CH，A 2为C，则应当理解为满足前文中当A 1、A 3、A 4为CH且A 2为C时Y不为键的限定条件。 The structures of formula IV' and formula V' mean that in the original formula IV, A 1 , A 3 , and A 4 are CH, and A 2 is C, so it should be understood that when A 1 , A 3 , and A 4 are CH and A When 2 is C, Y is not a limiting condition for a bond.
进一步地，式IV或式IV’中、式V或式V’，Y为NR 5；式VI中，Y选自键、O、NR 5。 Further, in formula IV or IV', in formula V or V', Y is NR 5 ; in formula VI, Y is selected from a bond, O, and NR 5 .
在本发明的具体实施方式中，式IV或式IV’中的
Figure PCTCN2022101219-appb-000050
选自如下结构： In a specific embodiment of the present invention, in formula IV or formula IV'
Figure PCTCN2022101219-appb-000050
Choose from the following structures:
Figure PCTCN2022101219-appb-000051
Figure PCTCN2022101219-appb-000051
式V或V’中，
Figure PCTCN2022101219-appb-000052
选自如下结构： Formula V or V',
Figure PCTCN2022101219-appb-000052
Choose from the following structures:
Figure PCTCN2022101219-appb-000053
Figure PCTCN2022101219-appb-000053
式VI中的
Figure PCTCN2022101219-appb-000054
选自如下结构： in formula VI
Figure PCTCN2022101219-appb-000054
Choose from the following structures:
Figure PCTCN2022101219-appb-000055
Figure PCTCN2022101219-appb-000055
进一步地，式IV或式IV’中，
Figure PCTCN2022101219-appb-000056
选自如下结构：
Figure PCTCN2022101219-appb-000057
式V或V’中，
Figure PCTCN2022101219-appb-000058
式VI中，
Figure PCTCN2022101219-appb-000059
为
Figure PCTCN2022101219-appb-000060
Further, in formula IV or formula IV',
Figure PCTCN2022101219-appb-000056
Choose from the following structures:
Figure PCTCN2022101219-appb-000057
Formula V or V',
Figure PCTCN2022101219-appb-000058
In formula VI,
Figure PCTCN2022101219-appb-000059
for
Figure PCTCN2022101219-appb-000060
进一步地，
Figure PCTCN2022101219-appb-000061
选自如下结构： further,
Figure PCTCN2022101219-appb-000061
Choose from the following structures:
Figure PCTCN2022101219-appb-000062
优选为
Figure PCTCN2022101219-appb-000063
Figure PCTCN2022101219-appb-000062
preferably
Figure PCTCN2022101219-appb-000063
进一步地，R 18每次出现时独立选自卤素、氰基、烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基任选地被一个或多个R 25取代，所述R i、R j、R k、R 19、R 25如前文所定义。 Further, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , wherein the alkyl group is optionally substituted by one or more R 25 , and the R i , R j , R k , R 19 , R 25 are as defined above.
进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、-OR i、-NR jR k，其中所述烷基任选地被一个或多个R 25取代，所述R i、R j、R k、R 25如前文所定义。 Further, each occurrence of R 18 is independently selected from halogen, cyano, C1～C6 alkyl, -OR i , -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 , The R i , R j , R k and R 25 are as defined above.
进一步地，R 18每次出现时独立选自卤素、C1～C3烷基、-NR jR k，其中所述烷基任选地被一个或多个R 25取代，所述R j、R k、R 25如前文所定义。 Further, each occurrence of R 18 is independently selected from halogen, C1～C3 alkyl, -NR j R k , wherein said alkyl is optionally substituted by one or more R 25 , said R j , R k , R 25 are as defined above.
在本发明的具体实施方式中，
Figure PCTCN2022101219-appb-000064
为如下结构：
Figure PCTCN2022101219-appb-000065
其中R 22、R 23、R 24分别独立选自H、卤素、氰基、C1～C6烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基任选地被一个或多个R 25取代，所述R i、R j、R k、R 19、R 25如前文所定义。 In a specific embodiment of the invention,
Figure PCTCN2022101219-appb-000064
For the following structure:
Figure PCTCN2022101219-appb-000065
Wherein R 22 , R 23 , and R 24 are independently selected from H, halogen, cyano, C1~C6 alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , wherein the alkyl group is optionally substituted by one or more R 25 , and the R i , R j , R k , R 19 , and R 25 are as defined above.
进一步地，R 22、R 23、R 24分别独立选自H、卤素、C1～C3烷基、-NR jR k，其中所述烷基任选地被一个或多个R 25取代，所述R j、R k、R 25如前文所定义。 Further, R 22 , R 23 , and R 24 are independently selected from H, halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 , the R j , R k , R 25 are as defined above.
在本发明的具体实施方式中，R 25每次出现时独立选自卤素、C1～C6烷基、-OR i、-NR jR k，优选卤素、C1～C3烷基、-OR i，更优选卤素；R i、R j、R k如前文所定义。 In a specific embodiment of the present invention, R 25 is independently selected from halogen, C1～C6 alkyl, -OR i , -NR j R k each occurrence, preferably halogen, C1～C3 alkyl, -OR i , more Halogen is preferred; R i , R j , R k are as defined above.
进一步地，R i、R j、R k、R d每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 i , R j , R k , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
进一步地，R i、R j、R k、R d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 i , R j , R k , and R d 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;
在本发明的具体实施方式中，R i、R j、R k、R d每次出现时独立选自H、甲基，优选H。 In a specific embodiment of the present invention, each occurrence of R i , R j , R k , R d is independently selected from H, methyl, preferably H.
在本发明的具体实施方式中，R 22选自H或卤素，优选为H或F，更优选为H；R 23选自C1～C3烷基、被卤素和/或羟基取代的C1～C3烷基，优选为甲基、二氟甲基、三氟甲基、CF 2CH 2OH、C(OH)CH 3CH 3，更优选为三氟甲基；R 24选自H、NH 2，优选为NH 2。 In a specific embodiment of the present invention, R 22 is selected from H or halogen, preferably H or F, more preferably H; R 23 is selected from C1～C3 alkyl, C1～C3 alkane substituted by halogen and/or hydroxyl group, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C(OH)CH 3 CH 3 , more preferably trifluoromethyl; R 24 is selected from H, NH 2 , preferably to NH 2 .
进一步地，本发明化合物具有式VII所示结构或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、药学上可接受的水合物、溶剂化物或盐，或，Further, the compound of the present invention has the structure shown in formula VII or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, pharmaceutically available Accepted hydrates, solvates or salts, or,
具有式VII所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、同位素标记物、药学上可接受的盐、共晶：Has the structure shown in formula VII or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts, co-crystals:
Figure PCTCN2022101219-appb-000066
Figure PCTCN2022101219-appb-000066
进一步地，R 1选自氢、卤素、氰基、C1～C6烷基、6～10元芳基、-OR e、-NR fR g、-C(O)R 15、-C(O)NR fR g、-C(O)OR e，其中，烷基任选地被一个或多个R 16取代，所述R e、R f、R g、R 15、R 16如前文所定义； Further, R 1 is selected from hydrogen, halogen, cyano, C1-C6 alkyl, 6-10 membered aryl, -OR e , -NR f R g , -C(O)R 15 , -C(O) NR f R g , -C(O)OR e , wherein the alkyl group is optionally substituted by one or more R 16 , and the R e , R f , R g , R 15 , and R 16 are as defined above;
进一步地，R 1选自氢、卤素、氰基、C1～C3烷基、-OR e、-NR fR g，其中，烷基任选地被一个或多个R 16取代，所述R e、R f、R g、R 16如前文所定义； Further, R 1 is selected from hydrogen, halogen, cyano, C1～C3 alkyl, -OR e , -NR f R g , wherein the alkyl group is optionally substituted by one or more R 16 , said R e , R f , R g , R 16 are as defined above;
在本发明的具体实施方式中，R 1选自卤素、C1～C3烷基。 In a specific embodiment of the present invention, R 1 is selected from halogen, C1-C3 alkyl.
在一实施方式中，R 1选自氢、卤素、C1～C6烷基，其中，烷基任选地被一个或多个R 16取代。 In one embodiment, R 1 is selected from hydrogen, halogen, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 16 .
进一步地，R 16每次出现时独立选自卤素、氰基、C1～C6烷基、-OR e、-NR fR g、-C(O)R 17、-C(O)NR fR g、-C(O)OR e。 Further, each occurrence of R 16 is independently selected from halogen, cyano, C1～C6 alkyl, -OR e , -NR f R g , -C(O)R 17 , -C(O)NR f R g , -C(O)OR e .
进一步地，R 16每次出现时独立选自卤素、C1～C3烷基、-OR e、-NR fR g。 Further, each occurrence of R 16 is independently selected from halogen, C1-C3 alkyl, -OR e , -NR f R g .
进一步地，R 16为-OR e。 Further, R 16 is -OR e .
进一步地，R e、R f、R g、R h每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 e , R f , R g , and Rh is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
进一步地，R e、R f、R g、R h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 e , R f , R g , and Rh 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，R e、R f、R g、R h每次出现时独立选自H、甲基、乙基。 Further, each occurrence of Re , Rf , Rg , Rh is independently selected from H, methyl, ethyl.
更进一步地，R e为H。 Further, R e is H.
进一步地，R 1选自H、Cl、Br、I、羟基、氰基、甲基、二氟甲基、乙基、-CH 2OH、-CH 2NH 2、-NHCH 3、-OCH 2CH 3，优选为甲基或Cl。进一步地，
Figure PCTCN2022101219-appb-000067
的构型为
Figure PCTCN2022101219-appb-000068
Further, R 1 is selected from H, Cl, Br, I, hydroxyl, cyano, methyl, difluoromethyl, ethyl, -CH 2 OH, -CH 2 NH 2 , -NHCH 3 , -OCH 2 CH 3 , preferably methyl or Cl. further,
Figure PCTCN2022101219-appb-000067
is configured as
Figure PCTCN2022101219-appb-000068
在一实施方式中，R 1选自H、Cl、Br、I、羟基、氰基、甲基、二氟甲基、乙基、-CH 2OH、-CH 2NH 2、-NHCH 3、-OCH 2CH 3，更优选为H、Cl、甲基、乙基、-CH 2CH 2OH；更优选为甲基或Cl； In one embodiment, R 1 is selected from H, Cl, Br, I, hydroxyl, cyano, methyl, difluoromethyl, ethyl, -CH 2 OH, -CH 2 NH 2 , -NHCH 3 , - OCH 2 CH 3 , more preferably H, Cl, methyl, ethyl, -CH 2 CH 2 OH; more preferably methyl or Cl;
优选地，R 1选自Cl、甲基、-CH 2CH 2OH、-CH 2CH 3、环丙烷基； Preferably, R 1 is selected from Cl, methyl, -CH 2 CH 2 OH, -CH 2 CH 3 , cyclopropanyl;
进一步地，
Figure PCTCN2022101219-appb-000069
的构型为
Figure PCTCN2022101219-appb-000070
further,
Figure PCTCN2022101219-appb-000069
is configured as
Figure PCTCN2022101219-appb-000070
进一步地，R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 is independently selected from H, C1-C6 alkyl, and the alkyl is optionally replaced by Substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1-C6 alkyl.
进一步地，R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 is independently selected from H, C1-C3 alkyl, and the alkyl is optionally replaced by Substituted by one or more of the following substituents: halogen, hydroxyl, amino, C1-C3 alkyl.
在本发明的具体实施方式中，所述化合物结构选自如下之一：In a specific embodiment of the invention, the compound structure is selected from one of the following:
Figure PCTCN2022101219-appb-000071
Figure PCTCN2022101219-appb-000071
Figure PCTCN2022101219-appb-000072
Figure PCTCN2022101219-appb-000072
Figure PCTCN2022101219-appb-000073
Figure PCTCN2022101219-appb-000073
Figure PCTCN2022101219-appb-000074
Figure PCTCN2022101219-appb-000074
Figure PCTCN2022101219-appb-000075
Figure PCTCN2022101219-appb-000075
本发明的另一方面，提供一种上述化合物的制备方法，所述制备方法包括选自以下合成方案的步骤：Another aspect of the present invention provides a kind of preparation method of above-mentioned compound, described preparation method comprises the step that is selected from following synthetic scheme:
合成方案1：Synthesis scheme 1:
式1-1化合物与式1-2化合物进行成环反应得式1-3化合物，式1-3化合物与POX 3进行反应得到式1-4化合物； The compound of formula 1-1 is reacted with the compound of formula 1-2 to obtain the compound of formula 1-3, and the compound of formula 1-3 is reacted with POX 3 to obtain the compound of formula 1-4;
Figure PCTCN2022101219-appb-000076
Figure PCTCN2022101219-appb-000076
其中，X表示卤素，优选地，选自氯或溴；A、A 1、A 2、A 3、A 4的定义同式(I)化合物； Wherein, X represents halogen, preferably selected from chlorine or bromine; the definitions of A, A 1 , A 2 , A 3 , and A 4 are the same as those of the compound of formula (I);
合成方案2：Synthesis Scheme 2:
路线A：式2-1化合物先与式2-2化合物进行取代反应得式2-3化合物，式2-3化合物再与式2-4化合物进行取代反应得式(I’)化合物；或，Route A: the compound of formula 2-1 is first substituted with the compound of formula 2-2 to obtain the compound of formula 2-3, and the compound of formula 2-3 is then substituted with the compound of formula 2-4 to obtain the compound of formula (I'); or,
路线B：式2-1化合物先与式2-4化合物进行取代反应得式2-3化合物，式2-3化合物再与式2-4化合物进行取代反应得式(I’)化合物；Route B: the compound of formula 2-1 is first substituted with the compound of formula 2-4 to obtain the compound of formula 2-3, and the compound of formula 2-3 is then substituted with the compound of formula 2-4 to obtain the compound of formula (I');
Figure PCTCN2022101219-appb-000077
Figure PCTCN2022101219-appb-000077
其中，X表示卤素，优选地，选自氯或溴；R 1、R 2、R 3、R 4、A、A 1、A 2、A 3、A 4、Y的定义同式(I)化合物；M与M’选自X或Y，条件是，M与M’不同时为X或Y； Wherein, X represents halogen, preferably selected from chlorine or bromine; the definitions of R 1 , R 2 , R 3 , R 4 , A, A 1 , A 2 , A 3 , A 4 , and Y are the same as the compounds of formula (I) ; M and M' are selected from X or Y, provided that M and M' are not X or Y at the same time;
E’、R1’、Ar’各自定义同式(I)化合物中的E、R1、Ar，条件是，当式(I)化合物中该三者中的取代基包括羟基时，所述羟基任选地被OTBS取代；任选地，步骤A和步骤B之后还包括脱去式(I’)化合物中TBS的步骤；E', R1', Ar' each define the same as E, R1, Ar in the compound of formula (I), with the proviso that when the substituents in the three in the compound of formula (I) include a hydroxyl group, the hydroxyl group is optionally is replaced by OTBS; Optionally, step A and step B also include the step of removing TBS in the compound of formula (I');
当(I)化合物中该三者中的取代基包括氨基时，所述氨基任选地被-NO 2或-C(O)OCH 2CH 3取代；任选地，步骤A和步骤B之后还包括将式(I’)化合物中的-NH 2还原为-NO 2的步骤或脱去-C(O)OCH 2CH 3保护基的步骤； When the substituents among the three in (I) compound include amino, said amino is optionally substituted by -NO 2 or -C(O)OCH 2 CH 3 ; optionally, after step A and step B, also Including the step of reducing -NH 2 in the compound of formula (I') to -NO 2 or removing the -C(O)OCH 2 CH 3 protecting group;
当(I)化合物中该三者中的取代基包括
Figure PCTCN2022101219-appb-000078
时，所述
Figure PCTCN2022101219-appb-000079
任选地被
Figure PCTCN2022101219-appb-000080
取代；任选地，步骤A和步骤B之后还包括将式(I’)化合物中的
Figure PCTCN2022101219-appb-000081
还原为
Figure PCTCN2022101219-appb-000082
的步骤； When the substituents among the three in compound (I) include
Figure PCTCN2022101219-appb-000078
when the
Figure PCTCN2022101219-appb-000079
optionally by
Figure PCTCN2022101219-appb-000080
Replacement; Optionally, after step A and step B, also include in the compound of formula (I')
Figure PCTCN2022101219-appb-000081
revert to
Figure PCTCN2022101219-appb-000082
A step of;
当(I)化合物中该三者中的取代基包括
Figure PCTCN2022101219-appb-000083
或乙基时，所述
Figure PCTCN2022101219-appb-000084
或乙基任选地被
Figure PCTCN2022101219-appb-000085
取代；任选地，步骤A和步骤B之后还包括将式(I’)化合物中的
Figure PCTCN2022101219-appb-000086
还原为
Figure PCTCN2022101219-appb-000087
或乙基的步骤； When the substituents among the three in compound (I) include
Figure PCTCN2022101219-appb-000083
or ethyl when the
Figure PCTCN2022101219-appb-000084
or ethyl is optionally
Figure PCTCN2022101219-appb-000085
Replacement; Optionally, after step A and step B, also include in the compound of formula (I')
Figure PCTCN2022101219-appb-000086
revert to
Figure PCTCN2022101219-appb-000087
or ethyl steps;
合成方案3：Synthesis Scheme 3:
式3-2化合物在Cs 2CO 3与18-冠醚-6存在下进行环化反应得式3-2化合物； The compound of formula 3-2 undergoes a cyclization reaction in the presence of Cs 2 CO 3 and 18-crown ether-6 to obtain the compound of formula 3-2;
Figure PCTCN2022101219-appb-000088
Figure PCTCN2022101219-appb-000088
其中，R 1、R 2、R 3、R 4、A、A 1、A 2、A 3、A 4、Y、Ar的定义同式(I)化合物； Wherein, the definition of R 1 , R 2 , R 3 , R 4 , A, A 1 , A 2 , A 3 , A 4 , Y, Ar is the same as that of the compound of formula (I);
合成方案4：Synthetic Scheme 4:
式4-1化合物与BBr 3进行脱甲基反应得式4-2化合物； Formula 4-1 compound and BBr 3 carry out demethylation reaction to obtain formula 4-2 compound;
Figure PCTCN2022101219-appb-000089
Figure PCTCN2022101219-appb-000089
其中，R 1、R 2、R 3、R 4、A、A 1、A 2、A 3、A 4、E环、Y的定义同式(I)化合物；N环选自苯基或吡啶基。 Among them, the definition of R 1 , R 2 , R 3 , R 4 , A, A 1 , A 2 , A 3 , A 4 , E ring, and Y is the same as that of the compound of formula (I); N ring is selected from phenyl or pyridyl .
本发明还提供了一种药用组合物，该药用组合物活性成份选自上述化合物或其立体异构体、溶剂化物、水合物、药学上可接受的盐或共晶中的一种或两种以上的组合。The present invention also provides a pharmaceutical composition, the active ingredient of which is selected from one of the above-mentioned compounds or their stereoisomers, solvates, hydrates, pharmaceutically acceptable salts or co-crystals or A combination of two or more.
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、同位素标记物、药学上可接受的盐或共晶、药物组合物在制备SOS1抑制剂中的用途。The present invention also provides the above compounds or their tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions used in the preparation of SOS1 inhibitors use.
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、同位素标记物、药学上可接受的盐或共晶、药物组合物在制备用于治疗由SOS1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, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions used for the treatment of SOS1 Use in medicines for mediated diseases.
进一步地，所述疾病选自：癌症、病原性皮疹病。Further, the disease is selected from: cancer, pathogenic rash 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、前列腺癌、慢性粒细胞白血病、结直肠癌、脑癌、肝癌、肾癌、胃癌、及乳腺癌。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, and breast cancer .
所述病原性皮疹病选自：努南综合症、心面皮肤综合症、I型遗传性牙龈纤维瘤病。The pathogenic rash disease is selected from the group consisting of Noonan syndrome, cardiofacial skin syndrome, and type I hereditary gingival fibromatosis.
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、同位素标记物、药学上可接受的盐或共晶、药物组合物在制备治疗致使SOS1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, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions in the preparation and treatment of excessive SOS1 protein Use in medicines for expressed diseases.
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、同位素标记物、药学上可接受的盐或共晶、药物组合物在制备治疗SOS1蛋白过度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, isotope labels, pharmaceutically acceptable salts or co-crystals, and pharmaceutical compositions for the preparation of SOS1 protein overexpression Use in medicines for disease-causing diseases.
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、同位素标记物、药学上可接受的盐或共晶的药物组合物中，可以含有药学上可接受的辅料。Pharmaceutical compositions containing the compound of the present invention or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable salts or co-crystals may contain pharmaceutically acceptable excipients .
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“同位素标记物”是指分子中一个或多个原子被具有不同原子质量或质量数的原子替代。可以掺入本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素，分别例如但不限于 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 35S、 18F、 36Cl、 123I和 125I。某些同位素标记的本发明化合物可用于药物和/或底物组织分布研究，放射性同位素氚即 3H和碳-14即 14C因其易于掺入和方便的检测手段而特别可用于该目的，例如，本发明化合物可以富含1％、2％、5％、10％、25％、50％、75％、90％、95％或99％的指定同位素。此外，用较重的同位素例如氘即2H取代的本发明化合物可以提供某些治疗优势。 The "isotopic label" in the present invention means that one or more atoms in a molecule are replaced by atoms with different atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen , carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine such as, but not limited to, 2H, 3H , 11C , 13C , 14C , respectively , 13 N, 15 N, 15 O, 17 O, 18 O, 35 S, 18 F, 36 Cl, 123 I and 125 I. Certain isotopically labeled compounds of the present invention are useful in drug and/or substrate tissue distribution studies, and the radioisotopes tritium, i.e. 3 H and carbon-14, i.e. 14 C, are particularly useful for this purpose due to their ease of incorporation and convenient means of detection, For example, a compound of the invention may be 1%, 2%, 5%, 10%, 25%, 50%, 75%, 90%, 95%, or 99% enriched for a given isotope. In addition, substitution of the compounds of the invention with heavier isotopes such as deuterium, 2H, may afford certain therapeutic advantages.
本发明所述“药学上可接受的盐”是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。本发明所述“药学上可接受的盐”优选盐酸盐、甲酸盐。The "pharmaceutically acceptable salt" in the present invention refers to the salt formed by the compound of the present invention and acid or base which is suitable for use as 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 "pharmaceutically acceptable salt" of the present invention is preferably hydrochloride and formate.
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、四氢呋哺、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。"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。粘合剂包含糖浆、阿拉伯胶、明胶、山梨醇、黄芪胶、纤维素及其衍生物(如微晶纤维素、羧甲基纤维素钠、乙基纤维素或羟丙甲基纤维素等)、明胶浆、糖浆、淀粉浆或聚乙烯吡咯烷酮等；填充剂包含乳糖、糖粉、糊精、淀粉及其衍生物、纤维素及其衍生物、无机钙盐(如硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等)、山梨醇或甘氨酸等；润滑剂包含微粉硅胶、硬脂酸镁、滑石粉、氢氧化铝、硼酸、氢化植物油、聚乙二醇等；崩解剂包含淀粉及其衍生物(如羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、玉米淀粉等)、聚乙烯吡咯烷酮或微晶纤维素等；湿润剂包含十二烷基硫酸钠、水或醇等；抗氧剂包含亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、二丁基苯酸等；抑菌剂包含0.5％苯酚、0.3％甲酚、0.5％三氯叔丁醇等；调节剂包含盐酸、枸橼酸、氢氧化钾(钠)、枸橼酸钠及缓冲剂(包括磷酸二氢钠和磷酸氢二钠)等；乳化剂包含聚山梨酯-80、没酸山梨坦、普流罗尼克F-68，卵磷酯、豆磷脂等；增溶剂包含吐温-80、胆汁、甘油等。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 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. Binders include syrup, gum arabic, gelatin, sorbitol, tragacanth, cellulose and its derivatives (such as microcrystalline cellulose, sodium carboxymethyl cellulose, ethyl cellulose or hydroxypropyl methyl cellulose, etc.) , gelatin slurry, syrup, starch slurry or polyvinylpyrrolidone, etc.; fillers include lactose, powdered sugar, dextrin, starch and its derivatives, cellulose and its derivatives, inorganic calcium salts (such as calcium sulfate, calcium phosphate, phosphoric acid Calcium hydrogen, precipitated calcium carbonate, etc.), sorbitol or glycine, etc.; lubricants include micropowder silica gel, magnesium stearate, talcum powder, aluminum hydroxide, boric acid, hydrogenated vegetable oil, polyethylene glycol, etc.; disintegrants include starch and Its derivatives (such as sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, modified starch, hydroxypropyl starch, corn starch, etc.), polyvinylpyrrolidone or microcrystalline cellulose, etc.; the humectant contains dodecane Sodium sulfite, water or alcohol, etc.; antioxidants include sodium sulfite, sodium bisulfite, sodium metabisulfite, dibutyl benzoic acid, etc.; antibacterial agents include 0.5% phenol, 0.3% cresol, 0.5% chlorobutanol etc.; regulators include hydrochloric acid, citric acid, potassium hydroxide (sodium), sodium citrate and buffers (including sodium dihydrogen phosphate and disodium hydrogen phosphate), etc.; emulsifiers include polysorbate-80, no acid Sorbitan, Pluronic F-68, lecithin, soybean lecithin, etc.; solubilizers include Tween-80, bile, glycerin, etc. 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 method of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative administration methods include (but are not limited to): oral, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. Liquid dosage forms may contain, in addition to the active compound, inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
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 compound. 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. Delivery to the route of administration may contribute to stability.
“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.
“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.
杂原子包括但不限于O、S、N、P、Si等。Heteroatoms include, but are not limited to, O, S, N, P, Si, and the like.
本发明中所述“键”，指该处仅为一个连接键，亦可理解为“无”。例如，式I中当Y为键时，表示Ar与A环直接相连。The "key" mentioned in the present invention means that there is only one connecting key, and it can also be understood as "none". For example, when Y is a bond in formula I, it means that Ar is directly connected to ring A.
“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 the substituent indicates the minimum value and the number of carbon atoms in the substituent Maximum, for example, "C1-C6 alkyl" refers to straight or branched chain alkyl groups 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.
“环烷基”指饱和的环状烃取代基。"Cycloalkyl" refers to a saturated cyclic hydrocarbon substituent.
“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化合物形成的取代基团。典型的脂杂环基包括但不限于："Heteroalicyclic group" refers to a substituent group formed by a compound containing at least one heteroatom in the ring skeleton and having no aromaticity. Typical heteroalicyclic groups include, but are not limited to:
Figure PCTCN2022101219-appb-000090
Figure PCTCN2022101219-appb-000090
“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电子系统并且含有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。典型的杂芳基包括但不限于："Heteroaryl" refers to a monocyclic or polycyclic group containing heteroatoms and having aromaticity. Typical heteroaryl groups include, but are not limited to:
Figure PCTCN2022101219-appb-000091
Figure PCTCN2022101219-appb-000091
在本发明的一些具体实施方式中，Ar可选杂芳基的互变异构体，如
Figure PCTCN2022101219-appb-000092
的互变异构体
Figure PCTCN2022101219-appb-000093
In some specific embodiments of the present invention, Ar can be a tautomer of heteroaryl, such as
Figure PCTCN2022101219-appb-000092
tautomers
Figure PCTCN2022101219-appb-000093
“N杂环己二烯酮基”是指环己二烯酮的环骨架上含有至少一个N原子的取代基，例如
Figure PCTCN2022101219-appb-000094
Figure PCTCN2022101219-appb-000095
"N heterocyclohexadienone group" refers to a substituent containing at least one N atom on the ring skeleton of cyclohexadienone, for example
Figure PCTCN2022101219-appb-000094
Figure PCTCN2022101219-appb-000095
“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-NH 2。 "Amino" refers to -NH2 .
“羟基”是指-OH。"Hydroxy" means -OH.
“(O)”是指＝O，如-C(O)R 12是指
Figure PCTCN2022101219-appb-000096
其余类似情况同理。 "(O)" means =O, such as -C(O)R 12 means
Figure PCTCN2022101219-appb-000096
The rest of the similar situations are the same.
“吡啶”结构式为
Figure PCTCN2022101219-appb-000097
The structural formula of "pyridine" is
Figure PCTCN2022101219-appb-000097
“吡唑”结构式为
Figure PCTCN2022101219-appb-000098
The structural formula of "pyrazole" is
Figure PCTCN2022101219-appb-000098
“哌啶”结构式为
Figure PCTCN2022101219-appb-000099
The structural formula of "piperidine" is
Figure PCTCN2022101219-appb-000099
“噻唑”结构式为
Figure PCTCN2022101219-appb-000100
The structural formula of "thiazole" is
Figure PCTCN2022101219-appb-000100
“咪唑”结构式为
Figure PCTCN2022101219-appb-000101
The structural formula of "imidazole" is
Figure PCTCN2022101219-appb-000101
本发明的有益效果是：本发明提供了一系列对SOS1蛋白具有明显的抑制作用的化合物，为以SOS1为治疗的靶点的疾病如癌症、病原性皮疹病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。The beneficial effects of the present invention are: the present invention provides a series of compounds with obvious inhibitory effect on SOS1 protein, which provides a new solution for the treatment of diseases such as cancer and pathogenic rash diseases with SOS1 as the target of treatment, which can be used It is used in the preparation of drugs for the treatment of related diseases and has broad application prospects.
具体实施方式detailed description
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-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，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)Sun Fire Prep C18 OBDTM 5μm，30x 150mm Column，0.06％甲酸水溶液/乙腈；(方法3)Xbridge Prep C18 OBDTM 5μm，30 x 150mm Column，10mM NH 4HCO 3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) Sun Fire Prep C18 OBDTM 5 μm, 30x 150mm Column, 0.06% formic acid in water/acetonitrile; (Method 3) Xbridge Prep C18 OBDTM 5 μm, 30 x 150mm Column, 10 mM NH 4 HCO 3 in water/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:
DMF：N，N-二甲基甲酰胺DMF: N,N-Dimethylformamide
THF：四氢呋喃THF: Tetrahydrofuran
DMSO：二甲基亚砜DMSO: dimethyl sulfoxide
DIPEA：N，N-二异丙基乙胺DIPEA: N,N-Diisopropylethylamine
HATU：O-(7-氮杂苯并三唑-1-基)-N，N，N′，N′-四甲基脲HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea
DBU：1，8-二氮杂二环[5.4.0]十一碳-7-烯DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
BOP：苯并三唑-1-基氧基三(二甲氨基)鳞六氟磷酸盐BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
DAST：二乙氨基三氟化硫DAST: Diethylaminosulfur trifluoride
DMF-DMA：N，N-二甲基甲酰胺二甲基缩醛DMF-DMA: N,N-dimethylformamide dimethyl acetal
LiHMDS：双(三甲基硅基)胺基锂LiHMDS: lithium bis(trimethylsilyl)amide
Prep-HPLC：制备型高效液相色谱仪Prep-HPLC: Preparative High Performance Liquid Chromatography
TBS：叔丁基二甲基甲硅基TBS: tert-butyldimethylsilyl
CHFN：四丁基氟化铵CHFN: Tetrabutylammonium fluoride
实施例1Example 1
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl )amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000102
Figure PCTCN2022101219-appb-000102
步骤a)：2-(5-溴-2-羟基苯基)-N，N-二甲基乙酰胺的制备Step a): Preparation of 2-(5-bromo-2-hydroxyphenyl)-N,N-dimethylacetamide
将2-(5-溴-2-羟苯基)乙酸(8.0g，34.625mmol)、二甲胺盐酸盐(3.7g，45.012mmol)、DIPEA(13.4g，103.875mmol)和DMF(160mL)加入反应瓶中，室温搅拌下加入HATU(19.7g，51.938mmol)，在室温下维持反应3h。反应结束后，加水(200mL)淬灭，用乙酸乙酯萃取(200mL×2)，合并有机相，依次用饱和碳酸氢钠水溶液(50mL×1)，饱和食盐水洗(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到2-(5-溴-2-羟基苯基)-N，N-二甲基乙酰胺，收率98.0％；ESI-MS(m/z)：258.0[M+H] +。 2-(5-Bromo-2-hydroxyphenyl)acetic acid (8.0 g, 34.625 mmol), dimethylamine hydrochloride (3.7 g, 45.012 mmol), DIPEA (13.4 g, 103.875 mmol) and DMF (160 mL) Add it into the reaction flask, add HATU (19.7 g, 51.938 mmol) under stirring at room temperature, and maintain the reaction at room temperature for 3 h. After the reaction was completed, add water (200mL) to quench, extract with ethyl acetate (200mL×2), combine the organic phases, wash with saturated aqueous sodium bicarbonate solution (50mL×1), and wash with saturated brine (100mL×2) successively. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(5-bromo-2-hydroxyphenyl)-N,N-dimethylacetamide with a yield of 98.0%; ESI-MS (m/z): 258.0[M+H] + .
步骤b)：2-(5-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): Preparation of 2-(5-bromo-2-methoxyphenyl)-N,N-dimethylacetamide
将2-(5-溴-2-羟基苯基)-N，N-二甲基乙酰胺(8.8g，33.933mmol)、碳酸钾(14.1g，101.799mmol)和DMF(150mL)加入反应瓶中，室温下搅拌条件加入碘甲烷(7.2g，50.900mmol)，维持室温搅拌反应过夜。反应结束后，加水(100mL)淬灭，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和食盐水(100mL×2)洗，有机相减压浓缩干，残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)，得2-(5-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺，收率51.4％；ESI-MS(m/z)：272.0[M+H]+。2-(5-Bromo-2-hydroxyphenyl)-N,N-dimethylacetamide (8.8 g, 33.933 mmol), potassium carbonate (14.1 g, 101.799 mmol) and DMF (150 mL) were added to the reaction flask Add iodomethane (7.2 g, 50.900 mmol) under stirring conditions at room temperature, and keep stirring at room temperature overnight. After the reaction, add water (100mL) to quench, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated brine (100mL×2), concentrate the organic phases under reduced pressure to dryness, and purify the residue with a silica gel column (eluent: petroleum ether/ethyl acetate=5/1), 2-(5-bromo-2-methoxyphenyl)-N,N-dimethylacetamide was obtained, the yield was 51.4%; ESI - MS (m/z): 272.0 [M+H]+.
步骤c)：(3-(2-(二甲基氨基)-2-氧乙基)-4-甲氧基苯基)氨基甲酸叔丁酯的制备Step c): Preparation of tert-butyl (3-(2-(dimethylamino)-2-oxyethyl)-4-methoxyphenyl)carbamate
将2-(5-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺(4.7g，17.426mmol)、氨基甲酸叔丁酯(3.1g，26.496mmol)、X-Phos(1.7g，3.564mmol)、Cs 2CO 3(17.0g，52.147mmol)、甲苯(95mL)和Pd(dba) 2(1.0g，1.739mmol)依次加入到反应瓶中，氮气置换三次，维持110℃搅拌反应3h。反应结束后，加水(100mL)淬灭，用乙酸乙酯萃取(100mL×2)，合并有机相，用饱和食盐水(100mL)洗涤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝7/3)，得(3-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯，收率60.5％；ESI-MS(m/z)：253.0[M+H-Bu t]+。 2-(5-Bromo-2-methoxyphenyl)-N,N-dimethylacetamide (4.7g, 17.426mmol), tert-butyl carbamate (3.1g, 26.496mmol), X-Phos (1.7g, 3.564mmol), Cs 2 CO 3 (17.0g, 52.147mmol), toluene (95mL) and Pd(dba) 2 (1.0g, 1.739mmol) were sequentially added into the reaction flask, replaced by nitrogen three times, maintaining 110 The reaction was stirred at ℃ for 3h. After the reaction, add water (100mL) to quench, extract with ethyl acetate (100mL×2), combine the organic phases, wash with saturated brine (100mL), concentrate the organic phases under reduced pressure to dryness, and purify the residue by silica gel column chromatography (Eluent: Petroleum ether/ethyl acetate=7/3) to obtain (3-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate tert-butyl Ester, yield 60.5%; ESI-MS (m/z): 253.0 [M+H-Bu t ]+.
步骤d)：2-(5-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step d): Preparation of 2-(5-amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride
将(3-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯(330mg，1.055mmol)和乙酸乙酯(3.0mL)加入反应瓶中，搅拌溶解，再加氯化氢乙酸乙酯溶液(4M，5.0mL)，室温下搅拌1h，有大量固体析出，减压浓缩除去溶剂，得2-(5-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐，产率99.9％；ESI-MS(m/z)：209.2[M+H] +。 (3-(2-(Dimethylamino)-2-oxoethyl)-2-methoxyphenyl)carbamate tert-butyl ester (330 mg, 1.055 mmol) and ethyl acetate (3.0 mL) were added to the reaction In the bottle, stir to dissolve, add hydrogen chloride ethyl acetate solution (4M, 5.0mL), stir at room temperature for 1h, a large amount of solid precipitates, concentrate under reduced pressure to remove the solvent, and obtain 2-(5-amino-2-methoxybenzene base)-N,N-dimethylacetamide hydrochloride, yield 99.9%; ESI-MS (m/z): 209.2 [M+H] + .
步骤e)：6-溴-4-氯-2-甲基喹唑啉的制备Step e): Preparation of 6-bromo-4-chloro-2-methylquinazoline
将6-溴-2-甲基喹唑啉-4(3H)-酮(4.8g，20.168mmol)加入1，2-二氯乙烷(100mL)中，搅拌下加入DIPEA(18.1g，140.310mmol)和POCl 3(18.4g，120.261mmol)，氮气保护下升温至90℃反应过夜，反应结束后，冷却至室温，减压蒸除溶剂，残余物加二氯甲烷(100mL)溶解，将混合物倒入冰块与碳酸氢钠的 混合液中淬灭，分液，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶层析柱纯化(洗脱剂：石油醚/乙酸乙酯＝20/1至10/1)，得6-溴-4-氯-2-甲基喹唑啉，收率87.2％；ESI-MS(m/z)：257.1[M+H] +。 Add 6-bromo-2-methylquinazolin-4(3H)-one (4.8g, 20.168mmol) into 1,2-dichloroethane (100mL), add DIPEA (18.1g, 140.310mmol) under stirring ) and POCl 3 (18.4g, 120.261mmol), under the protection of nitrogen, the temperature was raised to 90°C and reacted overnight. After the reaction was completed, it was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (100mL), and the mixture was poured Quenched in a mixture of ice cubes and sodium bicarbonate, separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate = 20 /1 to 10/1), 6-bromo-4-chloro-2-methylquinazoline was obtained with a yield of 87.2%; ESI-MS (m/z): 257.1[M+H] + .
步骤f)：(R)-6-溴-2-甲基-N-(1-(3-硝基-5-)三氟甲基)苯基)乙基)喹唑啉-4-胺的制备Step f): (R)-6-bromo-2-methyl-N-(1-(3-nitro-5-)trifluoromethyl)phenyl)ethyl)quinazolin-4-amine preparation
将6-溴-4-氯-2-甲基喹唑啉(2.2g，8.594mmol)、(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺盐酸盐(2.6g，9.453mmol)、DIPEA(3.3g，25.581mmol)、DMSO(20mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌反应2h。反应结束后，加饱和氯化铵溶液(30mL)，以乙酸乙酯萃取(50mL×2)，合并有机相，用饱和食盐水(100mL×1)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至3/1)，得(R)-6-溴-2-甲基-N-(1-(3-硝基-5-)三氟甲基)苯基)乙基)喹唑啉-4-胺，产率94.8％；ESI-MS(m/z)：455.0[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (2.2g, 8.594mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane- 1-Amine hydrochloride (2.6g, 9.453mmol), DIPEA (3.3g, 25.581mmol), and DMSO (20mL) were successively added into the reaction flask, and the temperature was raised to 80°C under nitrogen protection, and the reaction was stirred for 2h. After the reaction, add saturated ammonium chloride solution (30mL), extract with ethyl acetate (50mL×2), combine the organic phases, wash with saturated brine (100mL×1), concentrate the organic phase under reduced pressure, and wash the residue through silica gel Purified by column chromatography (eluent: petroleum ether/ethyl acetate = 10/1 to 3/1) to obtain (R)-6-bromo-2-methyl-N-(1-(3-nitro- 5-) Trifluoromethyl)phenyl)ethyl)quinazolin-4-amine, yield 94.8%; ESI-MS (m/z): 455.0[M+H] + .
步骤g)：(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step g): (R)-2-(2-methoxy-5-((2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethane Base) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将(R)-6-溴-2-甲基-N-(1-(3-硝基-5-)三氟甲基)苯基)乙基)喹唑啉-4-胺(300mg，0.659mmol)、2-(5-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐(193mg，0.791mmol)、X-Phos(63mg，0.132mmol)、Cs 2CO 3(430mg，1.318mmol)、甲苯(5mL)和Pd(dba) 2(61mg，0.066mmol)依次加入到反应瓶中，氮气置换三次，升温至回流搅拌反应3h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，合并有机相，用饱和食盐水(30mL×1)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至1/1)，得(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-)三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-N，N-二甲基乙酰胺，产率72.1％；ESI-MS(m/z)：583.2[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-)trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (300mg, 0.659 mmol), 2-(5-amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride (193mg, 0.791mmol), X-Phos (63mg, 0.132mmol), Cs 2 CO 3 (430mg, 1.318mmol), toluene (5mL) and Pd(dba) 2 (61mg, 0.066mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to reflux and stirred for 3h. After the reaction, add water (10mL) to quench the reaction, extract with ethyl acetate (20mL×2), combine the organic phases, wash with saturated brine (30mL×1), concentrate the organic phase under reduced pressure, and pass the residue through silica gel column layer Analysis and purification (eluent: petroleum ether/ethyl acetate=10/1 to 1/1), to obtain (R)-2-(2-methoxy-5-((2-methyl-4-(( 1-(3-nitro-5-)trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)-N,N-dimethylacetamide, yield 72.1%; ESI-MS (m/z): 583.2 [M+H] + .
步骤h)：(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step h): (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(100mg，0.172mmol)溶于甲醇(2mL)中，加入铁粉(48mg，0.859mmol)和饱和氯化铵水溶液(1mL)，将反应液升温至回流反应1h，待反应液冷却至室温后，加入乙酸乙酯(10mL)和水(10mL)，抽滤，滤液分液，水相用乙酸乙酯萃取(10mL×1)，合并有机相，以饱和食盐水洗涤(10mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品用制备薄层层析纯化(展开剂：二氯甲烷/甲醇＝15/1)，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，收率80.0％； 1H NMR(400MHz，DMSO-d 6)δ8.10(s，1H)，8.01(s，1H)，7.77(s，1H)，7.47(d，J＝8.8Hz，1H)，7.36(d，J＝8.8Hz，1H)，7.04(d，J＝8.4Hz，1H)，6.98(s，1H)，6.95-6.82(m，3H)，6.68(s，1H)，5.59-5.49(m，3H)，3.74(s，3H)，3.58(s，2H)，3.00(s，3H)，2.79(s，3H)，2.36(s，3H)，1.53(d，J＝6.4Hz，3H)；ESI-MS(m/z)：553.1[M+H] +。 (R)-2-(2-methoxy-5-((2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino )quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (100mg, 0.172mmol) was dissolved in methanol (2mL), iron powder (48mg, 0.859mmol) and saturated chlorine were added Ammonium chloride aqueous solution (1mL), the reaction solution was heated to reflux for 1h, after the reaction solution was cooled to room temperature, ethyl acetate (10mL) and water (10mL) were added, suction filtered, the filtrate was separated, and the aqueous phase was washed with ethyl acetate Extraction (10mL×1), combined organic phases, washed with saturated brine (10mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by preparative thin-layer chromatography (developing solvent: dichloro Methane/methanol=15/1), get (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2 -Methylquinazolin-6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 80.0%; 1 H NMR (400MHz, DMSO-d 6 )δ8 .10(s, 1H), 8.01(s, 1H), 7.77(s, 1H), 7.47(d, J=8.8Hz, 1H), 7.36(d, J=8.8Hz, 1H), 7.04(d, J=8.4Hz, 1H), 6.98(s, 1H), 6.95-6.82(m, 3H), 6.68(s, 1H), 5.59-5.49(m, 3H), 3.74(s, 3H), 3.58(s , 2H), 3.00(s, 3H), 2.79(s, 3H), 2.36(s, 3H), 1.53(d, J=6.4Hz, 3H); ESI-MS (m/z): 553.1 [M+ H] + .
实施例2Example 2
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl )amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000103
Figure PCTCN2022101219-appb-000103
将(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(27mg，0.049mmol)和二氯甲烷(1mL)加入反应瓶中，搅拌溶解，氮气置换3次，0℃搅拌5min，加入BBr 3(60mg，0.239mmol)，室温搅拌30min，加入饱和碳酸氢钠水溶液(5mL)和乙酸乙酯(5mL)，分液，水相用乙酸乙酯萃取(5mL×1)，合并有机相，以饱和食盐水洗涤(5mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品用制备薄层层析(展开剂：二氯甲烷/甲醇＝9/1)纯化，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺，收率30.8％； 1H NMR(400MHz，DMSO-d 6)δ9.26(s，1H)，8.13(s，1H)，8.00(s，1H)，7.70(s，1H)，7.45(d，J＝8.8Hz，1H)，7.33(d，J＝8.8Hz，1H)，6.96(s，1H)，6.91(d，J＝8.8Hz，1H)，6.88(s，1H)，6.84(s，1H)，6.77(d，J＝8.4Hz，1H)，6.68(s，1H)，5.61-5.46(m，3H)，3.57(s，2H)，3.02(s，3H)，2.80(s，3H)，2.36(s，3H)，1.53(d，J＝6.4Hz，3H)；ESI-MS(m/z)：539.1[M+H] +。 (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) amino)-2-methoxyphenyl)-N,N-dimethylacetamide (27mg, 0.049mmol) and dichloromethane (1mL) were added into the reaction flask, stirred and dissolved, replaced with nitrogen 3 times, 0 Stir at ℃ for 5 min, add BBr 3 (60 mg, 0.239 mmol), stir at room temperature for 30 min, add saturated aqueous sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL), separate the layers, and extract the aqueous phase with ethyl acetate (5 mL×1) , the organic phases were combined, washed with saturated brine (5mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. ) purification to obtain (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl) phenyl) ethyl) amino)-2-methylquinazoline -6-yl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide, yield 30.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.26 (s, 1H), 8.13(s, 1H), 8.00(s, 1H), 7.70(s, 1H), 7.45(d, J=8.8Hz, 1H), 7.33(d, J=8.8Hz, 1H), 6.96(s, 1H ), 6.91(d, J=8.8Hz, 1H), 6.88(s, 1H), 6.84(s, 1H), 6.77(d, J=8.4Hz, 1H), 6.68(s, 1H), 5.61-5.46 (m, 3H), 3.57(s, 2H), 3.02(s, 3H), 2.80(s, 3H), 2.36(s, 3H), 1.53(d, J=6.4Hz, 3H); ESI-MS ( m/z): 539.1 [M+H] + .
实施例3Example 3
(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl )amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000104
Figure PCTCN2022101219-appb-000104
步骤a)：2-(4-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step a): Preparation of 2-(4-bromo-2-methoxyphenyl)-N,N-dimethylacetamide
将2-(4-溴-2-甲氧基苯基)乙酸(1.10g，4.489mmol)、二甲胺盐酸盐(439mg，5.386mmol)和DIPEA(1.74g，13.467mmol)和二氯甲烷(20mL)加入到反应瓶中，室温下搅拌条件加入T 3P(4.28g，6.734mmol，50％乙酸乙酯溶液)，维持室温搅拌反应2h。反应结束后，加水(20mL)淬灭反应，用二氯甲烷萃取(20mL×3)，合并有机相，依次用饱和碳酸氢钠水溶液(20mL×1)和饱和食盐水(20mL×1)洗涤，有机相减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/3)，得2-(4-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率90.8％；ESI-MS(m/z)：272.0[M+H] +。 2-(4-Bromo-2-methoxyphenyl)acetic acid (1.10g, 4.489mmol), dimethylamine hydrochloride (439mg, 5.386mmol) and DIPEA (1.74g, 13.467mmol) and dichloromethane (20 mL) was added to the reaction flask, T 3 P (4.28 g, 6.734 mmol, 50% ethyl acetate solution) was added under stirring conditions at room temperature, and the reaction was maintained at room temperature for 2 h. After the reaction was completed, water (20 mL) was added to quench the reaction, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (20 mL×1) and saturated brine (20 mL×1), The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/3) to obtain 2-(4-bromo-2-methoxyphenyl)-N, N-Dimethylacetamide, yield 90.8%; ESI-MS (m/z): 272.0 [M+H] + .
步骤b)：2-(4-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): Preparation of 2-(4-amino-2-methoxyphenyl)-N,N-dimethylacetamide
将甲苯(30mL)、2-(4-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺(1.10g，4.042mmol)、氨基甲酸叔丁酯(710mg，6.063mmol)、X-Phos(386mg，0.808mmol)，Cs 2CO 3(3.95g，12.126mmol)和Pd 2(dba) 3(370mg，0.404mmol)依次加入到反应瓶中，氮气置换三次，维持110℃搅拌反应3h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(20mL×1)洗涤，有机相减压浓缩，残余物用4M氯化氢乙酸乙酯溶液(20mL)溶解，室温搅拌反应2h。反应结束后，加水(20mL)淬灭反应，用饱和碳酸氢钠溶液调节pH值至8-9。用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(20mL×1)洗涤，有机相减压浓缩，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/5)，得2-(4-氨基-2-甲氧基苯基-NN-二甲基乙酰胺，产率77.3％；ESI-MS(m/z)：209.0[M+H] +。 Toluene (30 mL), 2-(4-bromo-2-methoxyphenyl)-N,N-dimethylacetamide (1.10 g, 4.042 mmol), tert-butyl carbamate (710 mg, 6.063 mmol) , X-Phos (386mg, 0.808mmol), Cs 2 CO 3 (3.95g, 12.126mmol) and Pd 2 (dba) 3 (370mg, 0.404mmol) were sequentially added to the reaction flask, replaced with nitrogen three times, and kept stirring at 110°C Reaction 3h. After the reaction, add water (20mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20mL×1), concentrate the organic phase under reduced pressure, and wash the residue with 4M hydrogen chloride acetic acid Ethyl ester solution (20 mL) was dissolved and stirred at room temperature for 2 h. After the reaction was completed, water (20 mL) was added to quench the reaction, and the pH value was adjusted to 8-9 with saturated sodium bicarbonate solution. Extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20mL×1), concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate ester=3/5), to obtain 2-(4-amino-2-methoxyphenyl-NN-dimethylacetamide, yield 77.3%; ESI-MS (m/z): 209.0 [M+H ] + .
步骤c)：(R)-2-(2-甲氧基-4-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(2-methoxy-4-((2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethane Base) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将甲苯(5mL)、2-(4-氨基-2-甲氧基苯基)-N，N，二甲基乙酰胺(75mg，0.360mmol)、(R)-6-溴-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(136.5mg，0.300mmol)、X-Phos(57mg，0.120mmol)，Cs 2CO 3(195mg，0.600mmol)和Pd(dba) 2(34.5mg，0.060mmol)依次加入到反应瓶中，氮气置换三次，维持90℃搅拌反应3h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(10mL×1)洗涤，有机相减压浓缩干，残余物用硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(2-甲氧基-4-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，产率95.3％；ESI-MS(m/z)：583.0[M+H] +。 Toluene (5 mL), 2-(4-amino-2-methoxyphenyl)-N,N, dimethylacetamide (75 mg, 0.360 mmol), (R)-6-bromo-2-methyl -N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (136.5mg, 0.300mmol), X-Phos (57mg, 0.120mmol) , Cs 2 CO 3 (195mg, 0.600mmol) and Pd(dba) 2 (34.5mg, 0.060mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, and kept stirring at 90°C for 3h. After the reaction, add water (10mL) to quench the reaction, extract with ethyl acetate (10mL×3), combine the organic phases, wash with saturated brine (10mL×1), and concentrate the organic phases under reduced pressure to dryness. Chromatographic purification (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(2-methoxy-4-((2-methyl-4-((1-(3 -Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield 95.3%; ESI - MS (m/z): 583.0 [M+H] + .
步骤d)：(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide formate
将甲醇(3mL)、水(2mL)、(R)-2-(2-甲氧基-4-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(116mg，0.200mmol)、铁粉(56mg，1.000mmol)、饱和氯化铵水溶液(3ml)依次加入到反应瓶中，维持90℃搅拌反应2h。反应结束后，将反应液冷却至室温，过滤，固体用乙酸乙酯(5mL×3)淋洗，滤液分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和食盐水(10mL×1)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐，产率35.3％； 1H NMR(400MHz，DMSO-d 6)δ8.37(s，1H)8.22(d，J＝8.0Hz，1H)，8.15(s，1H)，8.08(s，1H)，7.51(d，J＝8.0Hz，1H)，7.42(d，J＝8.0Hz，1H)，6.95(d，J＝8.0Hz，1H)，6.89(s，1H)，6.84(s，2H)，6.68(s，1H)，6.61(d，J＝8.0Hz，1H)，5.52(m，3H)，3.72(s，3H)，3.49(s，2H)，3.00(s，3H)，2.83(s，3H)，2.36(s，3H)，1.51(d，J＝4.0Hz，3H)；ESI-MS(m/z)：553.1[M+H] +。 Methanol (3mL), water (2mL), (R)-2-(2-methoxy-4-((2-methyl-4-((1-(3-nitro-5-(trifluoro Methyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (116mg, 0.200mmol), iron powder (56mg, 1.000mmol), Saturated ammonium chloride aqueous solution (3ml) was successively added into the reaction flask, and the reaction was maintained at 90°C with stirring for 2h. After the reaction, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5mL×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10mL×2), the organic phases were combined, and washed with saturated salt Washed with water (10mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(4-((4-(( 1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)amino)-2-methoxyphenyl)-N, N-dimethylacetamide formate, yield 35.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.37(s, 1H) 8.22(d, J=8.0Hz, 1H), 8.15(s , 1H), 8.08(s, 1H), 7.51(d, J=8.0Hz, 1H), 7.42(d, J=8.0Hz, 1H), 6.95(d, J=8.0Hz, 1H), 6.89(s , 1H), 6.84(s, 2H), 6.68(s, 1H), 6.61(d, J=8.0Hz, 1H), 5.52(m, 3H), 3.72(s, 3H), 3.49(s, 2H) , 3.00(s, 3H), 2.83(s, 3H), 2.36(s, 3H), 1.51(d, J=4.0Hz, 3H); ESI-MS(m/z): 553.1[M+H] + .
实施例4Example 4
(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl )amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000105
Figure PCTCN2022101219-appb-000105
将(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(110mg，0.200mmol)和二氯甲烷(4mL)加入到反应瓶中，在冰水浴下，缓慢滴加三溴化硼(250mg，1.000mmol)。滴加完毕后，缓慢升至室温搅拌反应1h。反应结束后，加水(5mL)淬灭反应，用二氯甲烷(10mL×2)萃取，合并有机相，用饱和食盐水(10mL×1)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，所得粗品用甲醇(2mL)溶解，经Prep-HPLC(方法2)纯化，得(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐，产率64.0％； 1H NMR(400MHz，DMSO-d 6)δ9.63(brs，1H)，8.16(s，2H)，8.14(s，1H)，7.93(s，1H)，7.54-7.40(m，2H)，6.90(s，2H)，6.85(s，1H)，6.68(s，1H)，6.59(s，1H)，6.54(d，J＝8.0Hz，1H)，5.53(m，3H)，3.48(s，2H)，3.02(s，3H)，2.83(s，3H)，2.36(s，3H)，1.52(d，J＝5.5Hz，3H)；ESI-MS(m/z)：539.1[M+H] +。 (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) amino)-2-methoxyphenyl)-N,N-dimethylacetamide (110mg, 0.200mmol) and dichloromethane (4mL) were added to the reaction flask, and slowly added dropwise under ice-water bath Boron tribromide (250 mg, 1.000 mmol). After the dropwise addition was completed, the mixture was slowly raised to room temperature and stirred for 1 h. After the reaction, add water (5 mL) to quench the reaction, extract with dichloromethane (10 mL×2), combine the organic phases, wash with saturated brine (10 mL×1), dry over anhydrous sodium sulfate, filter, and decompress the filtrate Concentrated, the resulting crude product was dissolved in methanol (2 mL) and purified by Prep-HPLC (Method 2) to give (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethane Base) phenyl) ethyl) amino)-2-methylquinazolin-6-yl) amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate, yield 64.0% ; 1 H NMR (400MHz, DMSO-d 6 ) δ9.63(brs, 1H), 8.16(s, 2H), 8.14(s, 1H), 7.93(s, 1H), 7.54-7.40(m, 2H) , 6.90(s, 2H), 6.85(s, 1H), 6.68(s, 1H), 6.59(s, 1H), 6.54(d, J=8.0Hz, 1H), 5.53(m, 3H), 3.48( s, 2H), 3.02 (s, 3H), 2.83 (s, 3H), 2.36 (s, 3H), 1.52 (d, J=5.5Hz, 3H); ESI-MS (m/z): 539.1 [M +H] + .
实施例5Example 5
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl )amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000106
Figure PCTCN2022101219-appb-000106
步骤a)：2-(3-溴-2-羟基苯基)乙酸甲酯的制备Step a): Preparation of methyl 2-(3-bromo-2-hydroxyphenyl)acetate
将叔丁胺(1.35mL，0.94g，12.852mmol)和甲苯(43mL)加入反应瓶中，冷却至-30℃，滴加液溴(1.08g，6.740mmol)，滴加完毕，在-30℃维持反应1h。将反应液降温至-78℃，向反应液中缓慢滴加2-羟基苯乙酸甲酯(1.40g，8.425mmol)的二氯甲烷溶液(7mL)。滴加完毕后，将反应液缓慢升至室温反应过夜。反应结束后，加水(50mL)淬灭反应，以二氯甲烷萃取(50mL×3)，合并有机相，依次用饱和亚硫酸钠水溶液(50mL×1)，饱和食盐水(50mL×1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(3-溴-2-羟基苯基)乙酸甲酯，所得粗品无需纯化直接用于下一步反应；ESI-MS(m/z)：245.0[M+H] +。 Add tert-butylamine (1.35mL, 0.94g, 12.852mmol) and toluene (43mL) into the reaction flask, cool to -30°C, add liquid bromine (1.08g, 6.740mmol) dropwise, after the addition is complete, maintain the reaction at -30°C 1h. The reaction liquid was cooled to -78°C, and a dichloromethane solution (7 mL) of methyl 2-hydroxyphenylacetate (1.40 g, 8.425 mmol) was slowly added dropwise to the reaction liquid. After the dropwise addition, the reaction solution was slowly raised to room temperature and reacted overnight. After the reaction was over, add water (50mL) to quench the reaction, extract with dichloromethane (50mL×3), combine the organic phases, wash with saturated sodium sulfite aqueous solution (50mL×1), saturated brine (50mL×1) successively, and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain methyl 2-(3-bromo-2-hydroxyphenyl)acetate, which is directly used in the next reaction without purification; ESI-MS (m/z): 245.0 [M+H] + .
步骤b)：2-(3-溴-2-甲氧基苯基)乙酸甲酯Step b): Methyl 2-(3-bromo-2-methoxyphenyl)acetate
将2-(3-溴-2-羟基苯基)乙酸甲酯(2.10g，8.569mmol)、碳酸钾(2.37g，17.138mmol)和DMF(40mL)中，室温下搅拌条件加入碘甲烷(1.82g，12.853mmol)，维持室温搅拌反应3h，反应结束后，加水(100mL)淬灭反应，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和食盐水(50mL×2)洗，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)，得2-(3-溴-2-甲氧基苯基)乙酸甲酯，收率63.1％；ESI-MS(m/z)：259.0[M+H] +。 Methyl 2-(3-bromo-2-hydroxyphenyl)acetate (2.10g, 8.569mmol), potassium carbonate (2.37g, 17.138mmol) and DMF (40mL) was added with stirring at room temperature (1.82 g, 12.853mmol), kept stirring at room temperature for 3h, after the reaction was completed, quenched the reaction by adding water (100mL), extracted with ethyl acetate (100mL×3), combined the organic phases, washed with saturated brine (50mL×2), The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain methyl 2-(3-bromo-2-methoxyphenyl)acetate , yield 63.1%; ESI-MS (m/z): 259.0 [M+H] + .
步骤c)：2-(3-溴-2-甲氧基苯基)乙酸的制备Step c): Preparation of 2-(3-bromo-2-methoxyphenyl)acetic acid
将2-(3-溴-2-甲氧基苯基)乙酸甲酯(1.40g，5.403mmol)、THF(15mL)和水(15mL)加入反应瓶中，搅拌溶解，缓慢加入LiOH.H 2O(1.13g，27.017mmol)，室温搅拌2h。反应完毕后，逐滴加入1N的稀盐酸，调至反应液pH值为2～3，有固体析出，过滤，滤饼用水淋洗(10mL×2)，室温减压干燥，得2-(3-溴-2-甲氧基苯基)乙酸，收率83.1％； 1H NMR(400MHz，DMSO-d 6)δ12.36(s，1H)，7.53(d，J＝8.0Hz，1H)，7.28(d，J＝7.6Hz，1H)，7.04(t，J＝7.6Hz 1H)，3.74(s，3H)，3.63(s，2H)。 Add methyl 2-(3-bromo-2-methoxyphenyl)acetate (1.40g, 5.403mmol), THF (15mL) and water (15mL) into the reaction flask, stir to dissolve, slowly add LiOH.H 2 O (1.13g, 27.017mmol), stirred at room temperature for 2h. After the reaction was completed, 1N dilute hydrochloric acid was added dropwise to adjust the pH value of the reaction solution to 2 to 3. Solids were precipitated, filtered, and the filter cake was rinsed with water (10mL×2), and dried under reduced pressure at room temperature to obtain 2-(3 -Bromo-2-methoxyphenyl)acetic acid, yield 83.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.36 (s, 1H), 7.53 (d, J=8.0Hz, 1H), 7.28 (d, J = 7.6Hz, 1H), 7.04 (t, J = 7.6Hz 1H), 3.74 (s, 3H), 3.63 (s, 2H).
步骤d)：2-(3-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step d): Preparation of 2-(3-bromo-2-methoxyphenyl)-N,N-dimethylacetamide
将2-(3-溴-2-甲氧基苯基)乙酸(1.10g，4.489mmol)、二甲胺盐酸盐(439mg，5.386mmol)和DIPEA(1.74g，13.488mmol)加入到反应瓶中，室温下搅拌条件加入T3P(4.28g，6.734mmol，50％乙酸乙酯溶液)，维持室温搅拌反应2h。反应结束后，加水(20mL)淬灭反应，用二氯甲烷萃取(20mL×3)，合并有机相，依次用饱和碳酸氢钠水溶液(20mL×1)和饱和食盐水(20mL×1)洗涤，有机相减压浓缩，得2-(3-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺，收率90.8％；ESI-MS(m/z)：272.0[M+H] +。 2-(3-Bromo-2-methoxyphenyl)acetic acid (1.10 g, 4.489 mmol), dimethylamine hydrochloride (439 mg, 5.386 mmol) and DIPEA (1.74 g, 13.488 mmol) were added to the reaction flask , T3P (4.28 g, 6.734 mmol, 50% ethyl acetate solution) was added with stirring at room temperature, and the reaction was maintained at room temperature for 2 h. After the reaction was completed, water (20 mL) was added to quench the reaction, extracted with dichloromethane (20 mL×3), the organic phases were combined, washed successively with saturated aqueous sodium bicarbonate (20 mL×1) and saturated brine (20 mL×1), The organic phase was concentrated under reduced pressure to obtain 2-(3-bromo-2-methoxyphenyl)-N,N-dimethylacetamide with a yield of 90.8%; ESI-MS (m/z): 272.0 [M +H] + .
步骤e)：(3-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯的制备Step e): Preparation of tert-butyl (3-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate
将甲苯(22mL)、2-(3-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺(1.10g，4.042mmol)、氨基甲酸叔丁酯(710mg，6.063mmol)、X-Phos(386mg，0.808mmol)，Cs 2CO 3(3.95g，12.126mmol)和Pd 2(dba) 3(370mg，0.404mmol)依次加入到反应瓶中，以氮气置换三次，维持110℃搅拌反应3h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(20mL×1)洗涤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/7)，得(3-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯，收率72.3％；ESI-MS(m/z)：253.0[M+H-Bu t] +。 Toluene (22 mL), 2-(3-bromo-2-methoxyphenyl)-N,N-dimethylacetamide (1.10 g, 4.042 mmol), tert-butyl carbamate (710 mg, 6.063 mmol) , X-Phos (386mg, 0.808mmol), Cs 2 CO 3 (3.95g, 12.126mmol) and Pd 2 (dba) 3 (370mg, 0.404mmol) were sequentially added to the reaction flask, replaced with nitrogen three times, and maintained at 110°C The reaction was stirred for 3h. After the reaction, add water (20mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20mL×1), concentrate the organic phases under reduced pressure to dryness, and pass the residue through a silica gel column Chromatographic purification (eluent: petroleum ether/ethyl acetate=3/7) to obtain (3-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)amino Tert-butyl formate, yield 72.3%; ESI-MS (m/z): 253.0[M+H-Bu t ] + .
步骤f)：2-(3-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step f): Preparation of 2-(3-amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride
将(3-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯(200mg，0.649mmol)和4N的氯化氢乙酸乙酯溶液(4mL)加入到反应瓶中，维持室温搅拌反应1h。反应结束后，将反应液减压浓缩，得2-(3-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐，产率98.8％；ESI-MS(m/z)：209.0[M+H] +。 (3-(2-(Dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate tert-butyl ester (200mg, 0.649mmol) and 4N hydrogen chloride ethyl acetate solution (4mL ) was added to the reaction flask, and the mixture was stirred at room temperature for 1 h. After the reaction, the reaction solution was concentrated under reduced pressure to obtain 2-(3-amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride with a yield of 98.8%; ESI-MS ( m/z): 209.0 [M+H] + .
步骤g)：(R)-2-(2-甲氧基-3-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step g): (R)-2-(2-methoxy-3-((2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethane Base) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将甲苯(9mL)、2-(3-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐(157mg，0.641mmol)、(R)-6-溴-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(292mg，0.641mmol)、X-Phos(61mg，0.128mmol)，Cs 2CO 3(627mg，1.923mmol)和Pd(dba) 2(37mg，0.064mmol)依次加入到反应瓶中，以氮气置换三次，维持90℃搅拌反应3h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(20mL×1)洗涤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(2-甲氧基-3-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，产率96.0％；ESI-MS(m/z)：583.0[M+H] +。 Toluene (9mL), 2-(3-amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride (157mg, 0.641mmol), (R)-6-bromo-2 -Methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (292mg, 0.641mmol), X-Phos (61mg, 0.128 mmol), Cs 2 CO 3 (627mg, 1.923mmol) and Pd(dba) 2 (37mg, 0.064mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, and kept stirring at 90°C for 3h. After the reaction, add water (10mL) to quench the reaction, extract with ethyl acetate (10mL×3), combine the organic phases, wash with saturated brine (20mL×1), concentrate the organic phases under reduced pressure to dryness, and pass the residue through a silica gel column Chromatographic purification (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(2-methoxy-3-((2-methyl-4-((1-(3 -Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield 96.0%; ESI - MS (m/z): 583.0 [M+H] + .
步骤h)：(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step h): (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将乙醇(2mL)、水(2mL)、(R)-2-(2-甲氧基-3-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(100mg，0.172mmol)、铁粉(29mg，0.515mmol)、无水氯化铵(37mg，0.688mmol)依次加入到反应瓶中，维持80℃搅拌反应2h。反应结束后，将反应液冷却至室温，过滤，滤饼用乙酸乙酯(5mL×3)淋洗，滤液分液，水相用乙酸乙酯(5mL×1)萃取，合并有机相，用饱和氯化钠水溶液洗(10mL×1)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，收率24.2％； 1H NMR(400MHz，DMSO-d 6)δ8.08(d，J＝7.2Hz，1H)，7.92(s，1H)，7.75(s，1H)，7.50(s，2H)，7.14(d，J＝8.0Hz，1H)，6.90-6.96(m，2H)，6.84(s，1H)，6.69(d，J＝9.6Hz，2H)，5.51(s，3H)，3.67(s，2H)，3.64(s，3H)，3.05(s，3H)，2.84(s，3H)，2.36(s，3H)，1.52(d，J＝6.4Hz，3H)；ESI-MS(m/z)：553.1[M+H] +。 Ethanol (2mL), water (2mL), (R)-2-(2-methoxy-3-((2-methyl-4-((1-(3-nitro-5-(trifluoro Methyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (100mg, 0.172mmol), iron powder (29mg, 0.515mmol), Anhydrous ammonium chloride (37 mg, 0.688 mmol) was sequentially added into the reaction flask, and the reaction was maintained at 80° C. for 2 h with stirring. After the reaction, the reaction solution was cooled to room temperature, filtered, the filter cake was rinsed with ethyl acetate (5mL×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5mL×1), the organic phases were combined, and saturated with Wash with sodium chloride aqueous solution (10mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is purified by Prep-HPLC (method 3) to obtain (R)-2-(3-((4- ((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)amino)-2-methoxyphenyl)- N, N-Dimethylacetamide, yield 24.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.08 (d, J=7.2Hz, 1H), 7.92(s, 1H), 7.75(s , 1H), 7.50(s, 2H), 7.14(d, J=8.0Hz, 1H), 6.90-6.96(m, 2H), 6.84(s, 1H), 6.69(d, J=9.6Hz, 2H) , 5.51(s, 3H), 3.67(s, 2H), 3.64(s, 3H), 3.05(s, 3H), 2.84(s, 3H), 2.36(s, 3H), 1.52(d, J=6.4 Hz, 3H); ESI-MS (m/z): 553.1 [M+H] + .
实施例6Example 6
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl )amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000107
Figure PCTCN2022101219-appb-000107
将(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(100mg，0.181mmol)和二氯甲烷(4mL)加入反应瓶中，在冰水浴下，缓慢滴加三溴化硼(2.50g，10.000mmol)。滴加完毕后，维持室温搅拌反应1h。反应结束后，加水(5mL)淬灭反应，用二氯甲烷(5mL×2)萃取，合并有机相，用饱和食盐水洗(10mL×1)，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(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐，收率59.5％； 1H NMR(400MHz，DMSO-d 6)δ9.63(s，1H)，8.14(s，1H)，8.03(s，1H)，7.81(s，1H)，7.47(s，2H)，7.37(s，1H)，7.13(s，1H)，6.89(s，1H)，6.84(s，1H)，6.75(s，2H)，6.68(s，1H)，5.50(s，3H)，3.72(s，2H)，3.12(s，3H)，3.03(s，3H)，2.03(s，3H)，1.52(s，3H)；ESI-MS(m/z)：538.8[M+H] +。 (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) amino)-2-methoxyphenyl)-N,N-dimethylacetamide (100mg, 0.181mmol) and dichloromethane (4mL) were added to the reaction flask, and slowly added three Boron bromide (2.50 g, 10.000 mmol). After the dropwise addition was completed, the reaction was maintained at room temperature and stirred for 1 h. After the reaction was completed, add water (5 mL) to quench the reaction, extract with dichloromethane (5 mL×2), combine the organic phases, wash with saturated brine (10 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product was purified by Prep-HPLC (Method 2) to give (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino )-2-methylquinazolin-6-yl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate, yield 59.5%; 1 H NMR (400MHz, DMSO- d 6 )δ9.63(s, 1H), 8.14(s, 1H), 8.03(s, 1H), 7.81(s, 1H), 7.47(s, 2H), 7.37(s, 1H), 7.13(s , 1H), 6.89(s, 1H), 6.84(s, 1H), 6.75(s, 2H), 6.68(s, 1H), 5.50(s, 3H), 3.72(s, 2H), 3.12(s, 3H), 3.03(s, 3H), 2.03(s, 3H), 1.52(s, 3H); ESI-MS (m/z): 538.8 [M+H] + .
实施例7Example 7
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000108
Figure PCTCN2022101219-appb-000108
步骤a)：(3-(2-(二甲基氨基)-2-氧乙基)-4-甲氧基苯基)(甲基)氨基甲酸叔丁酯的制备Step a): Preparation of tert-butyl (3-(2-(dimethylamino)-2-oxyethyl)-4-methoxyphenyl)(methyl)carbamate
将(3-(2-(二甲基氨基)-2-氧乙基)-4-甲氧基苯基)氨基甲酸叔丁酯(400mg，1.297mmol)和四氢呋喃(10mL)加入反应瓶中，搅拌溶解，氮气置换3次，0℃搅拌5min，加入NaH(207mg，5.175mmol)，0℃搅拌30min，加入碘甲烷(276mg，1.944mmol)，升温至室温反应1h，加入乙酸乙酯(20mL)和饱和氯化铵水溶液(20mL)，分液，水相用乙酸乙酯萃取(10mL×1)，合并有机相，以饱和食盐水洗涤(10mL×1)，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＝1/1)，得(3-(2-(二甲基氨基)-2-氧乙基)-4-甲氧基苯基)(甲基)氨基甲酸叔丁酯，产率63.7％； 1H NMR(400MHz，DMSO-d 6)δ7.09(d，J＝8.8Hz，1H)，6.97(s，1H)，6.91(d，J＝8.4Hz，1H)，3.75(s，3H)，3.56(s，2H)，3.11(s，3H)，3.00(s，3H)，2.83(s，3H)，1.37(s，9H)；ESI-MS(m/z)：267.1[M+H] +。 (3-(2-(Dimethylamino)-2-oxoethyl)-4-methoxyphenyl)carbamate tert-butyl ester (400 mg, 1.297 mmol) and tetrahydrofuran (10 mL) were added to the reaction flask, Stir to dissolve, nitrogen replacement 3 times, stir at 0°C for 5min, add NaH (207mg, 5.175mmol), stir at 0°C for 30min, add iodomethane (276mg, 1.944mmol), warm to room temperature for 1h, add ethyl acetate (20mL) and saturated ammonium chloride aqueous solution (20mL), separated, the aqueous phase was extracted with ethyl acetate (10mL×1), the organic phases were combined, washed with saturated brine (10mL×1), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to obtain (3-(2-(dimethylamino)-2-oxyethyl)- tert-butyl 4-methoxyphenyl)(methyl)carbamate, yield 63.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ7.09 (d, J=8.8Hz, 1H), 6.97( s, 1H), 6.91(d, J=8.4Hz, 1H), 3.75(s, 3H), 3.56(s, 2H), 3.11(s, 3H), 3.00(s, 3H), 2.83(s, 3H ), 1.37 (s, 9H); ESI-MS (m/z): 267.1 [M+H] + .
步骤b)：2-(2-甲氧基-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step b): Preparation of 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride
将(3-(2-(二甲基氨基)-2-氧乙基)-4-甲氧基苯基)(甲基)氨基甲酸叔丁酯(260mg，0.806mmol)溶于氯化氢乙酸乙酯溶液(4M，2mL)中，室温反应4h，减压浓缩至干，得2-(2-甲氧基-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺盐酸盐，产率98.6％；ESI-MS(m/z)：223.1[M+H] +。 Dissolve tert-butyl (3-(2-(dimethylamino)-2-oxoethyl)-4-methoxyphenyl)(methyl)carbamate (260 mg, 0.806 mmol) in ethyl hydrogen chloride acetate solution (4M, 2mL), react at room temperature for 4h, and concentrate to dryness under reduced pressure to obtain 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride Salt, yield 98.6%; ESI-MS (m/z): 223.1 [M+H] + .
步骤c)：(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl ) ethyl) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将2-(2-甲氧基-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(206mg，0.796mmol)加入甲苯(10mL)中，搅拌条件下加入(R)-6-溴-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(369mg，0.811mmol)、碳酸铯(792mg，2.431mmol)、2-二环己基膦-2′，4′，6′-三异丙基联苯(154mg，0.323mmol)、三(二亚苄基丙酮)二钯(93mg，0.102mmol)，氮气置换3次，升温至105℃反应1h，反应结束后，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＝1/20)，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3- 硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，产率84.8％；ESI-MS(m/z)：597.2[M+H] +。 Add 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (206mg, 0.796mmol) into toluene (10mL), and add (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (369mg, 0.811mmol ), cesium carbonate (792mg, 2.431mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (154mg, 0.323mmol), tris(dibenzylideneacetone)dipalladium (93mg, 0.102mmol), replaced with nitrogen 3 times, heated to 105°C to react for 1h, after the reaction, concentrated under reduced pressure, the obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) , to get (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)) ethyl yl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield 84.8%; ESI-MS (m/z): 597.2 [M+H] + .
步骤d)：(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline -6-yl) (methyl) amino) -2-methoxyphenyl) -N, the preparation of N-dimethylacetamide formate
将(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(403mg，0.675mmol)溶于甲醇(6mL)中，加入铁粉(189mg，3.384mmol)和饱和氯化铵水溶液(6mL)，升温至回流反应1h，将反应液冷却至室温，加入乙酸乙酯(20mL)和水(10mL)，过滤，滤液分液，水相用乙酸乙酯萃取(10mL×1)，合并有机相，以饱和食盐水洗涤(10mL)，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(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐，产率77.0％； 1H NMR(400MHz，DMSO-d 6)δ11.17(s，1H)，8.1δ-8.11(m，2H)，7.62(s，1H)，7.35(d，J＝8.8Hz，1H)，7.07(d，J＝9.6Hz，1H)，7.03(s，1H)，6.96-7.01(m，1H)，6.91(s，2H)，6.88(s，1H)，6.70(s，1H)，5.52-5.63(m，3H)，3.76(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.78(s，3H)，2.35(s，3H)，1.57(d，J＝6.0Hz，3H)；ESI-MS(m/z)：567.2[M+H] +。 (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (403mg, 0.675mmol) was dissolved in methanol (6mL), iron powder (189mg, 3.384mmol) was added and Saturated ammonium chloride aqueous solution (6mL), heated to reflux for 1h, cooled the reaction solution to room temperature, added ethyl acetate (20mL) and water (10mL), filtered, the filtrate was separated, and the aqueous phase was extracted with ethyl acetate (10mL ×1), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-( 5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino) -2-Methoxyphenyl)-N,N-dimethylacetamide formate, yield 77.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.17(s, 1H), 8.1δ -8.11(m, 2H), 7.62(s, 1H), 7.35(d, J=8.8Hz, 1H), 7.07(d, J=9.6Hz, 1H), 7.03(s, 1H), 6.96-7.01( m, 1H), 6.91(s, 2H), 6.88(s, 1H), 6.70(s, 1H), 5.52-5.63(m, 3H), 3.76(s, 3H), 3.57(s, 2H), 3.33 (s, 3H), 2.99 (s, 3H), 2.78 (s, 3H), 2.35 (s, 3H), 1.57 (d, J=6.0Hz, 3H); ESI-MS (m/z): 567.2[ M+H] + .
实施例8Example 8
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000109
Figure PCTCN2022101219-appb-000109
将(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(100mg，0.176mmol)溶于二氯甲烷(2mL)中，氮气置换3次，0℃搅拌5min，加入三溴化硼(200mg，0.789mmol)，升温至室温反应2h，加入饱和碳酸氢钠水溶液(10ml)和乙酸乙酯(10mL)，分液，水相用乙酸乙酯萃取(10mL×1)，合并有机相，以饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟苯基)-N，N-二甲基乙酰胺甲酸盐，收率33.0％； 1H NMR(400MHz，DMSO-d 6)δ11.16(s，1H)，9.55(s，1H)，8.15-8.13(m，1H)，7.54(s，1H)，7.33(d，J＝9.2Hz，1H)，7.02(d，J＝9.2Hz，1H)，6.89(d，J＝9.6Hz，4H)，6.85-6.80(m，1H)，6.70(s，1H)，5.65-5.50(m，3H)，3.56(s，2H)，3.31(s，3H)，3.01(s，3H)，2.80(s，3H)，2.35(s，3H)，1.61-1.51(m，3H)；ESI-MS(m/z)：553.1[M+H] +。 (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide (100mg, 0.176mmol) was dissolved in dichloromethane (2mL), nitrogen replacement 3 times, 0 ℃ Stir for 5min, add boron tribromide (200mg, 0.789mmol), warm up to room temperature and react for 2h, add saturated aqueous sodium bicarbonate (10ml) and ethyl acetate (10mL), separate the layers, and extract the aqueous phase with ethyl acetate (10mL ×1), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(5 -((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)- 2-Hydroxyphenyl)-N,N-dimethylacetamide formate, yield 33.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.16(s, 1H), 9.55(s, 1H ), 8.15-8.13(m, 1H), 7.54(s, 1H), 7.33(d, J=9.2Hz, 1H), 7.02(d, J=9.2Hz, 1H), 6.89(d, J=9.6Hz , 4H), 6.85-6.80(m, 1H), 6.70(s, 1H), 5.65-5.50(m, 3H), 3.56(s, 2H), 3.31(s, 3H), 3.01(s, 3H), 2.80 (s, 3H), 2.35 (s, 3H), 1.61-1.51 (m, 3H); ESI-MS (m/z): 553.1 [M+H] + .
实施例9Example 9
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000110
Figure PCTCN2022101219-appb-000110
步骤a)：(3-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯的制备Step a): Preparation of tert-butyl (3-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)(methyl)carbamate
将(3-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯(308mg，1.000mmol)、NaH(120mg，3.000mmol，60％)和四氢呋喃(10mL)加入反应瓶中，冰浴条件搅拌下加入碘甲烷(142mg，1.000mmol)，30min后缓慢升至室温搅拌反应2h。反应结束后，加水(30mL)淬灭，用乙酸乙酯萃取(40mL×3)，合 并有机相，用饱和食盐水(50mL×2)洗，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/1)，得(3-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯，产率68.3％；ESI-MS(m/z)：323.0[M+H] +。 (3-(2-(Dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate tert-butyl ester (308mg, 1.000mmol), NaH (120mg, 3.000mmol, 60%) and tetrahydrofuran (10 mL) were added to the reaction flask, and methyl iodide (142 mg, 1.000 mmol) was added under stirring in an ice bath, and after 30 min, it was slowly raised to room temperature and stirred for 2 h. After the reaction, add water (30mL) to quench, extract with ethyl acetate (40mL×3), combine the organic phases, wash with saturated brine (50mL×2), concentrate the organic phase under reduced pressure, and the residue is subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate=3/1) to obtain (3-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)(methyl) Tert-butyl carbamate, yield 68.3%; ESI-MS (m/z): 323.0 [M+H] + .
步骤b)：2-(2-甲氧基-3-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step b): Preparation of 2-(2-methoxy-3-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride
将(3-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯(220mg，0.682mmol)和乙酸乙酯(2.5mL)加入反应瓶中，搅拌溶解，再加氯化氢乙酸乙酯溶液(4M，2.5mL)，室温下搅拌1h，有大量固体析出，减压浓缩，得2-(3-甲氧基-4-(甲氨基)苯基)-N，N-二甲基乙酰胺，产率99.9％；ESI-MS(m/z)：223.0M+H] +。 (3-(2-(Dimethylamino)-2-oxoethyl)-2-methoxyphenyl)(methyl)carbamate tert-butyl ester (220mg, 0.682mmol) and ethyl acetate (2.5mL ) into the reaction flask, stirred and dissolved, then added ethyl chloride hydrogen chloride solution (4M, 2.5mL), stirred at room temperature for 1h, a large amount of solids were precipitated, and concentrated under reduced pressure to obtain 2-(3-methoxy-4-( Methylamino)phenyl)-N,N-dimethylacetamide, yield 99.9%; ESI-MS (m/z): 223.0M+H] + .
步骤c)：(R)-2-(2-甲氧基-3-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(2-methoxy-3-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl ) ethyl) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将(R)-6-溴-2-甲基-N-(1-(3-硝基-5-)三氟甲基)苯基)乙基)喹唑啉-4-胺(163mg，0.359mmol)，2-(2-甲氧基-3-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(93mg，0.359mmol)、X-Phos(34mg，0.072mmol)、Cs 2CO 3(235mg，0.720mmol)、甲苯(10mL)和Pd(dba) 2(21mg，0.036mmol)依次加入到反应瓶中，氮气置换三次，升温至100℃搅拌反应3h。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯萃取(30mL×2)，合并有机相，用饱和食盐水(30mL)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(2-甲氧基-3-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，产率75.0％；ESI-MS(m/z)：597.3[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-)trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (163mg, 0.359 mmol), 2-(2-methoxy-3-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (93mg, 0.359mmol), X-Phos (34mg, 0.072mmol) , Cs 2 CO 3 (235mg, 0.720mmol), toluene (10mL) and Pd(dba) 2 (21mg, 0.036mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 100°C and stirred for 3h. After the reaction was completed, add water (30 mL) to quench the reaction, extract with ethyl acetate (30 mL×2), combine the organic phases, wash with saturated brine (30 mL), concentrate the organic phases under reduced pressure, and purify the residue by silica gel column chromatography (Eluent: dichloromethane/methanol=20/1), (R)-2-(2-methoxy-3-(methyl(2-methyl-4-((1-(3- Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield 75.0%; ESI- MS (m/z): 597.3 [M+H] + .
步骤d)：(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step d): (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-2-(2-甲氧基-3-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(160mg，0.270mmol)溶于甲醇(2mL)中，加入铁粉(75mg，1.350mmol)和饱和氯化铵水溶液(2mL)，将反应液升温至回流反应1h，待反应液冷却至室温后，加入乙酸乙酯(10mL)和水(10mL)，抽滤，滤液分液，水相用乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水洗涤(20ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率78.5％； 1H NMR(400MHz，DMSO-d 6)δ8.08(d，J＝8.0Hz，1H)，7.53(s，1H)，7.33(d，J＝8.0Hz，1H)，7.09-7.04(m，3H)，6.90(d，J＝12.0Hz，3H)，6.70(s，1H)，5.64-5.57(m，1H)，5.54(s，2H)，3.68(s，2H)，3.52(s，3H)，3.35(s，3H)，3.05(s，3H)，2.85(s，3H)，2.35(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：567.3[M+H] +。 (R)-2-(2-methoxy-3-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (160mg, 0.270mmol) was dissolved in methanol (2mL), iron powder (75mg, 1.350mmol) was added and Saturated ammonium chloride aqueous solution (2mL), the reaction solution was heated to reflux for 1h, after the reaction solution was cooled to room temperature, ethyl acetate (10mL) and water (10mL) were added, suction filtered, the filtrate was separated, and the aqueous phase was washed with acetic acid Ethyl ester extraction (20mL×2), the organic phases were combined, washed with saturated brine (20ml), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 3) to obtain (R )-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)( Methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 78.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.08 (d, J=8.0 Hz, 1H), 7.53(s, 1H), 7.33(d, J=8.0Hz, 1H), 7.09-7.04(m, 3H), 6.90(d, J=12.0Hz, 3H), 6.70(s, 1H ), 5.64-5.57(m, 1H), 5.54(s, 2H), 3.68(s, 2H), 3.52(s, 3H), 3.35(s, 3H), 3.05(s, 3H), 2.85(s, 3H), 2.35 (s, 3H), 1.58 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 567.3 [M+H] + .
实施例10Example 10
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000111
Figure PCTCN2022101219-appb-000111
将(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-甲氧基苯基)-N，N-二甲基乙酰胺(60mg，0.106mmol)和二氯甲烷(4mL)加入反应瓶中，搅拌溶解，氮气置换3次，0℃搅拌5min，加入BBr 3(2mL)，室温搅拌30min。反应完毕，加入饱和碳酸氢钠水溶液(50mL)和乙酸乙酯(50mL)，分液，水相用乙酸乙酯萃取(50mL×2)，合并有机相，以饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺，产率30.2％； 1H NMR(400MHz，DMSO-d 6)δ9.30(s，1H)，8.12(brs，1H)，7.48(s，1H)，7.31(d，J＝8.0Hz，1H)，7.05(d，J＝8.0Hz，1H)，6.97(d，J＝8.0Hz，1H)，6.92(s，1H)，6.88(s，1H)，6.82(t，J＝8.0Hz，1H)，6.75-6.71(m，2H)，5.65-5.58(m，1H)，5.54(s，2H)，3.70(s，2H)，3.24(s，3H)，3.08(s，3H)，2.86(s，3H)，2.35(s，3H)，1.58(d，J＝4.0Hz，3H)；ESI-MS(m/z)：553.3[M+H] +。 (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl)amino)-3-methoxyphenyl)-N,N-dimethylacetamide (60mg, 0.106mmol) and dichloromethane (4mL) were added to the reaction flask, stirred to dissolve, nitrogen replacement Three times, stirred at 0°C for 5 min, added BBr 3 (2 mL), and stirred at room temperature for 30 min. After completion of the reaction, add saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL), separate the layers, extract the aqueous phase with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (50 mL), and remove Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product is purified by Prep-HPLC (method 3) to give (R)-2-(3-((4-((1-(3-amino-5-( Trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide, Yield 30.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.30(s, 1H), 8.12(brs, 1H), 7.48(s, 1H), 7.31(d, J=8.0Hz, 1H) , 7.05(d, J=8.0Hz, 1H), 6.97(d, J=8.0Hz, 1H), 6.92(s, 1H), 6.88(s, 1H), 6.82(t, J=8.0Hz, 1H) , 6.75-6.71(m, 2H), 5.65-5.58(m, 1H), 5.54(s, 2H), 3.70(s, 2H), 3.24(s, 3H), 3.08(s, 3H), 2.86(s , 3H), 2.35 (s, 3H), 1.58 (d, J = 4.0 Hz, 3H); ESI-MS (m/z): 553.3 [M+H] + .
实施例11Example 11
(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-甲氧基苯 基)-N，N-二甲基乙酰胺的制备(R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-3-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000112
Figure PCTCN2022101219-appb-000112
步骤a)：2-(3-甲氧基-4-硝基苯基)丙二酸二乙酯的制备Step a): Preparation of diethyl 2-(3-methoxy-4-nitrophenyl)malonate
将4-溴-2-甲氧基-1-硝基苯(2.32g，10.000mmol)、丙二酸二乙酯(1.92g，12.000mmol)、X-Phos(954mg，2.000mmol)、Cs 2CO 3(6.52g，20.000mmol)、1，4-二氧六环(50mL)和Pd 2(dba) 3(575mg，1.000mmol)依次加入到反应瓶中，氮气置换三次，升温至回流搅拌反应2h。反应结束后，加水(200mL)淬灭，用乙酸乙酯萃取(200mL×2)，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得2-(3-甲氧基-4-硝基苯基)丙二酸二乙酯，产率96.4％；ESI-MS(m/z)：312.0[M+H] +。 4-Bromo-2-methoxy-1-nitrobenzene (2.32g, 10.000mmol), diethyl malonate (1.92g, 12.000mmol), X-Phos (954mg, 2.000mmol), Cs 2 CO 3 (6.52g, 20.000mmol), 1,4-dioxane (50mL) and Pd 2 (dba) 3 (575mg, 1.000mmol) were successively added to the reaction flask, replaced with nitrogen three times, heated to reflux and stirred for reaction 2h. After the reaction was completed, add water (200 mL) to quench, extract with ethyl acetate (200 mL×2), combine the organic phases, wash with saturated brine (100 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain diethyl 2-(3-methoxy-4-nitrophenyl)malonate, the yield 96.4%; ESI-MS (m/z): 312.0 [M+H] + .
步骤b)：2-(3-甲氧基-4-硝基苯基)乙酸的制备Step b): Preparation of 2-(3-methoxy-4-nitrophenyl)acetic acid
将2-(3-甲氧基-4-硝基苯基)丙二酸二乙酯(3.0g，9.646mmol)、一水合氢氧化锂(1.6g，38.584mmol)、甲醇(10mL)、四氢呋喃(10mL)和水(20mL)加入反应瓶中，室温下搅拌反应2h。减压浓缩除去有机溶剂，冰浴搅拌下缓慢滴加浓盐酸(20mL)，升温至60℃搅拌反应4h。反应结束后，减压浓缩，加水(100mL)稀释，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和食盐水(100mL×2)洗，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3∶1)，得2-(3-甲氧基-4-硝基苯基)乙酸，产率17.2％；ESI-MS(m/z)：212.0[M+H] +。 Diethyl 2-(3-methoxy-4-nitrophenyl)malonate (3.0 g, 9.646 mmol), lithium hydroxide monohydrate (1.6 g, 38.584 mmol), methanol (10 mL), tetrahydrofuran (10mL) and water (20mL) were added into the reaction flask, and the reaction was stirred at room temperature for 2h. Concentrated under reduced pressure to remove the organic solvent, slowly added concentrated hydrochloric acid (20 mL) dropwise with stirring in an ice bath, heated to 60°C and stirred for 4 h. After the reaction, concentrate under reduced pressure, add water (100mL) to dilute, extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated brine (100mL×2), and concentrate the organic phases under reduced pressure to dryness. Purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3:1) to obtain 2-(3-methoxy-4-nitrophenyl)acetic acid with a yield of 17.2%; ESI-MS ( m/z): 212.0 [M+H] + .
步骤c)：2-(3-甲氧基-4-硝基苯基)-N，N-二甲基乙酰胺的制备Step c): Preparation of 2-(3-methoxy-4-nitrophenyl)-N,N-dimethylacetamide
将2-(3-甲氧基-4-硝基苯基)乙酸(350mg，1.658mmol)、二甲胺盐酸盐(161mg，1.989mmol)、DIPEA(641mg，4.974mmol)和DMF(5mL)加入反应瓶中，室温搅拌下加入HATU(945mg，2.487mmol)，在室温下维持反应1h。反应结束后，加水(20mL)淬灭，用乙酸乙酯萃取(20mL×2)，合并有机相，依次用饱和碳酸氢钠水溶液(20mL)，饱和食盐水(10mL×2)洗涤，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)，得2-(3-甲氧基-4-硝基苯基)-N，N-二甲基乙酰胺，产率88.7％；ESI-MS(m/z)：239.0[M+H] +。 2-(3-Methoxy-4-nitrophenyl)acetic acid (350mg, 1.658mmol), dimethylamine hydrochloride (161mg, 1.989mmol), DIPEA (641mg, 4.974mmol) and DMF (5mL) Add it to the reaction flask, add HATU (945mg, 2.487mmol) under stirring at room temperature, and maintain the reaction at room temperature for 1h. After the reaction was completed, add water (20mL) to quench, extract with ethyl acetate (20mL×2), combine the organic phases, wash with saturated aqueous sodium bicarbonate (20mL), saturated brine (10mL×2) successively, and anhydrous sulfuric acid Na-dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain 2-(3-methoxy-4-nitrobenzene base)-N,N-dimethylacetamide, yield 88.7%; ESI-MS (m/z): 239.0 [M+H] + .
步骤d)：2-(4-氨基-3-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step d): Preparation of 2-(4-amino-3-methoxyphenyl)-N,N-dimethylacetamide
将2-(3-甲氧基-4-硝基苯基)-N，N-二甲基乙酰胺(350mg，1.470mmol)、钯碳(50mg，5％)和乙醇(10mL)依次加入反应瓶中，搅拌溶解，氢气置换3次，氢气氛围中室温下搅拌2h。反应完毕，过滤，滤液减压浓缩，得2-(4-氨基-3-甲氧基苯基)-N，N-二甲基乙酰胺，无需进一步纯化直接用于下一步反应；ESI-MS(m/z)：209.0[M+H] +。 2-(3-Methoxy-4-nitrophenyl)-N,N-dimethylacetamide (350 mg, 1.470 mmol), palladium on carbon (50 mg, 5%) and ethanol (10 mL) were sequentially added to the reaction In the bottle, stir to dissolve, replace with hydrogen 3 times, and stir at room temperature in a hydrogen atmosphere for 2 hours. The reaction was completed, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(4-amino-3-methoxyphenyl)-N,N-dimethylacetamide, which was directly used in the next reaction without further purification; ESI-MS (m/z): 209.0 [M+H] + .
步骤e)：(4-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯的制备Step e): Preparation of tert-butyl (4-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate
将2-(4-氨基-3-甲氧基苯基)-N，N-二甲基乙酰胺(306mg，1.470mmol)、DIPEA(569mg，4.410mmol)和四氢呋喃(10mL)依次加入反应瓶中，搅拌溶解，再滴加Boc 2O(352mg，1.617mmol)，升温至60℃搅拌反应4h。反应完毕，减压浓缩，得(4-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯，无需进一步纯化直接用于下一步反应；ESI-MS(m/z)：309.0[M+H] +。 Add 2-(4-amino-3-methoxyphenyl)-N,N-dimethylacetamide (306mg, 1.470mmol), DIPEA (569mg, 4.410mmol) and tetrahydrofuran (10mL) into the reaction flask sequentially , stirred to dissolve, then added Boc 2 O (352mg, 1.617mmol) dropwise, heated to 60°C and stirred for 4h. After the reaction was completed, it was concentrated under reduced pressure to obtain tert-butyl (4-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate, which was directly used in the next step without further purification ; ESI-MS (m/z): 309.0 [M+H] + .
步骤f)：(4-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯的制备Step f): Preparation of tert-butyl (4-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)(methyl)carbamate
将(4-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯(453mg，1.470mmol)、NaH(176.4mg，4.41mmol，60％)和四氢呋喃(10mL)加入反应瓶中，冰浴条件搅拌下加入碘甲烷(209mg，1.470mmol)， 30min后缓慢升至室温搅拌反应2h。反应结束后，加水(30mL)淬灭，用乙酸乙酯萃取(40mL×3)，合并有机相，用饱和食盐水(50mL×2)洗，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3∶1)，得(4-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯，产率46.5％；ESI-MS(m/z)：323.0[M+H] +。 (4-(2-(Dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate tert-butyl ester (453mg, 1.470mmol), NaH (176.4mg, 4.41mmol, 60% ) and tetrahydrofuran (10 mL) were added to the reaction flask, and methyl iodide (209 mg, 1.470 mmol) was added under stirring in an ice bath, and after 30 min, it was slowly raised to room temperature and stirred for 2 h. After the reaction, add water (30mL) to quench, extract with ethyl acetate (40mL×3), combine the organic phases, wash with saturated brine (50mL×2), concentrate the organic phase under reduced pressure, and the residue is subjected to silica gel column chromatography Purification (eluent: petroleum ether/ethyl acetate = 3:1) to give (4-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)(methyl) Tert-butyl carbamate, yield 46.5%; ESI-MS (m/z): 323.0 [M+H] + .
步骤g)：2-(3-甲氧基-4-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step g): Preparation of 2-(3-methoxy-4-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride
将(4-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯(220mg，0.683mmol)和乙酸乙酯(2.5mL)加入反应瓶中，搅拌溶解，再加氯化氢乙酸乙酯溶液(4M，2.5mL)，室温下搅拌1h，有大量固体析出，减压浓缩，得2-(3-甲氧基-4-(甲氨基)苯基)-N，N-二甲基乙酰胺，无需进一步纯化可直接用于下一步反应；ESI-MS(m/z)：223.0M+H] +。 (4-(2-(Dimethylamino)-2-oxoethyl)-2-methoxyphenyl)(methyl)carbamate tert-butyl ester (220mg, 0.683mmol) and ethyl acetate (2.5mL ) into the reaction flask, stirred and dissolved, then added ethyl chloride hydrogen chloride solution (4M, 2.5mL), stirred at room temperature for 1h, a large amount of solids were precipitated, and concentrated under reduced pressure to obtain 2-(3-methoxy-4-( Methylamino)phenyl)-N,N-dimethylacetamide was directly used in the next reaction without further purification; ESI-MS (m/z): 223.0M+H] + .
步骤h)：(R)-2-(3-甲氧基-4-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step h): (R)-2-(3-methoxy-4-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) ) ethyl) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将(R)-6-溴-2-甲基-N-(1-(3-硝基-5-)三氟甲基)苯基)乙基)喹唑啉-4-胺(184mg，0.404mmol)，2-(3-甲氧基-4-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(87mg，0-336mmol)、X-Phos(31mg，0.066mmol)、Cs 2CO 3(220mg，0.672mmol)、甲苯(10mL)和Pd(dba) 2(19mg，0.033mmol)依次加入到反应瓶中，氮气置换三次，升温至100℃搅拌反应3h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(40mL×2)，合并有机相，用饱和食盐水(30mL)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(3-甲氧基-4-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，产率83.4％；ESI-MS(m/z)：597.3[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-)trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (184mg, 0.404 mmol), 2-(3-methoxy-4-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (87mg, 0-336mmol), X-Phos (31mg, 0.066mmol ), Cs 2 CO 3 (220mg, 0.672mmol), toluene (10mL) and Pd(dba) 2 (19mg, 0.033mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 100°C and stirred for 3h. After the reaction, add water (10 mL) to quench the reaction, extract with ethyl acetate (40 mL×2), combine the organic phases, wash with saturated brine (30 mL), concentrate the organic phases under reduced pressure, and purify the residue by silica gel column chromatography (Eluant: dichloromethane/methanol=20/1), (R)-2-(3-methoxy-4-(methyl(2-methyl-4-((1-(3- Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield 83.4%; ESI- MS (m/z): 597.3 [M+H] + .
步骤i)：(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step i): (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-3-methoxyphenyl)-N,N-dimethylacetamide
将(R)-2-(3-甲氧基-4-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(167mg，0.280mmol)溶于甲醇(2mL)中，加入铁粉(157mg，2.800mmol)和饱和氯化铵水溶液(2mL)，将反应液升温至回流反应1h，待反应液冷却至室温后，加入乙酸乙酯(10mL)和水(10mL)，抽滤，滤液分液，水相用乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-甲氧基苯基)-N，N-二甲基乙酰胺，产率75.7％； 1H NMR(400MHz，DMSO-d 6)δ8.07(brs，1H)，7.44(s，1H)，7.29(d，J＝8.0Hz，1H)，7.11(d，J＝8.0Hz，1H)，7.01(d，J＝8.0Hz，1H)，6.92(s，1H)，6.88(s，1H)，6.85(d，J＝8.0Hz，1H)，6.72(d，J＝12.0Hz，2H)，5.64-5.57(m，1H)，5.55(s，2H)，3.72(s，2H)，3.69(s，3H)，3.27(s，3H)，3.05(s，3H)，2.86(s，3H)，2.23(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：567.3[M+H] +。 (R)-2-(3-methoxy-4-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (167mg, 0.280mmol) was dissolved in methanol (2mL), iron powder (157mg, 2.800mmol) was added and Saturated ammonium chloride aqueous solution (2mL), the reaction solution was heated to reflux for 1h, after the reaction solution was cooled to room temperature, ethyl acetate (10mL) and water (10mL) were added, suction filtered, the filtrate was separated, and the aqueous phase was washed with acetic acid Ethyl ester extraction (20mL×2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 3) to obtain (R )-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)( Methyl)amino)-3-methoxyphenyl)-N,N-dimethylacetamide, yield 75.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.07 (brs, 1H), 7.44(s, 1H), 7.29(d, J=8.0Hz, 1H), 7.11(d, J=8.0Hz, 1H), 7.01(d, J=8.0Hz, 1H), 6.92(s, 1H), 6.88(s, 1H), 6.85(d, J=8.0Hz, 1H), 6.72(d, J=12.0Hz, 2H), 5.64-5.57(m, 1H), 5.55(s, 2H), 3.72(s , 2H), 3.69(s, 3H), 3.27(s, 3H), 3.05(s, 3H), 2.86(s, 3H), 2.23(s, 3H), 1.58(d, J=8.0Hz, 3H) ; ESI-MS (m/z): 567.3 [M+H] + .
实施例12Example 12
(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-3-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000113
Figure PCTCN2022101219-appb-000113
将(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-甲氧基苯基)-N，N-二甲基乙酰胺(60mg，0.106mmol)和二氯甲烷(4mL)加入反应瓶中，搅拌溶解，氮气置换3次，0℃搅拌5min，加入BBr 3(2ml)，室温搅拌30min。反应完毕，加入饱和碳酸氢钠水溶液(50mL)和乙酸乙酯(50mL)，分液，水相用乙酸乙酯萃取(50mL×2)，合并有机相，以饱和食盐水洗涤(50mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-羟基苯基)-N，N-二甲基乙酰胺，产率10.5％； 1H NMR(4((MHz，DMSO-d 6)δ9.39(s，1H)，8.06(d，J＝8.0Hz，1H)，7.43(s，1H)，7.29(d，J＝8.0Hz，1H)，7.02(d，J＝8.0Hz，1H)，6.92(s，1H)，6.88(s，1H)，6.84(s，1H)，6.76-6.70(m，3H)，5.64-5.56(m，1H)，5.54(s，2H)，3.63(s，2H)，3.26(s，3H)，3.02(s，3H)，2.85(s，3H)，2.34(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：553.3[M+H] +。 (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl)amino)-3-methoxyphenyl)-N,N-dimethylacetamide (60mg, 0.106mmol) and dichloromethane (4mL) were added to the reaction flask, stirred to dissolve, nitrogen replacement Three times, stirred at 0°C for 5 min, added BBr 3 (2 ml), and stirred at room temperature for 30 min. After completion of the reaction, add saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (50 mL), separate the layers, extract the aqueous phase with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (50 mL), and remove Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product is purified by Prep-HPLC (method 3) to give (R)-2-(4-((4-((1-(3-amino-5-( Trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-3-hydroxyphenyl)-N,N-dimethylacetamide, Yield 10.5%; 1 H NMR (4((MHz, DMSO-d 6 )δ9.39(s, 1H), 8.06(d, J=8.0Hz, 1H), 7.43(s, 1H), 7.29(d , J=8.0Hz, 1H), 7.02(d, J=8.0Hz, 1H), 6.92(s, 1H), 6.88(s, 1H), 6.84(s, 1H), 6.76-6.70(m, 3H) , 5.64-5.56(m, 1H), 5.54(s, 2H), 3.63(s, 2H), 3.26(s, 3H), 3.02(s, 3H), 2.85(s, 3H), 2.34(s, 3H ), 1.58 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 553.3 [M+H] + .
实施例13Example 13
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-4-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinolin-6-yl) Preparation of (methyl)amino)-4-methoxyphenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000114
Figure PCTCN2022101219-appb-000114
步骤a)：(5-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯的制备Step a): Preparation of tert-butyl (5-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)(methyl)carbamate
将(5-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯(500mg，1.621mmol)和四氢呋喃(10mL)加入反应瓶中，氮气置换3次，冷却至0℃，加入NaH(207mg，5.175mmol，60％)，维持在0℃搅拌30min，滴加碘甲烷(276mg，1.944mmol)，加毕，自然升温至室温反应1h。反应结束后，加入和饱和氯化铵水溶液(20mL)萃灭，用乙酸乙酯(15mL×3)萃取，合并有机相，以饱和食盐水洗涤(20mL)，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＝1/1)，得(5-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯，产率78.6％；ESI-MS(m/z)：267.1[M+H] +。 Add (5-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate tert-butyl ester (500mg, 1.621mmol) and tetrahydrofuran (10mL) into the reaction flask, nitrogen Replaced 3 times, cooled to 0°C, added NaH (207mg, 5.175mmol, 60%), maintained at 0°C and stirred for 30min, added dropwise methyl iodide (276mg, 1.944mmol), after addition, naturally warmed to room temperature for 1h. After the reaction, add and saturated ammonium chloride aqueous solution (20mL) to extract, extract with ethyl acetate (15mL×3), combine the organic phases, wash with saturated brine (20mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (5-(2-(dimethylamino)-2-oxyethyl)-2 -Methoxyphenyl)(methyl)carbamate, tert-butyl, yield 78.6%; ESI-MS (m/z): 267.1 [M+H] + .
步骤b)：2-(4-甲氧基-3-(甲氨基)苯基)-N，N-二甲基乙酰胺的制备Step b): Preparation of 2-(4-methoxy-3-(methylamino)phenyl)-N,N-dimethylacetamide
将(5-(2-(二甲氨基)-2-氧乙基)-2-甲氧基苯基)(甲基)氨基甲酸叔丁酯(410mg，1.273mmol)溶于氯化氢乙酸乙酯溶液(4M，5mL)中，室温搅拌反应2h。反应结束后，加入饱和碳酸氢钠水溶液(50mL)萃灭，用乙酸乙酯(15mL×3)萃取，合并有机相，以饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(4-甲氧基-3-(甲氨基)苯基)-N，N-二甲基乙酰胺，产率89.5％；ESI-MS(m/z)：223.1[M+H] +。 Dissolve tert-butyl (5-(2-(dimethylamino)-2-oxoethyl)-2-methoxyphenyl)(methyl)carbamate (410 mg, 1.273 mmol) in ethyl hydrogen chloride acetate solution (4M, 5mL), stirred at room temperature for 2h. After the reaction, add saturated aqueous sodium bicarbonate solution (50mL) to extract, extract with ethyl acetate (15mL×3), combine the organic phases, wash with saturated brine (20mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure to give 2-(4-methoxy-3-(methylamino)phenyl)-N,N-dimethylacetamide with a yield of 89.5%; ESI-MS (m/z): 223.1 [M +H] + .
步骤c)：(R)-2-(4-甲氧基-3-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(4-methoxy-3-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl ) ethyl) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
将(R)-6-溴-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(517mg，1.139mmol)、2-(4-甲氧基-3-(甲氨基)苯基)-N，N-二甲基乙酰胺(253mg，1.139mmol)、Cs 2CO 3(743mg，2.278mmol)、XPhos(218mg，0.456mmol)、Pd 2(dba) 3(208mg，0.228mmol)和甲苯(8mL)加入到反应瓶中，氮气置换三次，温度维持在90℃搅拌反应16h。反应结束后，加水(15mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(10mL)洗涤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(4-甲氧基-3-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，产率39.4％；ESI-MS(m/z)：597.2[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (517mg, 1.139 mmol), 2-(4-methoxy-3-(methylamino)phenyl)-N,N-dimethylacetamide (253mg, 1.139mmol), Cs2CO3 ( 743mg , 2.278mmol), XPhos (218mg, 0.456mmol), Pd 2 (dba) 3 (208mg, 0.228mmol) and toluene (8mL) were added into the reaction flask, replaced with nitrogen three times, and the temperature was maintained at 90°C and the reaction was stirred for 16h. After the reaction was completed, add water (15 mL) to quench the reaction, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated brine (10 mL), and concentrate the organic phases to dryness under reduced pressure. The residue was subjected to silica gel column chromatography Purify (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(4-methoxy-3-(methyl(2-methyl-4-((1-(3 -Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield 39.4%; ESI - MS (m/z): 597.2 [M+H] + .
步骤d)：(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-4-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐制备Step d): (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinoline- Preparation of 6-yl)(methyl)amino)-4-methoxyphenyl)-N,N-dimethylacetamide formate
将(R)-2-(4-甲氧基-3-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(254mg，0.426mmol)溶于甲醇(3mL)中，加入铁粉(119mg，2.131mmol)和饱和氯化铵水溶液(3mL)，升温至回流反应2h。反应结束后，将反应液冷却至室温，加入乙酸乙酯(20mL)和水(10mL)，过滤，滤液用乙酸乙酯萃取(15mL×3)，合并有机相，以饱和食盐水洗涤(20ml)，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：甲醇/二氯甲烷＝1/20)，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-4-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐，产率95.1％； 1H NMR(400MHz，DMSO-d 6)δ12.77(s，1H)，8.15(s，1H)，8.06(d，J＝8.0Hz，1H)，7.45(s，1H)，7.29(d，J＝9.2Hz，1H)，7.13-7.06(m，2H)，7.04(s，1H)，6.91(s，1H)，6.88(s，1H)，6.75(d，J＝11.6Hz，1H)，6.70(s，1H)，5.64-5.57(m，1H)，5.54(s，2H)，3.70(s，3H)，3.61(s，2H)，3.28(s，3H)，2.98(s，3H)，2.80(s，3H)，2.34(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：567.2[M+H] +。 (R)-2-(4-methoxy-3-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide (254mg, 0.426mmol) was dissolved in methanol (3mL), iron powder (119mg, 2.131mmol) was added and Saturated ammonium chloride aqueous solution (3 mL) was heated to reflux for 2 h. After the reaction, the reaction solution was cooled to room temperature, ethyl acetate (20mL) and water (10mL) were added, filtered, the filtrate was extracted with ethyl acetate (15mL×3), the combined organic phases were washed with saturated brine (20ml) , dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the obtained crude product was purified by Prep-HPLC (method 2), Get (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinolin-6-yl )(methyl)amino)-4-methoxyphenyl)-N,N-dimethylacetamide formate, yield 95.1%; 1 H NMR (400MHz, DMSO-d 6 )δ12.77( s, 1H), 8.15(s, 1H), 8.06(d, J=8.0Hz, 1H), 7.45(s, 1H), 7.29(d, J=9.2Hz, 1H), 7.13-7.06(m, 2H ), 7.04(s, 1H), 6.91(s, 1H), 6.88(s, 1H), 6.75(d, J=11.6Hz, 1H), 6.70(s, 1H), 5.64-5.57(m, 1H) , 5.54(s, 2H), 3.70(s, 3H), 3.61(s, 2H), 3.28(s, 3H), 2.98(s, 3H), 2.80(s, 3H), 2.34(s, 3H), 1.58 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 567.2 [M+H] + .
实施例14Example 14
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-4-羟基苯基)-N，N- 二甲基乙酰胺甲酸盐的制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-4-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000115
Figure PCTCN2022101219-appb-000115
将(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-4-甲氧基苯基)-N，N-二甲基乙酰胺(100mg，0.176mmol)加入二氯甲烷(2mL)中，0℃搅拌条件下加入BBr 3(300mg，1.200mmol)加毕，室温反应16h。将反应液倒入冰水中淬灭，用二氯甲烷(20mL×3)萃取，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(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-4-羟基苯基)-N，N-二甲基乙酰胺甲酸盐；产率35.0％； 1H NMR(400MHz，DMSO-d 6)δ12.71(s，1H)，9.31(s，1H)，8.15(s，1H)，8.07(d，J＝8.0Hz，1H)，7.44(s，1H)，7.30(d，J＝9.2Hz，1H)，6.99-6.85(m，5H)，6.78(d，J＝8.8Hz，1H)，6.70(s，1H)，5.62(d，J＝7.2Hz，1H)，5.54(s，2H)，3.56(s，2H)，3.26(s，3H)，2.96(s，3H)，2.79(s，3H)，2.34(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.2[M+H] +。 (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinolin-6-yl )(methyl)amino)-4-methoxyphenyl)-N,N-dimethylacetamide (100mg, 0.176mmol) was added into dichloromethane (2mL), and BBr 3 was added under stirring at 0°C ( 300mg, 1.200mmol) was added, and reacted at room temperature for 16h. The reaction solution was quenched by pouring into ice water, extracted with dichloromethane (20mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by Prep-HPLC (method 2) to obtain (R) -2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl base)amino)-4-hydroxyphenyl)-N,N-dimethylacetamide formate; yield 35.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.71(s, 1H), 9.31(s, 1H), 8.15(s, 1H), 8.07(d, J=8.0Hz, 1H), 7.44(s, 1H), 7.30(d, J=9.2Hz, 1H), 6.99-6.85(m , 5H), 6.78(d, J=8.8Hz, 1H), 6.70(s, 1H), 5.62(d, J=7.2Hz, 1H), 5.54(s, 2H), 3.56(s, 2H), 3.26 (s, 3H), 2.96 (s, 3H), 2.79 (s, 3H), 2.34 (s, 3H), 1.58 (d, J=7.2Hz, 3H); ESI-MS (m/z): 553.2[ M+H] + .
实施例15Example 15
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000116
Figure PCTCN2022101219-appb-000116
步骤a)：2-(2-甲氧基-5-硝基吡啶-3-基)丙二酸二乙酯的制备Step a): Preparation of diethyl 2-(2-methoxy-5-nitropyridin-3-yl)malonate
将3-溴-2-甲氧基-5-硝基吡啶(5.00g，21.457mmol)、丙二酸二乙酯(13.75g，85.829mmol)、溴化亚铜(12.31g，85.829mmol)、1，4-二氧六环(100mL)加入反应瓶中，0℃加入NaH(3.43g，85.829mmol)，搅拌15min，升温至100℃搅拌2h。反应结束后，冷却至室温，抽滤，滤液加饱和氯化铵水溶液(100mL)，乙酸乙酯萃取(100mL)，有机相饱以和食盐水(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)，得2-(2-甲氧基-5-硝基吡啶-3-基)丙二酸二乙酯，产率74.6％；ESI-MS(m/z)：313.0[M+H] +。 3-Bromo-2-methoxy-5-nitropyridine (5.00g, 21.457mmol), diethyl malonate (13.75g, 85.829mmol), cuprous bromide (12.31g, 85.829mmol), 1,4-Dioxane (100 mL) was added to the reaction flask, NaH (3.43 g, 85.829 mmol) was added at 0°C, stirred for 15 min, then heated to 100°C and stirred for 2 h. After the reaction, cool to room temperature, filter with suction, add saturated ammonium chloride aqueous solution (100mL) to the filtrate, extract with ethyl acetate (100mL), wash the organic phase with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain 2-(2-methoxy-5-nitropyridin-3-yl)propane Diethyl diacid, yield 74.6%; ESI-MS (m/z): 313.0 [M+H] + .
步骤b)：2-(2-甲氧基-5-硝基吡啶-3-基)乙酸乙酯的制备Step b): Preparation of ethyl 2-(2-methoxy-5-nitropyridin-3-yl)acetate
将2-(2-甲氧基-5-硝基吡啶-3-基)丙二酸二乙酯(5.01g，16.043mmol)、氯化锂(2.921g，68.919mmol)、DMSO(60mL)和水(3mL)加入反应瓶中，100℃反应24h。冷却至室温，加水(100mL)稀释，乙酸乙酯萃取(100mL)，有机相以饱和食盐水(50mL×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：乙酸乙酯/石油醚＝1/5)，得2-(2-甲氧基-5-硝基吡啶-3-基)乙酸乙酯，产率33.7％； 1H NMR(400MHz，DMSO-d 6)δ9.03(s，1H)，8.52(s，1H)，4.13-4.08(m，2H)，4.00(s，3H)，3.77(s，2H)，1.20-1.18(m，3H)；ESI-MS(m/z)：241.0[M+H] +。 Diethyl 2-(2-methoxy-5-nitropyridin-3-yl)malonate (5.01 g, 16.043 mmol), lithium chloride (2.921 g, 68.919 mmol), DMSO (60 mL) and Water (3 mL) was added into the reaction flask, and reacted at 100° C. for 24 h. Cool to room temperature, dilute with water (100mL), extract with ethyl acetate (100mL), wash the organic phase with saturated brine (50mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Analysis and purification (eluent: ethyl acetate/petroleum ether = 1/5) gave ethyl 2-(2-methoxy-5-nitropyridin-3-yl)acetate with a yield of 33.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.03(s, 1H), 8.52(s, 1H), 4.13-4.08(m, 2H), 4.00(s, 3H), 3.77(s, 2H), 1.20- 1.18 (m, 3H); ESI-MS (m/z): 241.0 [M+H] + .
步骤c)：2-(2-甲氧基-5-硝基吡啶-3-基)乙酸的制备Step c): Preparation of 2-(2-methoxy-5-nitropyridin-3-yl)acetic acid
将2-(2-甲氧基-5-硝基吡啶-3-基)乙酸乙酯(1.30g，5.417mmol)、氢氧化锂水溶液(4M，5.4mL)、甲醇(2mL)和THF(6mL)加入反应瓶中，室温反应0.5h。反应结束后，以1N盐酸调至pH＝1-2，乙酸乙酯萃取(20mL)，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，得2-(2-甲氧基-5-硝基吡啶-3-基)乙酸，无需进一步纯化直接用于下一步反应，产率83.3％；ESI-MS(m/z)：213.1[M+H] +。 Ethyl 2-(2-methoxy-5-nitropyridin-3-yl)acetate (1.30 g, 5.417 mmol), aqueous lithium hydroxide (4M, 5.4 mL), methanol (2 mL) and THF (6 mL ) was added into the reaction flask, and reacted at room temperature for 0.5h. After the reaction, the pH was adjusted to 1-2 with 1N hydrochloric acid, extracted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(2-methyl Oxy-5-nitropyridin-3-yl)acetic acid was directly used in the next reaction without further purification, with a yield of 83.3%; ESI-MS (m/z): 213.1[M+H] + .
步骤d)：2-(2-甲氧基-5-硝基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step d): Preparation of 2-(2-methoxy-5-nitropyridin-3-yl)-N,N-dimethylacetamide
将2-(2-甲氧基-5-硝基吡啶-3-基)乙酸(957mg，4.511mmol)、二甲胺盐酸盐(441mg，5.413mmol)、DIPEA(1.455g，11.277mmol)、二氯甲烷(10mL)和T 3P(3.445g，5.413mmol)加入反应瓶中，室温反应2h。反应结束后，加水(20mL)稀释，以乙酸乙酯萃取(30mL×2)，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝2/1)，得2-(2-甲氧基-5-硝基吡啶-3-基)-N，N-二甲基乙酰胺，产率59.3％；ESI-MS(m/z)：240.0[M+H] + 2-(2-Methoxy-5-nitropyridin-3-yl)acetic acid (957mg, 4.511mmol), dimethylamine hydrochloride (441mg, 5.413mmol), DIPEA (1.455g, 11.277mmol), Dichloromethane (10 mL) and T 3 P (3.445 g, 5.413 mmol) were added into the reaction flask, and reacted at room temperature for 2 h. After the reaction, dilute with water (20mL), extract with ethyl acetate (30mL×2), wash with saturated brine (20mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=2/1), to get 2-(2-methoxy-5-nitropyridin-3-yl)-N,N-dimethylacetamide, yield 59.3%; ESI-MS (m/z): 240.0 [M+H] +
步骤e)：2-(5-氨基-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step e): Preparation of 2-(5-amino-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
将2-(2-甲氧基-5-硝基吡啶-3-基)-N，N-二甲基乙酰胺(640mg，2.675mmol)、铁粉(747mg，13.376mmol)、饱和氯化铵水液(6mL)、甲醇(12mL)加入反应瓶中，回流反应0.5h。反应结束后，冷却至室温，加饱和氯化钠水溶液(10mL)和乙腈(30mL)，过滤，分液，水相用乙腈萃取(20mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(5-氨基-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，无需进一步直接用于下一步反应；ESI-MS(m/z)：210.1[M+H] +。 2-(2-Methoxy-5-nitropyridin-3-yl)-N,N-dimethylacetamide (640mg, 2.675mmol), iron powder (747mg, 13.376mmol), saturated ammonium chloride Water (6mL) and methanol (12mL) were added to the reaction flask, and the reaction was refluxed for 0.5h. After the reaction, cool to room temperature, add saturated aqueous sodium chloride solution (10mL) and acetonitrile (30mL), filter, separate the liquids, extract the aqueous phase with acetonitrile (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure to obtain 2-(5-amino-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, which was directly used in the next step without further reaction; ESI-MS (m /z): 210.1[M+H] + .
步骤f)：(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)氨基甲酸叔丁酯的制备Step f): Preparation of tert-butyl (5-(2-(dimethylamino)-2-oxyethyl)-6-methoxypyridin-3-yl)carbamate
将2-(5-氨基-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺(547mg，2.615mmol)、二碳酸二叔丁酯(582mg，2.667mmol)、二氧六环(12mL)依次加入反应瓶中，升温至100℃搅拌20min。冷却至室温，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＝3/1)，得(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)氨基甲酸叔丁酯，产率98.9％；ESI-MS(m/z)：254.1[M+H-Bu t]+。 2-(5-Amino-2-methoxypyridin-3-yl)-N,N-dimethylacetamide (547mg, 2.615mmol), di-tert-butyl dicarbonate (582mg, 2.667mmol), di Oxycycline (12 mL) was sequentially added into the reaction flask, and the temperature was raised to 100° C. and stirred for 20 min. Cooled to room temperature, concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=3/1) to obtain (5-(2-(dimethylamino)-2-oxoethyl yl)-6-methoxypyridin-3-yl) tert-butyl carbamate, yield 98.9%; ESI-MS (m/z): 254.1 [M+H-But ]+.
步骤g)：(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基甲酸叔丁酯的制备Step g): Preparation of tert-butyl (5-(2-(dimethylamino)-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)carbamate
将(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)氨基甲酸叔丁酯(400mg，1.293mmol)溶于THF(8mL)中，在0℃加NaH(207mg，5.172mmol)，搅拌15min，加碘甲烷(220mg，1.552mmol)，室温搅拌30min，加饱和氯化铵(10mL)淬灭，以乙酸乙酯萃取(20mL)，饱和食盐水(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：乙酸乙酯/石油醚＝1/1)，得(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基甲酸叔丁酯，产率66.2％； 1H NMR(400MHz，DMSO-d 6)δ7.97(s，1H)，7.43(s，1H)，3.83(s，3H)3.59(s，2H)，3.14(s，3H)，3.04(s，3H)，2.83(s，3H)，1.38(s，9H)；ESI-MS(m/z)：268.1[M+H-Bu t]+。 (5-(2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)carbamate tert-butyl ester (400 mg, 1.293 mmol) was dissolved in THF (8 mL), Add NaH (207mg, 5.172mmol) at 0°C, stir for 15min, add iodomethane (220mg, 1.552mmol), stir at room temperature for 30min, add saturated ammonium chloride (10mL) to quench, extract with ethyl acetate (20mL), saturate Wash with brine (10 mL), 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=1/1) to obtain (5-( 2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)(methyl)carbamate tert-butyl ester, yield 66.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ7.97(s, 1H), 7.43(s, 1H), 3.83(s, 3H), 3.59(s, 2H), 3.14(s, 3H), 3.04(s, 3H), 2.83(s, 3H ), 1.38 (s, 9H); ESI-MS (m/z): 268.1 [M+H-Bu t ]+.
步骤h)：2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐的制备Step h): Preparation of 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide hydrochloride
将(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基甲酸叔丁酯(272mg，0.841mmol)和盐酸乙酸乙酯(4M，4mL)加入反应瓶中，室温反应1.5h。减压浓缩，得2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐，所得粗品无需纯化直接用于下一步反应，产率65.0％；ESI-MS(m/z)：224.1[M+H] + (5-(2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)(methyl)carbamate tert-butyl ester (272 mg, 0.841 mmol) and ethyl acetate hydrochloride Ester (4M, 4mL) was added into the reaction flask and reacted at room temperature for 1.5h. Concentrate under reduced pressure to obtain 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide hydrochloride, the obtained crude product is directly used in the next reaction without purification , yield 65.0%; ESI-MS (m/z): 224.1[M+H] +
步骤i)：(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备Step i): (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) ) ethyl) amino) quinazoline-6-yl) amino) pyridin-3-yl)-N, the preparation of N-dimethylacetamide
将2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐(162mg，0.624mmol)、(R)-6-溴-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(293mg，0.644mmol)、X-Phos(238mg，0.499mmol)、Cs 2CO 3(1.220g，3.744mmol)、Pd 2(dba) 3(229mg，0.250mmol)和甲苯(20mL)依次加入到反应瓶中，氮气置换三次，105℃搅拌反应2h。冷却至室温，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＝1/20)，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺，产率92.3％；ESI-MS(m/z)：598.2[M+H] +。 2-(2-Methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide hydrochloride (162 mg, 0.624 mmol), (R)-6-bromo- 2-Methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (293mg, 0.644mmol), X-Phos (238mg, 0.499mmol), Cs 2 CO 3 (1.220g, 3.744mmol), Pd 2 (dba) 3 (229mg, 0.250mmol) and toluene (20mL) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at 105°C for 2h. Cooled to room temperature, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to obtain (R)-2-(2-methoxy-5-(methyl Base (2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl )-N,N-dimethylacetamide, yield 92.3%; ESI-MS (m/z): 598.2[M+H] + .
步骤j)：(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备Step j): (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino-2-methylquinazoline- Preparation of 6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
将(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺(344mg，0.576mmol)溶于甲醇(8mL)中，加入铁粉(161mg，2.880mmol)和饱和氯化铵水溶液(4ml)，回流反应0.5h。冷却至室温，加入乙酸乙酯(20mL)和水(10mL)，抽滤，滤液分取有机相，以饱和食盐水洗涤(10ml)，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(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率5.2％； 1H NMR(400MHz，DMSO-d 6)δ12.73(s，1H)，8.22(s，1H)，8.13(s，1H)，7.94(s，1H)，7.70(s，1H)，7.41(d，J＝8.8Hz，1H)，7.35(s，1H)，7.11(d，J＝9.2Hz，1H)， 6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.66-5.49(m，3H)，3.85(s，3H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.38(s，3H)1.57(d，J＝6.8Hz，3H)；ESI-MS(m/z)：568.0[M+H] +。 (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide (344mg, 0.576mmol) was dissolved in methanol (8mL), iron powder (161mg, 2.880 mmol) and saturated aqueous ammonium chloride (4ml), reflux for 0.5h. Cool to room temperature, add ethyl acetate (20mL) and water (10mL), filter with suction, separate the organic phase from the filtrate, wash with saturated brine (10ml), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product Purification by Prep-HPLC (Method 2) afforded (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino-2 -Methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate, yield 5.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.73(s, 1H), 8.22(s, 1H), 8.13(s, 1H), 7.94(s, 1H), 7.70(s, 1H), 7.41(d, J=8.8Hz, 1H), 7.35(s, 1H), 7.11(d, J=9.2Hz, 1H), 6.90(s, 1H), 6.87(s, 1H), 6.70(s, 1H), 5.66- 5.49(m, 3H), 3.85(s, 3H), 3.59(s, 2H), 3.36(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.38(s, 3H) 1.57( d, J = 6.8 Hz, 3H); ESI-MS (m/z): 568.0 [M+H] + .
实施例16Example 16
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000117
Figure PCTCN2022101219-appb-000117
将(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺(150mg，0.264mmol)、溴化氢醋酸溶液(33％，5mL)加入反应瓶中，80℃搅拌1h。降至室温，加饱和碳酸氢钠水溶液(100mL)调pH 7-8，乙酸乙酯萃取(20mL)，饱和食盐水(10mL)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3)纯化，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率5.3％； 1H NMR(400MHz，DMSO-d 6)δ11.59(s，1H)，8.06(s，1H)，7.52(s，1H)，7.39(d，J＝9.2Hz，1H)，7.25(s，1H)，7.17(s，1H)，7.07(d，J＝8.8Hz，1H)，6.89(s，1H)，6.87(s，1H)，6.70(s，1H)，5.65-5.47(m，3H)，3.41(s，2H)，3.26(s，3H)，3.00(s，3H)，2.78(s，3H)，2.35(s，3H)，1.57(d，J＝6.8Hz，3H)；ESI-MS(m/z)：554.0[M+H] +。 (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino-2-methylquinazolin-6-yl )(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide (150mg, 0.264mmol), hydrogen bromide acetic acid solution (33%, 5mL) into the reaction flask , stirred at 80°C for 1 h. Lowered to room temperature, added saturated aqueous sodium bicarbonate (100 mL) to adjust the pH to 7-8, extracted with ethyl acetate (20 mL), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting crude product was purified by Prep-HPLC (Method 3) to give (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl )ethyl)amino-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 5.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.59(s, 1H), 8.06(s, 1H), 7.52(s, 1H), 7.39(d, J=9.2Hz, 1H), 7.25(s, 1H), 7.17(s, 1H), 7.07(d, J=8.8Hz, 1H), 6.89(s, 1H), 6.87(s, 1H), 6.70(s, 1H), 5.65-5.47(m, 3H ), 3.41(s, 2H), 3.26(s, 3H), 3.00(s, 3H), 2.78(s, 3H), 2.35(s, 3H), 1.57(d, J=6.8Hz, 3H); ESI - MS (m/z): 554.0 [M+H] + .
实施例17Example 17
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloroquinazolin-6-yl)( Preparation of methyl) amino)-2-methoxyphenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000118
Figure PCTCN2022101219-appb-000118
步骤a)：(R)-6-溴-2-氯-N-(1-(3-硝基-5-三氟甲基苯基)乙基)喹唑啉-4-胺的制备Step a): Preparation of (R)-6-bromo-2-chloro-N-(1-(3-nitro-5-trifluoromethylphenyl)ethyl)quinazolin-4-amine
将6-溴-2，4-二氯喹唑啉(618mg，2.222mmol)、(R)-1-(3-硝基-5-(三氟甲基)苯基)乙烷-1-胺盐酸盐(500mg，1.852mmol)、DIPEA(717mg，5.556mmol)、DMSO(10mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌反应1h。反应结束后，加饱和氯化铵水溶液(30mL)，以乙酸乙酯萃取(50mL×2)，合并有机相，用饱和食盐水(50mL)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至5/1)，得(R)-6-溴-2-氯-N-(1-(3-硝基-5-三氟甲基苯基)乙基)喹唑啉-4-胺，产率92.0％；ESI-MS(m/z)：475.0[M+H] +。 6-Bromo-2,4-dichloroquinazoline (618mg, 2.222mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethane-1-amine salt Acetyl chloride (500mg, 1.852mmol), DIPEA (717mg, 5.556mmol), and DMSO (10mL) were sequentially added into the reaction flask, heated to 80°C under nitrogen protection, and stirred for 1h. After the reaction, add saturated aqueous ammonium chloride (30 mL), extract with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (50 mL), concentrate the organic phases under reduced pressure, and pass the residue through a silica gel column layer Analysis and purification (eluent: petroleum ether/ethyl acetate = 10/1 to 5/1) to obtain (R)-6-bromo-2-chloro-N-(1-(3-nitro-5-tri Fluoromethylphenyl)ethyl)quinazolin-4-amine, yield 92.0%; ESI-MS (m/z): 475.0 [M+H] + .
步骤b)：(R)-2-(5-(2-氯-4-(1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)(甲基氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(5-(2-chloro-4-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -base) (methylamino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
将(R)-6-溴-2-氯-N-(1-(3-硝基-5-三氟甲基苯基)乙基)喹唑啉-4-胺(143mg，0.300mmol)，2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(78mg，0.300mmol)、X-Phos(28mg，0.060mmol)、Cs 2CO 3(195mg，0.6mmol)、甲苯(5mL)和Pd(dba) 2(17mg，0.030mmol)依次加入到反应瓶中，氮气置换三次，升温至100℃搅拌反应3h。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯萃取(30mL×2)，合并有机相，用饱和食盐水(30mL)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(5-(2-氯-4-(1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)(甲基氨基)-2-甲 氧基苯基)-N，N-二甲基乙酰胺，产率37.8％；ESI-MS(m/z)：617.0[M+H] +。 (R)-6-Bromo-2-chloro-N-(1-(3-nitro-5-trifluoromethylphenyl)ethyl)quinazolin-4-amine (143mg, 0.300mmol), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (78mg, 0.300mmol), X-Phos (28mg, 0.060mmol), Cs 2 CO 3 (195mg, 0.6mmol), toluene (5mL) and Pd(dba) 2 (17mg, 0.030mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 100°C and stirred for 3h. After the reaction was completed, add water (30 mL) to quench the reaction, extract with ethyl acetate (30 mL×2), combine the organic phases, wash with saturated brine (30 mL), concentrate the organic phases under reduced pressure, and purify the residue by silica gel column chromatography (Eluent: dichloromethane/methanol=20/1), to get (R)-2-(5-(2-chloro-4-(1-(3-nitro-5-(trifluoromethyl) Phenyl) ethyl) amino) quinazoline-6-yl) (methylamino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 37.8%; ESI-MS ( m/z): 617.0 [M+H] + .
步骤c)：(R)-2-(5-(4-(1-(3-氨基-5-(三氟甲基苯基)乙基)氨基)-2-氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(5-(4-(1-(3-amino-5-(trifluoromethylphenyl)ethyl)amino)-2-chloroquinazolin-6-yl) Preparation of (methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-2-(5-(2-氯-4-(1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)(甲基氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(70mg，0.113mmol)溶于甲醇(1.5mL)中，加入铁粉(32mg，0.565mmol)和氯化铵水溶液(1.5ml)至反应瓶中，维持90℃搅拌反应2h。反应结束后，将反应液冷却至室温，过滤，固体用乙酸乙酯(5mL×3)淋洗，滤液分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，(R)-2-(5-(4-(1-(3-氨基-5-(三氟甲基苯基)乙基)氨基)-2-氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率37.7％； 1H NMR(400MHz，DMSO-d 6)δ8.64(d，J＝8.0Hz，1H)，7.62(s，1H)，7.36(d，J＝8.0Hz，1H)，7.10-7.07(m，2H)，7.01(d，J＝8.0Hz，1H)，6.95(s，1H)，6.88(s，1H)，6.85(s，1H)，6.73(s，1H)，5.95(s，2H)，5.52-5.45(m，1H)，3.78(s，3H)，3.52(s，2H)，3.33(s，3H)，3.00(s，3H)，2.80(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：587.0[M+H] +。 (R)-2-(5-(2-chloro-4-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl) (Methylamino)-2-methoxyphenyl)-N,N-dimethylacetamide (70 mg, 0.113 mmol) was dissolved in methanol (1.5 mL), iron powder (32 mg, 0.565 mmol) and chlorine Aqueous ammonium chloride solution (1.5ml) was added to the reaction flask, and the mixture was stirred at 90°C for 2h. After the reaction, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5mL×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10mL×2), the organic phases were combined, and washed with saturated salt Washed with water (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, the obtained crude product was purified by Prep-HPLC (method 3), (R)-2-(5-(4-(1-(3- Amino-5-(trifluoromethylphenyl)ethyl)amino)-2-chloroquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethyl Acetamide, yield 37.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.64(d, J=8.0Hz, 1H), 7.62(s, 1H), 7.36(d, J=8.0Hz, 1H), 7.10-7.07(m, 2H), 7.01(d, J=8.0Hz, 1H), 6.95(s, 1H), 6.88(s, 1H), 6.85(s, 1H), 6.73(s, 1H ), 5.95(s, 2H), 5.52-5.45(m, 1H), 3.78(s, 3H), 3.52(s, 2H), 3.33(s, 3H), 3.00(s, 3H), 2.80(s, 3H), 1.59 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 587.0 [M+H] + .
实施例18Example 18
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloroquinazolin-6-yl)( Preparation of methyl) amino)-2-methoxyphenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000119
Figure PCTCN2022101219-appb-000119
步骤a)：(R)-2-(4-((2-氯-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step a): (R)-2-(4-((2-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline Preparation of -6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-6-溴-2-氯-N-(1-(3-硝基-5-三氟甲基苯基)乙基)喹唑啉-4-胺(300mg，0.63mmol)，2-(4-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐(154mg，0.63mmol)、X-Phos(60mg，0.126mmol)、Cs 2CO 3(410mg，1.260mmol)、甲苯(50mL)和Pd(dba) 2(36mg，0.063mmol)依次加入到反应瓶中，氮气置换三次，升温至100℃搅拌反应3h。反应结束后，加水(50mL)淬灭反应，用乙酸乙酯萃取(50mL×2)，合并有机相，用饱和食盐水(50mL×1)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得(R)-2-(4-((2-氯-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率21.0％；ESI-MS(m/z)：603.0[M+H] +。 (R)-6-Bromo-2-chloro-N-(1-(3-nitro-5-trifluoromethylphenyl)ethyl)quinazolin-4-amine (300mg, 0.63mmol), 2-(4-Amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride (154mg, 0.63mmol), X-Phos (60mg, 0.126mmol), Cs 2 CO 3 ( 410mg, 1.260mmol), toluene (50mL) and Pd(dba) 2 (36mg, 0.063mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 100°C and stirred for 3h. After the reaction, add water (50mL) to quench the reaction, extract with ethyl acetate (50mL×2), combine the organic phases, wash with saturated brine (50mL×1), concentrate the organic phase under reduced pressure, and pass the residue through silica gel column layer Analysis and purification (eluent: dichloromethane/methanol=30/1), to obtain (R)-2-(4-((2-chloro-4-((1-(3-nitro-5-(tri Fluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 21.0%; ESI-MS (m/z): 603.0 [M+H] + .
步骤b)：(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-氯喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloroquinazoline-6 Preparation of -yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将((R)-2-(4-((2-氯-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(80mg，0.132mmol)溶于甲醇(1.5mL)中，加入铁粉(37mg，0.66mmol)和氯化铵水溶液(1.5ml)至反应瓶中，维持90℃搅拌反应2h。反应结束后，将反应液冷却至室温，过滤，固体用乙酸乙酯(5mL×3)淋洗，滤液分液，水相用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-氯喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率66.7％； 1H NMR(400MHz，DMSO-d 6)δ8.75(d，J＝8.0Hz，1H)，8.53(s，1H)，8.42(s，1H)，7.54-7.46(m，2H)，6.98(d，J＝8.0Hz，1H)，6.88(s，1H)，6.86(s，1H)，6.81(s，1H)，6.71(s，1H)，6.64(d，J＝8.0Hz，1H)，5.54(s，2H)，5.46-5.39(m，1H)，3.72(s，3H)，3.50(s，2H)，3.01(s，3H)，2.83(s，3H)，1.53(d，J＝8.0Hz，3H)；ESI-MS(m/z)：573.0[M+H] +。 ((R)-2-(4-((2-chloro-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide (80 mg, 0.132 mmol) was dissolved in methanol (1.5 mL), iron powder (37 mg, 0.66 mmol) and chlorine Aqueous ammonium chloride solution (1.5ml) was added to the reaction flask, and the reaction was maintained at 90°C for 2h. After the reaction, the reaction solution was cooled to room temperature, filtered, and the solid was rinsed with ethyl acetate (5mL×3), and the filtrate was separated into water and The phase was extracted with ethyl acetate (10mL×2), the organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 3) , to get (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloroquinazolin-6-yl )amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 66.7%; 1 H NMR (400MHz, DMSO-d 6 )δ8.75 (d, J=8.0Hz, 1H), 8.53(s, 1H), 8.42(s, 1H), 7.54-7.46(m, 2H), 6.98(d, J=8.0Hz, 1H), 6.88(s, 1H), 6.86(s, 1H ), 6.81(s, 1H), 6.71(s, 1H), 6.64(d, J=8.0Hz, 1H), 5.54(s, 2H), 5.46-5.39(m, 1H), 3.72(s, 3H) , 3.50(s, 2H), 3.01(s, 3H), 2.83(s, 3H), 1.53(d, J=8.0Hz, 3H); ESI-MS(m/z): 573.0[M+H] + .
实施例19Example 19
(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-氯喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-chloroquinazolin-6-yl)amino )-2-hydroxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000120
Figure PCTCN2022101219-appb-000120
将(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-甲氧基苯基)-N，N-二甲基乙酰胺(40mg，0.070mmol)和二氯甲烷(2mL)加入反应瓶中，搅拌溶解，氮气置换3次，0℃搅拌5min，加入BCl 3(1M，2mL)，室温搅拌30min。反应完毕，加入饱和碳酸氢钠水溶液(20mL)和乙酸乙酯(20mL)，分液，水相用乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水洗涤(30mL)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(放法3)纯化，得(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-氯喹唑啉-6-基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺，产率51.2％； 1H NMR(400MHz，DMSO-d 6)δ9.48(s，1H)，8.72(d，J＝8.0Hz，1H)，8.32(s，1H)，7.97(s，1H)，7.51(s，2H)，6.94(d，J＝8.0Hz，1H)，6.88(s，1H)，6.84(s，1H)，6.70(s，1H)，6.63(s，1H)，6.59(d，J＝8.0Hz，1H)，5.54(s，2H)，5.39-5.46(m，1H)，3.50(s，2H)，3.03(s，3H)，2.83(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：559.0[M+H] +。 (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl)amino)-3-methoxyphenyl)-N,N-dimethylacetamide (40mg, 0.070mmol) and dichloromethane (2mL) were added to the reaction flask, stirred to dissolve, nitrogen replacement Three times, stirred at 0°C for 5 min, added BCl 3 (1M, 2 mL), stirred at room temperature for 30 min. After completion of the reaction, add saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL), separate the layers, extract the aqueous phase with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (30 mL), and remove Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The resulting crude product is purified by Prep-HPLC (Method 3) to obtain (R)-2-(4-((4-((1-(3-amino-5- (Trifluoromethyl)phenyl)ethyl)amino)-2-chloroquinazolin-6-yl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide, yield 51.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.48(s, 1H), 8.72(d, J=8.0Hz, 1H), 8.32(s, 1H), 7.97(s, 1H), 7.51(s, 2H), 6.94(d, J=8.0Hz, 1H), 6.88(s, 1H), 6.84(s, 1H), 6.70(s, 1H), 6.63(s, 1H), 6.59(d, J=8.0 Hz, 1H), 5.54(s, 2H), 5.39-5.46(m, 1H), 3.50(s, 2H), 3.03(s, 3H), 2.83(s, 3H), 1.54(d, J=8.0Hz , 3H); ESI-MS (m/z): 559.0 [M+H] + .
实施例20Example 20
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000121
Figure PCTCN2022101219-appb-000121
步骤a)：1-溴-3-二氟甲基-2-氟苯的制备Step a): Preparation of 1-bromo-3-difluoromethyl-2-fluorobenzene
将3-溴-2-氟苯甲醛(20.0g，98.522mmol)和二氯甲烷(200mL)加入反应瓶中，搅拌溶解，氮气置换3次，冷却至0℃，滴加二乙胺基三氟化硫(24.1g，147.789mmol)，滴加完毕后，自然升至室温，搅拌16h。反应结束后，缓慢滴加饱和碳酸氢钠水溶液调至pH＝7-8萃灭反应，用二氯甲烷(150mL×3)萃取，合并有机相，用200mL饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝100/1)，得1-溴-3-二氟甲基-2-氟苯，产率88.0％； 1H NMR(400MHz，CDCl 3)δ7.68(t，J＝8.0Hz，8.0Hz 1H)，7.55(t，J＝7.0Hz，7.0Hz 1H)，7.14(d，J＝8.0Hz，2H)，6.89(t，J＝54.8Hz，1H)；19FNMR(376MHz，CDCl 3)δ-114.27(s，1F)，-114.26(s，1F)，-113.08(s，1F)。 Add 3-bromo-2-fluorobenzaldehyde (20.0g, 98.522mmol) and dichloromethane (200mL) into the reaction flask, stir to dissolve, replace with nitrogen three times, cool to 0°C, add diethylaminotrifluoro Sulfur sulfide (24.1g, 147.789mmol), after the dropwise addition was completed, it was naturally raised to room temperature and stirred for 16h. After the reaction is over, slowly add saturated aqueous sodium bicarbonate solution dropwise to adjust to pH = 7-8 to extract the reaction, extract with dichloromethane (150mL×3), combine the organic phases, wash with 200mL saturated brine, and dry over anhydrous sodium sulfate , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column (eluent: petroleum ether/ethyl acetate=100/1) to obtain 1-bromo-3-difluoromethyl-2-fluorobenzene, the yield 88.0%; 1 H NMR (400MHz, CDCl 3 ) δ7.68(t, J=8.0Hz, 8.0Hz 1H), 7.55(t, J=7.0Hz, 7.0Hz 1H), 7.14(d, J=8.0Hz , 2H), 6.89 (t, J=54.8Hz, 1H); 19FNMR (376MHz, CDCl 3 ) δ-114.27(s, 1F), -114.26(s, 1F), -113.08(s, 1F).
步骤b)：1-(3-(二氟甲基)-2-氟苯基)乙基-1-酮的制备Step b): Preparation of 1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-one
将1-溴-3-二氟甲基-2-氟苯(19.5g，87.053mmol)、三丁基(1-乙氧基乙烯基)锡烷(40.8g，113.170mmol)、Pd(PPh 3) 2Cl 2(611mg，0.871mmol)、三乙胺(17.6g，174.106mmol)加入1，4-二氧六环(200mL)中，反应液持续鼓入氮气5min，在加压釜中升温至100℃反应过夜。反应结束后，将反应液冷却至室温，加入2M的稀盐酸调至pH＝2-3，室温搅拌1h，浓缩除去溶剂，将饱和碳酸氢钠水溶液加入混合物中，用乙酸乙酯萃取(150mL×3)，合并有机相，以饱和食盐水(150mL)洗涤，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＝100/1)，得1-(3-(二氟甲基)-2-氟苯基)乙基-1-酮，产率72.1％； 1H NMR(400MHz，CDCl 3)δ8.00(t，J＝7.2Hz，1H)，7.79(t，J＝7.2Hz，6.4Hz，1H)，7.34(t，J＝7.6Hz，1H)，6.95(t，J＝54.8Hz，1H)，2.67(d，J＝5.2Hz，3H)。 1-Bromo-3-difluoromethyl-2-fluorobenzene (19.5g, 87.053mmol), tributyl (1-ethoxyvinyl) stannane (40.8g, 113.170mmol), Pd(PPh 3 ) 2 Cl 2 (611mg, 0.871mmol), triethylamine (17.6g, 174.106mmol) were added into 1,4-dioxane (200mL), and the reaction solution was continuously blown with nitrogen for 5min, and the temperature was raised to React overnight at 100°C. After the reaction, the reaction liquid was cooled to room temperature, 2M dilute hydrochloric acid was added to adjust the pH to 2-3, stirred at room temperature for 1 h, concentrated to remove the solvent, saturated aqueous sodium bicarbonate solution was added to the mixture, extracted with ethyl acetate (150 mL× 3), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100 /1), to obtain 1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-one, yield 72.1%; 1 H NMR (400MHz, CDCl 3 ) δ8.00(t, J=7.2Hz, 1H), 7.79(t, J=7.2Hz, 6.4Hz, 1H), 7.34(t, J=7.6Hz, 1H), 6.95(t, J=54.8Hz, 1H), 2.67(d , J=5.2Hz, 3H).
步骤c)：(R，E)-N-(1-(3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step c): Preparation of (R,E)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide
将1-(3-(二氟甲基)-2-氟苯基)乙-1-酮(12.1g，64.362mmol)和(R)-(+)-叔丁基亚磺酰胺(9.3g，77.234mmol)和THF(150mL)加入反应瓶中，搅拌溶解，室温下加入钛酸四乙酯(33.8g，96.489mmol，65％)，加毕，在封闭的反应瓶中80℃搅拌3h。反应结束后，冷却至室温，加水(200mL)，析出大量固体，过滤，滤饼用乙酸乙酯(50mL)洗涤，滤液以乙酸乙酯萃取(150mL×3)，合并有机相，以饱和食盐水(200mL)洗涤，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)，得(R，E)-N-(1-(3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺，产率81.0％；ESI-MS(m/z)：292.1[M+H] +。 1-(3-(Difluoromethyl)-2-fluorophenyl)ethan-1-one (12.1 g, 64.362 mmol) and (R)-(+)-tert-butylsulfinamide (9.3 g, 77.234mmol) and THF (150mL) were added into the reaction flask, stirred to dissolve, and tetraethyl titanate (33.8g, 96.489mmol, 65%) was added at room temperature, and after the addition was completed, it was stirred at 80°C for 3h in a closed reaction flask. After the reaction, cool to room temperature, add water (200mL), precipitate a large amount of solid, filter, wash the filter cake with ethyl acetate (50mL), extract the filtrate with ethyl acetate (150mL×3), combine the organic phases, and wash with saturated brine (200mL) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R, E)- N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide, yield 81.0%; ESI-MS (m/z ): 292.1 [M+H] + .
步骤d)：(R)-1-(3-(二氟甲基)-2-氟苯基)乙基-1-胺盐酸盐的制备Step d): Preparation of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine hydrochloride
将(R，E)-N-(1-(3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(15.1g，51.546mmol)和四氢呋喃/水混合液(160mL，v/v＝15/1)加入反应瓶中，搅拌溶解，在-78℃搅拌条件下，缓慢加入NaBH 4(2.4g，63.158mmol)，加毕，维持-78℃反应1h。反应结束后，自然升温至室温，加入饱和食盐水(100mL)淬灭反应，分液，有机相再用饱和食盐水(100mL)洗一次，干燥浓缩，残余物经硅胶柱层析纯化，收集目标成分，所得中间体溶于THF(80mL)中，加盐酸二氧六环溶液(4M，30mL)，室温搅拌3h，将溶剂减压浓缩干，所得固体加乙酸乙酯/石油醚(100mL，v/v＝1/1)室温打浆1h，过滤，所得固体经减压干燥得(R)-1-(3-(二氟甲基)-2-氟苯基)乙基-1-胺盐酸盐，产率78.1％； 1H NMR(400MHz，DMSO-d 6)δ8.80(s，3H)，7.94(t，J＝7.6Hz，1H)，7.66(t，J＝7.2Hz，1H)，7.44(t，J＝7.6Hz，1H)，7.25(t，J＝54.0Hz，1H)，4.65(q，J＝6.0Hz，1H)，1.55(d，J＝6.8Hz，3H)；ESI-MS(m/z)：190.1[M+H] +。 (R, E)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfinamide (15.1g, 51.546mmol ) and tetrahydrofuran/water mixture (160mL, v/v=15/1) were added to the reaction flask, stirred and dissolved, and NaBH 4 (2.4g, 63.158mmol) was slowly added under the stirring condition of -78°C. Reaction at -78°C for 1h. After the reaction was completed, the temperature was naturally raised to room temperature, and saturated brine (100 mL) was added to quench the reaction, the layers were separated, the organic phase was washed once with saturated brine (100 mL), dried and concentrated, the residue was purified by silica gel column chromatography, and the target Components, the obtained intermediate was dissolved in THF (80mL), added dioxane hydrochloride solution (4M, 30mL), stirred at room temperature for 3h, the solvent was concentrated under reduced pressure to dryness, and the obtained solid was added with ethyl acetate/petroleum ether (100mL, v /v=1/1) beating at room temperature for 1h, filtering, and drying the obtained solid under reduced pressure to obtain (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine hydrochloride Salt, yield 78.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.80(s, 3H), 7.94(t, J=7.6Hz, 1H), 7.66(t, J=7.2Hz, 1H) , 7.44(t, J=7.6Hz, 1H), 7.25(t, J=54.0Hz, 1H), 4.65(q, J=6.0Hz, 1H), 1.55(d, J=6.8Hz, 3H); ESI - MS (m/z): 190.1 [M+H] + .
步骤e)(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step e) Preparation of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine
将6-溴-4-氯-2-甲基喹唑啉(200mg，0.733mmol)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙基-1-胺盐酸盐(165mg，0.733mmol)和DIPEA(283mg，2.198mmol)溶解在DMSO(5mL)中，将反应液加热至80℃搅拌1h，反应结束后，将反应液冷却至室温，加入水(50mL)萃灭，用乙酸乙酯萃取(30mL×3)，合并有机相，以饱和食盐水(50mL)洗涤，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＝1/1)，得(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺，产率95.1％； 1H NMR(400MHz，DMSO-d 6)δ8.72(s，1H)，8.55(d，J＝7.2Hz，1H)，7.84(d，J＝8.4Hz，1H)，7.68(t，J＝7.6Hz，1H)，7.53(d，J＝8.8Hz，1H)，7.50(t，J＝7.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.23(t，J＝54.4Hz，1H)，5.81-5.74(m，1H)，2.34(s，3H)，1.60(d，J＝6.8Hz，3H)；ESI-MS(m/z)：411.2[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (200mg, 0.733mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1- Amine hydrochloride (165 mg, 0.733 mmol) and DIPEA (283 mg, 2.198 mmol) were dissolved in DMSO (5 mL), and the reaction solution was heated to 80° C. and stirred for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, and water ( 50 mL), extracted with ethyl acetate (30 mL×3), combined the organic phases, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Eluent: petroleum ether/ethyl acetate=1/1), to obtain (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) -2-Methylquinazolin-4-amine, yield 95.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.72(s, 1H), 8.55(d, J=7.2Hz, 1H), 7.84(d, J=8.4Hz, 1H), 7.68(t, J=7.6Hz, 1H), 7.53(d, J=8.8Hz, 1H), 7.50(t, J=7.2Hz, 1H), 7.29( t, J=7.6Hz, 1H), 7.23(t, J=54.4Hz, 1H), 5.81-5.74(m, 1H), 2.34(s, 3H), 1.60(d, J=6.8Hz, 3H); ESI-MS (m/z): 411.2 [M+H] + .
步骤f)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step f): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(260mg，0.636mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(164mg，0.636mmol)、Cs 2CO 3(622mg，1.908mmol)、X-Phos(61mg，0.127mmol)、Pd 2(dba) 3(59mg，0.064mmol)和甲苯(7mL)加入到反应瓶中，氮气置换三次，升温至90℃搅拌反应16h。反应结束后，加水(15mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(10mL)洗涤，有机相减压浓缩干，残余物经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率39.9％； 1H NMR(400MHz，DMSO-d 6)δ8.18(d，J＝7.6Hz，1H)，7.70(t，J＝7.6Hz，1H)，7.65(s，1H)，7.49(t，J＝7.2Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.10-7.02(m，2H)，6.99(d，J＝8.8Hz，1H)，6.91(s，1H)，5.87-5.80(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.29(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] +。 (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine (260mg, 0.636mmol ), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (164mg, 0.636mmol), Cs 2 CO 3 (622mg, 1.908mmol) , X-Phos (61mg, 0.127mmol), Pd 2 (dba) 3 (59mg, 0.064mmol) and toluene (7mL) were added to the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred for 16h. After the reaction was finished, add water (15 mL) to quench the reaction, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated brine (10 mL), and concentrate the organic phases to dryness under reduced pressure. The residue was subjected to Prep-HPLC ( Method 3) purification to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl) ethyl) amino)-2-methylquin Azolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 39.9%; 1 H NMR (400MHz, DMSO-d 6 )δ8 .18(d, J=7.6Hz, 1H), 7.70(t, J=7.6Hz, 1H), 7.65(s, 1H), 7.49(t, J=7.2Hz, 1H), 7.35(d, J=7.6Hz, 1H) 9.2Hz, 1H), 7.29(t, J=7.6Hz, 1H), 7.24(t, J=54.4Hz, 1H), 7.10-7.02(m, 2H), 6.99(d, J=8.8Hz, 1H) , 6.91(s, 1H), 5.87-5.80(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.35(s, 3H), 2.99(s, 3H), 2.79(s, 3H ), 2.29 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 552.2 [M+H] + .
实施例21Example 21
(S)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(S)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000122
Figure PCTCN2022101219-appb-000122
步骤a)：(S)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step a): Preparation of (S)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine
将6-溴-4-氯-2-甲基喹唑啉(200mg，0.777mmol)、(S)-1-(3-(二氟甲基)-2-氟苯基)乙基-1-胺盐酸盐(175mg，0.777mmol)和DIPEA(301mg，2.331mmol)溶解在DMSO(5mL)中，将反应加热至80℃搅拌1h，反应结束后，将反应液冷却至室温，加水(50mL)淬灭，用乙酸乙酯萃取(30mL×3)，合并有机相，以饱和食盐水(50mL)洗涤，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＝1/1)，得(S)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺，产率90.8％； 1H NMR(400MHz，DMSO-d 6)δ8.72(s，1H)，8.56(d，J＝7.2Hz，1H)，7.85(d，J＝6.8Hz，1H)，7.68(t，J＝7.6Hz，1H)，7.53(d，J＝9.2Hz，1H)，7.49(d，J＝7.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.23(t，J＝54.4Hz，1H)，5.81-5.74(m，1H)，2.34(s，3H)，1.60(d，J＝6.8Hz，3H)；ESI-MS(m/z)：411.2[M+H] +。 6-bromo-4-chloro-2-methylquinazoline (200mg, 0.777mmol), (S)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1- Amine hydrochloride (175mg, 0.777mmol) and DIPEA (301mg, 2.331mmol) were dissolved in DMSO (5mL), and the reaction was heated to 80°C and stirred for 1h. After the reaction was completed, the reaction solution was cooled to room temperature, and water (50mL) was added. Quenched, extracted with ethyl acetate (30mL×3), combined the organic phases, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (washing Removal agent: petroleum ether/ethyl acetate=1/1), to get (S)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2 -Methylquinazolin-4-amine, yield 90.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.72(s, 1H), 8.56(d, J=7.2Hz, 1H), 7.85( d, J=6.8Hz, 1H), 7.68(t, J=7.6Hz, 1H), 7.53(d, J=9.2Hz, 1H), 7.49(d, J=7.2Hz, 1H), 7.29(t, J=7.6Hz, 1H), 7.23(t, J=54.4Hz, 1H), 5.81-5.74(m, 1H), 2.34(s, 3H), 1.60(d, J=6.8Hz, 3H); ESI- MS (m/z): 411.2 [M+H] + .
步骤b)：(S)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step b): (S)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline -6-yl) (methyl) amino) -2-methoxyphenyl) -N, the preparation of N-dimethylacetamide formate
将(S)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(260mg，0.636mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(164mg，0.636mmol)、Cs 2CO 3(622mg，1.908mmol)、X-Phos(121mg，0.254mmol)、Pd(dba) 2(76mg，0.127mmol)和甲苯(7mL)加入到反应瓶中，氮气置换三次，温度维持在90℃搅拌反应16h。反应结束后，加水(15mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(10mL)洗涤，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(S)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-一二甲基乙酰胺甲酸盐，产率55.1％； 1H NMR(400MHz，DMSO-d 6)δ12.75(s，1H)，8.20(d，J＝7.6Hz，1H)，8.14(s，1H)，7.70(t，J＝7.5Hz，1H)，7.65(s，1H)，7.49(t，J＝7.2Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.30(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.10-7.02(m，2H)，6.99(d，J＝8.8Hz，1H)，6.91(s，1H)，5.87-5.80(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.30(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H]+。 (S)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine (260mg, 0.636mmol ), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (164mg, 0.636mmol), Cs 2 CO 3 (622mg, 1.908mmol) , X-Phos (121mg, 0.254mmol), Pd(dba) 2 (76mg, 0.127mmol) and toluene (7mL) were added to the reaction flask, replaced with nitrogen three times, and the temperature was maintained at 90°C and the reaction was stirred for 16h. After the reaction was completed, add water (15 mL) to quench the reaction, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The material was purified by Prep-HPLC (method 2) to give (S)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino) -2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N - dimethylacetamide formate, yield 55.1%; NMR (400MHz, DMSO-d 6 ) δ12.75(s, 1H), 8.20(d, J=7.6Hz, 1H), 8.14(s, 1H), 7.70(t, J=7.5Hz, 1H), 7.65 (s, 1H), 7.49(t, J=7.2Hz, 1H), 7.35(d, J=9.2Hz, 1H), 7.30(t, J=7.6Hz, 1H), 7.24(t, J=54.4Hz , 1H), 7.10-7.02(m, 2H), 6.99(d, J=8.8Hz, 1H), 6.91(s, 1H), 5.87-5.80(m, 1H), 3.77(s, 3H), 3.57( s, 2H), 3.35(s, 3H), 2.99(s, 3H), 2.79(s, 3H), 2.30(s, 3H), 1.62(d, J=7.2Hz, 3H); ESI-MS(m /z): 552.2 [M+H]+.
实施例22Example 22
(R)-2-(4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-6-yl)amino)-2 -Methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000123
Figure PCTCN2022101219-appb-000123
步骤a)：(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)喹唑啉-4-胺的制备Step a): Preparation of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)quinazolin-4-amine
将6-溴-4-氯喹唑啉(300mg，1.240mmol)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(421mg，1.612mmol)和二甲亚砜(5mL)加入反应瓶中，搅拌溶解，加入DIPEA(481mg，3.720mmol)，将反应液升温至80℃反应2h，反应结束后，将反应液冷却到室温，加水(20mL)稀释，乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水洗涤(30mL×3)，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至5/1)，得(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)喹唑啉-4-胺，产率81.7％；ESI-MS(m/z)：396.0[M+H] +。 6-bromo-4-chloroquinazoline (300mg, 1.240mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine hydrochloride (421mg , 1.612mmol) and dimethyl sulfoxide (5mL) were added to the reaction flask, stirred and dissolved, and DIPEA (481mg, 3.720mmol) was added, and the reaction solution was heated to 80°C for 2h. After the reaction, the reaction solution was cooled to room temperature. Dilute with water (20mL), extract with ethyl acetate (20mL×2), combine the organic phases, wash with saturated brine (30mL×3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue through a silica gel column layer Analysis and purification (eluent: petroleum ether/ethyl acetate = 10/1 to 5/1), to obtain (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluoro Phenyl)ethyl)quinazolin-4-amine, yield 81.7%; ESI-MS (m/z): 396.0 [M+H] + .
步骤b)：(R)-2-(4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-6-yl) Preparation of amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)喹唑啉-4-胺(200mg，0.506mmol)，2-(4-氨基-2-甲氧基苯基)-N，N-一二甲基乙酰胺盐酸盐(136mg，0.557mmol)、X-Phos(48mg，0.0.102mmol)、Cs 2CO 3(363mg，1.113mmol)、甲苯(5mL)和Pd 2(dba) 3(46mg，0.0.051mmol)依次加入到反应瓶中，氮气置换三次，升温至100℃搅拌反应4h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，合并有机相，用饱和食盐水(30mL)洗涤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至1/1)，得(R)-2-(4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率67.9％； 1H NMR(400MHz，DMSO-d 6)δ8.50(s，1H)，8.38(d，J＝8.0Hz，1H)，8.23(s，1H)，8.16(s，1H)，7.66-7.59(m，2H)，7.48(d，J＝8.0Hz，2H)，7.37-7.10(m，2H)，6.99(d，J＝8.0Hz，1H)，6.92(s，1H)，6.66(d，J＝8.0Hz，1H)，5.82-5.75(m，1H)，3.76(s，3H)，3.51(s，2H)，3.02(s，3H)，2.84(s，3H)，1.57(d，J＝8.0Hz，3H)；ESI-MS(m/z)：524.2[M+H] +。 (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)quinazolin-4-amine (200mg, 0.506mmol), 2-( 4-amino-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride (136mg, 0.557mmol), X-Phos (48mg, 0.0.102mmol), Cs 2 CO 3 (363mg , 1.113mmol), toluene (5mL) and Pd 2 (dba) 3 (46mg, 0.0.051mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 100°C and stirred for 4h. After the reaction, add water (10 mL) to quench the reaction, extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (30 mL), concentrate the organic phases under reduced pressure, and purify the residue by silica gel column chromatography (Eluant: Petroleum ether/ethyl acetate=10/1 to 1/1), get (R)-2-(4-((4-((1-(3-(difluoromethyl)-2 -Fluorophenyl)ethyl)amino)quinazolin-6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 67.9%; 1 H NMR (400MHz , DMSO-d 6 ) δ8.50(s, 1H), 8.38(d, J=8.0Hz, 1H), 8.23(s, 1H), 8.16(s, 1H), 7.66-7.59(m, 2H), 7.48(d, J=8.0Hz, 2H), 7.37-7.10(m, 2H), 6.99(d, J=8.0Hz, 1H), 6.92(s, 1H), 6.66(d, J=8.0Hz, 1H ), 5.82-5.75(m, 1H), 3.76(s, 3H), 3.51(s, 2H), 3.02(s, 3H), 2.84(s, 3H), 1.57(d, J=8.0Hz, 3H) ; ESI-MS (m/z): 524.2 [M+H] + .
实施例23Example 23
(R)-2-(4-((2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐的制备(R)-2-(4-((2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-6-yl) Preparation of amino)-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride
Figure PCTCN2022101219-appb-000124
Figure PCTCN2022101219-appb-000124
步骤a)：2-((叔丁氧羰基)氨基)-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)氨基)苯甲酸甲酯的制备Step a): 2-((tert-butoxycarbonyl)amino)-5-((4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl)amino)benzoic acid Preparation of methyl esters
将5-溴-2-((叔丁氧羰基)氨基)苯甲酸甲酯(3.0g，8.980mmol)，2-(4-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺(1.81g，8.163mmol)、X-Phos(780mg，1.632mmol)、Cs 2CO 3(5.3g，16.326mmol)、甲苯(30mL)和Pd(dba) 2(470mg，0.816mmol)依次加入到反应瓶中，氮气置换三次，升温至110℃搅拌反应3h。反应结束后，冷却至室温用硅藻土减压过滤，滤饼用乙酸乙酯(30mL)洗一次，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2-((叔丁氧羰基)氨基)-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)氨基)苯甲酸甲酯，产率48.6％； 1H NMR(400MHz，CDCl 3)δ10.02(s，1H)，8.34(d，J＝8.0Hz，1H)，7.77(s，1H)，7.30-7.26(m，2H)，7.07(d，J＝8.0Hz，1H)，6.53(s，1H)，3.89(s，3H)，3.74(s，3H)，3.62(s，2H)，3.00(s，6H)，1.52(s，9H)；ESI-MS(m/z)：458.2[M+H] +。 Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)benzoate (3.0g, 8.980mmol), 2-(4-amino-2-methoxyphenyl)-N,N-dimethyl Acetamide (1.81g, 8.163mmol), X-Phos (780mg, 1.632mmol), Cs 2 CO 3 (5.3g, 16.326mmol), toluene (30mL) and Pd(dba) 2 (470mg, 0.816mmol) followed by Add it into the reaction flask, replace it with nitrogen three times, raise the temperature to 110°C and stir for 3h. After the reaction, cool to room temperature and filter with diatomaceous earth under reduced pressure, wash the filter cake once with ethyl acetate (30mL), concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate Ester=10/1 to 1/1), to get 2-((tert-butoxycarbonyl)amino)-5-((4-(2-(dimethylamino)-2-oxyethyl)-3-methoxy phenyl)amino)methylbenzoate, yield 48.6%; 1 H NMR (400MHz, CDCl 3 ) δ10.02(s, 1H), 8.34(d, J=8.0Hz, 1H), 7.77(s, 1H), 7.30-7.26(m, 2H), 7.07(d, J=8.0Hz, 1H), 6.53(s, 1H), 3.89(s, 3H), 3.74(s, 3H), 3.62(s, 2H ), 3.00 (s, 6H), 1.52 (s, 9H); ESI-MS (m/z): 458.2 [M+H] + .
步骤b)：2-氨基-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)氨基)苯甲酸甲酯的制备Step b): Preparation of methyl 2-amino-5-((4-(2-(dimethylamino)-2-oxyethyl)-3-methoxyphenyl)amino)benzoate
将2-((叔丁氧羰基)氨基)-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)氨基)苯甲酸甲酯(1.8g，3.939mmol)溶于乙酸乙酯(5mL)中，加入氯化氢乙酸乙酯溶液(4M，15mL)，室温反应过夜，浓缩除去有机溶剂，残余物加饱和碳酸氢钠溶液调pH＝8-9，用乙酸乙酯(50mL×2)萃取，合并有机相，无水硫酸钠干燥，过滤，将滤液减压浓缩，得2-氨基-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)氨基)苯甲酸甲酯，产率78.6％；ESI-MS(m/z)：358.2[M+H] +。 Methyl 2-((tert-butoxycarbonyl)amino)-5-((4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl)amino)benzoate ( 1.8g, 3.939mmol) was dissolved in ethyl acetate (5mL), added hydrogen chloride ethyl acetate solution (4M, 15mL), reacted at room temperature overnight, concentrated to remove the organic solvent, and the residue was added with saturated sodium bicarbonate solution to adjust the pH = 8- 9. Extract with ethyl acetate (50mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-amino-5-((4-(2-(dimethylamino) -2-Oxoethyl)-3-methoxyphenyl)amino)benzoic acid methyl ester, yield 78.6%; ESI-MS (m/z): 358.2 [M+H] + .
步骤c)：2-(4-((2，4-二氧基-1，2，3，4-四氢喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step c): 2-(4-((2,4-Dioxy-1,2,3,4-tetrahydroquinazolin-6-yl)amino)-2-methoxyphenyl)-N , Preparation of N-dimethylacetamide
将2-氨基-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)氨基)苯甲酸甲酯(1.8g，3.939mmol)和尿素(5g，83.333mmol)混合加入反应瓶中，将反应置于160℃的油浴中加热搅拌3h，反应结束后冷却至室温，加入水(30mL)搅拌1h进行打浆处理，过滤，滤饼用水(30mL)洗一次，收集滤饼，减压干燥得2-(4-((2，4-二氧基-1，2，3，4-四氢喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率43.3％； 1H NMR(400MHz，DMSO-d 6)δ11.17(s，1H)，10.96(s，1H)，8.21(s，1H)，7.56(s，1H)，7.39(d，J＝12.0Hz，1H)，7.09(d，J＝8.0Hz，1H)，6.93(d，J＝8.0Hz，1H)，6.61-6.57(m，2H)，3.71(s，3H)，3.49(s，2H)，3.00(s，3H)，2.83(s，3H)；ESI-MS(m/z)：369.1[M+H] +。 2-Amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl) amino)methyl benzoate (1.8g, 3.939mmol) and urea (5g, 83.333mmol) were mixed and added to the reaction flask, the reaction was placed in an oil bath at 160°C and heated and stirred for 3h, cooled to room temperature after the reaction, added water (30mL) and stirred for 1h for beating treatment, filtered, and the filter cake was water ( 30 mL) was washed once, the filter cake was collected, and dried under reduced pressure to obtain 2-(4-((2,4-dioxy-1,2,3,4-tetrahydroquinazolin-6-yl)amino)-2 -Methoxyphenyl)-N,N-dimethylacetamide, yield 43.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.17(s, 1H), 10.96(s, 1H), 8.21(s, 1H), 7.56(s, 1H), 7.39(d, J=12.0Hz, 1H), 7.09(d, J=8.0Hz, 1H), 6.93(d, J=8.0Hz, 1H), 6.61-6.57(m, 2H), 3.71(s, 3H), 3.49(s, 2H), 3.00(s, 3H), 2.83(s, 3H); ESI-MS(m/z): 369.1[M+ H] + .
步骤d)：2-(4-((2，4-二氯喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step d): Preparation of 2-(4-((2,4-dichloroquinazolin-6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将2-(4-((2，4-二氧基-1，2，3，4-四氢喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(100mg，0.273mmol)加入到甲苯(5mL)中，室温下加入POCl 3(208mg，1.365mmol)和DIPEA(211mg，1.638mmol)，将反应置于90℃油浴中加热搅拌20min，反应结束后冷却至室温，将反应液倒入冰水中，用饱和碳酸氢钠水溶液调至pH＝8-9，以乙酸乙酯(20mL)萃取，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(4-((2，4-二氯喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，无需纯化直接用于下一步反应。 2-(4-((2,4-Dioxy-1,2,3,4-tetrahydroquinazolin-6-yl)amino)-2-methoxyphenyl)-N,N- Dimethylacetamide (100mg, 0.273mmol) was added to toluene (5mL), POCl 3 (208mg, 1.365mmol) and DIPEA (211mg, 1.638mmol) were added at room temperature, and the reaction was heated and stirred in an oil bath at 90°C After 20 minutes, cool to room temperature after the reaction, pour the reaction solution into ice water, adjust the pH to 8-9 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (20 mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure to give 2-(4-((2,4-dichloroquinazolin-6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, which can be directly used without purification react in the next step.
步骤e)：(R)-2-(4-((2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step e): (R)-2-(4-((2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazoline- Preparation of 6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide hydrochloride
将2-(4-((2，4-二氯喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(63mg，0.156mmol)加入到DMSO(5mL)中，室温下加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(42mg，0.172mmol)和DIPEA(60mg，0.468mmol)，将反应升温至80℃搅拌反应30min，反应结束后，冷却至室温，将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯(20mL×2)萃取，合并有机相，饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得残余物经Prep-HPLC(方法1)纯化，得(R)-2-(4-((2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐，产率13.2％； 1H NMR(400MHz，DMSO-d 6)δ14.71(s，1H)，8.87(d，J＝8.0Hz，1H)，8.57(s，1H)，8.16(s，1H)，7.67-6.89(m， 8H)，6.66(s，1H)，5.76-5.69(m，1H)，3.74(s，3H)，3.51(s，2H)，3.02(s，3H)，2.84(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：558.0[M+H] +。 2-(4-((2,4-Dichloroquinazolin-6-yl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide (63mg, 0.156mmol) was added to In DMSO (5 mL), add (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (42 mg, 0.172 mmol) and DIPEA (60 mg , 0.468mmol), the reaction was warmed up to 80°C and stirred for 30min. After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20mL×2), and the organic phases were combined. Washed with saturated brine (30mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by Prep-HPLC (method 1) to obtain (R)-2-(4-((2- Chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-6-yl)amino)-2-methoxyphenyl)-N , N-dimethylacetamide hydrochloride, yield 13.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ14.71 (s, 1H), 8.87 (d, J=8.0Hz, 1H), 8.57 (s, 1H), 8.16(s, 1H), 7.67-6.89(m, 8H), 6.66(s, 1H), 5.76-5.69(m, 1H), 3.74(s, 3H), 3.51(s, 2H ), 3.02 (s, 3H), 2.84 (s, 3H), 1.58 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 558.0 [M+H] + .
实施例24Example 24
(R)-2-(4-((2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐的制备(R)-2-(4-((2-chloro-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-6-yl) (Methyl)amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide hydrochloride
Figure PCTCN2022101219-appb-000125
Figure PCTCN2022101219-appb-000125
步骤a)：2-((叔丁氧羰基)氨基)-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)(甲基)氨基)苯甲酸甲酯的制备Step a): 2-((tert-butoxycarbonyl)amino)-5-((4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl)(methyl) Preparation of amino) methyl benzoate
将5-溴-2-((叔丁氧羰基)氨基)苯甲酸甲酯(570mg，1.727mmol)，2-(4-氨基-2-甲氧基苯基)-N，N-二甲基乙酰胺(490mg，1.900mmol)、Pd 2(dba) 3(158mg，0.173mmol)、Cs 2CO 3(1.1g，3.545mmol)、甲苯(5mL)和X-Phos(165mg，0.346mmol)依次加入到反应瓶中，氮气置换三次，升温至110℃搅拌反应3h。反应结束后，冷却至室温用硅藻土减压过滤，滤饼用乙酸乙酯(20mL)洗一次，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2-((叔丁氧羰基)氨基)-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)(甲基)氨基)苯甲酸甲酯，产率52.9％；ESI-MS(m/z)：472.2[M+H] +。 Methyl 5-bromo-2-((tert-butoxycarbonyl)amino)benzoate (570mg, 1.727mmol), 2-(4-amino-2-methoxyphenyl)-N,N-dimethyl Acetamide (490 mg, 1.900 mmol), Pd 2 (dba) 3 (158 mg, 0.173 mmol), Cs 2 CO 3 (1.1 g, 3.545 mmol), toluene (5 mL) and X-Phos (165 mg, 0.346 mmol) were added sequentially Into the reaction flask, replaced with nitrogen three times, heated to 110°C and stirred for 3h. After the reaction, cool to room temperature and filter with diatomaceous earth under reduced pressure, wash the filter cake once with ethyl acetate (20mL), concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate Ester=10/1 to 1/1), to get 2-((tert-butoxycarbonyl)amino)-5-((4-(2-(dimethylamino)-2-oxyethyl)-3-methoxy phenyl)(methyl)amino)methylbenzoate, yield 52.9%; ESI-MS (m/z): 472.2 [M+H] + .
步骤b)：2-氨基-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)(甲基)氨基)苯甲酸甲酯的制备Step b): Preparation of methyl 2-amino-5-((4-(2-(dimethylamino)-2-oxyethyl)-3-methoxyphenyl)(methyl)amino)benzoate
将2-((叔丁氧羰基)氨基)-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)(甲基)氨基)苯甲酸甲酯(430mg，0.913mmol)溶于乙酸乙酯(5mL)中，加入含氯化氢乙酸乙酯溶液(4M，8mL)，室温反应过夜，减压蒸除溶剂，得2-氨基-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)(甲基)氨基)苯甲酸甲酯，产率99.9％；ESI-MS(m/z)：358.2[M+H] +。 2-((tert-butoxycarbonyl)amino)-5-((4-(2-(dimethylamino)-2-oxyethyl)-3-methoxyphenyl)(methyl)amino)benzene Methyl formate (430mg, 0.913mmol) was dissolved in ethyl acetate (5mL), and ethyl acetate solution containing hydrogen chloride (4M, 8mL) was added, reacted overnight at room temperature, and the solvent was distilled off under reduced pressure to obtain 2-amino-5-( (4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl)(methyl)amino)methyl benzoate, yield 99.9%; ESI-MS (m/z ): 358.2[M+H] + .
步骤c)：2-(4-((2，4-一二氧基-1，2，3，4-四氢喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-一二甲基乙酰胺的制备Step c): 2-(4-((2,4-Dioxy-1,2,3,4-tetrahydroquinazolin-6-yl)(methyl)amino)-2-methoxy Phenyl)-N, the preparation of N-dimethylacetamide
将2-氨基-5-((4-(2-(二甲氨基)-2-氧乙基)-3-甲氧基苯基)(甲基)氨基)苯甲酸甲酯(340mg，0.913mmol)和尿素(2.0g，33.333mmol)混合加入反应瓶中，将反应升温至160℃反应3h。反应结束后冷却至室温，加入水(30mL)搅拌1h进行打浆处理，过滤，滤饼用水(20mL)洗一次，收集滤饼，减压干燥得2-(4-((2，4-二氧基-1，2，3，4-四氢喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率80.8％；ESI-MS(m/z)：383.2[M+H] +。 Methyl 2-amino-5-((4-(2-(dimethylamino)-2-oxoethyl)-3-methoxyphenyl)(methyl)amino)benzoate (340mg, 0.913mmol ) and urea (2.0 g, 33.333 mmol) were mixed and added into the reaction flask, and the reaction temperature was raised to 160° C. for 3 h. After the reaction, cool to room temperature, add water (30mL) and stir for 1h for beating treatment, filter, wash the filter cake once with water (20mL), collect the filter cake, and dry under reduced pressure to obtain 2-(4-((2,4-dioxo Base-1,2,3,4-tetrahydroquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 80.8% ; ESI-MS (m/z): 383.2 [M+H] + .
步骤d)：2-(4-((2，4-一二氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step d): 2-(4-((2,4-dichloroquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide preparation of
将2-(4-((2，4-一二氧基-1，2，3，4-四氢喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(250mg，0.654mmol)加入到甲苯(5mL)中，室温下加入POCl 3(150mg，0.981mmol)和DIPEA(140mg，1.046mmol)，升温至90℃反应30min。反应结束后，冷却至室温，将反应液倒入冰水中，用饱和碳酸氢钠调至pH＝8-9，用乙酸乙酯(20mL)萃取，无水硫酸钠干燥，过滤，将滤液减压浓缩得2-(4-((2，4-一二氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，无需纯化直接用于下一步反应。 2-(4-((2,4-Dioxyl-1,2,3,4-tetrahydroquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl) -N,N-Dimethylacetamide (250mg, 0.654mmol) was added to toluene (5mL), POCl 3 (150mg, 0.981mmol) and DIPEA (140mg, 1.046mmol) were added at room temperature, and the temperature was raised to 90°C for 30min . After the reaction, cool to room temperature, pour the reaction solution into ice water, adjust the pH to 8-9 with saturated sodium bicarbonate, extract with ethyl acetate (20 mL), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate to give 2-(4-((2,4-dichloroquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide without Purification was used directly in the next reaction.
步骤e)：(R)-2-(4-(2-氯-4-(1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐的制备Step e): (R)-2-(4-(2-Chloro-4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazoline-6- Base) (methyl) amino) -2-methoxyphenyl) -N, the preparation of N-dimethylacetamide hydrochloride
将2-(4-((2，4-二氯喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(35mg，0.084mmol)加入到DMSO(3mL)中，室温下加入(R)-1-(3-(二氟甲基)-2-氟苯基)乙烷-1-胺盐酸盐(21mg，0.092mmol)和DIPEA(24mg，0.185mmol)，升温至80℃反应30min，反应结束后冷却至室温，将反应液倒入饱和氯化铵水溶液中，用乙酸乙酯(20mL×2)萃取，合并有机相，饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经Prep-HPLC(方法1)纯化，得(R)-2-(4-((2-氯-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺盐酸盐，产率10.6％； 1H NMR(400MHz，DMSO-d 6)δ14.72(s，1H)，8.89(d，J＝8.0Hz，1H)，7.90(s，1H)，7.73(s，1H)，7.56-7.04(m，6H)，6.76(s，1H)， 6.66(d，J＝8.0Hz，1H)，5.79-5.73(m，1H)，3.71(s，3H)，3.55(s，2H)，3.46(s，3H)，3.02(s，3H)，2.84(s，3H)，1.64(d，J＝8.0Hz，3H)；ESI-MS(m/z)：572.0[M+H] +。 2-(4-((2,4-dichloroquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide (35 mg, 0.084 mmol) was added to DMSO (3 mL), and (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride (21 mg, 0.092 mmol) was added at room temperature and DIPEA (24 mg, 0.185 mmol), heated to 80 ° C for 30 min, cooled to room temperature after the reaction, poured the reaction solution into saturated ammonium chloride aqueous solution, extracted with ethyl acetate (20 mL × 2), combined the organic phases, Wash with saturated brine (20mL×2), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by Prep-HPLC (method 1) to obtain (R)-2-(4-((2-chloro- 4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-6-yl)amino)-2-methoxyphenyl)-N,N - Dimethylacetamide hydrochloride, yield 10.6%; 1 H NMR (400MHz, DMSO-d 6 ) δ14.72(s, 1H), 8.89(d, J=8.0Hz, 1H), 7.90(s , 1H), 7.73(s, 1H), 7.56-7.04(m, 6H), 6.76(s, 1H), 6.66(d, J=8.0Hz, 1H), 5.79-5.73(m, 1H), 3.71( s, 3H), 3.55(s, 2H), 3.46(s, 3H), 3.02(s, 3H), 2.84(s, 3H), 1.64(d, J=8.0Hz, 3H); ESI-MS(m /z): 572.0[M+H] + .
实施例25Example 25
(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline Preparation of -6-yl)amino)phenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000126
Figure PCTCN2022101219-appb-000126
步骤a)：(R，E)-2-甲基-N-(1-(3-(三氟甲基)苯基)亚乙基)丙烷-2-亚磺酰胺的制备Step a): Preparation of (R,E)-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide
将间三氟甲基苯乙酮(5.00g，26.574mmol)、(R)-(+)-叔丁基亚磺酰胺(3.86g，31.848mmol)、钛酸四乙酯(13.99g，39.864mmol)和THF(100mL)加入反应瓶中，升温至80℃反应3h。反应结束后，冷却至室温，加冰水(100mL)和乙酸乙酯(100mL)混匀，抽滤，滤液分液，水相用乙酸乙酯(30mL)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)，得(R，E)-2-甲基-N-(1-(3-(三氟甲基)苯基)亚乙基)丙烷-2-亚磺酰胺，产率63.0％； 1H NMR(400MHz，DMSO-d 6)δ8.19(d，J＝7.6Hz，1H)，8.16(s，1H)，7.96-7.90(m，1H)，7.79-7.71(m，1H)，2.78(s，3H)，1.23(s，9H)；ESI-MS(m/z)：292.0[M+H] +。 m-Trifluoromethylacetophenone (5.00g, 26.574mmol), (R)-(+)-tert-butylsulfinamide (3.86g, 31.848mmol), tetraethyl titanate (13.99g, 39.864mmol ) and THF (100 mL) were added to the reaction flask, and the temperature was raised to 80° C. for 3 h. After the reaction, cool to room temperature, add ice water (100mL) and ethyl acetate (100mL) and mix well, filter with suction, separate the filtrate, extract the aqueous phase with ethyl acetate (30mL), combine the organic phases, and wash with saturated brine ( 50 mL), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain (R, E)-2 -Methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide, yield 63.0%; 1 H NMR (400MHz, DMSO-d 6 )δ8 .19(d, J=7.6Hz, 1H), 8.16(s, 1H), 7.96-7.90(m, 1H), 7.79-7.71(m, 1H), 2.78(s, 3H), 1.23(s, 9H) ); ESI-MS (m/z): 292.0 [M+H] + .
步骤b)：(R)-2-甲基-N-((R)-1-(3-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺的制备Step b): Preparation of (R)-2-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide
将(R，E)-2-甲基-N-(1-(3-(三氟甲基)苯基)亚乙基)丙烷-2-亚磺酰胺(4.9g，16.747mmol)溶于THF(50mL)和水(1mL)中，降温至-78℃，加入硼氢化钠(950mg，25.112mmol)，室温反应1h。反应结束后，加冰水(50mL)稀释，乙酸乙酯萃取(100mL)，有机相以饱和食盐水(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＝1/3)，得(R)-2-甲基-N-((R)-1-(3-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺，产率54.8％； 1H NMR(400MHz，DMSO-d 6)δ7.79(s，1H)，7.71(d，J＝7.2Hz，1H)，7.62-7.54(m，2H)，5.85(d，J＝8.0Hz，1H)，4.49(m，1H)，1.42(d，J＝6.8Hz，3H)，1.12(s，9H)；ESI-MS(m/z)：294.1[M+H] +。 (R,E)-2-Methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (4.9 g, 16.747 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to -78°C, added sodium borohydride (950 mg, 25.112 mmol), and reacted at room temperature for 1 h. After the reaction, dilute with ice water (50mL), extract with ethyl acetate (100mL), wash the organic phase with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Analysis and purification (eluent: ethyl acetate/petroleum ether = 1/3) to obtain (R)-2-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl) Ethyl)propane-2-sulfinamide, yield 54.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ7.79(s, 1H), 7.71(d, J=7.2Hz, 1H), 7.62- 7.54(m, 2H), 5.85(d, J=8.0Hz, 1H), 4.49(m, 1H), 1.42(d, J=6.8Hz, 3H), 1.12(s, 9H); ESI-MS(m /z): 294.1[M+H] + .
步骤c)：(R)-1-(3-(三氟甲基)苯基)乙基-1-胺盐酸盐的制备Step c): Preparation of (R)-1-(3-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride
将(R)-2-甲基-N-((R)-1-(3-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺(2.7g，9.177mmol)溶于二氧六环(5mL)中，加入盐酸二氧六环溶液(4M，5mL)，室温反应1h。减压浓缩，石油醚/乙酸乙酯混合溶剂打浆(30mL，v/v＝5∶1)，过滤，减压真空干燥，得(R)-1-(3-(三氟甲基)苯基)乙基-1-胺盐酸盐，产率92.0％；ESI-MS(m/z)：190.0[M+H] +。 Dissolve (R)-2-methyl-N-((R)-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (2.7g, 9.177mmol) in Dioxane hydrochloride solution (4M, 5 mL) was added to dioxane (5 mL), and reacted at room temperature for 1 h. Concentrate under reduced pressure, make a slurry with petroleum ether/ethyl acetate mixed solvent (30mL, v/v=5:1), filter, and dry under reduced pressure to obtain (R)-1-(3-(trifluoromethyl)phenyl ) Ethyl-1-amine hydrochloride, yield 92.0%; ESI-MS (m/z): 190.0 [M+H] + .
步骤d)：(R)-6-溴-2-甲基-N-(1-(3-(三氟甲基)苯基)乙基)喹唑啉-4-胺的制备Step d): Preparation of (R)-6-bromo-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine
将6-溴-4-氯-2-甲基喹唑啉(200mg，0.777mmol)、(R)-1-(3-(三氟甲基)苯基)乙-1-胺盐酸盐(165mg，0.731mmol)、DIPEA(283mg，2.190mmol)、DMSO(4mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌3h。反应结束后，冷却至室温，加饱和食盐水(20mL)，以乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水(10mL×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：乙酸乙酯/石油醚＝1/3)，得(R)-6-溴-2-甲基-N-(1-(3-(三氟甲基)苯基)乙基)喹唑啉-4-胺，产率89.7％； 1H NMR(400MHz，DMSO-d 6)δ8.67(s，1H)，8.53(d，J＝7.6Hz，1H)，7.87-7.80(m，2H)，7.76(d，J＝7.2Hz，1H)，7.63-7.50(m，3H)，5.63(m，1H)，2.38(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：410.0[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (200mg, 0.777mmol), (R)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride ( 165mg, 0.731mmol), DIPEA (283mg, 2.190mmol), and DMSO (4mL) were sequentially added into the reaction flask, heated to 80°C under nitrogen protection and stirred for 3h. After the reaction, cool to room temperature, add saturated brine (20 mL), extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (10 mL×2), dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to obtain (R)-6-bromo-2-methyl-N-(1-( 3-(Trifluoromethyl)phenyl)ethyl)quinazolin-4-amine, yield 89.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.67(s, 1H), 8.53(d , J=7.6Hz, 1H), 7.87-7.80(m, 2H), 7.76(d, J=7.2Hz, 1H), 7.63-7.50(m, 3H), 5.63(m, 1H), 2.38(s, 3H), 1.61 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 410.0 [M+H] + .
步骤e)：(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-一二甲基乙酰胺甲酸盐的制备Step e): (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino ) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide formate
将(R)-6-溴-2-甲基-N-(1-(3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(269mg，0.656mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(170mg，0.657mmol)、X-Phos(126mg，0.264mmol)、Cs 2CO 3(645mg，1.980mmol)、Pd 2(dba) 3(119mg，0.130mmol)和甲苯(20mL)依次加入到反应瓶中，以氮气置换三 次，升温至105℃搅拌反应1h。反应结束后，冷却至室温，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∶20)，再经Prep-HPLC(方法2)纯化，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐，产率39.2％； 1H NMR(400MHz，DMSO-d 6)δ11.73(s，1H)，8.17(s，1H)，8.14(s，1H)，7.83(s，1H)，7.78(d，J＝6.4Hz，1H)，7.62-7.54(m，3H)，7.35(d，J＝9.2Hz，1H)，7.10-6.97(m，3H)，6.91(s，1H)，5.73-5.64(m，1H)，3.77(s，3H)，3.57(s，2H)，3.34(s，3H)，2.99(s，3H)，2.78(s，3H)，2.33(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (269mg, 0.656mmol), 2- (2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (170mg, 0.657mmol), X-Phos (126mg, 0.264mmol), Cs 2 CO 3 (645mg, 1.980mmol), Pd 2 (dba) 3 (119mg, 0.130mmol) and toluene (20mL) were sequentially added to the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 1h. After the reaction was completed, it was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1:20), and then purified by Prep-HPLC (method 2) to obtain (R )-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 -yl)amino)phenyl)-N,N-dimethylacetamide formate, yield 39.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.73(s, 1H), 8.17(s , 1H), 8.14(s, 1H), 7.83(s, 1H), 7.78(d, J=6.4Hz, 1H), 7.62-7.54(m, 3H), 7.35(d, J=9.2Hz, 1H) , 7.10-6.97(m, 3H), 6.91(s, 1H), 5.73-5.64(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.34(s, 3H), 2.99(s , 3H), 2.78 (s, 3H), 2.33 (s, 3H), 1.64 (d, J=7.2Hz, 3H); ESI-MS (m/z): 552.2 [M+H] + .
实施例26Example 26
(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(2-Hydroxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 Preparation of -yl)amino)phenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000127
Figure PCTCN2022101219-appb-000127
将(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(100mg，0.181mmol)和二氯甲烷(4mL)加入反应瓶中，搅拌溶解，氮气置换3次，冷却至0℃加入三溴化硼(200mg，0.789mmol)，室温反应1h。反应结束后，加入饱和碳酸氢钠水溶液(20mL)和乙酸乙酯(20mL)，分液，有机相以饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐，产率21.2％； 1H NMR(400MHz，DMSO-d 6)δ12.79(s，1H)，9.53(s，1H)，8.16(s，1H)，8.13(s，1H)，7.83(s，1H)，7.78(d，J＝6.0Hz，1H)，7.62-7.55(m，2H)，7.52(s，1H)，7.32(d，J＝9.2Hz，1H)，7.02(d，J＝9.2Hz，1H)，6.94-6.88(m，2H)，6.82(d，J＝8.4Hz，1H)，5.74-5.63(m，1H)，3.56(s，2H)，3.31(s，3H)，3.01(s，3H)，2.80(s，3H)，2.33(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：538.2[M+H] +。 (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazole Phenyl-6-yl)amino)phenyl)-N,N-dimethylacetamide (100mg, 0.181mmol) and dichloromethane (4mL) were added into the reaction flask, stirred and dissolved, replaced with nitrogen 3 times, and cooled to 0 Add boron tribromide (200 mg, 0.789 mmol) at ℃ and react at room temperature for 1 h. After the reaction, add saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL), separate the layers, wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purification by Prep-HPLC (Method 2) gave (R)-2-(2-hydroxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide formate, yield 21.2%; 1 H NMR (400MHz, DMSO-d 6 )δ12. 79(s, 1H), 9.53(s, 1H), 8.16(s, 1H), 8.13(s, 1H), 7.83(s, 1H), 7.78(d, J=6.0Hz, 1H), 7.62-7.55 (m, 2H), 7.52(s, 1H), 7.32(d, J=9.2Hz, 1H), 7.02(d, J=9.2Hz, 1H), 6.94-6.88(m, 2H), 6.82(d, J=8.4Hz, 1H), 5.74-5.63(m, 1H), 3.56(s, 2H), 3.31(s, 3H), 3.01(s, 3H), 2.80(s, 3H), 2.33(s, 3H) ), 1.64 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 538.2 [M+H] + .
实施例27Example 27
(S)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备(S)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline Preparation of -6-yl)amino)phenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000128
Figure PCTCN2022101219-appb-000128
步骤a)：(R)-2-甲基-N-((S)-1-(3-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺的制备Step a): Preparation of (R)-2-methyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide
将(R，E)-2-甲基-N-(1-(3-(三氟甲基)苯基)亚乙基)丙烷-2-亚磺酰胺(4.879g，16.747mmol)溶于THF(50mL)和水(1mL)中，冷却至至-78℃，加入硼氢化钠(0.950g，25.112mmol)，室温反应1h。反应结束后，加冰水(50mL)淬灭，以乙酸乙酯萃取(100mL)，有机相以饱和食盐水(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＝1/1)，得(R)-2-甲基-N-((S)-1-(3-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺，产率17.7％； 1H NMR(400MHz，DMSO-d 6)δ7.72(s，1H)，7.67(d，J＝7.2Hz，1H)，7.65-7.61(m，2H)，5.52(d，J＝5.2Hz，1H)，4.60-4.49(m，1H)，1.48(d，J＝6.8Hz，3H )，1.11(s，9H)；ESI-MS(m/z)：294.1[M+H] + (R,E)-2-Methyl-N-(1-(3-(trifluoromethyl)phenyl)ethylidene)propane-2-sulfinamide (4.879 g, 16.747 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to -78°C, added sodium borohydride (0.950 g, 25.112 mmol), and reacted at room temperature for 1 h. After the reaction was completed, it was quenched with ice water (50 mL), extracted with ethyl acetate (100 mL), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to obtain (R)-2-methyl-N-((S)-1-(3-(trifluoromethyl)benzene yl)ethyl)propane-2-sulfinamide, yield 17.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ7.72(s, 1H), 7.67(d, J=7.2Hz, 1H), 7.65-7.61(m, 2H), 5.52(d, J=5.2Hz, 1H), 4.60-4.49(m, 1H), 1.48(d, J=6.8Hz, 3H ) , 1.11(s, 9H); ESI -MS(m/z): 294.1[M+H] +
步骤b)：(S)-1-(3-(三氟甲基)苯基)乙基-1-胺盐酸盐的制备Step b): Preparation of (S)-1-(3-(trifluoromethyl)phenyl)ethyl-1-amine hydrochloride
将(R)-2-甲基-N-((S)-1-(3-(三氟甲基)苯基)乙基)丙烷-2-亚磺酰胺(0.87g，2.966mmol)溶于1，4-二氧六环(2mL)中，加入盐酸二氧六环溶液(4M，2mL)，室温反应1h。减压浓缩，石油醚/乙酸乙酯混合溶剂打浆(10mL，v/v＝5；1)，过滤，所得固体经减压真空干燥得(S)-1-(3-(三氟甲基)苯基)乙基-1-胺盐酸盐，产率80.8％；ESI-MS(m/z)：190.0[M+H] +。 Dissolve (R)-2-methyl-N-((S)-1-(3-(trifluoromethyl)phenyl)ethyl)propane-2-sulfinamide (0.87g, 2.966mmol) in To 1,4-dioxane (2 mL), add dioxane hydrochloride solution (4M, 2 mL) and react at room temperature for 1 h. Concentrate under reduced pressure, make a slurry with petroleum ether/ethyl acetate mixed solvent (10 mL, v/v=5; 1), filter, and dry the obtained solid under reduced pressure to obtain (S)-1-(3-(trifluoromethyl) Phenyl)ethyl-1-amine hydrochloride, yield 80.8%; ESI-MS (m/z): 190.0 [M+H] + .
步骤c)：(S)-6-溴-2-甲基-N-(1-(3-(三氟甲基)苯基)乙基)喹唑啉-4-胺的制备Step c): Preparation of (S)-6-bromo-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine
将6-溴-4-氯-2-甲基喹唑啉(189mg，0.734mmol)、(S)-1-(3-(三氟甲基)苯基)乙-1-胺盐酸盐(165mg，0.731mmol)、DIPEA(283mg，2.190mmol)、DMSO(4mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌反应2h。反应结束后，冷却至室温，加饱和食盐水(20mL)，以乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水(10mL×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：乙酸乙酯/石油醚＝1/3)，得(S)-6-溴-2-甲基-N-(1-(3-(三氟甲基)苯基)乙基)喹唑啉-4-胺，产率84.7％； 1H NMR(400MHz，DMSO-d 6)δ8.67(s，1H)，8.53(d，J＝7.6Hz，1H)，7.86-7.80(m，2H)，7.76(d，J＝7.2Hz，1H)，7.61-7.52(m，3H)，5.63(m，1H)2.38(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：410.0[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (189 mg, 0.734 mmol), (S)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride ( 165mg, 0.731mmol), DIPEA (283mg, 2.190mmol), and DMSO (4mL) were sequentially added into the reaction flask, heated to 80°C under nitrogen protection, and stirred for 2h. After the reaction, cool to room temperature, add saturated brine (20 mL), extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (10 mL×2), dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to obtain (S)-6-bromo-2-methyl-N-(1-( 3-(Trifluoromethyl)phenyl)ethyl)quinazolin-4-amine, yield 84.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.67(s, 1H), 8.53(d , J=7.6Hz, 1H), 7.86-7.80(m, 2H), 7.76(d, J=7.2Hz, 1H), 7.61-7.52(m, 3H), 5.63(m, 1H), 2.38(s, 3H ), 1.61 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 410.0 [M+H] + .
步骤d)：(S)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (S)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino ) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide formate
将(S)-6-溴-2-甲基-N-(1-(3-(三氟甲基)苯基)乙基)喹唑啉-4-胺(250mg，0.609mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(158mg，0.609mmol)、X-Phos(116mg，0.244mmol)、Cs 2CO 3(595g，1.827mmol)、Pd 2(dba) 3(111mg，0.122mmol)和甲苯(20mL)依次加入到反应瓶中，以氮气置换三次，升温至105℃搅拌反应1h。反应结束后，冷却至室温，减压浓缩，加水(20mL)和乙酸乙酯(20mL)稀释，抽滤，滤液分液，有机相饱以和食盐水洗涤(10mL×2)，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(S)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐，产率33.5％； 1H NMR(400MHz，DMSO-d 6)δ12.78(s，1H)，8.19-8.13(m，2H)，7.83(s，1H)，7.78(d，J＝6.0Hz，1H)，7.62-7.56(m，3H)，7.35(d，J＝9.2Hz，1H)，7.10-7.02(m，2H)，7.01-7.10(m，1H)，6.91(s，1H)，5.74-5.64(m，1H)，3.77(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.78(s，3H)，2.33(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] +。 (S)-6-bromo-2-methyl-N-(1-(3-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (250mg, 0.609mmol), 2- (2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (158mg, 0.609mmol), X-Phos (116mg, 0.244mmol), Cs 2 CO 3 (595g, 1.827mmol), Pd 2 (dba) 3 (111mg, 0.122mmol) and toluene (20mL) were sequentially added to the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 1h. After the reaction, cool to room temperature, concentrate under reduced pressure, dilute with water (20mL) and ethyl acetate (20mL), filter with suction, separate the filtrate, wash the organic phase with saturated brine (10mL×2), and dry over anhydrous sodium sulfate , filtered, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 2) to obtain (S)-2-(2-methoxy-5-(methyl(2-methyl-4-((1 -(3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide formate, yield 33.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.78(s, 1H), 8.19-8.13(m, 2H), 7.83(s, 1H), 7.78(d, J=6.0Hz, 1H), 7.62- 7.56(m, 3H), 7.35(d, J=9.2Hz, 1H), 7.10-7.02(m, 2H), 7.01-7.10(m, 1H), 6.91(s, 1H), 5.74-5.64(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.33(s, 3H), 2.99(s, 3H), 2.78(s, 3H), 2.33(s, 3H), 1.64(d, J =7.2 Hz, 3H); ESI-MS (m/z): 552.2 [M+H] + .
实施例28Example 28
(S)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备(S)-2-(2-Hydroxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazoline-6 Preparation of -yl)amino)phenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000129
Figure PCTCN2022101219-appb-000129
将(S)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺(150mg，0.272mmol)溶于二氯甲烷(4mL)中，氮气置换3次，0℃加入三溴化硼(300mg，1.197mmol)，升温至室温反应1h。反应结束后，加入饱和碳酸氢钠水溶液(20mL)和乙酸乙酯(20mL)淬灭反应，分液，有机相以饱和食盐水洗涤(10mL)，无水硫酸钠干燥，过滤，减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(S)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐，产率4.4％； 1H NMR(400MHz，DMSO-d 6)δ12.78(s，1H)，9.57(s，1H)，8.13(s，1H)，7.84(s，1H)，7.78(d，J＝6.8Hz，1H)，7.63-7.51(m，4H)，7.35(d，J＝8.5Hz，1H)，7.06(d，J＝8.4Hz，1H)，6.95-6.88(m，2H)，6.84(d，J＝8.4Hz，1H)，5.73(s，1H)，3.57(s，2H)，3.31(s，3H)，3.01(s，3H)，2.80(s，3H)，2.37(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：538.2[M+H] +。 (S)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)quinazole Lin-6-yl)amino)phenyl)-N,N-dimethylacetamide (150mg, 0.272mmol) was dissolved in dichloromethane (4mL), replaced with nitrogen for 3 times, and added boron tribromide ( 300mg, 1.197mmol), warmed up to room temperature and reacted for 1h. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium bicarbonate (20 mL) and ethyl acetate (20 mL), and the layers were separated. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by Prep-HPLC (Method 2) to give (S)-2-(2-hydroxy-5-(methyl(2-methyl-4-((1-(3-(trifluoromethyl) phenyl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide formate, yield 4.4%; 1 H NMR (400MHz, DMSO-d 6 )δ12.78(s, 1H), 9.57(s, 1H), 8.13(s, 1H), 7.84(s, 1H), 7.78(d, J=6.8Hz, 1H), 7.63-7.51(m, 4H ), 7.35(d, J=8.5Hz, 1H), 7.06(d, J=8.4Hz, 1H), 6.95-6.88(m, 2H), 6.84(d, J=8.4Hz, 1H), 5.73(s , 1H), 3.57(s, 2H), 3.31(s, 3H), 3.01(s, 3H), 2.80(s, 3H), 2.37(s, 3H), 1.66(d, J=7.2Hz, 3H) ; ESI-MS (m/z): 538.2 [M+H] + .
实施例29Example 29
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基))-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-methoxyphenyl)) -N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000130
Figure PCTCN2022101219-appb-000130
步骤a)：1-溴-3-(二氟甲基)-2-甲基苯的制备Step a): Preparation of 1-bromo-3-(difluoromethyl)-2-methylbenzene
将3-溴-2-甲基苯甲醛(5.00g，25.119mmol)溶于二氯甲烷(50mL)中，0℃滴加二乙胺基三氟化硫(DAST，8.10g，50.251mmol)，加毕，室温反应24h。反应结束后，将反应液倾入饱和碳酸氢钠水溶液(50mL)中，分取有机相，以饱和食盐水(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：石油醚/乙酸乙酯＝100/1)，得1-溴-3-(二氟甲基)-2-甲基苯，产率86.6％； 1H NMR(400MHz，DMSO-d 6)δ7.79(d，J＝8.0Hz，1H)，7.57(d，J＝8.0Hz，1H)，7.38-7.15(m，2H)，2.44(s，3H)。 3-Bromo-2-methylbenzaldehyde (5.00g, 25.119mmol) was dissolved in dichloromethane (50mL), diethylaminosulfur trifluoride (DAST, 8.10g, 50.251mmol) was added dropwise at 0°C, After addition, react at room temperature for 24h. After the reaction, the reaction solution was poured into saturated aqueous sodium bicarbonate solution (50mL), the organic phase was separated, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by column chromatography (eluent: petroleum ether/ethyl acetate=100/1) to obtain 1-bromo-3-(difluoromethyl)-2-methylbenzene with a yield of 86.6%; 1 H NMR ( 400 MHz, DMSO-d 6 ) δ 7.79 (d, J=8.0 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.38-7.15 (m, 2H), 2.44 (s, 3H).
步骤b)：1-(3-(二氟甲基)-2-甲基苯基)乙基-1-酮的制备Step b): Preparation of 1-(3-(difluoromethyl)-2-methylphenyl)ethyl-1-one
将1-溴-3-(二氟甲基)-2-甲基苯(4.809g，21.756mmol)、三丁基(1-乙氧基乙烯)锡(9.429g，26.107mmol)、Pd(PPh 3)Cl 2(0.764g，1.088mmol)、三乙胺(5.493g，54.284mmol)和二氧六环(50mL)加入反应瓶中，100℃封管反应16h。反应结束后，冷却至室温，加饱和氟化钾水溶液(50mL)和乙酸乙酯(50mL)，搅拌0.5h，抽滤，滤液分液，无水硫酸钠干燥，过滤，浓缩至体积约(30mL)，加入盐酸乙酸乙酯(4M，20mL)，搅拌0.5h，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＝1/100)，得1-(3-(二氟甲基)-2-甲基苯基)乙基-1-酮，产率90.4％；ESI-MS(m/z)：185.0[M+H] +。 1-Bromo-3-(difluoromethyl)-2-methylbenzene (4.809g, 21.756mmol), tributyl(1-ethoxyethylene)tin (9.429g, 26.107mmol), Pd(PPh 3 ) Cl 2 (0.764g, 1.088mmol), triethylamine (5.493g, 54.284mmol) and dioxane (50mL) were added into the reaction flask, and the tube was sealed at 100°C for 16h. After the reaction, cool to room temperature, add saturated potassium fluoride aqueous solution (50mL) and ethyl acetate (50mL), stir for 0.5h, filter with suction, separate the filtrate, dry over anhydrous sodium sulfate, filter, and concentrate to a volume of about (30mL ), added ethyl acetate hydrochloride (4M, 20mL), stirred for 0.5h, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/100) to obtain 1-( 3-(Difluoromethyl)-2-methylphenyl)ethyl-1-one, yield 90.4%; ESI-MS (m/z): 185.0 [M+H] + .
步骤c)：(R，E)-N-(1-(3-(二氟甲基)-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step c): Preparation of (R,E)-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide
将1-(3-(二氟甲基)-2-甲基苯基)乙基-1-酮(3.624g，19.675mmol)、(R)-(+)-叔丁基亚磺酰胺(2.862g，23.610mmol)、钛酸四乙酯(10.357g，29.512mmol)和THF(70mL)加入反应瓶中，80℃反应16h，反应结束后，冷却至室温，加水(100mL)和乙酸乙酯(100mL)混匀，抽滤，分取滤液有机相，水相用乙酸乙酯萃(30mL)，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)，得(R，E)-N-(1-(3-(二氟甲基)-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺，产率88.4％；ESI-MS(m/z)：288.1[M+H] +。 1-(3-(Difluoromethyl)-2-methylphenyl)ethyl-1-one (3.624g, 19.675mmol), (R)-(+)-tert-butylsulfinamide (2.862 g, 23.610mmol), tetraethyl titanate (10.357g, 29.512mmol) and THF (70mL) were added to the reaction flask, reacted at 80°C for 16h, after the reaction was completed, cooled to room temperature, added water (100mL) and ethyl acetate ( 100 mL), mixed with suction, and the organic phase of the filtrate was separated, the aqueous phase was extracted with ethyl acetate (30 mL), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain (R,E)-N-(1-(3-(difluoromethyl)-2-methanol (phenyl)ethylidene)-2-methylpropane-2-sulfinamide, yield 88.4%; ESI-MS (m/z): 288.1 [M+H] + .
步骤d)：(R)-N-((R)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step d): (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide preparation
将(R，E)-N-(1-(3-(二氟甲基)-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(5.00g，17.399mmol)溶于THF(50mL)和水(1mL)中，冷却至-78℃，加入硼氢化钠(0.987g，26.099mmol)，室温反应1h，加冰水(50mL)淬灭，乙酸乙酯萃取(100mL)，有机相以饱和食盐水(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＝1/3)，得(R)-N-((R)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺，产率37.8％； 1H NMR(400MHz，DMSO-d 6)δ7.65(d，J＝7.6Hz，1H)，7.45-7.38(m，1H)，7.38-7.32(m，1H)，7.32-7.05(m，1H)，5.71(d，J＝6.4Hz，1H)，4.69(m，1H)，2.36(s，3H)，1.37(d，J＝6.8Hz，3H)，1.08(s，9H)；ESI-MS(m/z)：290.1[M+H] + (R, E)-N-(1-(3-(Difluoromethyl)-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (5.00g, 17.399 mmol) was dissolved in THF (50mL) and water (1mL), cooled to -78°C, added sodium borohydride (0.987g, 26.099mmol), reacted at room temperature for 1h, quenched with ice water (50mL), extracted with ethyl acetate (100mL), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, 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/ 3), to get (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide, Yield 37.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ7.65 (d, J=7.6Hz, 1H), 7.45-7.38 (m, 1H), 7.38-7.32 (m, 1H), 7.32- 7.05(m, 1H), 5.71(d, J=6.4Hz, 1H), 4.69(m, 1H), 2.36(s, 3H), 1.37(d, J=6.8Hz, 3H), 1.08(s, 9H ); ESI-MS (m/z): 290.1[M+H] +
步骤e)：(R)-1-(3-(二氟甲基)-2-甲基苯基)乙基-1-胺盐酸盐的制备Step e): Preparation of (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl-1-amine hydrochloride
将(R)-N-((R)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(1.906g，6.586mmol)溶于二氧六环(5mL)中，加入盐酸二氧六环溶液(4M，5mL)，室温反应0.5h，加石油醚(20mL)，过滤， 收集固体，得(R)-1-(3-(二氟甲基)-2-甲基苯基)乙基-1-胺盐酸盐，收率98.1％；ESI-MS(m/z)：186.1[M+H] +。 (R)-N-((R)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (1.906g, 6.586mmol) was dissolved in dioxane (5mL), added dioxane hydrochloride solution (4M, 5mL), reacted at room temperature for 0.5h, added petroleum ether (20mL), filtered, and collected the solid to obtain (R)-1 -(3-(Difluoromethyl)-2-methylphenyl)ethyl-1-amine hydrochloride, yield 98.1%; ESI-MS (m/z): 186.1[M+H] + .
步骤f)：(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step f): (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine preparation
将6-溴-4-氯-2-甲基喹唑啉(400mg，1.553mmol)、(R)-1-(3-(二氟甲基)-2-甲基苯基)乙-1-胺盐酸盐(324mg，1.462mmol)、DIPEA(567mg，4.386mmol)、DMSO(8mL)依次加入反应瓶中，氮气保护下80℃搅拌反应1h。反应结束后，冷却至室温，加饱和食盐水(20mL)，乙酸乙酯萃(20mL×2)，合并有机相，饱和食盐水(10mL×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：乙酸乙酯/石油醚＝1/3)，得(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺，收率82.5％；ESI-MS(m/z)：406.0[M+H] +。 6-bromo-4-chloro-2-methylquinazoline (400mg, 1.553mmol), (R)-1-(3-(difluoromethyl)-2-methylphenyl)ethane-1- Amine hydrochloride (324mg, 1.462mmol), DIPEA (567mg, 4.386mmol), and DMSO (8mL) were sequentially added into the reaction flask, and stirred at 80°C for 1h under nitrogen protection. After the reaction, cool to room temperature, add saturated brine (20mL), extract with ethyl acetate (20mL×2), combine the organic phases, wash with saturated brine (10mL×2), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to obtain (R)-6-bromo-N-(1-(3-(difluoromethyl )-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine, yield 82.5%; ESI-MS (m/z): 406.0[M+H] + .
步骤g)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基))-N，N-二甲基乙酰胺甲酸盐的制备Step g): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazole Preparation of phen-6-yl)(methyl)amino)-2-methoxyphenyl))-N,N-dimethylacetamide formate
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺(300mg，0.738mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(191mg，0.738mmol)、X-Phos(141mg，0.295mmol)、Cs 2CO 3(721g，2.214mmol)、Pd 2(dba) 3(135mg，0.147mmol)和甲苯(10mL)依次加入到反应瓶中，氮气置换三次，105℃搅拌24h。反应结束后，冷却至室温，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＝1/20)，再经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基))-N，N-二甲基乙酰胺甲酸盐，收率3.2％； 1H NMR(400MHz，DMSO-d 6)δ12.78(s，1H)，8.22(s，1H)，8.14(s，1H)，7.70(d，J＝7.6Hz，1H)，7.65(s，1H)，7.40-7.22(m，4H)，7.09-7.02(m，2H)，7.00-6.97(m，1H)，6.90(s，1H)，5.84-5.74(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.57(s，3H)，2.31(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：548.2[M+H] +。 (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine (300mg, 0.738 mmol), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (191mg, 0.738mmol), X-Phos (141mg, 0.295mmol) , Cs 2 CO 3 (721g, 2.214mmol), Pd 2 (dba) 3 (135mg, 0.147mmol) and toluene (10mL) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at 105°C for 24h. After the reaction, it was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and then purified by Prep-HPLC (method 2) to obtain (R )-2-(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl) (Methyl)amino)-2-methoxyphenyl))-N,N-dimethylacetamide formate, yield 3.2%; 1 H NMR (400MHz, DMSO-d 6 )δ12.78( s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.70 (d, J = 7.6Hz, 1H), 7.65 (s, 1H), 7.40-7.22 (m, 4H), 7.09-7.02 (m, 2H), 7.00-6.97(m, 1H), 6.90(s, 1H), 5.84-5.74(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.35(s, 3H ), 2.99(s, 3H), 2.79(s, 3H), 2.57(s, 3H), 2.31(s, 3H), 1.56(d, J=7.2Hz, 3H); ESI-MS(m/z) : 548.2[M+H] + .
实施例30Example 30
(S)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基))-N，N-二甲基乙酰胺甲酸盐的制备(S)-2-(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-methoxyphenyl)) -N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000131
Figure PCTCN2022101219-appb-000131
步骤a)：(R)-N-((S)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step a): (R)-N-((S)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide preparation
将(R，E)-N-(1-(3-(二氟甲基)-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(5.00g，17.399mmol)溶于THF(50mL)和水(1mL)中，冷却至-78℃，加入硼氢化钠(0.987g，26.099mmol)，室温反应1h。加冰水(50mL)淬灭，以乙酸乙酯(100mL)萃取，有机相以饱和食盐水(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＝1/1)，得(R)-N-((S)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺，产率40.0％； 1H NMR(400MHz，DMSO-d 6)δ7.59(d，J＝7.6Hz，1H)，7.44-7.37(m，1H)，7.37-7.32(m，1H)，7.30-7.05(m，1H)，5.37(d，J＝5.2Hz，1H)，4.72(m，1H)，2.36(s，3H)，1.45(d，J＝6.8Hz，3H)，1.10(s，9H)；ESI-MS(m/z)：290.1[M+H] +。 (R, E)-N-(1-(3-(Difluoromethyl)-2-methylphenyl)ethylene)-2-methylpropane-2-sulfinamide (5.00g, 17.399 mmol) was dissolved in THF (50 mL) and water (1 mL), cooled to -78°C, added sodium borohydride (0.987 g, 26.099 mmol), and reacted at room temperature for 1 h. Quenched with ice water (50 mL), extracted with ethyl acetate (100 mL), washed the organic phase with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (Eluent: ethyl acetate/petroleum ether=1/1), to obtain (R)-N-((S)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl )-2-methylpropane-2-sulfinamide, yield 40.0%; 1 H NMR (400MHz, DMSO-d 6 )δ7.59 (d, J=7.6Hz, 1H), 7.44-7.37 (m, 1H), 7.37-7.32(m, 1H), 7.30-7.05(m, 1H), 5.37(d, J=5.2Hz, 1H), 4.72(m, 1H), 2.36(s, 3H), 1.45(d , J = 6.8 Hz, 3H), 1.10 (s, 9H); ESI-MS (m/z): 290.1 [M+H] + .
步骤b)：(S)-1-(3-(二氟甲基)-2-甲基苯基)乙基-1-胺盐酸盐的制备Step b): Preparation of (S)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl-1-amine hydrochloride
将(R)-N-((S)-1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(2.014g，6.959mmol)溶于二氧六环(5mL)中，加入盐酸二氧六环溶液(4M，5mL)，室温反应0.5h。加石油醚(20mL)打浆，过滤，干燥，得(S)-1-(3-(二氟甲基)-2-甲基苯基)乙-1-胺盐酸盐，产率87.2％；ESI-MS(m/z)：186.1[M+H] +。 (R)-N-((S)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (2.014g, 6.959mmol) was dissolved in dioxane (5mL), added dioxane hydrochloride solution (4M, 5mL), and reacted at room temperature for 0.5h. Add petroleum ether (20 mL) for slurry, filter, and dry to obtain (S)-1-(3-(difluoromethyl)-2-methylphenyl)ethan-1-amine hydrochloride with a yield of 87.2%; ESI-MS (m/z): 186.1 [M+H] + .
步骤c)：(S)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step c): (S)-6-bromo-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine preparation
将6-溴-4-氯-2-甲基喹唑啉(400mg，1.553mmol)、(S)-1-(3-(二氟甲基)-2-甲基苯基)乙基-1-胺盐酸盐(324mg，1.462mmol)、DIPEA(567mg，4.386mmol)、DMSO(8mL)依次加入反应瓶中，氮气保护下80℃搅拌1h。反应结束后，冷却至室温，加饱和食盐水(20mL)，以乙酸乙酯萃取(20mL×2)，合并 有机相，饱和食盐水(10mL×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：乙酸乙酯/石油醚＝1/3)，得(S)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺，产率74.5％；ESI-MS(m/z)：406.0[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (400mg, 1.553mmol), (S)-1-(3-(difluoromethyl)-2-methylphenyl)ethyl-1 - Amine hydrochloride (324mg, 1.462mmol), DIPEA (567mg, 4.386mmol), DMSO (8mL) were sequentially added to the reaction flask, stirred at 80°C for 1h under nitrogen protection. After the reaction, cool to room temperature, add saturated brine (20mL), extract with ethyl acetate (20mL×2), combine the organic phases, wash with saturated brine (10mL×2), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/3) to obtain (S)-6-bromo-N-(1-(3-(difluoromethane yl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine, yield 74.5%; ESI-MS (m/z): 406.0[M+H] + .
步骤d)：(S)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基))-N，N-一二甲基乙酰胺甲酸盐的制备Step d): (S)-2-(5-((4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazole Preparation of hydrin-6-yl)(methyl)amino)-2-methoxyphenyl))-N,N-dimethylacetamide formate
将(S)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺(200mg，0.492mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(127mg，0.492mmol)、X-Phos(94mg，0.197mmol)、Cs 2CO 3(481g，1.476mmol)、Pd 2(dba) 3(90mg，0.098mmol)和甲苯(20mL)依次加入到反应瓶中，氮气置换三次，105℃搅拌反应24h。反应结束后，冷却至室温，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＝1/20)，再经Prep-HPLC(方法2)纯化，得(S)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基))-N，N-二甲基乙酰胺甲酸盐，产率4.9％； 1H NMR(400MHz，DMSO-d 6)δ12.78(s，1H)，8.25(s，1H)，8.13(s，1H)，7.70(d，J＝7.6Hz，1H)，7.65(s，1H)，7.40-7.22(m，4H)，7.10-7.03(m，2H)，7.01-6.96(m，1H)，6.91(s，1H)，5.84-5.73(m，1H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.79(s，3H)，2.57(s，3H)，2.32(s，3H)，1.56(d，J＝6.8Hz，3H)；ESI-MS(m/z)：548.2[M+H] +。 (S)-6-bromo-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine (200mg, 0.492 mmol), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (127mg, 0.492mmol), X-Phos (94mg, 0.197mmol) , Cs 2 CO 3 (481g, 1.476mmol), Pd 2 (dba) 3 (90mg, 0.098mmol) and toluene (20mL) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at 105°C for 24h. After the reaction, it was cooled to room temperature and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and then purified by Prep-HPLC (method 2) to obtain (S )-2-(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl) (Methyl)amino)-2-methoxyphenyl))-N,N-dimethylacetamide formate, yield 4.9%; 1 H NMR (400MHz, DMSO-d 6 )δ12.78( s, 1H), 8.25(s, 1H), 8.13(s, 1H), 7.70(d, J=7.6Hz, 1H), 7.65(s, 1H), 7.40-7.22(m, 4H), 7.10-7.03 (m, 2H), 7.01-6.96(m, 1H), 6.91(s, 1H), 5.84-5.73(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.35(s, 3H ), 2.99(s, 3H), 2.79(s, 3H), 2.57(s, 3H), 2.32(s, 3H), 1.56(d, J=6.8Hz, 3H); ESI-MS(m/z) : 548.2[M+H] + .
实施例31Example 31
(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000132
Figure PCTCN2022101219-appb-000132
步骤a)：1-(1，1-二氟乙基)-3-碘苯的制备Step a): Preparation of 1-(1,1-difluoroethyl)-3-iodobenzene
将3-碘苯乙酮(2.46g，9.998mmol)和THF(30mL)加入反应瓶中，搅拌溶解，氮气置换3次，冷却至0℃，滴加二乙胺基三氟化硫(8.1g，49.990mmol)，滴加完毕后滴入甲醇(0.5mL)，自然升至室温，搅拌1h。升温至80℃反应过夜。反应结束后，缓慢滴加饱和碳酸氢钠水溶液调至pH＝7-8淬灭反应，用二氯甲烷(150mL×3)萃取，合并有机相，用饱和食盐水(50mL×2)洗涤，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＝100/1)，得1-(1，1-二氟乙基)-3-碘苯，产率85.0％。Add 3-iodoacetophenone (2.46g, 9.998mmol) and THF (30mL) into the reaction flask, stir to dissolve, replace nitrogen three times, cool to 0°C, add diethylaminosulfur trifluoride (8.1g , 49.990mmol), after the dropwise addition, methanol (0.5mL) was added dropwise, allowed to rise to room temperature naturally, and stirred for 1h. Raise the temperature to 80°C and react overnight. After the reaction was completed, slowly add saturated aqueous sodium bicarbonate solution to adjust to pH = 7-8 to quench the reaction, extract with dichloromethane (150mL × 3), combine the organic phases, wash with saturated brine (50mL × 2), no Dry over sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1) to obtain 1-(1,1-difluoroethyl) -3-iodobenzene, yield 85.0%.
步骤b)：1-(3-(1，1-二氟乙基)苯基-1-酮的制备Step b): Preparation of 1-(3-(1,1-difluoroethyl)phenyl-1-one
将1-(1，1-二氟乙基)-3-碘苯(2.3g，8.498mmol)、三丁基(1-乙氧基乙烯基)锡烷(3.99g，11.047mmol)、Pd(PPh 3)Cl 2(298mg，0.425mmol)、三乙胺(1.716g，16.996mmol)加入1，4-二氧六环(30mL)中，反应液持续鼓入氮气5min，在水热釜中升温至100℃反应过夜。反应结束后，将反应液冷却至室温，加入2N的稀盐酸调至pH＝2-3，室温搅拌1h，减压浓缩除去溶剂，将饱和碳酸氢钠水溶液加入混合物中，用乙酸乙酯萃取(50mL×3)，合并有机相，以饱和食盐水(150mL)洗涤，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＝50/1)，得1-(3-(1，1-二氟乙基)苯基-1-酮，产率72.0％。 1-(1,1-Difluoroethyl)-3-iodobenzene (2.3g, 8.498mmol), tributyl(1-ethoxyvinyl)stannane (3.99g, 11.047mmol), Pd( PPh 3 )Cl 2 (298mg, 0.425mmol), triethylamine (1.716g, 16.996mmol) were added to 1,4-dioxane (30mL), the reaction solution was continuously blown with nitrogen for 5min, and the temperature was raised in a hydrothermal kettle React overnight at 100°C. After the reaction, the reaction solution was cooled to room temperature, 2N dilute hydrochloric acid was added to adjust the pH to 2-3, stirred at room temperature for 1 h, concentrated under reduced pressure to remove the solvent, saturated aqueous sodium bicarbonate solution was added to the mixture, extracted with ethyl acetate ( 50mL×3), the organic phases were combined, washed with saturated brine (150mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =50/1) to obtain 1-(3-(1,1-difluoroethyl)phenyl-1-one with a yield of 72.0%.
步骤c)：(R)-N-(1-(3-(1，1-二氟乙基)苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step c): Preparation of (R)-N-(1-(3-(1,1-difluoroethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide
将1-(3-(1，1-二氟乙基)苯基-1-酮(0.7g，3.800mmol)和(R)-(+)-叔丁基亚磺酰胺(0.69g，5.700mmol)和THF(15mL)加入反应瓶中，搅拌溶解，室温下加入钛酸四乙酯(2.665g，7.600mmol，65％)，加毕升温至80℃搅拌3h。反应结束后，冷却至室温，加水(20mL)，析出大量固体，过滤，滤饼用乙酸乙酯(50mL)洗涤，滤液用乙酸乙酯萃取(50mL×3)，合并有机相，以饱和食盐水(20mL)洗涤，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)，得((R)-N-(1-(3-(1，1-二氟乙基)苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺，产率97.0％；ESI-MS(m/z)：288.3[M+H] +。 1-(3-(1,1-difluoroethyl)phenyl-1-one (0.7g, 3.800mmol) and (R)-(+)-tert-butylsulfinamide (0.69g, 5.700mmol ) and THF (15mL) were added to the reaction flask, stirred and dissolved, and tetraethyl titanate (2.665g, 7.600mmol, 65%) was added at room temperature, and the temperature was raised to 80°C and stirred for 3h after the addition. After the reaction, cooled to room temperature, Add water (20mL), precipitate a large amount of solid, filter, wash the filter cake with ethyl acetate (50mL), extract the filtrate with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (20mL), anhydrous sulfuric acid Na-dried, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain ((R)-N-(1-(3-( 1,1-difluoroethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide, yield 97.0%; ESI-MS (m/z): 288.3[M+H] + .
步骤d)：(R)-N-((R)-1-(3-(1，1-二氟乙基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step d): Preparation of (R)-N-((R)-1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide
将((R)-N-(1-(3-(1，1-二氟乙基)苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(1.059g，3.686mmol)和THF/水混合液(15mL，v/v＝50/1)加入反应瓶中，搅拌溶解，在-78℃搅拌条件下，缓慢加入NaBH 4(0.278g，7.372mmol)，加毕，维持-78℃反应1h。反应结束后，自然升温至室温，加入饱和食盐水(100mL)淬灭反应，分液，有机相再用饱和食盐水(100mL)洗涤，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)，得(R)-N-((R)-1-(3-(1，1-二氟乙基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺，产率70.3％；ESI-MS(m/z)：290.3[M+H] +。 ((R)-N-(1-(3-(1,1-difluoroethyl)phenyl)ethylene)-2-methylpropane-2-sulfinamide (1.059g, 3.686mmol) Add THF/water mixture (15mL, v/v=50/1) into the reaction flask, stir to dissolve, and slowly add NaBH 4 (0.278g, 7.372mmol) under the stirring condition of -78°C, after the addition is complete, keep- React at 78°C for 1 h. After the reaction, naturally warm up to room temperature, add saturated brine (100mL) to quench the reaction, separate the layers, wash the organic phase with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R)-N-((R)-1-(3-(1,1- Difluoroethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide, yield 70.3%; ESI-MS (m/z): 290.3[M+H] + .
步骤e)：(R)-1-(3-(1，1-二氟乙基)苯基)乙-1-胺盐酸盐的制备Step e): Preparation of (R)-1-(3-(1,1-difluoroethyl)phenyl)ethan-1-amine hydrochloride
将(R)-N-((R)-1-(3-(1，1-二氟乙基)苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(0.75g，2.592mmol)和THF(2mL)加入反应瓶中，搅拌溶解，在0℃搅拌条件下，缓慢加入氯化氢1，4二氧六环溶液(3mL，4M)，加毕，自然升温至室温反应1h。反应完毕，减压浓缩，残余物用少量乙酸乙酯溶解，搅拌下分批加入大量石油醚析出大量白色沉淀，过滤，石油醚洗涤，得(R)-1-(3-(1，1-二氟乙基)苯基)乙-1-胺盐酸盐，产率95.7％；ESI-MS(m/z)：186.2[M+H] +。 (R)-N-((R)-1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylpropane-2-sulfinamide (0.75g, 2.592 mmol) and THF (2mL) were added to the reaction flask, stirred and dissolved, and hydrogen chloride 1,4-dioxane solution (3mL, 4M) was slowly added under the condition of stirring at 0°C. After completion of the reaction, concentrate under reduced pressure, dissolve the residue with a small amount of ethyl acetate, add a large amount of petroleum ether in batches under stirring to precipitate a large amount of white precipitate, filter, and wash with petroleum ether to obtain (R)-1-(3-(1,1- Difluoroethyl)phenyl)ethan-1-amine hydrochloride, yield 95.7%; ESI-MS (m/z): 186.2 [M+H] + .
步骤f)：(R)-6-溴-N-(1-(3-(1，1-二氟乙基)苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step f): Preparation of (R)-6-bromo-N-(1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylquinazolin-4-amine
将6-溴-4-氯-2-甲基喹唑啉(200mg，0.733mmol)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙基-1-胺盐酸盐(162mg，0.733mmol)和DIPEA(283mg，2.198mmol)溶解在DMSO(5mL)中，将反应液加热至80℃搅拌1h，反应结束后，将反应液冷却至室温，加入水(50mL)淬灭，用乙酸乙酯萃取(30mL×3)，合并有机相，以饱和食盐水(50mL)洗涤，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)，得(R)-6-溴-N-(1-(3-(1，1-二氟乙基)苯基)乙基)-2-甲基喹唑啉-4-胺，产率95.0％；ESI-MS(m/z)：406.2[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (200mg, 0.733mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1- Amine hydrochloride (162 mg, 0.733 mmol) and DIPEA (283 mg, 2.198 mmol) were dissolved in DMSO (5 mL), and the reaction solution was heated to 80° C. and stirred for 1 h. After the reaction was completed, the reaction solution was cooled to room temperature, and water ( 50 mL), extracted with ethyl acetate (30 mL×3), combined organic phases, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Eluent: Petroleum ether/ethyl acetate=5/1) to obtain (R)-6-bromo-N-(1-(3-(1,1-difluoroethyl)phenyl)ethyl) -2-Methylquinazolin-4-amine, yield 95.0%; ESI-MS (m/z): 406.2 [M+H] + .
步骤g)：((R)-2-(5-((4-((1-(3-(1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-一二甲基乙酰胺的制备Step g): ((R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquinazole Preparation of hydrin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-6-溴-N-(1-(3-(1，1-二氟乙基)苯基)乙基)-2-甲基喹唑啉-4-胺(120mg，0.300mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(77mg，0.300mmol)、Cs 2CO 3(217mg，0.600mmol)、X-Phos(28mg，0.060mmol)、Pd(dba) 2(17mg，0.003mmol)和甲苯(7mL)加入到反应瓶中，氮气置换三次，升温至90℃搅拌反应16h。反应结束后，加水(25mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压过滤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，所得粗品经Prep-HPLC(方法3)纯化，得((R)-2-(5-((4-((1-(3-(1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率49.8％； 1H NMR(400MHz，CD3OD)δ7.63(d，J＝8.0Hz，1H)，7.55(d，J＝4.0Hz，1H)，7.41-7.38(m，2H)，7.26-7.21(m，2H)，7.12-7.09(m，1H)，7.02-6.97(m，3H)，5.89-5.84(m，1H)，3.85(s，3H)，3.69(s，2H)，3.38(s，3H)，3.11(s，3H)，2.94(s，3H)，2.60(s，3H)，2.41(t，J＝12.0Hz，，3H)，1.63(d，J＝8.0Hz，3H)；ESI-MS(m/z)：548.6[M+H] +。 (R)-6-Bromo-N-(1-(3-(1,1-difluoroethyl)phenyl)ethyl)-2-methylquinazolin-4-amine (120mg, 0.300mmol ), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (77mg, 0.300mmol), Cs 2 CO 3 (217mg, 0.600mmol) , X-Phos (28mg, 0.060mmol), Pd(dba) 2 (17mg, 0.003mmol) and toluene (7mL) were added into the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred for 16h. After the reaction, add water (25mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter under reduced pressure, and depressurize the organic phase Concentrate, and the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1), and the obtained crude product is purified by Prep-HPLC (method 3) to obtain ((R)-2-(5-( (4-((1-(3-(1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2- Methoxyphenyl)-N,N-dimethylacetamide, yield 49.8%; 1 H NMR (400MHz, CD3OD) δ7.63 (d, J=8.0Hz, 1H), 7.55 (d, J= 4.0Hz, 1H), 7.41-7.38(m, 2H), 7.26-7.21(m, 2H), 7.12-7.09(m, 1H), 7.02-6.97(m, 3H), 5.89-5.84(m, 1H) , 3.85(s, 3H), 3.69(s, 2H), 3.38(s, 3H), 3.11(s, 3H), 2.94(s, 3H), 2.60(s, 3H), 2.41(t, J=12.0 Hz,, 3H), 1.63 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 548.6 [M+H] + .
实施例32Example 32
(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000133
Figure PCTCN2022101219-appb-000133
步骤a)：(R)-6-溴-N-(1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step a): (R)-6-Bromo-N-(1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylquinazoline-4 - Preparation of amines
将6-溴-4-氯-2-甲基喹唑啉(172mg，0.628mmol)、(R)-1-(3-(1，1-二氟乙基)-2-氟苯基)乙烷-1-胺盐酸盐(150mg，0.628mmol)、DIPEA(244mg，1.884mmol)、DMSO(5mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌反应2h。反应结束后，加饱和氯化铵溶液(30mL)淬灭，以乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，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)，得(R)-6-溴-N-(1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺，收率93.9％；ESI-MS(m/z)：424.0[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (172 mg, 0.628 mmol), (R)-1-(3-(1,1-difluoroethyl)-2-fluorophenyl) ethyl Alkane-1-amine hydrochloride (150mg, 0.628mmol), DIPEA (244mg, 1.884mmol), and DMSO (5mL) were sequentially added into the reaction flask, heated to 80°C under nitrogen protection, and stirred for 2h. After the reaction, add saturated ammonium chloride solution (30mL) to quench, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and reduce pressure Concentrate, and the residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R)-6-bromo-N-(1-(3-(1,1-di Fluoroethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine, yield 93.9%; ESI-MS (m/z): 424.0[M+H] + .
步骤b)：(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methanol Preparation of (quinazolin-6-yl) (methyl) amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-6-溴-N-(1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(90mg，0.212mmol)，2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(61mg，0.233mmol)、X-Phos(42mg，0.085mmol)、Cs 2CO 3(208mg，0.636mmol)、Pd(dba) 2(25mg，0.043mmol)和甲苯(5mL)依次加入到反应瓶中，氮气置换三次，升温至105℃搅拌反应过夜。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率33.3％； 1H NMR(400MHz，DMSO-d 6)δ8.18(d，J＝7.2Hz，1H)，7.68-7.61(m，2H)，7.42(t，J＝7.6Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.24(t，J＝7.6Hz，1H)，7.11-7.02(m，2H)，6.98(d，J＝8.8Hz，1H)，6.91(d，J＝2.8Hz，1H)，5.86-5.78(m，1H)，3.76(s，3H)，3.57(s，2H)，3.37(s，3H)，2.99(s，3H)，2.78(s，3H)，2.29(s，3H)，2.04(t，J＝18.8Hz，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：566.3[M+H] +。 (R)-6-bromo-N-(1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine ( 90mg, 0.212mmol), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (61mg, 0.233mmol), X-Phos (42mg, 0.085mmol), Cs 2 CO 3 (208mg, 0.636mmol), Pd(dba) 2 (25mg, 0.043mmol) and toluene (5mL) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred overnight. After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the residue Purification by Prep-HPLC (Method 3) gave (R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl )amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 33.3%; 1 H NMR (400MHz, DMSO-d 6 )δ8.18(d, J=7.2Hz, 1H), 7.68-7.61(m, 2H), 7.42(t, J=7.6Hz, 1H), 7.35(d, J=9.2 Hz, 1H), 7.24(t, J=7.6Hz, 1H), 7.11-7.02(m, 2H), 6.98(d, J=8.8Hz, 1H), 6.91(d, J=2.8Hz, 1H), 5.86-5.78(m, 1H), 3.76(s, 3H), 3.57(s, 2H), 3.37(s, 3H), 2.99(s, 3H), 2.78(s, 3H), 2.29(s, 3H) , 2.04 (t, J = 18.8 Hz, 3H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 566.3 [M+H] + .
实施例33Example 33
(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline -6-yl)(methyl)amino)-2-hydroxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000134
Figure PCTCN2022101219-appb-000134
步骤a)：2-(2-羟基-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺的制备Step a): Preparation of 2-(2-hydroxy-5-(methylamino)phenyl)-N,N-dimethylacetamide
将2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺(300mg，1.110mol)溶于二氯甲烷(5mL)中，降温到0℃，滴加三溴化硼(1mL)，滴加完毕后，温度升至室温，反应液搅拌16h，加水(10mL)淬灭，以饱和碳酸氢钠水溶液调至pH＝8～9，用二氯甲烷(20mL×3)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，减压浓缩，得2-(2-羟基-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺，收率81.4％；ESI-MS(m/z)：209.1[M+H] +。 Dissolve 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide (300mg, 1.110mol) in dichloromethane (5mL), cool to 0°C, Boron tribromide (1 mL) was added dropwise. After the dropwise addition, the temperature rose to room temperature. The reaction solution was stirred for 16 h, quenched by adding water (10 mL), adjusted to pH = 8-9 with saturated aqueous sodium bicarbonate solution, and washed with dichloromethane (20mL×3) extraction, the organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(2-hydroxy-5-(methylamino)phenyl) -N,N-Dimethylacetamide, yield 81.4%; ESI-MS (m/z): 209.1[M+H] + .
步骤b)：2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺的制备Step b): Preparation of 2-(2-((tert-butyldimethylsilyl)oxy)-5-(methylamino)phenyl)-N,N-dimethylacetamide
将2-(2-羟基-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺(188mg，0.899mmol)、叔丁基二甲基氯硅烷(163mg，1.079mmol)、三乙胺(137mg，1.349mmol)、二氯甲烷(5mL)依次加入反应瓶中，反应液在室温搅拌16h。反应结束后，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∶4)，得2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺，收率82.6％；ESI-MS(m/z)：323.2[M+H] +。 2-(2-Hydroxy-5-(methylamino)phenyl)-N,N-dimethylacetamide (188mg, 0.899mmol), tert-butyldimethylsilyl chloride (163mg, 1.079mmol), Triethylamine (137mg, 1.349mmol) and dichloromethane (5mL) were successively added into the reaction flask, and the reaction solution was stirred at room temperature for 16h. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1:4) to obtain 2-(2-((tert-butyldimethylsilyl )oxy)-5-(methylamino)phenyl)-N,N-dimethylacetamide, yield 82.6%; ESI-MS (m/z): 323.2[M+H] + .
步骤c)：(R)-2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(2-((tert-butyldimethylsilyl)oxy)-5-((4-((1-(3-(1,1-difluoroethyl Base)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)phenyl)-N, the preparation of N-dimethylacetamide
将(R)-6-溴-N-(1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(92mg，0.217mmol)，2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺(70mg，0.217mmol)、X-Phos(42mg，0.086mmol)、Cs 2CO 3(141mg，0.434mmol)、Pd(dba) 2(25mg，0.043mmol)和甲苯(5mL)依次加入到反应瓶中，氮气置换三次，升温至105℃搅拌反应过夜。反应结束后，加水(20mL)淬灭反应，以乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)，得(R)-2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)苯基)-N，N-二甲基乙酰胺，产率79.7％；ESI-MS(m/z)：666.3[M+H] +。 (R)-6-bromo-N-(1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine ( 92mg, 0.217mmol), 2-(2-((tert-butyldimethylsilyl)oxy)-5-(methylamino)phenyl)-N,N-dimethylacetamide (70mg, 0.217mmol), X-Phos (42mg, 0.086mmol), Cs 2 CO 3 (141mg, 0.434mmol), Pd(dba) 2 (25mg, 0.043mmol) and toluene (5mL) were successively added to the reaction flask, nitrogen replacement Three times, the temperature was raised to 105°C and the reaction was stirred overnight. After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the residue Purified by silica gel column chromatography (dichloromethane/methanol=20/1) to obtain (R)-2-(2-((tert-butyldimethylsilyl)oxy)-5-((4- ((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)phenyl )-N,N-dimethylacetamide, yield 79.7%; ESI-MS (m/z): 666.3[M+H] + .
步骤d)：(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methanol Preparation of (quinazolin-6-yl) (methyl) amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate
将(R)-2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)苯基)-N，N-二甲基乙酰胺(115mg，0.171mmol)溶于THF(3mL)中，加入四丁基氟化铵(0.26mL，1M)，室温搅拌30min。反应完全后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)， 合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经Pre-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐，产率15.9％； 1H NMR(400MHz，DMSO-d 6)δ12.60(s，1H)，9.53(s，1H)，8.16(s，1H)，8.14(s，1H)，7.65(t，J＝6.4Hz，1H)，7.57(s，1H)，7.42(t，J＝7.6Hz，1H)，7.32(d，J＝9.2Hz，1H)，7.25(t，J＝7.6Hz，1H)，7.02(m，1H)，6.94-6.87(m，2H)，6.83(d，J＝8.4Hz，1H)，5.83(q，J＝7.2Hz，1H)，3.57(s，2H)，3.33(s，3H)，3.01(s，3H)，2.80(s，3H)，2.29(s，3H)，2.04(t，J＝18.8Hz，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] +。 (R)-2-(2-((tert-butyldimethylsilyl)oxy)-5-((4-((1-(3-(1,1-difluoroethyl)- 2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)phenyl)-N,N-dimethylacetamide (115mg, 0.171mmol) To THF (3 mL), add tetrabutylammonium fluoride (0.26 mL, 1 M), and stir at room temperature for 30 min. After the reaction was complete, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and the residue Purification by Pre-HPLC (Method 2) gave (R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)-2-fluorophenyl)ethyl )amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate, yield 15.9%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.60(s, 1H), 9.53(s, 1H), 8.16(s, 1H), 8.14(s, 1H), 7.65(t, J=6.4Hz, 1H) , 7.57(s, 1H), 7.42(t, J=7.6Hz, 1H), 7.32(d, J=9.2Hz, 1H), 7.25(t, J=7.6Hz, 1H), 7.02(m, 1H) , 6.94-6.87(m, 2H), 6.83(d, J=8.4Hz, 1H), 5.83(q, J=7.2Hz, 1H), 3.57(s, 2H), 3.33(s, 3H), 3.01( s, 3H), 2.80(s, 3H), 2.29(s, 3H), 2.04(t, J=18.8Hz, 3H), 1.62(d, J=7.2Hz, 3H); ESI-MS (m/z ): 552.2[M+H] + .
实施例34Example 34
(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000135
Figure PCTCN2022101219-appb-000135
制备方法参考实施例33，经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺，产率45.7％； 1H NMR(400MHz，CD3OD)δ7.56(d，J＝8.0Hz，1H)，7.40(d，J＝4.0Hz，1H)，7.33-7.29(m，2H)，7.20-7.16(m，1H)，7.12-7.09(m，1H)，6.92-6.89(m，3H)，6.81-6.78(m，1H)，5.83-5.78(m，1H)，3.64(s，2H)，3.29(s，3H)，3.06(s，3H)，2.88(s，3H)，2.53(s，3H)，2.34(t，J＝12.0Hz，3H)，，1.55(d，J＝8.0Hz，3H)；ESI-MS(m/z)：534.6[M+H] +。 The preparation method refers to Example 33 and is purified by Prep-HPLC (Method 3) to obtain (R)-2-(5-((4-((1-(3-(1,1-difluoroethyl)phenyl )ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide, yield 45.7%; 1 H NMR (400MHz, CD3OD) δ7.56 (d, J = 8.0Hz, 1H), 7.40 (d, J = 4.0Hz, 1H), 7.33-7.29 (m, 2H), 7.20-7.16 (m, 1H), 7.12-7.09(m, 1H), 6.92-6.89(m, 3H), 6.81-6.78(m, 1H), 5.83-5.78(m, 1H), 3.64(s, 2H), 3.29(s, 3H), 3.06(s, 3H), 2.88(s, 3H), 2.53(s, 3H), 2.34(t, J=12.0Hz, 3H), 1.55(d, J=8.0Hz, 3H); ESI-MS ( m/z): 534.6 [M+H] + .
实施例35Example 35
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl )(Methyl)amino)-2-methoxypyridine)-3-
基)-N，N-二甲基乙酰胺甲酸盐的制备base)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000136
Figure PCTCN2022101219-appb-000136
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(413mg，1.009mmol)，2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(150mg，0.673mmol)、X-Phos(128mg，0.269mmol)、Cs 2CO 3(439mg，1.346mmol)、Pd(dba) 2(76mg，0.134mmol)和甲苯(8mL)依次加入到反应瓶中，氮气置换三次，升温至105℃搅拌反应过夜。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺甲酸盐，产率53.7％； 1H NMR(400MHz，DMSO-d 6)δ12.60(s，1H)，8.21(d，J＝7.2Hz，1H)，8.14(s，1H)，7.94(d，J＝2.8Hz，1H)，7.73(s，1H)，7.69(t，J＝7.6Hz，1H)，7.49(t，J＝7.2Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.35(s，1H)，7.29(t，J＝7.6Hz，1H)，7.24(s，1H)，7.10(m，1H)，5.82(q，J＝7.2Hz，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.30(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.2[M+H] +。 (R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine (413mg, 1.009mmol ), 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (150mg, 0.673mmol), X-Phos (128mg, 0.269mmol), Cs 2 CO 3 (439mg, 1.346mmol), Pd(dba) 2 (76mg, 0.134mmol) and toluene (8mL) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred overnight. After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, the residue Purification by Prep-HPLC (Method 2) gave (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate, yield 53.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.60(s, 1H), 8.21(d, J=7.2Hz, 1H), 8.14(s, 1H), 7.94(d, J=2.8Hz, 1H) , 7.73(s, 1H), 7.69(t, J=7.6Hz, 1H), 7.49(t, J=7.2Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.35(s, 1H) , 7.29(t, J=7.6Hz, 1H), 7.24(s, 1H), 7.10(m, 1H), 5.82(q, J=7.2Hz, 1H), 3.85(s, 3H), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.30(s, 3H), 1.62(d, J=7.2Hz, 3H); ESI-MS (m/z ): 553.2[M+H] + .
实施例36Example 36
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-methoxypyridinium) -3-yl) -N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000137
Figure PCTCN2022101219-appb-000137
制备方法参考实施例35，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺甲酸盐，产率2.3％； 1H NMR(400MHz，DMSO-d 6)δ12.70(s，1H)，8.31(s，1H)，8.14(s，1H)，7.94-7.95(m，1H)，7.77-7.67(m，2H)，7.40-7.08(m，6H)，5.80(s，1H)，3.85(s，3H)，3.60(s，2H)，3.38(s，3H)，3.02(s，3H)，2.81(s，3H)，2.57(s，3H)，2.33(s，3H)，1.57(d，J＝7.2Hz，3H)；ESI-MS(m/z)：549.3[M+H] +。 The preparation method refers to Example 35 to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2- Methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate, yield 2.3%; 1 H NMR (400MHz, DMSO-d 6 )δ12.70(s, 1H), 8.31(s, 1H), 8.14(s, 1H), 7.94-7.95(m, 1H), 7.77-7.67(m, 2H), 7.40-7.08(m, 6H), 5.80(s, 1H), 3.85(s, 3H), 3.60(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.81(s, 3H) , 2.57 (s, 3H), 2.33 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 549.3 [M+H] + .
实施例37Example 37
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶)-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-hydroxypyridinium) -3-yl) -N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000138
Figure PCTCN2022101219-appb-000138
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺(626mg，1.540mmol)、2-(2-羟基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐(161mg，0.770mmol)、Cs 2CO 3(753mg，2.310mmol)、X-Phos(294mg，0.616mmol)、Pd(dba) 2(175mg，0.308mmol)和甲苯(10mL)加入到反应瓶中，氮气置换三次，维持105℃搅拌反应16h。降至室温，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶)-3-基)-N，N-二甲基乙酰胺甲酸盐，产率4.7％； 1H NMR(400MHz，DMSO-d 6)δ12.70(s，1H)，11.60(s，1H)，8.17(s，1H)，8.20(d，J＝7.2Hz，1H)，7.70(d，J＝7.6Hz，1H)，7.55(m，1H)，7.41-7.34(m，2H)，7.33-7.13(m，4H)，7.07-7.04(m，1H)，5.79(m 1H)，3.42(s，2H)，3.29(s，3H)，3.02(s，3H)，2.79(s，3H)，2.57(s，3H)，2.31(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.0[M+H] +。 (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine (626mg, 1.540 mmol), 2-(2-hydroxyl-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide hydrochloride (161mg, 0.770mmol), Cs 2 CO 3 (753mg, 2.310 mmol), X-Phos (294mg, 0.616mmol), Pd(dba) 2 (175mg, 0.308mmol) and toluene (10mL) were added into the reaction flask, replaced with nitrogen three times, and kept stirring at 105°C for 16h. Lowered to room temperature, concentrated under reduced pressure, the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2 -(5-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl )amino)-2-hydroxypyridin)-3-yl)-N,N-dimethylacetamide formate, yield 4.7%; 1 H NMR (400MHz, DMSO-d 6 )δ12.70(s, 1H), 11.60(s, 1H), 8.17(s, 1H), 8.20(d, J=7.2Hz, 1H), 7.70(d, J=7.6Hz, 1H), 7.55(m, 1H), 7.41- 7.34(m, 2H), 7.33-7.13(m, 4H), 7.07-7.04(m, 1H), 5.79(m 1H), 3.42(s, 2H), 3.29(s, 3H), 3.02(s, 3H ), 2.79(s, 3H), 2.57(s, 3H), 2.31(s, 3H), 1.56(d, J=7.2Hz, 3H); ESI-MS (m/z): 535.0[M+H] + .
实施例38Example 38
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000139
Figure PCTCN2022101219-appb-000139
将(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺(200mg，0.363mmol)，溴化氢的乙酸溶液(5mL，33％)依次加入到反应瓶中，升温至80℃搅拌20min。反应结束后，加入饱和碳酸氢钠水溶液(50mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩，残余物经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率25.5％； 1H NMR(400MHz，DMSO-d 6)δ11.60(s，1H)，8.20(s，1H)，7.68(t，J＝7.6Hz，1H)，7.55(s，1H)，7.49(t，J＝7.2Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.31-7.26(m，2H)，7.24(t，J＝54.4Hz，1H)，7.19(d，J＝2.8Hz，1H)，7.08(m，1H)，5.82(q，J＝7.2Hz，1H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.78(s，3H)，2.30(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：539.2[M+H] +。 (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl)amino)-2-methoxypyridin)-3-yl)-N,N-dimethylacetamide (200mg, 0.363mmol), hydrogen bromide in acetic acid (5mL, 33%) Add them to the reaction flask in turn, raise the temperature to 80°C and stir for 20 minutes. After the reaction was complete, add saturated aqueous sodium bicarbonate (50 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and reduce Concentrate under reduced pressure, and the residue is purified by Prep-HPLC (method 3) to give (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) Base)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 25.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.60(s, 1H), 8.20(s, 1H), 7.68(t, J=7.6Hz, 1H), 7.55(s, 1H), 7.49(t, J =7.2Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.31-7.26(m, 2H), 7.24(t, J=54.4Hz, 1H), 7.19(d, J=2.8Hz, 1H ), 7.08(m, 1H), 5.82(q, J=7.2Hz, 1H), 3.42(s, 2H), 3.28(s, 3H), 3.01(s, 3H), 2.78(s, 3H), 2.30 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 539.2 [M+H] + .
实施例39Example 39
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-1-(吡咯烷-1-基)乙基-1-酮甲酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxypyridin)-3-yl)-1-(pyrrolidin-1-yl) ethyl-1-one formic acid salt
Figure PCTCN2022101219-appb-000140
Figure PCTCN2022101219-appb-000140
步骤a)：2-(5-溴-2-甲氧基吡啶-3-基)乙酸盐酸盐的制备Step a): Preparation of 2-(5-bromo-2-methoxypyridin-3-yl)acetic acid hydrochloride
将2-(5-溴-2-甲氧基吡啶-3-基)乙酸乙酯(500mg，1.824mmol)、氢氧化锂水溶液(4M，1.8mL)、THF(1.5mL)和甲醇(0.5mL)加入反应瓶中，室温反应15min。加入0.2N的盐酸调至pH＝2-3，加入乙酸乙酯萃取(20mL×2)，合并有机相，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(5-溴-2-甲氧基吡啶-3-基)乙酸盐酸盐，产率91.5％；ESI-MS(m/z)：246.0[M+H] +。 Ethyl 2-(5-bromo-2-methoxypyridin-3-yl)acetate (500mg, 1.824mmol), aqueous lithium hydroxide (4M, 1.8mL), THF (1.5mL) and methanol (0.5mL ) into the reaction flask, and reacted at room temperature for 15 minutes. Add 0.2N hydrochloric acid to adjust the pH to 2-3, add ethyl acetate to extract (20mL×2), combine the organic phases, wash with saturated brine (10mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(5-Bromo-2-methoxypyridin-3-yl)acetic acid hydrochloride, yield 91.5%; ESI-MS (m/z): 246.0 [M+H] + .
步骤b)：2-(5-溴-2-甲氧基吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮的制备Step b): Preparation of 2-(5-bromo-2-methoxypyridin-3-yl)-1-(pyrrolidin-1-yl)ethyl-1-one
将2-(5-溴-2-甲氧基吡啶-3-基)乙酸盐酸盐(471.0mg，1.667mmol)，四氢吡咯(163.5mg，2.299mmol)，DIPEA(618.2mg，4.783mmol)，HATU(1.1g，2.893mmol)和二氯甲烷(5mL)加入反应瓶中，室温搅拌1h。反应结束后，加入饱和碳酸氢钠水溶液(20mL)和乙酸乙酯(20mL)搅拌，分液，有机相经饱和氯化铵水溶液(20mL)洗涤，饱和食盐水洗(15mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/1)，得2-(5-溴-2-甲氧基吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮，产率94.4％；ESI-MS(m/z)：299.0[M+H] +。 2-(5-Bromo-2-methoxypyridin-3-yl)acetic acid hydrochloride (471.0mg, 1.667mmol), tetrahydropyrrole (163.5mg, 2.299mmol), DIPEA (618.2mg, 4.783mmol ), HATU (1.1g, 2.893mmol) and dichloromethane (5mL) were added into the reaction flask, stirred at room temperature for 1h. After the reaction, add saturated aqueous sodium bicarbonate (20mL) and ethyl acetate (20mL) and stir, separate the layers, wash the organic phase with saturated aqueous ammonium chloride (20mL), wash with saturated brine (15mL), wash with anhydrous sodium sulfate Dry, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel chromatography (eluent: ethyl acetate/petroleum ether=1/1) to obtain 2-(5-bromo-2-methoxypyridine-3- yl)-1-(pyrrolidin-1-yl)ethyl-1-one, yield 94.4%; ESI-MS (m/z): 299.0[M+H] + .
步骤c)：(6-甲氧基-5-(2-氧代-2-(吡咯烷-1-基)乙基)吡啶-3-基)氨基甲酸叔丁酯的制备Step c): Preparation of tert-butyl (6-methoxy-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-3-yl)carbamate
将2-(5-溴-2-甲氧基吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮(220.0mg，0.735mmol)，氨基甲酸叔丁酯(103.3mg，0.882mmol)，Pd(dba) 2(83.5mg，0.147mmol)，X-Phos(140.1mg，0.294mmol)，Cs 2CO 3(479.6mg，1.472mmol)和甲苯(5mL)依次加入到反应瓶中，氮气置换三次，升温至110℃搅拌反应2h。过滤，滤饼经乙酸乙酯(10mL)淋洗，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＝1/2)，得(6-甲氧基-5-(2-氧代-2-(吡咯烷-1-基)乙基)吡啶-3-基)氨基甲酸叔丁酯；产率73.6％；ESI-MS(m/z)：280.2[M+H-But] +。 2-(5-Bromo-2-methoxypyridin-3-yl)-1-(pyrrolidin-1-yl)ethyl-1-one (220.0 mg, 0.735 mmol), tert-butyl carbamate ( 103.3mg, 0.882mmol), Pd(dba) 2 (83.5mg, 0.147mmol), X-Phos (140.1mg, 0.294mmol), Cs 2 CO 3 (479.6mg, 1.472mmol) and toluene (5mL) were added to In the reaction flask, nitrogen was replaced three times, and the temperature was raised to 110° C. and the reaction was stirred for 2 h. Filtration, the filter cake was rinsed with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/2) to obtain (6-methoxy tert-butyl-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-3-yl)carbamate; yield 73.6%; ESI-MS (m/z): 280.2 [M+H-But] + .
步骤d)：(6-甲氧基-5-(2-氧-2-(吡咯烷-1-基)乙基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的制备Step d): Preparation of tert-butyl (6-methoxy-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-3-yl)(methyl)carbamate
将(6-甲氧基-5-(2-氧代-2-(吡咯烷-1-基)乙基)吡啶-3-基)氨基甲酸叔丁酯(181.0mg，0.539mmol)，NaH(86.3mg，2.157mmol，60％)和四氢呋哺(3mL)加入反应瓶中，冰浴条件搅拌下加入碘甲烷(92.5mg，0.651mmol)，室温搅拌0.5h。反应结束后，加饱和氯化铵水溶液(10mL)淬灭，用乙酸乙酯萃取(20mL)，饱和食盐水(20mL)洗涤，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：乙酸乙酯/石油醚＝2∶1)，得(6-甲氧基-5-(2-氧-2-(吡咯烷-1-基)乙基)吡啶-3-基)(甲基)氨基甲酸叔丁酯，产率52.9％；ESI-MS(m/z)：294.2[M+H] +。 (6-Methoxy-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-3-yl)carbamate tert-butyl ester (181.0 mg, 0.539 mmol), NaH ( 86.3mg, 2.157mmol, 60%) and tetrahydrofuran (3mL) were added to the reaction flask, and methyl iodide (92.5mg, 0.651mmol) was added under stirring in an ice bath, and stirred at room temperature for 0.5h. After the reaction was completed, it was quenched by adding saturated aqueous ammonium chloride (10 mL), extracted with ethyl acetate (20 mL), washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by column chromatography (eluent: ethyl acetate/petroleum ether=2:1) to obtain (6-methoxy-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridine -3-yl)(methyl)carbamate tert-butyl ester, yield 52.9%; ESI-MS (m/z): 294.2 [M+H] + .
步骤e)：2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮的制备Step e): Preparation of 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-1-(pyrrolidin-1-yl)ethyl-1-one
将(6-甲氧基-5-(2-氧-2-(吡咯烷-1-基)乙基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(100.0mg，0.286mmol)，三氟乙酸(130.3mg，1.143mmol)和二氯甲烷(1mL)加入反应瓶中，室温搅拌3h。将反应液减压浓缩至干，加入二氯甲烷(15mL)和饱和碳酸氢钠水溶液(10mL)搅拌，分液，水相以二氯甲烷(10mL×2)萃取，合并有机相，饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮，产率70.4％；ESI-MS(m/z)：250.1[M+H] +。 (6-Methoxy-5-(2-oxo-2-(pyrrolidin-1-yl)ethyl)pyridin-3-yl)(methyl)carbamate tert-butyl ester (100.0mg, 0.286mmol) , trifluoroacetic acid (130.3mg, 1.143mmol) and dichloromethane (1mL) were added into the reaction flask, stirred at room temperature for 3h. Concentrate the reaction solution to dryness under reduced pressure, add dichloromethane (15mL) and saturated aqueous sodium bicarbonate (10mL) and stir, separate the layers, extract the aqueous phase with dichloromethane (10mL×2), combine the organic phases, and add saturated saline (10mL), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-1-(pyrrolidin-1-yl ) ethyl-1-one, yield 70.4%; ESI-MS (m/z): 250.1 [M+H] + .
步骤f)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-1-(吡咯烷-1-基)乙基-1-酮甲酸盐的制备Step f): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-1-(pyrrolidin-1-yl)ethyl-1-one formate
将2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮(50mg，0.200mmol)，(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(82mg，0.201mmol)，Pd(dba) 2(24mg，0.041mmol)，X-Phos(39mg，0.081mmol)，Cs 2CO 3(130mg，0.399mmol)和甲苯(2mL)依次加入到反应瓶中，氮 气置换三次，升温至90℃搅拌16h。过滤，滤饼经乙酸乙酯(10mL)淋洗，滤液减压浓缩至干，残余物经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/25)，所得粗品再经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-1-(吡咯烷-1-基)乙基-1-酮甲酸盐，产率35.3％； 1H NMR(400MHz，DMSO-d 6)δ12.74(s，1H)，8.21(d，J＝7.6Hz，1H)，8.14(s，1H)，7.94(s，1H)，7.75-7.65(m，2H)，7.49(t，J＝6.8Hz，1H)，7.41-7.36(m，2H)，7.29(t，J＝7.6Hz，1H)，7.38-7.11(m，1H)，7.12(s，1H)，5.83(s，1H)，3.85(s，3H)，3.54(s，2H)，3.47(t，J＝6.8Hz，2H)，3.38(s，3H)，3.25(t，J＝6.8Hz，2H)，2.30(s，3H)，1.90-1.83(m，2H)，1.75(m，2H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：579.4[M+H] +。 2-(2-Methoxy-5-(methylamino)pyridin-3-yl)-1-(pyrrolidin-1-yl)ethyl-1-one (50mg, 0.200mmol), (R)- 6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine (82mg, 0.201mmol), Pd(dba ) 2 (24mg, 0.041mmol), X-Phos (39mg, 0.081mmol), Cs 2 CO 3 (130mg, 0.399mmol) and toluene (2mL) were sequentially added to the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred 16h. Filtration, the filter cake was rinsed with ethyl acetate (10 mL), the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/25), and the obtained crude product was subjected to Prep - HPLC (method 2) purification to give (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- Methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-1-(pyrrolidin-1-yl)ethyl-1-one formate, Yield 35.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.74(s, 1H), 8.21(d, J=7.6Hz, 1H), 8.14(s, 1H), 7.94(s, 1H) , 7.75-7.65(m, 2H), 7.49(t, J=6.8Hz, 1H), 7.41-7.36(m, 2H), 7.29(t, J=7.6Hz, 1H), 7.38-7.11(m, 1H ), 7.12(s, 1H), 5.83(s, 1H), 3.85(s, 3H), 3.54(s, 2H), 3.47(t, J=6.8Hz, 2H), 3.38(s, 3H), 3.25 (t, J=6.8Hz, 2H), 2.30(s, 3H), 1.90-1.83(m, 2H), 1.75(m, 2H), 1.62(d, J=7.2Hz, 3H); ESI-MS ( m/z): 579.4 [M+H] + .
实施例40Example 40
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮甲酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-1-(pyrrolidin-1-yl) ethyl-1-one formic acid salt preparation
Figure PCTCN2022101219-appb-000141
Figure PCTCN2022101219-appb-000141
制备方法参考实施例38，经Pre-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-1-(吡咯烷-1-基)乙基-1-酮甲酸盐，产率51.7％； 1H NMR(400MHz，DMSO-d 6)δ12.76(s，1H)，11.59(s，1H)，8.16(d，J＝6.8Hz，1H)，8.14(s，1H)，7.69(t，J＝7.2Hz，1H)，7.55(s，1H)，7.49(t，J＝6.8Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.38-7.10(m，1H)，7.32-7.25(m，2H)，7.22-7.21(m，1H)，7.09-7.07(m，1H)，5.83(d，J＝7.2Hz，1H)，3.48(t，J＝6.8Hz，2H)，3.37(s，2H)，3.29(s，3H)，3.23(t，J＝6.8Hz，2H)，2.29(s，3H)，1.86(s，2H)，1.74(s，2H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：565.3[M+H] +。 The preparation method refers to Example 38 and is purified by Pre-HPLC (method 2) to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl) ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -1-(pyrrolidin-1-yl) ethyl-1 - Keto formate, yield 51.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.76(s, 1H), 11.59(s, 1H), 8.16(d, J=6.8Hz, 1H), 8.14(s, 1H), 7.69(t, J=7.2Hz, 1H), 7.55(s, 1H), 7.49(t, J=6.8Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.38-7.10(m, 1H), 7.32-7.25(m, 2H), 7.22-7.21(m, 1H), 7.09-7.07(m, 1H), 5.83(d, J=7.2Hz, 1H), 3.48( t, J=6.8Hz, 2H), 3.37(s, 2H), 3.29(s, 3H), 3.23(t, J=6.8Hz, 2H), 2.29(s, 3H), 1.86(s, 2H), 1.74 (s, 2H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 565.3 [M+H] + .
实施例41Example 41
(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxypyridinium)-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000142
Figure PCTCN2022101219-appb-000142
步骤a)：6-甲氧基-N-甲基-5-硝基吡啶-2-胺的制备Step a): Preparation of 6-methoxy-N-methyl-5-nitropyridin-2-amine
将2-甲氧基-3-硝基-6-氯吡啶(5.0g，26.511mmol)、二甲胺盐酸盐(3.6g，53.022mmol)、碳酸钾(7.3g，53.022)和DMF(50mL)加入密闭的反应瓶中，升温至80℃，搅拌3h。反应结束后，冷却至室温，加水(100mL)淬灭反应，以乙酸乙酯萃取(50mL×3)，合并有机相，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6-甲氧基-N-甲基-5-硝基吡啶-2-胺，产率98.2％；ESI-MS(m/z)：184.0[M+H] +。 2-Methoxy-3-nitro-6-chloropyridine (5.0 g, 26.511 mmol), dimethylamine hydrochloride (3.6 g, 53.022 mmol), potassium carbonate (7.3 g, 53.022) and DMF (50 mL ) into a closed reaction flask, heated up to 80°C, and stirred for 3h. After the reaction, cool to room temperature, add water (100mL) to quench the reaction, extract with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure to obtain 6-methoxy-N-methyl-5-nitropyridin-2-amine with a yield of 98.2%; ESI-MS (m/z): 184.0 [M+H] + .
步骤b)：(6-甲氧基-5-硝基吡啶-2-基)(甲基)氨基甲酸苄酯的制备Step b): Preparation of benzyl (6-methoxy-5-nitropyridin-2-yl)(methyl)carbamate
将6-甲氧基-N-甲基-5-硝基吡啶-2-胺(4.8g，26.229mmol)溶于四氢呋喃(60mL)和DMF(10mL)中，冰浴下加入氢化钠(2.3g，57.703mmol，60％)，搅拌反应15min，滴加氯甲酸苄酯(5.4g，31.475mmol)，加毕，升至室温搅拌30min。反应结束后，加水(100mL)淬灭反应，以乙酸乙酯萃取(50mL×3)，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，残余物经硅胶柱层析纯 化(洗脱剂：石油醚/乙酸乙酯＝8/1)，得(6-甲氧基-5-硝基吡啶-2-基)(甲基)氨基甲酸苄酯，产率87.8％； 1H NMR(400MHz，DMSO-d 6)δ8.34(d，J＝9.2Hz，1H)，7.47-7.35(m，5H)，7.31(d，J＝9.2Hz，1H)，5.26(s，2H)，3.47(s，3H)，3.02(d，J＝4.8Hz，3H)；ESI-MS(m/z)：318.1[M+H] +。 6-Methoxy-N-methyl-5-nitropyridin-2-amine (4.8g, 26.229mmol) was dissolved in tetrahydrofuran (60mL) and DMF (10mL), and sodium hydride (2.3g , 57.703mmol, 60%), stirred for 15min, benzyl chloroformate (5.4g, 31.475mmol) was added dropwise, after the addition was complete, it was raised to room temperature and stirred for 30min. After the reaction was completed, add water (100 mL) to quench the reaction, extract with ethyl acetate (50 mL×3), 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 product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=8/1) to obtain benzyl (6-methoxy-5-nitropyridin-2-yl)(methyl)carbamate , yield 87.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.34(d, J=9.2Hz, 1H), 7.47-7.35(m, 5H), 7.31(d, J=9.2Hz, 1H ), 5.26 (s, 2H), 3.47 (s, 3H), 3.02 (d, J=4.8Hz, 3H); ESI-MS (m/z): 318.1 [M+H] + .
步骤c)：(5-氨基-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯的制备Step c): Preparation of benzyl (5-amino-6-methoxypyridin-2-yl)(methyl)carbamate
将(6-甲氧基-5-硝基吡啶-2-基)(甲基)氨基甲酸苄酯(2.5g，7.886mmol)溶于甲醇(20mL)和水(10mL)中，加入铁粉(2.2g，39.432mmol)和氯化铵(2.1g，39.433mmol)，升温至回流，搅拌2h。反应结束后，冷却至室温，加水(50mL)和乙酸乙酯(30mL)搅拌混匀，过滤，滤液分液，水相以乙酸乙酯萃取(30mL×2)，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，得(5-氨基-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯；收率99.1％；ESI-MS(m/z)：288.1[M+H] +。 Benzyl (6-methoxy-5-nitropyridin-2-yl)(methyl)carbamate (2.5 g, 7.886 mmol) was dissolved in methanol (20 mL) and water (10 mL), and iron powder ( 2.2g, 39.432mmol) and ammonium chloride (2.1g, 39.433mmol), heated to reflux and stirred for 2h. After the reaction, cool to room temperature, add water (50mL) and ethyl acetate (30mL), stir and mix, filter, separate the filtrate, extract the aqueous phase with ethyl acetate (30mL×2), combine the organic phases, and wash with saturated saline (100mL), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain benzyl (5-amino-6-methoxypyridin-2-yl)(methyl)carbamate; yield 99.1%; ESI - MS (m/z): 288.1 [M+H] + .
步骤d)：(5-溴-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯的制备Step d): Preparation of benzyl (5-bromo-6-methoxypyridin-2-yl)(methyl)carbamate
将溴化铜(2.1g，9.198mmol)，乙腈(20mL)加入反应瓶中，氮气置换3次，冷却至0℃，加入亚硝酸异戊酯(13g，11.498mmol)的乙腈溶液(10mL)，搅拌15min，再滴加(5-溴-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯(2.2g，7.665mmol)的乙腈溶液(10mL)，加毕，保持0℃继续搅拌1h。反应结束后，加水(100mL)淬灭反应，以乙酸乙酯萃取(50mL×3)，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，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得(5-溴-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯，产率35.0％； 1H NMR(400MHz，CDCl 3)δ7.72(d，J＝8.4Hz，1H)，7.42-7.33(m，5H)，7.31(d，J＝8.4Hz，1H)，5.24(s，2H)，3.96(s，3H)，3.46(s，3H)；ESI-MS(m/z)：350.0[M+H] +。 Add copper bromide (2.1g, 9.198mmol) and acetonitrile (20mL) into the reaction flask, replace with nitrogen 3 times, cool to 0°C, add isoamyl nitrite (13g, 11.498mmol) in acetonitrile solution (10mL), Stir for 15 min, then add dropwise (5-bromo-6-methoxypyridin-2-yl)(methyl)carbamate benzyl ester (2.2g, 7.665mmol) in acetonitrile solution (10mL), after addition, keep at 0°C Stirring was continued for 1 h. After the reaction was completed, add water (100 mL) to quench the reaction, extract with ethyl acetate (50 mL×3), 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 product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain benzyl (5-bromo-6-methoxypyridin-2-yl)(methyl)carbamate, Yield 35.0%; 1 H NMR (400MHz, CDCl 3 ) δ7.72 (d, J=8.4Hz, 1H), 7.42-7.33 (m, 5H), 7.31 (d, J=8.4Hz, 1H), 5.24 (s, 2H), 3.96 (s, 3H), 3.46 (s, 3H); ESI-MS (m/z): 350.0 [M+H] + .
步骤e)：(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯的制备Step e): Preparation of benzyl (5-(2-(dimethylamino)-2-oxyethyl)-6-methoxypyridin-2-yl)(methyl)carbamate
将(5-溴-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯(900mg，2.571mmol)、(2-(二甲氨基)-2-氧乙基)溴化镁的四氢呋喃溶液(5.2mL，5.141mmol，1M)、Pd(dba) 2(148mg，0.257mmol)、X-phos(244mg，0.514mmol)和四氢呋喃(15mL)加入到反应瓶中，氮气置换三次，升温至80℃，搅拌反应2h。反应结束后，冷却至室温，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＝1/1)，得(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯，收率95.3％；ESI-MS(m/z)：357.1[M+H] +。 Benzyl (5-bromo-6-methoxypyridin-2-yl)(methyl)carbamate (900 mg, 2.571 mmol), (2-(dimethylamino)-2-oxoethyl)magnesium bromide Tetrahydrofuran solution (5.2mL, 5.141mmol, 1M), Pd(dba) 2 (148mg, 0.257mmol), X-phos (244mg, 0.514mmol) and tetrahydrofuran (15mL) were added in the reaction flask, replaced with nitrogen three times, and the temperature was raised To 80 ° C, stirring the reaction for 2h. After the reaction, cool to room temperature, filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (5-(2-(dimethyl Amino)-2-oxyethyl)-6-methoxypyridin-2-yl)(methyl)benzyl carbamate, yield 95.3%; ESI-MS (m/z): 357.1[M+H] + .
步骤f)：2-(2-甲氧基-6-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备Step f): Preparation of 2-(2-methoxy-6-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide
将(5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-2-基)(甲基)氨基甲酸苄酯(900mg，2.549mmol)溶于甲醇中(15mL)，加入钯碳(270.0mg，0.255mmol)，氢气置换三次，室温搅拌3h。过滤，滤液减压浓缩，得2-(2-甲氧基-6-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺，收率93.2％；ESI-MS(m/z)：224.1[M+H] +。 Benzyl (5-(2-(dimethylamino)-2-oxoethyl)-6-methoxypyridin-2-yl)(methyl)carbamate (900 mg, 2.549 mmol) was dissolved in methanol ( 15 mL), add palladium carbon (270.0 mg, 0.255 mmol), replace with hydrogen three times, and stir at room temperature for 3 h. Filtration, and the filtrate was concentrated under reduced pressure to give 2-(2-methoxy-6-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide with a yield of 93.2%; ESI-MS (m /z): 224.1[M+H] + .
步骤g)：(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺的制备Step g): (R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline -6-yl)(methyl)amino)-2-methoxypyridinium)-3-yl)-N, the preparation of N-dimethylacetamide
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(187mg，0.455mmol)、2-(2-甲氧基-6-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(102mg，0.455mmol)、Cs 2CO 3(297mg，0.910mmol)、X-Phos(43mg，0.091mmol)、Pd 2(dba) 3(26mg，0.045mmol)和甲苯(7mL)加入到反应瓶中，氮气置换三次，升温至105℃搅拌反应16h。将反应液冷却至室温，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＝20/1)，得(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-N，N-二甲基乙酰胺，产率43.8％； 1H NMR(400MHz，DMSO-d 6)δ8.41-8.31(m，2H)，7.70-7.65(m，2H)，7.58(d，J＝8.8Hz，1H)，7.49(t，J＝6.8Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.24(s，1H)，7.22(t，J＝60.4Hz，1H)，6.15(d，J＝8.0Hz，1H)，5.81(m，1H)，3.75(s，3H)，3.51(s，3H)，3.45(s，2H)，3.01(s，3H)，2.82(s，3H)，2.35(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.2[M+H] +。 (R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine (187mg, 0.455mmol ), 2-(2-methoxy-6-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (102mg, 0.455mmol), Cs2CO3 ( 297mg , 0.910mmol) , X-Phos (43mg, 0.091mmol), Pd 2 (dba) 3 (26mg, 0.045mmol) and toluene (7mL) were added to the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 16h. The reaction liquid was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(6-(( 4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methyl Oxypyridin)-3-yl)-N,N-dimethylacetamide, yield 43.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.41-8.31 (m, 2H), 7.70-7.65 (m, 2H), 7.58(d, J=8.8Hz, 1H), 7.49(t, J=6.8Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.24(s, 1H), 7.22 (t, J=60.4Hz, 1H), 6.15(d, J=8.0Hz, 1H), 5.81(m, 1H), 3.75(s, 3H), 3.51(s, 3H), 3.45(s, 2H) , 3.01(s, 3H), 2.82(s, 3H), 2.35(s, 3H), 1.58(d, J=7.2Hz, 3H); ESI-MS(m/z): 553.2[M+H] + .
实施例42Example 42
(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000143
Figure PCTCN2022101219-appb-000143
制备方法参考实施例38，得(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率43.8％； 1H NMR(400MHz，DMSO-d 6)δ10.52(s，1H)，8.37(d，J＝7.2Hz，1H)，8.23(s，1H)，7.67(t，J＝7.6Hz，1H)，7.57(s，2H)，7.49(t，J＝7.2Hz，1H)，7.28(t，J＝7.6Hz， 1H)，7.23(t，J＝54.4Hz，1H)，7.15(d，J＝8.0Hz，1H)，5.81(p，J＝7.2Hz，2H)，3.43(s，3H)，3.39(s，2H)，3.01(s，3H)，2.82(s，3H)，2.34(s，3H)，1.59(d，J＝7.2Hz，3H)；ESI-MS(m/z)：539.2[M+H] +。 The preparation method refers to Example 38 to obtain (R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methano ylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 43.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ10.52(s, 1H), 8.37(d, J=7.2Hz, 1H), 8.23(s, 1H), 7.67(t, J=7.6Hz, 1H), 7.57(s, 2H), 7.49 (t, J=7.2Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23(t, J=54.4Hz, 1H), 7.15(d, J=8.0Hz, 1H), 5.81(p , J=7.2Hz, 2H), 3.43(s, 3H), 3.39(s, 2H), 3.01(s, 3H), 2.82(s, 3H), 2.34(s, 3H), 1.59(d, J= 7.2 Hz, 3H); ESI-MS (m/z): 539.2 [M+H] + .
实施例43Example 43
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino) -2-oxypyridin-1 (2H)-yl) -N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000144
Figure PCTCN2022101219-appb-000144
将(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(100mg，0.273mmol)，2-(5-溴-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺(108mg，0.417mmol)，叔丁醇钠(80mg，0.833mmol)，X-phos(88mg，0.222mmol)、Pd(dba) 2(64mg，0.111mmol)和甲苯(2ml)加入反应瓶中，氮气置换3次，升温至110℃搅拌16h。反应结束后，冷却至室温，加入乙酸乙酯(10mL)室温搅拌10min，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率2.8％； 1H NMR(400MHz，DMSO-d 6)δ8.14(s，2H)，7.68(t，J＝12.0Hz，1H)，7.57(s，2H)，7.51-7.47(m，1H)，7.42(s，1H)，7.39(s，1H)，7.29(t，J＝15.2Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.11(d，J＝12.0Hz，1H)，6.46(d，J＝8.0Hz，1H)，5.85-5.81(m，1H)，4.79(s，2H)，3.30(s，3H)，3.04(s，3H)，2.85(s，3H)，2.29(s，3H)，1.63(d，J＝8.0Hz，3H)；ESI-MS(m/z)：539.0[M+H] +。 (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine ( 100mg, 0.273mmol), 2-(5-bromo-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide (108mg, 0.417mmol), sodium tert-butoxide (80mg, 0.833mmol), X-phos (88mg, 0.222mmol), Pd(dba) 2 (64mg, 0.111mmol) and toluene (2ml) were added into the reaction flask, replaced with nitrogen three times, heated to 110°C and stirred for 16h. After the reaction, cool to room temperature, add ethyl acetate (10mL) and stir at room temperature for 10min, filter, the filtrate is concentrated under reduced pressure, and the residue is purified by Prep-HPLC (method 2) to obtain (R)-2-(5-(( 4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxo Pyridin-1(2H)-yl)-N,N-dimethylacetamide formate, yield 2.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.14(s, 2H), 7.68( t, J=12.0Hz, 1H), 7.57(s, 2H), 7.51-7.47(m, 1H), 7.42(s, 1H), 7.39(s, 1H), 7.29(t, J=15.2Hz, 1H ), 7.24(t, J=54.4Hz, 1H), 7.11(d, J=12.0Hz, 1H), 6.46(d, J=8.0Hz, 1H), 5.85-5.81(m, 1H), 4.79(s , 2H), 3.30(s, 3H), 3.04(s, 3H), 2.85(s, 3H), 2.29(s, 3H), 1.63(d, J=8.0Hz, 3H); ESI-MS(m/ z): 539.0 [M+H] + .
实施例44Example 44
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-(2-羟乙基)喹唑啉-6-基)(甲基)氨基))-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-(2-hydroxyethyl)quinazole Preparation of hydrin-6-yl)(methyl)amino))-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000145
Figure PCTCN2022101219-appb-000145
步骤a)：2-(6-溴-4-氧代-3，4-二氢喹唑啉-2-基)乙酸乙酯的制备Step a): Preparation of ethyl 2-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)acetate
将2-氨基-5-溴苯甲酸甲酯(5.0g，0.022mol)，氰基乙酸乙酯(2.7g，0.024mol)和氯化氢二氧六环溶液(4M，50mL)加入恒容反应器中，100℃反应16h。反应结束后，冷却至室温，减压浓缩，残余物加水(100mL)和饱和碳酸氢钠水溶液(20mL)调节pH至中性，室温搅拌5min，过滤，滤饼加入石油醚/乙酸乙酯混合溶剂(100mL，v/v＝10∶1)，室温搅拌10min，过滤，滤饼减压干燥，得2-(6-溴-4-氧代-3，4-二氢喹唑啉-2-基)乙酸乙酯，产率59.2％；ESI-MS(m/z)：311.0[M+H] +。 Methyl 2-amino-5-bromobenzoate (5.0 g, 0.022 mol), ethyl cyanoacetate (2.7 g, 0.024 mol) and hydrogen chloride dioxane solution (4M, 50 mL) were added to a constant volume reactor , 100°C for 16h. After the reaction, cool to room temperature, concentrate under reduced pressure, add water (100mL) and saturated aqueous sodium bicarbonate solution (20mL) to the residue to adjust the pH to neutral, stir at room temperature for 5min, filter, add petroleum ether/ethyl acetate mixed solvent to the filter cake (100mL, v/v=10:1), stirred at room temperature for 10min, filtered, and the filter cake was dried under reduced pressure to obtain 2-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl ) ethyl acetate, yield 59.2%; ESI-MS (m/z): 311.0 [M+H] + .
步骤b)：(R)-2-(6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-2-基)乙酸乙酯的制备Step b): (R)-2-(6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-2-yl) Preparation of ethyl acetate
将2-(6-溴-4-氧代-3，4-二氢喹唑啉-2-基)乙酸乙酯(1.6g，5.142mmol)，(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐(1.3g，5.761mmol)，BOP(2.8g，6.331mmol)，DBU(2.0g，13.137mmol)和DMF(16mL)加入反应瓶中，室温反应1h。向反应液中加入乙酸乙酯(80mL)和饱和氯化钠溶液(60mL)，分液，水相用乙酸乙酯萃取(50mL×2)，合并有机相，有机相以饱和食盐水洗涤(50mL×3)，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＝1/5)，得(R)-2-(6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-2-基)乙酸乙酯，产率43.9％；ESI-MS(m/z)：482.1[M+H] +。 Ethyl 2-(6-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)acetate (1.6g, 5.142mmol), (R)-1-(3-(difluoro Methyl)-2-fluorophenyl)ethan-1-amine hydrochloride (1.3g, 5.761mmol), BOP (2.8g, 6.331mmol), DBU (2.0g, 13.137mmol) and DMF (16mL) were added to the reaction In the bottle, react at room temperature for 1h. Add ethyl acetate (80mL) and saturated sodium chloride solution (60mL) to the reaction solution, separate the layers, extract the aqueous phase with ethyl acetate (50mL×2), combine the organic phases, and wash the organic phase with saturated brine (50mL ×3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/5) to obtain (R)-2-( 6-Bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-2-yl)ethyl acetate, yield 43.9%; ESI- MS (m/z): 482.1 [M+H] + .
步骤c)：(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙酸乙酯的制备Step c): (R)-2-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(difluoromethyl) Preparation of methylamino)-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)amino)quinazolin-2-yl)ethyl acetate
将(R)-2-(6-溴-4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)喹唑啉-2-基)乙酸乙酯(200.0mg，0.415mmol)，2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(93.5mg，0.419mmol)，X-Phos(79.0mg，0.166mmol)，Cs 2CO 3(270.3mg，0.830mmol)，Pd(dba)2(47.1mg，0.083mmol)和甲苯(4mL)依次加入到反应瓶中，氮气置换三次，95℃搅拌反应2h。将反应液降至室温，过滤，滤饼经乙酸乙酯(10mL)淋洗，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＝1/20)，得(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙酸乙酯，产率87.3％；ESI-MS(m/z)：625.3[M+H] +。 (R)-2-(6-bromo-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)quinazolin-2-yl)ethyl acetate (200.0 mg, 0.415 mmol), 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (93.5 mg, 0.419 mmol), X-Phos (79.0mg, 0.166mmol), Cs 2 CO 3 (270.3mg, 0.830mmol), Pd(dba)2 (47.1mg, 0.083mmol) and toluene (4mL) were sequentially added to the reaction flask, nitrogen replacement three times, 95 ℃ The reaction was stirred for 2h. The reaction solution was lowered to room temperature, filtered, the filter cake was rinsed with ethyl acetate (10 mL), the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), Get (R)-2-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(dimethylamino )-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)amino)quinazolin-2-yl)ethyl acetate, yield 87.3%; ESI-MS (m/z ): 625.3[M+H] + .
步骤d)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-(2-羟乙基)喹唑啉-6-基)(甲基)氨基))-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-(2-hydroxyethyl Base) quinazoline-6-yl) (methyl) amino))-2-methoxypyridin-3-yl)-N, the preparation of N-dimethylacetamide formate
将(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙酸乙酯(226.0mg，0.362mmol)，硼氢化钠(18.1mg，0.478mmol)，三氟化硼乙醚络合物(56.2mg，0.396mmol)和THF(4mL)依次加入反应瓶中，氮气置换三次，室温搅拌反应2h。向反应液中加入乙酸乙酯(20mL)和饱和碳酸氢钠(20mL)，分液，有机相经饱和氯化钠水溶液(20mL)洗涤，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：甲醇/二氯甲烷＝1/20)，所得粗品再经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-(2-羟乙基)喹唑啉-6-基)(甲基)氨基))-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率4.7％； 1H NMR(400MHz，DMSO-d 6)δ12.68(s，1H)，8.25(d，J＝6.8Hz，1H)，8.14(s，1H)，7.93-7.92(s，1H)，7.75(s，1H)，7.67(t，J＝7.2Hz，1H)，7.53-7.46(m，2H)，7.42(d，J＝9.2Hz，1H)，7.29(t，J＝7.6Hz，1H)，7.37-7.10(m，1H)，7.14(d，J＝9.2Hz，1H)，5.79(s，1H)，4.44(s，1H)，3.90(s，3H)，3.74-3.61(m，2H)，3.38(s，2H)，2.89(s，3H)，2.75-2.69(m，2H)，2.55(s，6H)，1.63(d，J＝7.2Hz，3H)；ESI-MS(m/z)：583.0[M+H] +。 (R)-2-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(Dimethylamino )-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)amino)quinazolin-2-yl)ethyl acetate (226.0mg, 0.362mmol), sodium borohydride (18.1 mg, 0.478mmol), boron trifluoride etherate (56.2mg, 0.396mmol) and THF (4mL) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at room temperature for 2h. Add ethyl acetate (20mL) and saturated sodium bicarbonate (20mL) to the reaction solution, separate the layers, wash the organic phase with a saturated aqueous sodium chloride solution (20mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The product was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(5-((4- ((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-(2-hydroxyethyl)quinazolin-6-yl)(methyl)amino)) -2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate, yield 4.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.68 (s, 1H) , 8.25(d, J=6.8Hz, 1H), 8.14(s, 1H), 7.93-7.92(s, 1H), 7.75(s, 1H), 7.67(t, J=7.2Hz, 1H), 7.53- 7.46(m, 2H), 7.42(d, J=9.2Hz, 1H), 7.29(t, J=7.6Hz, 1H), 7.37-7.10(m, 1H), 7.14(d, J=9.2Hz, 1H ), 5.79(s, 1H), 4.44(s, 1H), 3.90(s, 3H), 3.74-3.61(m, 2H), 3.38(s, 2H), 2.89(s, 3H), 2.75-2.69( m, 2H), 2.55 (s, 6H), 1.63 (d, J=7.2Hz, 3H); ESI-MS (m/z): 583.0 [M+H] + .
实施例45Example 45
(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙基-1-醇的制备(R)-2-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(Dimethylamino) Preparation of ethyl)-6-methoxypyridin-3-yl)(methyl)amino)quinazolin-2-yl)ethyl-1-ol
Figure PCTCN2022101219-appb-000146
Figure PCTCN2022101219-appb-000146
将(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙酸乙酯(958.0mg，1.534mmol)，硼氢化钠(580.3mg，15.340mmol)，三氟化硼乙醚络合物(2.2g，15.501mmol)和THF(20mL)依次加入反应瓶中，氮气置换三次，0℃搅拌反应1h。反应结束后，加入乙酸乙酯(50mL)和饱和碳酸氢钠(50mL)，分液，有机相经饱和氯化钠(50mL)洗涤，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：甲醇/二氯甲烷＝1/20)，所得粗品再经Prep-HPLC(方法3)纯化，得(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙基-1-醇，产率6.3％； 1H NMR(400MHz，DMSO-d 6)δ8.24(d，J＝6.8Hz，1H)，7.89(s，1H)，7.72(s，1H)，7.67(t，J＝7.2Hz，1H)，7.49(t，J＝6.8Hz，1H)，7.45(s，1H)，7.40(d，J＝9.2Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.37-7.10(m，1H)，7.13(d，J＝9.2Hz，1H)，5.79(s，1H)，4.44(m，1H)，3.88(s，3H)，3.75-3.59(m，2H)，3.38(s，3H)，2.76-2.62(m，4H)，2.44-2.39(m，2H)，2.14(s，6H)，1.63(d，J＝7.2Hz，3H)；ESI-MS(m/z)：569.0[M+H] +。 (R)-2-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(Dimethylamino )-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)amino)quinazolin-2-yl)ethyl acetate (958.0mg, 1.534mmol), sodium borohydride (580.3 mg, 15.340mmol), boron trifluoride etherate (2.2g, 15.501mmol) and THF (20mL) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at 0°C for 1h. After the reaction, add ethyl acetate (50mL) and saturated sodium bicarbonate (50mL), separate the layers, wash the organic phase with saturated sodium chloride (50mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, the residue Purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), the obtained crude product was purified by Prep-HPLC (method 3) to obtain (R)-2-(4-((1-( 3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(dimethylamino)ethyl)-6-methoxypyridin-3-yl )(methyl)amino)quinazolin-2-yl)ethyl-1-ol, yield 6.3%; 1 H NMR (400MHz, DMSO-d 6 )δ8.24 (d, J=6.8Hz, 1H ), 7.89(s, 1H), 7.72(s, 1H), 7.67(t, J=7.2Hz, 1H), 7.49(t, J=6.8Hz, 1H), 7.45(s, 1H), 7.40(d , J=9.2Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.37-7.10(m, 1H), 7.13(d, J=9.2Hz, 1H), 5.79(s, 1H), 4.44 (m, 1H), 3.88(s, 3H), 3.75-3.59(m, 2H), 3.38(s, 3H), 2.76-2.62(m, 4H), 2.44-2.39(m, 2H), 2.14(s , 6H), 1.63 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 569.0 [M+H] + .
实施例46Example 46
(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-2-乙基-N 6-甲基喹唑啉-4，6-二氨甲酸盐的制备 (R)-N 4 -(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-N 6 -(5-(2-(Dimethylamino)ethyl)-6- Preparation of methoxypyridin-3-yl)-2-ethyl-N 6 -methylquinazoline-4,6-dicarbamate
Figure PCTCN2022101219-appb-000147
Figure PCTCN2022101219-appb-000147
将(R)-2-(4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-6-((5-(2-(二甲基氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)喹唑啉-2-基)乙酸乙酯(958mg，1.534mmol)，硼氢化钠(580mg，15.340mmol)，三氟化硼乙醚溶液(2.2g，15.501mmol)和THF(20mL)依次加入反应瓶中，氮气置换三次，0℃搅拌反应1h。反应结束后，加入乙酸乙酯(50mL)和饱和碳酸氢钠(50mL)搅拌稀释，分液，有机相经饱和氯化钠水溶液(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩至干，残余物经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)，所得粗品再经Prep-HPLC(方法2)纯化，得(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-2-乙基-N 6-甲基喹唑啉-4，6-二氨甲酸盐，产率2.0％； 1H NMR(400MHz，DMSO-d 6)δ12.76(s，1H)，8.23(d，J＝6.8Hz，1H)，8.15(s，1H)，7.89(s，1H)，7.73(s，1H)，7.66(t，J＝7.2Hz，1H)，7.51-7.44(m，2H)，7.40(d，J＝9.2Hz，1H)，7.27(t，J＝7.6Hz，1H)，7.36-7.09(m，1H)，7.11(d，J＝9.2Hz，1H)，5.78(s，1H)，3.88(s，3H)，3.38(s，3H)，2.76-2.63(m，2H)，2.61-2.52(m，4H)，2.20(s，6H)，1.63(d，J＝7.2Hz，3H)，1.05(t，J＝7.6Hz，3H)；ESI-MS(m/z)：553.3[M+H] +。 (R)-2-(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-6-((5-(2-(Dimethylamino )-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)amino)quinazolin-2-yl)ethyl acetate (958mg, 1.534mmol), sodium borohydride (580mg, 15.340mmol), boron trifluoride ether solution (2.2g, 15.501mmol) and THF (20mL) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at 0°C for 1h. After the reaction, add ethyl acetate (50mL) and saturated sodium bicarbonate (50mL) to stir and dilute, separate the layers, wash the organic phase with saturated aqueous sodium chloride solution (50mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure To dryness, the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20), and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-N 4 -(1 -(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-N 6 -(5-(2-(Dimethylamino)ethyl)-6-methoxypyridin-3-yl) -2-Ethyl-N 6 -methylquinazoline-4,6-dicarbamate, yield 2.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.76 (s, 1H), 8.23(d, J=6.8Hz, 1H), 8.15(s, 1H), 7.89(s, 1H), 7.73(s, 1H), 7.66(t, J=7.2Hz, 1H), 7.51-7.44(m , 2H), 7.40(d, J=9.2Hz, 1H), 7.27(t, J=7.6Hz, 1H), 7.36-7.09(m, 1H), 7.11(d, J=9.2Hz, 1H), 5.78 (s, 1H), 3.88(s, 3H), 3.38(s, 3H), 2.76-2.63(m, 2H), 2.61-2.52(m, 4H), 2.20(s, 6H), 1.63(d, J = 7.2 Hz, 3H), 1.05 (t, J = 7.6 Hz, 3H); ESI-MS (m/z): 553.3 [M+H] + .
实施例47Example 47
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氧基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) Oxygen)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000148
Figure PCTCN2022101219-appb-000148
步骤a)：2-(5-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step a): Preparation of 2-(5-bromo-2-methoxyphenyl)-N,N-dimethylacetamide
将2-(5-溴-2-甲氧基苯基)乙酸(2.70g，11.017mmol)和二氯甲烷(50mL)加入到反应瓶中，室温下依次缓慢加入二甲胺盐酸盐(1.17g，14.322mmol)、DIPEA(4.27g，33.051mmol)和HATU(6.28g，16.526mmol)，维持室温搅拌反应2h。反应结束后，加水(50mL)淬灭反应，用二氯甲烷萃取(50mL×3)，合并有机相，依次用饱和碳酸氢钠水溶液(50mL)和饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干，得2-(5-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率98.7％。无需进一步进一步纯化直接用于下一步反应；ESI-MS(m/z)＝272.1[M+H] +。 2-(5-Bromo-2-methoxyphenyl)acetic acid (2.70g, 11.017mmol) and dichloromethane (50mL) were added to the reaction flask, and dimethylamine hydrochloride (1.17 g, 14.322mmol), DIPEA (4.27g, 33.051mmol) and HATU (6.28g, 16.526mmol), kept stirring at room temperature for 2h. After the reaction, add water (50mL) to quench the reaction, extract with dichloromethane (50mL×3), combine the organic phases, wash with saturated aqueous sodium bicarbonate (50mL) and saturated brine (50mL) successively, anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated to dryness under reduced pressure to obtain 2-(5-bromo-2-methoxyphenyl)-N,N-dimethylacetamide with a yield of 98.7%. It was directly used in the next reaction without further purification; ESI-MS (m/z) = 272.1 [M+H] + .
步骤b)：2-(2-甲氧基-5-(4，4，5，5-四甲基-1，3，2-二氧硼烷-2-基)苯基)-N，N-二甲基乙酰胺的制备Step b): 2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N - Preparation of dimethylacetamide
将2-(5-溴-2-甲氧基苯基)-N，N-二甲基乙酰胺(2.96g，9.273mmol)、乙酸钾(2.73g，27.819mmol)、联硼酸频那醇酯(3.53g，13.910mmol)和1，4-二氧六环(45mL)加入到反应瓶中，最后加入Pd(dppf)Cl 2(339mg，0.464mmol)，氮气置换三次，升温至80℃搅拌反应6h。反应结束后，加水(50mL)淬灭反应，用乙酸乙酯萃取(50mL×3)，合并有机相，饱和食盐水(30mL)洗涤，无水硫酸钠干燥，过滤，有机相减压浓缩干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2/3)，得2-(2-甲氧基-5-(4，4，5，5-四甲基-1，3，2-二氧硼烷-2-基)苯基)-N，N-二甲基乙酰胺，产率89.3％；ESI-MS(m/z)＝320.3[M+H] +。 2-(5-bromo-2-methoxyphenyl)-N,N-dimethylacetamide (2.96g, 9.273mmol), potassium acetate (2.73g, 27.819mmol), biboronic acid pinacol ester (3.53g, 13.910mmol) and 1,4-dioxane (45mL) were added to the reaction flask, and finally Pd(dppf)Cl 2 (339mg, 0.464mmol) was added, nitrogen was replaced three times, and the temperature was raised to 80°C to stir the reaction 6h. After the reaction was completed, add water (50 mL) to quench the reaction, extract with ethyl acetate (50 mL×3), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the organic phases under reduced pressure to dryness. The residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/3) to obtain 2-(2-methoxy-5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylacetamide, yield 89.3%; ESI-MS (m/z)=320.3[M+H] + .
步骤c)：2-(5-羟基-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step c): Preparation of 2-(5-hydroxy-2-methoxyphenyl)-N,N-dimethylacetamide
将2-(2-甲氧基-5-(4，4，5，5-四甲基-1，3，2-二氧硼烷-2-基)苯基)-N，N-二甲基乙酰胺(3.10g，9.71mmol)和四氢呋喃(90mL)加入到反应瓶中，0℃下搅拌条件滴加双氧水(2.00g，19.423mmol，33％)。滴加完毕后， 室温搅拌反应2h。反应结束后，将反应液减压浓缩干，残余物用硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得2-(5-羟基-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率54.1％；ESI-MS(m/z)：210.2[M+H] +。 2-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethyl Acetamide (3.10 g, 9.71 mmol) and tetrahydrofuran (90 mL) were added to the reaction flask, and hydrogen peroxide (2.00 g, 19.423 mmol, 33%) was added dropwise with stirring at 0°C. After the dropwise addition, the reaction was stirred at room temperature for 2 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column (eluent: petroleum ether/ethyl acetate=1/1) to obtain 2-(5-hydroxy-2-methoxyphenyl )-N,N-dimethylacetamide, yield 54.1%; ESI-MS (m/z): 210.2[M+H] + .
步骤d)：5-(3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯氧基)-2-硝基苯甲酸甲酯的制备Step d): Preparation of methyl 5-(3-(2-(dimethylamino)-2-oxyethyl)-4-methoxyphenoxy)-2-nitrobenzoate
将2-(5-羟基-2-甲氧基苯基)-N，N-二甲基乙酰胺(900mg，4.301mmol)、5-氟-2-硝基苯甲酸甲酯(867mg，4.301mmol)、碳酸钾(1.19g，8.602mmol)和DMF(18mL)加入反应瓶中，室温搅拌反应2h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干，残余物经硅胶柱纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得5-(3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯氧基)-2-硝基苯甲酸甲酯，产率95.8％；ESI-MS(m/z)：389.0[M+H] +。 2-(5-Hydroxy-2-methoxyphenyl)-N,N-dimethylacetamide (900mg, 4.301mmol), methyl 5-fluoro-2-nitrobenzoate (867mg, 4.301mmol ), potassium carbonate (1.19g, 8.602mmol) and DMF (18mL) were added into the reaction flask, and the reaction was stirred at room temperature for 2h. After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. The product was purified by silica gel column (eluent: petroleum ether/ethyl acetate=1/1) to obtain 5-(3-(2-(dimethylamino)-2-oxyethyl)-4-methoxybenzene Oxy)-methyl 2-nitrobenzoate, yield 95.8%; ESI-MS (m/z): 389.0 [M+H] + .
步骤e)：2-氨基-5-(3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯氧基)苯甲酸甲酯的制备Step e): Preparation of methyl 2-amino-5-(3-(2-(dimethylamino)-2-oxyethyl)-4-methoxyphenoxy)benzoate
将甲醇(32mL)、5-(3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯氧基)-2-硝基苯甲酸甲酯(1.60g，4.120mmol)和钯碳(160mg，5％)依次加入反应瓶中，氢气置换3次，并在氢气氛围中室温搅拌2h。反应完毕，过滤，滤液减压浓缩，得2-氨基-5-(3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯氧基)苯甲酸甲酯，无需进一步纯化直接用于下一步反应；ESI-MS(m/z)：359.2[M+H] +。 Methanol (32 mL), methyl 5-(3-(2-(dimethylamino)-2-oxoethyl)-4-methoxyphenoxy)-2-nitrobenzoate (1.60 g, 4.120 mmol) and palladium on carbon (160 mg, 5%) were sequentially added into the reaction flask, hydrogen was replaced 3 times, and stirred at room temperature for 2 h in a hydrogen atmosphere. After completion of the reaction, filter, and concentrate the filtrate under reduced pressure to obtain methyl 2-amino-5-(3-(2-(dimethylamino)-2-oxyethyl)-4-methoxyphenoxy)benzoate, It was directly used in the next reaction without further purification; ESI-MS (m/z): 359.2[M+H] + .
步骤f)：2-(5-((4-羟基-2-甲基喹唑啉-6-基)氧基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step f): 2-(5-((4-hydroxyl-2-methylquinazolin-6-yl)oxy)-2-methoxyphenyl)-N,N-dimethylacetamide preparation
将2-氨基-5-(3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯氧基)苯甲酸甲酯(1.1g，3.069mmol)、乙腈(22mL)和4M的盐酸二氧六环溶液(22mL)加入到恒容反应瓶中，维持110℃搅拌反应16h。反应结束后，将反应液减压浓缩干，残余物用4N的氨水(30mL)室温打浆1h，过滤，固体用DMF(10mL)溶解，经C18柱纯化(洗脱剂：水/乙腈＝3/2)，得2-(5-((4-羟基-2-甲基喹唑啉-6-基)氧基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率17.7％；ESI-MS(m/z)：368.2[M+H] +。 2-Amino-5-(3-(2-(dimethylamino)-2-oxoethyl)-4-methoxyphenoxy)methyl benzoate (1.1g, 3.069mmol), acetonitrile (22mL ) and 4M dioxane hydrochloride solution (22 mL) were added into a constant volume reaction flask, and the reaction was maintained at 110° C. and stirred for 16 h. After the reaction, the reaction liquid was concentrated to dryness under reduced pressure, the residue was beaten with 4N ammonia water (30 mL) at room temperature for 1 h, filtered, the solid was dissolved in DMF (10 mL), and purified by a C18 column (eluent: water/acetonitrile=3/ 2), to get 2-(5-((4-hydroxyl-2-methylquinazolin-6-yl) oxy)-2-methoxyphenyl)-N,N-dimethylacetamide, Yield 17.7%; ESI-MS (m/z): 368.2 [M+H] + .
步骤g)：(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)苯基)-N，N-二甲基乙酰胺的制备Step g): (R)-2-(2-methoxy-5-((2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethane Base) amino) quinazoline-6-yl) oxy) phenyl) -N, the preparation of N-dimethylacetamide
将2-(5-((4-羟基-2-甲基喹唑啉-6-基)氧基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(200mg，0.544mmol)和DMF(5mL)加入到反应瓶中，室温下依次缓慢加入(R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺盐酸盐(177mg，0.653mmol)、DBU(248mg，1.632mmol)和BOP(481mg，1.088mmol)，室温搅拌反应16h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝15/1)，得(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)苯基)-N，N-二甲基乙酰胺，产率47.2％；ESI-MS(m/z)：584.2[M+H] +。 2-(5-((4-Hydroxy-2-methylquinazolin-6-yl)oxy)-2-methoxyphenyl)-N,N-dimethylacetamide (200mg, 0.544 mmol) and DMF (5mL) were added to the reaction flask, and (R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride ( 177mg, 0.653mmol), DBU (248mg, 1.632mmol) and BOP (481mg, 1.088mmol), stirred at room temperature for 16h. After the reaction, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=15/1) to obtain (R)-2-(2-methoxy-5-((2-methyl-4-( (1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)phenyl)-N,N-dimethylacetamide, Yield 47.2%; ESI-MS (m/z): 584.2 [M+H] + .
步骤h)：(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)苯基)-N，N-二甲基乙酰胺的制备Step h): (R)-2-(2-methoxy-5-((2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl))ethane Base) amino) quinazoline-6-yl) oxy) phenyl) -N, the preparation of N-dimethylacetamide
将乙醇(2mL)、水(2mL)、(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)苯基)-N，N-二甲基乙酰胺(150mg，0.257mmol)、铁粉(58mg，1.028mmol)、无水氯化铵(55mg，1.028mmol)依次加入到反应瓶中，维持80℃搅拌反应2h。反应结束后，将反应液冷却至室温，过滤，固体用乙酸乙酯(5mL×3)淋洗，滤液分液，水相用乙酸乙酯(5mL)萃取，合并有机相，用饱和食盐水(10mL)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3)纯化，得(R)-2-(2-甲氧基-5-((2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氧基)苯基)-N，N-二甲基乙酰胺产率24.2％；1H NMR(400MHz，DMSO-d6)δ8.28(d，J＝8.0Hz，1H)，8.20(s，1H)，7.64(d，J＝9.2Hz，1H)，7.44(d，J＝8.8Hz，1H)，7.05(d，J＝8.4Hz，1H)，6.89(s，1H)，6.85(s，1H)，6.72(s，1H)，6.69(s，1H)，6.45(d，J＝8.0Hz，1H)，5.57-5.49(m，3H)，3.72(s，3H)，3.54(s，2H)，3.01(s，3H)，2.83(s，3H)，2.40(s，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：554.0[M+H] +。 Ethanol (2mL), water (2mL), (R)-2-(2-methoxy-5-((2-methyl-4-((1-(3-nitro-5-(trifluoro Methyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)phenyl)-N,N-dimethylacetamide (150mg, 0.257mmol), iron powder (58mg, 1.028mmol) , anhydrous ammonium chloride (55 mg, 1.028 mmol) were sequentially added into the reaction flask, and the reaction was maintained at 80° C. and stirred for 2 h. After the reaction, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5mL×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5mL), the organic phases were combined, and washed with saturated brine ( 10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting crude product was purified by Prep-HPLC (method 3) to obtain (R)-2-(2-methoxy-5-((2-methoxy Base-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)oxy)phenyl)-N,N-two The yield of methylacetamide is 24.2%; 1H NMR (400MHz, DMSO-d6) δ8.28(d, J=8.0Hz, 1H), 8.20(s, 1H), 7.64(d, J=9.2Hz, 1H) , 7.44(d, J=8.8Hz, 1H), 7.05(d, J=8.4Hz, 1H), 6.89(s, 1H), 6.85(s, 1H), 6.72(s, 1H), 6.69(s, 1H), 6.45(d, J=8.0Hz, 1H), 5.57-5.49(m, 3H), 3.72(s, 3H), 3.54(s, 2H), 3.01(s, 3H), 2.83(s, 3H ), 2.40 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 554.0 [M+H] + .
实施例48Example 48
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氧基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) Oxygen group)-2-Hydroxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000149
Figure PCTCN2022101219-appb-000149
将(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氧基)-2-甲氧基苯基)-N，N-二 甲基乙酰胺(50mg，0.093mmol)和二氯甲烷(2mL)加入到反应瓶中，在冰水浴下，缓慢滴加三溴化硼(232mg，0.927mmol)。滴加完毕后，维持室温搅拌反应1h。反应结束后，加甲醇(5mL)淬灭反应，将反应液减压浓缩干，所得粗品经Pre-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)氧基)-2-羟基苯基)-N，N-二甲基乙酰胺，产率59.5％；1H NMR(400MHz，DMSO-d6)δ9.70(s，1H)，8.27(d，J＝8.0Hz，1H)，7.64(d，J＝9.2Hz，1H)，7.44(d，J＝8.0Hz，1H)，7.02(d，J＝8.8Hz，1H)，6.89(s，1H)，8.17(s，1H)，6.84(s，1H)，6.69(s，1H)，6.42-6.39(m，2H)，5.54-5.51(m，3H)，3.52(s，2H)，3.02(s，3H)，2.83(s，3H)，2.41(s，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：540.0[M+H] +。 (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- Base) oxy)-2-methoxyphenyl)-N,N-dimethylacetamide (50mg, 0.093mmol) and dichloromethane (2mL) were added to the reaction flask, under ice-water bath, slowly drop Add boron tribromide (232 mg, 0.927 mmol). After the dropwise addition was completed, the reaction was maintained at room temperature and stirred for 1 h. After the reaction was completed, methanol (5 mL) was added to quench the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the obtained crude product was purified by Pre-HPLC (method 3) to obtain (R)-2-(5-((4-((1 -(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)oxy)-2-hydroxyphenyl)-N,N- Dimethylacetamide, yield 59.5%; 1H NMR (400MHz, DMSO-d6) δ9.70(s, 1H), 8.27(d, J=8.0Hz, 1H), 7.64(d, J=9.2Hz, 1H), 7.44(d, J=8.0Hz, 1H), 7.02(d, J=8.8Hz, 1H), 6.89(s, 1H), 8.17(s, 1H), 6.84(s, 1H), 6.69( s, 1H), 6.42-6.39(m, 2H), 5.54-5.51(m, 3H), 3.52(s, 2H), 3.02(s, 3H), 2.83(s, 3H), 2.41(s, 3H) , 1.52 (d, J=7.2 Hz, 3H); ESI-MS (m/z): 540.0 [M+H] + .
实施例49Example 49
(R)-1-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-甲基咪唑烷-2-酮的制备(R)-1-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl)amino)-2-methoxypyridin-3-yl)-3-methylimidazolidin-2-one preparation
Figure PCTCN2022101219-appb-000150
Figure PCTCN2022101219-appb-000150
步骤a)：1-(2-甲氧基-5-硝基吡啶-3-基)咪唑烷-2-酮的制备Step a): Preparation of 1-(2-methoxy-5-nitropyridin-3-yl)imidazolidin-2-one
将甲苯(20mL)、3-溴-2-甲氧基-5-硝基吡啶(1.00g，4.291mmol)、咪唑烷-2-酮(443mg，5.150mmol)、X-Phos(205mg，0.429mmol)，Cs 2CO 3(4.20g，12.874mmol)和Pd(dba) 2(123mg，0.215mmol)依次加入反应瓶中，氮气置换三次，110℃搅拌反应3h。反应结束后，加水(30mL)淬灭反应，用乙酸乙酯萃取(30mL×2)，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，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝3/7)，得1-(2-甲氧基-5-硝基吡啶-3-基)咪唑烷-2-酮，产率78.3％；ESI-MS(m/z)＝239.1[M+H] +。 Toluene (20mL), 3-bromo-2-methoxy-5-nitropyridine (1.00g, 4.291mmol), imidazolidin-2-one (443mg, 5.150mmol), X-Phos (205mg, 0.429mmol ), Cs 2 CO 3 (4.20g, 12.874mmol) and Pd(dba) 2 (123mg, 0.215mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, and stirred at 110°C for 3h. After the reaction was completed, add water (30 mL) to quench the reaction, extract with ethyl acetate (30 mL×2), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/7) to obtain 1-(2-methoxy-5-nitropyridin-3-yl)imidazolidin-2-one , yield 78.3%; ESI-MS (m/z) = 239.1 [M+H] + .
步骤b)：1-(2-甲氧基-5-硝基吡啶-3-基)-3-甲基咪唑烷-2-酮的制备Step b): Preparation of 1-(2-methoxy-5-nitropyridin-3-yl)-3-methylimidazolidin-2-one
将1-(2-甲氧基-5-硝基吡啶-3-基)咪唑烷-2-酮(800mg，3.359mmol)、NaH(403mg，10.076mmol，60％)和THF(16mL)加入反应瓶中，冰浴条件下搅拌20min，保持冰水浴下加入碘甲烷(142mg，1.000mmol)，缓慢升至室温搅拌反应2h。反应结束后，加水(30mL)淬灭，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品直接用于下一步反应；ESI-MS(m/z)：252.1[M+H] +。 1-(2-Methoxy-5-nitropyridin-3-yl)imidazolidin-2-one (800 mg, 3.359 mmol), NaH (403 mg, 10.076 mmol, 60%) and THF (16 mL) were added to the reaction Stir in the bottle for 20 min under ice-bath conditions, add iodomethane (142 mg, 1.000 mmol) under ice-water bath, slowly rise to room temperature and stir for 2 h. After the reaction was completed, add water (30 mL) to quench, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The obtained crude product was directly used in the next reaction; ESI-MS (m/z): 252.1[M+H] + .
步骤c)：1-(5-氨基-2-甲氧基吡啶-3-基)-3-甲基咪唑烷-2-酮的制备Step c): Preparation of 1-(5-amino-2-methoxypyridin-3-yl)-3-methylimidazolidin-2-one
将乙醇(8mL)、水(8mL)、1-(5-氨基-2-甲氧基吡啶-3-基)-3-甲基咪唑烷-2-酮(800mg，3.172mmol)、铁粉(710mg，12.687mmol)、无水氯化铵(679mg，12.687mmol)依次加入到反应瓶中，维持80℃搅拌反应2h。反应结束后，将反应液冷却至室温，过滤，固体用乙酸乙酯(10mL×3)淋洗，滤液分液，水相用乙酸乙酯(10mL)萃取，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干，所得无需进一步纯化直接用于下一步反应；ESI-MS(m/z)：223.1[M+H] +。 Ethanol (8 mL), water (8 mL), 1-(5-amino-2-methoxypyridin-3-yl)-3-methylimidazolidin-2-one (800 mg, 3.172 mmol), iron powder ( 710mg, 12.687mmol), anhydrous ammonium chloride (679mg, 12.687mmol) were sequentially added into the reaction flask, and the reaction was maintained at 80°C for 2h with stirring. After the reaction, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (10mL×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (10mL), washed with saturated brine (10mL), Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. The obtained product is directly used in the next reaction without further purification; ESI-MS (m/z): 223.1[M+H] + .
步骤d)：(6-甲氧基-5-(3-甲基-2-氧代咪唑啉-1-基)吡啶-3-基)氨基甲酸叔丁酯的制备Step d): Preparation of tert-butyl (6-methoxy-5-(3-methyl-2-oxoimidazolin-1-yl)pyridin-3-yl)carbamate
将1-(5-氨基-2-甲氧基吡啶-3-基)-3-甲基咪唑烷-2-酮(500mg，2.250mmol)、DIPEA(871mg，6.749mmol)和二氯甲烷(10mL)依次加入反应瓶中，搅拌溶解，再滴加Boc 2O(729mg，3.375mmol)，室温搅拌反应4h。反应完毕，减压浓缩干，残余物用硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得(6-甲氧基-5-(3-甲基-2-氧代咪唑啉-1-基)吡啶-3-基)氨基甲酸叔丁酯，产率24.8％；ESI-MS(m/z)：323.2[M+H] +。 1-(5-Amino-2-methoxypyridin-3-yl)-3-methylimidazolidin-2-one (500 mg, 2.250 mmol), DIPEA (871 mg, 6.749 mmol) and dichloromethane (10 mL ) into the reaction flask in turn, stirred to dissolve, then added Boc 2 O (729mg, 3.375mmol) dropwise, and stirred at room temperature for 4h. After the reaction was completed, it was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (6-methoxy-5-(3-methyl-2 -Oxoimidazolin-1-yl)pyridin-3-yl)carbamate tert-butyl ester, yield 24.8%; ESI-MS (m/z): 323.2 [M+H] + .
步骤e)：(6-甲氧基-5-(3-甲基-2-氧代咪唑啉-1-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯的制备Step e): Preparation of (6-methoxy-5-(3-methyl-2-oxoimidazolin-1-yl)pyridin-3-yl)(methyl)carbamate tert-butyl ester
将(6-甲氧基-5-(3-甲基-2-氧代咪唑啉-1-基)吡啶-3-基)氨基甲酸叔丁酯(180mg，0.558mmol)、NaH(67 mg，1.675mmol，60％)和四氢呋喃(5mL)加入反应瓶中，冰浴条件下搅拌20min，保持冰水浴下加入碘甲烷(119mg，0.838mmol)，缓慢升至室温搅拌反应2h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，合并有机相，用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝1/1)，得(6-甲氧基-5-(3-甲基-2-氧代咪唑啉-1-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯，产率79.7％；ESI-MS(m/z)：337.2[M+H] +。 (6-Methoxy-5-(3-methyl-2-oxoimidazolin-1-yl)pyridin-3-yl)carbamate tert-butyl ester (180 mg, 0.558 mmol), NaH (67 mg, 1.675mmol, 60%) and tetrahydrofuran (5mL) were added to the reaction flask, stirred in ice bath for 20min, then added iodomethane (119mg, 0.838mmol) in ice-water bath, slowly raised to room temperature and stirred for 2h. After the reaction, add water (10mL) to quench the reaction, extract with ethyl acetate (10mL×3), combine the organic phases, wash with saturated brine (10mL×2), dry over anhydrous sodium sulfate, filter, and depressurize the organic phase Concentrate to dryness, and the residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (6-methoxy-5-(3-methyl-2-oxoimidazoline -1-yl)pyridin-3-yl)tert-butyl (methyl)carbamate, yield 79.7%; ESI-MS (m/z): 337.2 [M+H] + .
步骤f)：1-(2-甲氧基-5-(甲基氨基)吡啶-3-基)-3-甲基咪唑烷-2-酮盐酸盐的制备Step f): Preparation of 1-(2-methoxy-5-(methylamino)pyridin-3-yl)-3-methylimidazolidin-2-one hydrochloride
将(6-甲氧基-5-(3-甲基-2-氧代咪唑啉-1-基)吡啶-3-基)(甲基)氨基甲酸叔丁酯(150mg，0.446mmol)和氯化氢乙酸乙酯溶液(4mL，4M)加入反应瓶中，室温搅拌反应1h。反应结束后，将反应液减压浓缩干，得1-(2-甲氧基-5-(甲基氨基)吡啶-3-基)-3-甲基咪唑烷-2-酮盐酸盐，产率98.8％；ESI-MS(m/z)：237.1[M+H] +。 (6-Methoxy-5-(3-methyl-2-oxoimidazolin-1-yl)pyridin-3-yl)(methyl)carbamate tert-butyl ester (150 mg, 0.446 mmol) and hydrogen chloride Ethyl acetate solution (4 mL, 4M) was added into the reaction flask, and the reaction was stirred at room temperature for 1 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure to obtain 1-(2-methoxy-5-(methylamino)pyridin-3-yl)-3-methylimidazolidin-2-one hydrochloride, Yield 98.8%; ESI-MS (m/z): 237.1 [M+H] + .
步骤g)：(R)-1-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-3-甲基咪唑烷-2-酮的制备Step g): (R)-1-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl ) ethyl) amino) quinazoline-6-yl) amino) pyridin-3-yl) preparation of -3-methylimidazolidin-2-one
将甲苯(5mL)、1-(2-甲氧基-5-(甲基氨基)吡啶-3-基)-3-甲基咪唑烷-2-酮盐酸盐(157mg，0.641mmol)、(R)-6-溴-2-甲基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(292mg，0.641mmol)、X-Phos(61mg，0.128mmol)，Cs 2CO 3(627mg，1.923mmol)和Pd(dba)2(37mg，0.064mmol)依次加入反应瓶中，氮气置换三次，升温至90℃搅拌反应3h。反应结束后，加水(10mL)淬灭反应，用乙酸乙酯萃取(10mL×3)，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，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-1-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-3-甲基咪唑烷-2-酮，产率66.1％；ESI-MS(m/z)：611.2[M+H] +。 Toluene (5 mL), 1-(2-methoxy-5-(methylamino)pyridin-3-yl)-3-methylimidazolidin-2-one hydrochloride (157 mg, 0.641 mmol), ( R)-6-bromo-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (292mg, 0.641mmol) , X-Phos (61mg, 0.128mmol), Cs 2 CO 3 (627mg, 1.923mmol) and Pd(dba)2 (37mg, 0.064mmol) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred for 3h . After the reaction was completed, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-1-(2-methoxy-5-(methyl(2-methyl-4- ((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-3-methylimidazolidine- 2-Kone, yield 66.1%; ESI-MS (m/z): 611.2 [M+H] + .
步骤h)：(R)-1-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-甲基咪唑烷-2-酮的制备Step h): (R)-1-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-3-methylimidazolidin-2-one
将乙醇(2mL)、水(2mL)、(3-(2-(二甲基氨基)-2-氧乙基)-2-甲氧基苯基)氨基甲酸叔丁酯(180mg，0.295mmol)、铁粉(66mg，1.180mmol)、无水氯化铵(63mg，1.180mmol)依次加入到反应瓶中，维持80℃搅拌反应2h。反应结束后，将反应液降至室温，过滤，固体用乙酸乙酯(5mL×3)淋洗，滤液分液，水相用乙酸乙酯(5mL)萃取，合并有机相，用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤，将滤液减压浓缩干，所得粗品经Prep-HPLC(方法3)纯化，得(R)-1-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-甲基咪唑烷-2-酮，产率28.3％； 1H NMR(400MHz，DMSO-d 6)δ8.11(d，J＝8.0Hz，1H)，7.88(s，1H)，7.74(s，1H)，7.55(s，1H)，7.42(d，J＝9.2Hz，1H)，7.20(d，J＝8.0Hz，1H)，6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.62-5.56(m，1H)，5.53(brs，2H)，3.89(s，3H)，3.75-3.71(m，2H)，3.42-3.38(m，2H)，3.37(s，3H)，2.70(s，3H)，2.36(s，3H)，1.56(d，J＝6.8Hz，3H)；ESI-MS(m/z)：581.0[M+H] +。 Ethanol (2 mL), water (2 mL), tert-butyl (3-(2-(dimethylamino)-2-oxyethyl)-2-methoxyphenyl)carbamate (180 mg, 0.295 mmol) , iron powder (66mg, 1.180mmol), and anhydrous ammonium chloride (63mg, 1.180mmol) were sequentially added into the reaction flask, and kept stirring at 80°C for 2h. After the reaction, the reaction solution was cooled to room temperature, filtered, the solid was rinsed with ethyl acetate (5mL×3), the filtrate was separated, the aqueous phase was extracted with ethyl acetate (5mL), the organic phases were combined, and washed with saturated brine ( 10 mL), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 3) to obtain (R)-1-(5-((4-((1-( 3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl )-3-methylimidazolidin-2-one, yield 28.3%; 1 H NMR (400MHz, DMSO-d 6 )δ8.11 (d, J=8.0Hz, 1H), 7.88(s, 1H), 7.74(s, 1H), 7.55(s, 1H), 7.42(d, J=9.2Hz, 1H), 7.20(d, J=8.0Hz, 1H), 6.90(s, 1H), 6.87(s, 1H ), 6.70(s, 1H), 5.62-5.56(m, 1H), 5.53(brs, 2H), 3.89(s, 3H), 3.75-3.71(m, 2H), 3.42-3.38(m, 2H), 3.37 (s, 3H), 2.70 (s, 3H), 2.36 (s, 3H), 1.56 (d, J = 6.8 Hz, 3H); ESI-MS (m/z): 581.0 [M+H] + .
实施例50Example 50
(R)-1-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑烷-2-酮的制备(R)-1-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl)amino)-2-hydroxypyridin-3-yl)-3-methylimidazolidin-2-one preparation
Figure PCTCN2022101219-appb-000151
Figure PCTCN2022101219-appb-000151
制备方法参考实施例48，得(R)-1-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑烷-2-酮，产率61.6％； 1H NMR(400MHz，DMSO-d 6)δ11.83(brs，1H)，8.20(brs，1H)，7.54(s，1H)，7.47(s，1H)，8.41(d，J＝9.2Hz，1H)，7.23(s，1H)，7.15(d，J＝9.2Hz，1H)，6.90(s，1H)，6.86(s，1H)，6.70(s，1H)，5.62-5.58(m，1H)，5.54(s，2H)，3.91-3.85(m，2H)，3.37-3.35(m，2H)，3.27(s，3H)，2.69(s，3H)，2.37(s，3H)，1.57(d，J＝5.2Hz，3H)；ESI-MS(m/z)：567.0[M+H] +。 The preparation method refers to Example 48 to obtain (R)-1-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl ylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-3-methylimidazolidin-2-one, yield 61.6%; 1 H NMR (400MHz, DMSO- d 6 )δ11.83(brs, 1H), 8.20(brs, 1H), 7.54(s, 1H), 7.47(s, 1H), 8.41(d, J=9.2Hz, 1H), 7.23(s, 1H ), 7.15(d, J=9.2Hz, 1H), 6.90(s, 1H), 6.86(s, 1H), 6.70(s, 1H), 5.62-5.58(m, 1H), 5.54(s, 2H) , 3.91-3.85(m, 2H), 3.37-3.35(m, 2H), 3.27(s, 3H), 2.69(s, 3H), 2.37(s, 3H), 1.57(d, J=5.2Hz, 3H ); ESI-MS (m/z): 567.0 [M+H] + .
实施例51Example 51
(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-3-yl)ethyl)amino)-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000152
Figure PCTCN2022101219-appb-000152
制备方法参考实施例32，得(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率43.0％； 1H NMR(400MHz，DMSO-d 6)δ8.79(s，1H)，8.18(d，J＝8.0Hz，1H)，8.04(d，J＝8.0Hz，1H)，7.67(d，J＝8.0Hz，1H)，7.60(s，1H)，7.35(d，J＝9.2Hz，1H)，7.09-7.03(m，2H)，6.98(d，J＝8.8Hz，1H)，6.92(t，J＝56.0Hz，1H)，6.91(s，1H)，5.71-5.61(m，1H)，3.77(s，3H)，3.57(s，2H)，3.34(s，3H)，2.99(s，3H)，2.78(s，3H)，2.33(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.4[M+H] +。 The preparation method refers to Example 32 to obtain (R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-3-yl)ethyl)amino)-2-methyl Quinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 43.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.79(s, 1H), 8.18(d, J=8.0Hz, 1H), 8.04(d, J=8.0Hz, 1H), 7.67(d, J=8.0Hz, 1H), 7.60(s, 1H ), 7.35(d, J=9.2Hz, 1H), 7.09-7.03(m, 2H), 6.98(d, J=8.8Hz, 1H), 6.92(t, J=56.0Hz, 1H), 6.91(s , 1H), 5.71-5.61(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.34(s, 3H), 2.99(s, 3H), 2.78(s, 3H), 2.33( s, 3H), 1.66 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 535.4 [M+H] + .
实施例52Example 52
(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl)ethyl)amino)-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000153
Figure PCTCN2022101219-appb-000153
制备方法参考实施例32，得(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率33.3％； 1H NMR(400MHz，DMSO-d 6)δ8.22(d，J＝7.6Hz，1H)，7.94(t，J＝8.0Hz，1H)，7.64-7.61(m，2H)，7.56(d，J＝7.6Hz，1H)，7.36(d，J＝9.2Hz，1H)，7.10-7.04(m，2H)，6.99(d，J＝8.8Hz，1H)，6.92(s，1H)，6.82(d，J＝52.0Hz，1H)，5.72-5.64(m，1H)，3.77(s，3H)，3.57(s，2H)，3.34(s，3H)，2.99(s，3H)，2.78(s，3H)，2.30(s，3H)，1.65(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.0[M+H] +。 The preparation method refers to Example 32 to obtain (R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl)ethyl)amino)-2-methyl Quinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 33.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.22(d, J=7.6Hz, 1H), 7.94(t, J=8.0Hz, 1H), 7.64-7.61(m, 2H), 7.56(d, J=7.6Hz, 1H), 7.36(d , J=9.2Hz, 1H), 7.10-7.04(m, 2H), 6.99(d, J=8.8Hz, 1H), 6.92(s, 1H), 6.82(d, J=52.0Hz, 1H), 5.72 -5.64(m, 1H), 3.77(s, 3H), 3.57(s, 2H), 3.34(s, 3H), 2.99(s, 3H), 2.78(s, 3H), 2.30(s, 3H), 1.65 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 535.0 [M+H] + .
实施例53Example 53
(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl)ethyl)amino)-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000154
Figure PCTCN2022101219-appb-000154
制备方法参考实施例35，经Pre-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率14.0％； 1H NMR(400MHz，DMSO-d 6)δ8.25(d，J＝8.0Hz，1H)，7.96-7.92(m，2H)，7.72(s，1H)，7.62(d，J＝8.0Hz，1H)，7.56(d，J＝8.0Hz，1H)，7.40(d，J＝12.0Hz，1H)，7.36(s，1H)，7.12(d，J＝8.0Hz，1H)，6.95(t，J＝56.0Hz，1H)，5.71-5.64(m，1H)，3.85(s，3H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.31(s，3H)，1.65(d，J＝8.0Hz，3H)；ESI-MS(m/z)：536.3[M+H] +。 The preparation method refers to Example 35, and is purified by Pre-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 14.0 %; 1 H NMR (400MHz, DMSO-d 6 ) δ8.25(d, J=8.0Hz, 1H), 7.96-7.92(m, 2H), 7.72(s, 1H), 7.62(d, J=8.0 Hz, 1H), 7.56(d, J=8.0Hz, 1H), 7.40(d, J=12.0Hz, 1H), 7.36(s, 1H), 7.12(d, J=8.0Hz, 1H), 6.95( t, J=56.0Hz, 1H), 5.71-5.64(m, 1H), 3.85(s, 3H), 3.59(s, 2H), 3.36(s, 3H), 3.02(s, 3H), 2.80(s , 3H), 2.31 (s, 3H), 1.65 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 536.3 [M+H] + .
实施例54Example 54
(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-NN-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl)ethyl)amino)-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-hydroxypyridin-3-yl)-NN-dimethylacetamide
Figure PCTCN2022101219-appb-000155
Figure PCTCN2022101219-appb-000155
制备方法参考实施例38，得(R)-2-(5-((4-((1-(6-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率84.0％； 1H NMR(400MHz，DMSO-d 6)δ11.60(s，1H)，8.21(d，J＝8.0Hz，1H)，7.94(t，J＝8.0Hz，1H)，7.61(d，J＝8.0Hz，1H)，7.57-7.54(m，2H)，7.40(d，J＝12.0Hz，1H)，7.26(s，1H)，7.19(s，1H)，7.09(d，J＝8.0Hz，1H)，6.95(t，J＝52.0Hz，1H)，5.72-5.65(m，1H)，3.42(s，2H)，3.27(s，3H)，3.01(s，3H)，2.78(s，3H)，2.30(s，3H)，1.65(d，J＝8.0Hz，3H)；ESI-MS(m/z)：522.0[M+H] +。 The preparation method refers to Example 38 to obtain (R)-2-(5-((4-((1-(6-(difluoromethyl)pyridin-2-yl)ethyl)amino)-2-methyl Quinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 84.0%; 1 H NMR (400MHz, DMSO-d 6 )δ11.60(s, 1H), 8.21(d, J=8.0Hz, 1H), 7.94(t, J=8.0Hz, 1H), 7.61(d, J=8.0Hz, 1H), 7.57-7.54( m, 2H), 7.40(d, J=12.0Hz, 1H), 7.26(s, 1H), 7.19(s, 1H), 7.09(d, J=8.0Hz, 1H), 6.95(t, J=52.0 Hz, 1H), 5.72-5.65(m, 1H), 3.42(s, 2H), 3.27(s, 3H), 3.01(s, 3H), 2.78(s, 3H), 2.30(s, 3H), 1.65 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 522.0 [M+H] + .
实施例55Example 55
(R)-2-(5-((4-((1-(5-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(5-(difluoromethyl)pyridin-2-yl)ethyl)amino)-2-methylquinazolin-6-yl) Preparation of (methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000156
Figure PCTCN2022101219-appb-000156
制备方法参考实施例35，经Pre-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(5-(二氟甲基)吡啶-2-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率15.0％； 1H NMR(400MHz，DMSO-d 6)δ8.79(s，1H)，8.21(d，J＝8.0Hz，1H)，8.04(d，J＝8.0Hz，1H)，7.94(s，1H)，7.68-7.66(m，2H)，7.40(d，J＝8.0Hz，1H)，7.35(s，1H)，7.10(d，J＝8.0Hz，1H)，6.92(t，J＝56.0Hz，1H)，5.71-5.65(m，1H)，3.84(s，3H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.34(s，3H)，1.66(d，J＝8.0Hz，3H)；ESI-MS(m/z)：536.0[M+H] +。 The preparation method refers to Example 35 and is purified by Pre-HPLC (Method 3) to obtain (R)-2-(5-((4-((1-(5-(difluoromethyl)pyridin-2-yl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 15.0 %; 1 H NMR (400MHz, DMSO-d 6 ) δ8.79(s, 1H), 8.21(d, J=8.0Hz, 1H), 8.04(d, J=8.0Hz, 1H), 7.94(s, 1H), 7.68-7.66(m, 2H), 7.40(d, J=8.0Hz, 1H), 7.35(s, 1H), 7.10(d, J=8.0Hz, 1H), 6.92(t, J=56.0 Hz, 1H), 5.71-5.65(m, 1H), 3.84(s, 3H), 3.59(s, 2H), 3.36(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.34 (s, 3H), 1.66 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 536.0 [M+H] + .
实施例56Example 56
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3，4-d]嘧啶-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4- d] Preparation of pyrimidin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000157
Figure PCTCN2022101219-appb-000157
步骤a)：6-氯-2-甲基吡啶并[3，4-d]嘧啶-4(3H)-酮的制备Step a): Preparation of 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one
将3-氨基-6-氯吡啶甲酸甲酯(1.00g，5.359mmol)、氯化氢二氧六环溶液(4M，2.5mL)和乙腈(2.5mL)加入高压釜中，升温至100℃搅拌反应16h。反应结束后，冷却至室温，将反应液减压浓缩，残余物加水(30mL)稀释，搅拌下滴加氨水调节pH至中性，继续搅拌1h，过滤，滤饼用水(30mL)洗涤，收集滤饼，减压干燥得6-氯-2-甲基吡啶并[3，4-d]嘧啶-4(3H)-酮，产率85.7％；ESI-MS(m/z)：196.0[M+H] +。 Add 3-amino-6-chloropicolinate methyl ester (1.00g, 5.359mmol), hydrogen chloride dioxane solution (4M, 2.5mL) and acetonitrile (2.5mL) into the autoclave, heat up to 100°C and stir for 16h . After the reaction, cool to room temperature, concentrate the reaction solution under reduced pressure, dilute the residue with water (30mL), add ammonia water dropwise under stirring to adjust the pH to neutral, continue stirring for 1h, filter, wash the filter cake with water (30mL), collect and filter The cake was dried under reduced pressure to obtain 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one with a yield of 85.7%; ESI-MS (m/z): 196.0 [M+ H] + .
步骤b)：4，6-二氯-2-甲基吡啶并[3，4-d]嘧啶的制备Step b): Preparation of 4,6-dichloro-2-methylpyrido[3,4-d]pyrimidine
将6-氯-2-甲基吡啶并[3，4-d]嘧啶-4(3H)-酮(350mg，1.795mmol)加入1，2-二氯乙烷(20mL)中，搅拌下加入DIPEA(1.6g，12.403mmol)和POCl 3(1.6g，10.456mmol)，氮气保护下升温至90℃反应过夜，反应结束后，冷却至室温，减压蒸除溶剂，残余物加二氯甲烷(100mL)溶解，将混合物倒入冰块与碳酸氢钠的混合液中淬灭，分液，无水硫酸钠干燥，过滤，滤液减压浓缩，得4，6-二氯-2-甲基吡啶并[3，4-d]嘧啶，无需进一步纯化直接用于下一步反应；ESI-MS(m/z)：214.0[M+H] +。 Add 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one (350mg, 1.795mmol) into 1,2-dichloroethane (20mL), add DIPEA under stirring (1.6g, 12.403mmol) and POCl 3 (1.6g, 10.456mmol), under the protection of nitrogen, the temperature was raised to 90°C and reacted overnight. After the reaction, cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was added dichloromethane (100mL ) was dissolved, the mixture was poured into a mixture of ice cubes and sodium bicarbonate to quench, separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 4,6-dichloro-2-picoline [3,4-d]pyrimidine was directly used in the next reaction without further purification; ESI-MS (m/z): 214.0[M+H] + .
步骤c)：(R)-6-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[3，4-d]嘧啶-4-胺的制备Step c): (R)-6-Chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d] Preparation of pyrimidin-4-amine
将4，6-二氯-2-甲基吡啶并[3，4-d]嘧啶(385mg，1.799mmol)、(R)-1-(3-(二氟甲基)-2-氟苯基)乙-1-胺盐酸盐(405mg，1.800mmol)、DIPEA(697mg，5.395mmol)、DMSO(8mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌反应1h。反应结束后，加饱和氯化铵溶液(30mL)稀释，以乙酸乙酯萃取(50mL×2)，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，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1至5/1)，得(R)-6-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[3，4-d]嘧啶-4-胺，产率48.9％； 1H NMR(400MHz，CDCl 3)δ8.98(s，1H)，7.61(s，1H)，7.56-7.51(m，2H)，7.23(t，J＝8.0Hz，1H)，7.39(s，1H)，6.92(t，J＝56.0Hz，1H)，6.11(s，1H)，5.83-5.76(m，1H)，2.59(s，3H)，1.73(d，J＝8.0Hz，3H)；ESI-MS(m/z)：367.1[M+H] +。 4,6-dichloro-2-methylpyrido[3,4-d]pyrimidine (385 mg, 1.799 mmol), (R)-1-(3-(difluoromethyl)-2-fluorophenyl ) Ethan-1-amine hydrochloride (405mg, 1.800mmol), DIPEA (697mg, 5.395mmol), DMSO (8mL) were sequentially added into the reaction flask, heated to 80°C under nitrogen protection and stirred for 1h. After the reaction, dilute with saturated ammonium chloride solution (30mL), extract with ethyl acetate (50mL×2), combine the organic phases, wash with saturated brine (50mL), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate, and the residue is purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1 to 5/1) to obtain (R)-6-chloro-N-(1-(3-(di Fluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine, yield 48.9%; 1 H NMR (400MHz, CDCl 3 ) δ8. 98(s, 1H), 7.61(s, 1H), 7.56-7.51(m, 2H), 7.23(t, J=8.0Hz, 1H), 7.39(s, 1H), 6.92(t, J=56.0Hz , 1H), 6.11(s, 1H), 5.83-5.76(m, 1H), 2.59(s, 3H), 1.73(d, J=8.0Hz, 3H); ESI-MS(m/z): 367.1[ M+H] + .
步骤d)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3，4-d]嘧啶-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step d): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[ Preparation of 3,4-d]pyrimidin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide
将(R)-6-氯-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基吡啶并[3，4-d]嘧啶-4-胺(100mg，0.273mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺、(80mg，0.310mmol)、Cs 2CO 3(245mg，0.754mmol)、Pd(dba) 2(30mg，0.052mmol)、X-phos(50mg，0.105mmol)和甲苯(6mL)依次加入到反应瓶中，氮气置换三次，升温至105℃搅拌反应3h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，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Pre-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基吡啶并[3，4-d]嘧啶-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率77.0％； 1H NMR(400MHz，DMSO-d 6)δ8.60(s，1H)，8.38(s，1H)，7.64(t，J＝8.0Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.39(s，1H)，7.28(t，J＝8.0Hz，1H)，7.23(t，J＝52.0Hz，1H)，7.16(d，J＝8.0Hz，1H)，7.03-6.99(m，2H)，5.60-5.73(m，1H)，3.79(s，3H)，3.59(s，2H)，3.42(s，3H)，3.01(s，3H)，2.79(s，3H)，2.30(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：553.4[M+H] +。 (R)-6-chloro-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4 -amine (100mg, 0.273mmol), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide, (80mg, 0.310mmol), Cs 2 CO 3 ( 245mg, 0.754mmol), Pd(dba) 2 (30mg, 0.052mmol), X-phos (50mg, 0.105mmol) and toluene (6mL) were sequentially added to the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 3h . After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The crude product was purified by Pre-HPLC (Method 3) to give (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino) -2-methylpyrido[3,4-d]pyrimidin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 77.0% ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.60(s, 1H), 8.38(s, 1H), 7.64(t, J=8.0Hz, 1H), 7.49(t, J=8.0Hz, 1H ), 7.39(s, 1H), 7.28(t, J=8.0Hz, 1H), 7.23(t, J=52.0Hz, 1H), 7.16(d, J=8.0Hz, 1H), 7.03-6.99(m , 2H), 5.60-5.73(m, 1H), 3.79(s, 3H), 3.59(s, 2H), 3.42(s, 3H), 3.01(s, 3H), 2.79(s, 3H), 2.30( s, 3H), 1.59 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 553.4 [M+H] + .
实施例57Example 57
(R)-2-(5-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethylamino)-2-methylquinazole Preparation of hydrin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000158
Figure PCTCN2022101219-appb-000158
步骤a)：2-(3-溴-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step a): Preparation of ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate
将1-溴-2-氟-3-碘苯(7.5g，24.926mmol)、2-溴-2，2-二氟乙酸乙酯(15.15g，74.780mmol)和THF(100mL)加入反应瓶中，搅拌溶解，氮气置换3次，加入铜粉(4.77g，74.780mmol)，升温至80℃反应过夜。反应完毕，冷却反应液至室温，加入乙酸乙酯(200mL)稀释，冰浴下缓慢滴加水(400mL)萃灭反应，过滤，滤液用乙酸乙酯(200mL×2)萃取，合并有机相，用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥， 减压过滤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝100/1)，得到2-(3-溴-2-氟苯基)-2，2-二氟乙酸乙酯，产率87.3％。1-Bromo-2-fluoro-3-iodobenzene (7.5 g, 24.926 mmol), ethyl 2-bromo-2,2-difluoroacetate (15.15 g, 74.780 mmol) and THF (100 mL) were added to the reaction flask , stirred to dissolve, replaced with nitrogen 3 times, added copper powder (4.77g, 74.780mmol), heated to 80°C and reacted overnight. After completion of the reaction, cool the reaction solution to room temperature, add ethyl acetate (200mL) to dilute, slowly add water (400mL) dropwise under an ice bath to extract the reaction, filter, and extract the filtrate with ethyl acetate (200mL×2), combine the organic phases, and use Wash with saturated brine (100 mL×2), dry over anhydrous sodium sulfate, filter under reduced pressure, concentrate the organic phase under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1) , to obtain ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate with a yield of 87.3%.
步骤b)：2-(3-乙酰基-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step b): Preparation of ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate
将2-(3-溴-2-氟苯基)-2，2-二氟乙酸乙酯(6.46g，21.746mmol)、三丁基(1-乙氧基乙烯基)锡烷(10.207g，28.276mmol)、Pd(PPh 3)Cl 2(763mg，1.087mmol)、三乙胺(4.39g，43.492mmol)、1，4-二氧六环(100mL)加入至反应瓶中，氮气置换3次，升温至100℃反应过夜。反应结束后，将反应液冷却至室温，加入2N的稀盐酸调至pH＝2-3，室温搅拌1h，浓缩除去溶剂，将饱和碳酸氢钠水溶液加入混合物中调至pH＝7-8，用乙酸乙酯萃取(100mL×3)，合并有机相，用饱和食盐水(150mLl×1)洗涤，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＝50/1)，得2-(3-乙酰基-2-氟苯基)-2，2-二氟乙酸乙酯，产率44.3％。 Ethyl 2-(3-bromo-2-fluorophenyl)-2,2-difluoroacetate (6.46g, 21.746mmol), tributyl(1-ethoxyvinyl)stannane (10.207g, 28.276mmol), Pd(PPh 3 )Cl 2 (763mg, 1.087mmol), triethylamine (4.39g, 43.492mmol), 1,4-dioxane (100mL) were added to the reaction flask, and nitrogen replacement was performed 3 times , heated to 100°C for overnight reaction. After the reaction, cool the reaction liquid to room temperature, add 2N dilute hydrochloric acid to adjust to pH=2-3, stir at room temperature for 1 h, concentrate to remove solvent, add saturated aqueous sodium bicarbonate solution to the mixture to adjust to pH=7-8, use Extracted with ethyl acetate (100mL×3), combined the organic phases, washed with saturated brine (150mL1×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent : Petroleum ether/ethyl acetate=50/1) to obtain ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate with a yield of 44.3%.
步骤c)：(R)-2-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step c): Preparation of ethyl (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate
将2-(3-乙酰基-2-氟苯基)-2，2-二氟乙酸乙酯(2.5g，9.615mmol)和(R)-(+)-叔丁基亚磺酰胺(2.327g，19.230mmol)和THF(50mL)加入反应瓶中，搅拌溶解，室温下加入钛酸四乙酯(10.117g，28.845mmol，65％)，加毕升温至80℃搅拌3h。反应结束后，冷却至室温，加水(20mL)，析出大量固体，过滤，滤饼用乙酸乙酯(50mL)洗涤，滤液以乙酸乙酯萃取(50mL×3)，合并有机相，用饱和食盐水(50mL×1)洗涤，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)，得(R)-2-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯，产率67.5％；ESI-MS(m/z)：364.4[M+H] +。 Ethyl 2-(3-acetyl-2-fluorophenyl)-2,2-difluoroacetate (2.5g, 9.615mmol) and (R)-(+)-tert-butylsulfinamide (2.327g , 19.230mmol) and THF (50mL) were added into the reaction flask, stirred and dissolved, and tetraethyl titanate (10.117g, 28.845mmol, 65%) was added at room temperature, and the temperature was raised to 80°C and stirred for 3h after the addition. After the reaction, cool to room temperature, add water (20mL), precipitate a large amount of solid, filter, wash the filter cake with ethyl acetate (50mL), and extract the filtrate with ethyl acetate (50mL×3), combine the organic phases, wash with saturated brine (50mL×1), washed with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R)- 2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester, yield 67.5%; ESI-MS ( m/z): 364.4 [M+H] + .
步骤d)：(R)-2-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step d): Preparation of ethyl (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate
将(R)-2-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯(2.35g，6.474mmol)和THF(15mL)加入反应瓶中，搅拌溶解，在-78℃搅拌条件下，缓慢加入DIBAL-H(19.422mL，19.422mmol)的THF溶液(1.0M)，维持-78℃反应1h。反应结束后，自然升温至室温，加入饱和食盐水(100mL)淬灭反应，析出大量固体，过滤，滤饼用乙酸乙酯(50mL)洗涤，滤液用乙酸乙酯萃取(50mL×3)，合并有机相，用饱和食盐水(50mL×1)洗涤，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)，得(R)-2-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯，产率71.8％；ESI-MS(m/z)：366.4[M+H] +。 Ethyl (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate (2.35g, 6.474 mmol) and THF (15 mL) were added into the reaction flask, stirred to dissolve, and a THF solution (1.0 M) of DIBAL-H (19.422 mL, 19.422 mmol) was slowly added under stirring at -78 °C, and the reaction was maintained at -78 °C for 1 h. After the reaction was completed, the temperature was naturally raised to room temperature, and saturated brine (100 mL) was added to quench the reaction, a large amount of solid was precipitated, filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (50 mL×3), and the combined The organic phase was washed with saturated brine (50mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1 ), to get (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester, yield 71.8%; ESI-MS (m/z): 366.4 [M+H] + .
步骤e)：(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2，2-二氟乙酸乙酯盐酸盐的制备Step e): Preparation of (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester hydrochloride
将(R)-2-(3-(1-((叔丁基亚磺酰基)亚氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯(1.7g，4.652mmol)和THF(10mL)加入反应瓶中，搅拌溶解，在0℃搅拌条件下，缓慢加入氯化氢1，4二氧六环溶液(20mL，4M)，加毕自然升温至室温反应1h。反应完毕，减压浓缩，残余物用少量乙酸乙酯溶解，搅拌下分批加入大量石油醚析出大量白色沉淀，过滤，滤饼用适量石油醚洗涤，真空干燥，得(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2，2-二氟乙酸乙酯盐酸盐，产率86.6％；ESI-MS(m/z)：262.2[M+H] +。 Ethyl (R)-2-(3-(1-((tert-butylsulfinyl)imino)ethyl)-2-fluorophenyl)-2,2-difluoroacetate (1.7g, 4.652 mmol) and THF (10 mL) were added into the reaction flask, stirred and dissolved, and hydrogen chloride 1,4-dioxane solution (20 mL, 4M) was slowly added under stirring condition at 0°C, and the temperature was naturally raised to room temperature for 1 h after the addition. After completion of the reaction, concentrate under reduced pressure, dissolve the residue with a small amount of ethyl acetate, add a large amount of petroleum ether in batches under stirring to precipitate a large amount of white precipitate, filter, wash the filter cake with an appropriate amount of petroleum ether, and dry in vacuo to obtain (R)-2-( 3-(1-Aminoethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester hydrochloride, yield 86.6%; ESI-MS (m/z): 262.2 [M+H] + .
步骤f)：(R)-2-(3-(1-(6-溴-2-基喹唑啉-4-基)氨基乙基)-2，2-二氟乙酸乙酯的制备Step f): Preparation of ethyl (R)-2-(3-(1-(6-bromo-2-ylquinazolin-4-yl)aminoethyl)-2,2-difluoroacetate
将6-溴-4-氯-2-甲基喹唑啉(577mg，2.240mmol)、(R)-2-(3-(1-氨基乙基)-2-氟苯基)-2，2-二氟乙酸乙酯盐酸盐(800mg，2.680mmol)和DIPEA(870mg，6.720mmol)和DMSO(10mL)加入反应瓶中，将反应液加热至80℃搅拌1h，反应结束后，将反应液冷却至室温，加入水(50mL)淬灭，用乙酸乙酯萃取(50mL×3)，合并有机相，以饱和食盐水(50mL)洗涤，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)，得(R)-2-(3-(1-(6-溴-2-基喹唑啉-4-基)氨基乙基)-2，2-二氟乙酸乙酯，产率90.0％；ESI-MS(m/z)：482.2[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (577mg, 2.240mmol), (R)-2-(3-(1-aminoethyl)-2-fluorophenyl)-2,2 - Ethyl difluoroacetate hydrochloride (800mg, 2.680mmol), DIPEA (870mg, 6.720mmol) and DMSO (10mL) were added to the reaction flask, and the reaction solution was heated to 80°C and stirred for 1h. After the reaction, the reaction solution was Cool to room temperature, add water (50 mL) to quench, extract with ethyl acetate (50 mL×3), 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 product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain (R)-2-(3-(1-(6-bromo-2-ylquinazoline-4 -yl)aminoethyl)-2,2-ethyl difluoroacetate, yield 90.0%; ESI-MS (m/z): 482.2 [M+H] + .
步骤g)：(R)-2-(3-(1-((6-((3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step g): (R)-2-(3-(1-((6-((3-(2-(dimethylamino)-2-oxoethyl)-4-methoxyphenyl)(methyl Base) amino) -2-methylquinazolin-4-yl)) amino) ethyl) -2-fluorophenyl) -2, the preparation of 2-difluoroacetic acid ethyl ester
将((R)-2-(3-(1-(6-溴-2-甲基喹唑啉-4-基)氨基乙基)-2，2-二氟乙酸乙酯(150mg，0.310mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(80mg，0.310mmol)、Cs2CO3(202mg，0.620mmol)、X-Phos(30mg，0.062mmol)、Pd(dba)2(18mg，0.003mmol)和甲苯(7mL)加入到反应瓶中，氮气置换三次， 升温至90℃搅拌反应16h。反应结束后，加水(25ml)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得(R)-2-(3-(1-((6-((3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯，产率59.9％；ESI-MS(m/z)：624.6[M+H]+。Ethyl ((R)-2-(3-(1-(6-bromo-2-methylquinazolin-4-yl)aminoethyl)-2,2-difluoroacetate (150mg, 0.310mmol ), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (80mg, 0.310mmol), Cs2CO3 (202mg, 0.620mmol), X- Phos (30mg, 0.062mmol), Pd(dba)2 (18mg, 0.003mmol) and toluene (7mL) were added to the reaction flask, replaced by nitrogen three times, heated to 90°C and stirred for 16h. After the reaction, add water (25ml) The reaction was quenched, extracted with ethyl acetate (20mL×3), the organic phases were combined, washed with saturated brine (30mL), the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloro Methane/methanol=30/1), to get (R)-2-(3-(1-((6-((3-(2-(dimethylamino)-2-oxyethyl))-4-methoxy phenyl) (methyl)amino)-2-methylquinazolin-4-yl))amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester, yield 59.9 %; ESI-MS (m/z): 624.6 [M+H]+.
步骤h)：(R)-2-(5-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step h): (R)-2-(5-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethylamino)-2- Preparation of methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide formate
将(R)-2-(3-(1-((6-((3-(2-(二甲氨基)-2-氧乙基)-4-甲氧基苯基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯(100mg，0.160mmol)和THF/H2O混合液(5mL，v/v＝50/1)加入反应瓶中，搅拌溶解，在-78℃搅拌条件下，缓慢加入NaBH4(12.13mg，0.320mmol)，维持-78℃反应1h。反应结束后，自然升温至室温，加入饱和食盐水(10mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，有机相再用饱和食盐水(100mL)洗涤，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(R)-2-(5-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐，产率85.7％；1HNMR(400MHz，DMSO-d6)δ8.19(d，J＝8.0Hz，1H)，8.15(s，1H)，7.69-7.65(m，2H)，7.43-7.40(m，1H)，7.35(d，J＝8.0Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.10-7.04(m，2H)，6.99(d，J＝8.0Hz，1H)，6.92(s，1H)，5.88-5.81(m，1H)，5.72(s，1H)，3.95(t，J＝12.0Hz，2H)，3.77(s，3H)，3.58(s，2H)，3.36(s，3H)，3.00(s，3H)，2.79(s，3H)，2.31(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：582.6[M+H] +。 (R)-2-(3-(1-((6-((3-(2-(dimethylamino)-2-oxyethyl)-4-methoxyphenyl)(methyl)amino )-2-methylquinazolin-4-yl))amino)ethyl)-2-fluorophenyl)-2,2-difluoroethyl acetate (100mg, 0.160mmol) and THF/H2O mixture ( 5mL, v/v=50/1) was added into the reaction flask, stirred to dissolve, and NaBH4 (12.13mg, 0.320mmol) was slowly added under the condition of stirring at -78°C, and the reaction was maintained at -78°C for 1h. After the reaction was completed, the temperature was naturally raised to room temperature, and saturated brine (10 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered , the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to obtain (R)-2-(5-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl )-2-fluorophenyl)ethylamino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide Formate salt, yield 85.7%; 1HNMR (400MHz, DMSO-d6) δ8.19(d, J=8.0Hz, 1H), 8.15(s, 1H), 7.69-7.65(m, 2H), 7.43-7.40 (m, 1H), 7.35(d, J=8.0Hz, 1H), 7.26(t, J=8.0Hz, 1H), 7.10-7.04(m, 2H), 6.99(d, J=8.0Hz, 1H) , 6.92(s, 1H), 5.88-5.81(m, 1H), 5.72(s, 1H), 3.95(t, J=12.0Hz, 2H), 3.77(s, 3H), 3.58(s, 2H), 3.36(s, 3H), 3.00(s, 3H), 2.79(s, 3H), 2.31(s, 3H), 1.62(d, J=8.0Hz, 3H); ESI-MS(m/z): 582.6 [M+H] + .
实施例58Example 58
((R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备((R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2 Preparation of -methylquinazolin-6-yl (methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000159
Figure PCTCN2022101219-appb-000159
步骤a)：(R)-2-(3-(1-((6-((4-((叔丁基二甲基甲硅烷基)氧基)-3-(2-(二甲基氨基)-2-氧乙基)苯基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step a): (R)-2-(3-(1-((6-((4-((tert-butyldimethylsilyl)oxy)-3-(2-(dimethylamino )-2-oxyethyl)phenyl)(methyl)amino)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid Preparation of ethyl ester
将(R)-2-(3-(1-(6-溴-2-基喹唑啉-4-基)氨基乙基)-2，2-二氟乙酸乙酯(241mg，0.500mmol)、2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-(甲基氨基)苯基)-N，N-二甲基乙酰胺(161mg，0.500mmol)、Cs 2CO 3(326mg，1.000mmol)、X-Phos(48mg，1.000mmol)、Pd(dba) 2(29mg，0.050mmol)和甲苯(10mL)加入到反应瓶中，氮气置换三次，升温至90℃搅拌反应16h。反应结束后，加水(25ml)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压过滤，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得(R)-2-(3-(1-((6-((4-((叔丁基二甲基甲硅烷基)氧基)-3-(2-(二甲基氨基)-2-氧乙基)苯基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯，产率45.5％；ESI-MS(m/z)：724.9[M+H] +。 Ethyl (R)-2-(3-(1-(6-bromo-2-ylquinazolin-4-yl)aminoethyl)-2,2-difluoroacetate (241mg, 0.500mmol), 2-(2-((tert-butyldimethylsilyl)oxy)-5-(methylamino)phenyl)-N,N-dimethylacetamide (161mg, 0.500mmol), Cs 2 CO 3 (326mg, 1.000mmol), X-Phos (48mg, 1.000mmol), Pd(dba) 2 (29mg, 0.050mmol) and toluene (10mL) were added to the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred React for 16h. After the reaction, add water (25ml) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter under reduced pressure, organic The phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain (R)-2-(3-(1-((6-((4- ((tert-butyldimethylsilyl)oxy)-3-(2-(dimethylamino)-2-oxyethyl)phenyl)(methyl)amino)-2-methylquinazole Phenyl-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroethyl acetate, yield 45.5%; ESI-MS (m/z): 724.9[M+H] + .
步骤b)：(R)-2-(3-(1-((6-((3-(2-(二甲氨基)-2-氧乙基)-4-羟基苯基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯的制备Step b): (R)-2-(3-(1-((6-((3-(2-(dimethylamino)-2-oxoethyl)-4-hydroxyphenyl)(methyl) Preparation of amino)-2-methylquinazolin-4-yl))amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester
将(R)-2-(3-(1-((6-((4-((叔丁基二甲基甲硅烷基)氧基)-3-(2-(二甲基氨基)-2-氧乙基)苯基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯(170mg，0.235mmol)和THF(5mL)加入反应瓶中，搅拌溶解，在0℃搅拌条件下，缓慢加入TBAF的THF溶液(0.305mL，1.0M)，加毕，自然升温至室温反应1h。反应完毕，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(3-(1-((6-((3-(2-(二甲氨基)-2-氧乙基)-4-羟基苯基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯，产率85.7％；ESI-MS(m/z)：610.6[M+H] +。 (R)-2-(3-(1-((6-((4-((tert-butyldimethylsilyl)oxy)-3-(2-(dimethylamino)-2 -Oxyethyl)phenyl)(methyl)amino)-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester ( 170mg, 0.235mmol) and THF (5mL) were added into the reaction flask, stirred to dissolve, and the THF solution of TBAF (0.305mL, 1.0M) was slowly added under the condition of stirring at 0°C. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(3-(1-((6-(( 3-(2-(Dimethylamino)-2-oxoethyl)-4-hydroxyphenyl)(methyl)amino)-2-methylquinazolin-4-yl))amino)ethyl)- Ethyl 2-fluorophenyl)-2,2-difluoroacetate, yield 85.7%; ESI-MS (m/z): 610.6 [M+H] + .
步骤c)：((R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step c): ((R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl) Preparation of amino)-2-methylquinazolin-6-yl (methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate
将(R)-2-(3-(1-((6-((3-(2-(二甲氨基)-2-氧乙基)-4-羟基苯基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙酸乙酯(97mg，0.160mmol)和THF/水混合液(5mL，v/v＝50/1)加入反应瓶中，搅拌溶解，在-78℃搅拌条件下，缓慢加入NaBH4(12.13mg，0.320mmol)，维持-78℃反应1h。反应结束后，自然升温至室温，加入饱和食盐水(10mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，有机相用饱和食盐水(100mL×1)洗涤，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((R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐，产率85.0％；1H NMR(400MHz，DMSO-d6)δ9.55(s，1H)，8.16-8.13(m，2H)，7.69-7.66(m，1H)，7.57(s，1H)，7.43(t，J＝8.0Hz，1H)，7.33(d，J＝12.0Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.04-7.01(m，1H)，6.94-6.89(m，2H)，6.83(d，J＝8.0Hz，1H)，5.88-5.80(m，1H)，5.72(s，1H)，3.95(t，J＝12.0Hz，2H)，3.57(s，2H)，3.33(s，3H)，3.01(s，3H)，2.81(s，3H)，2.30(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：568.6[M+H] +。 (R)-2-(3-(1-((6-((3-(2-(dimethylamino)-2-oxoethyl)-4-hydroxyphenyl)(methyl)amino)- 2-Methylquinazolin-4-yl))amino)ethyl)-2-fluorophenyl)-2,2-difluoroacetic acid ethyl ester (97mg, 0.160mmol) and THF/water mixture (5mL, v/v=50/1) was added into the reaction flask, stirred and dissolved, and NaBH4 (12.13mg, 0.320mmol) was slowly added under the condition of stirring at -78°C, and the reaction was maintained at -78°C for 1h. After the reaction, the temperature was naturally raised to room temperature, and saturated brine (10 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (100 mL×1), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Method 2) to obtain ((R)-2-(5-(4-(4-(1-(3-(1,1-difluoro- 2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl(methyl)amino)-2-hydroxyphenyl)-N,N-dimethyl Acetamide formate, yield 85.0%; 1H NMR (400MHz, DMSO-d6) δ9.55 (s, 1H), 8.16-8.13 (m, 2H), 7.69-7.66 (m, 1H), 7.57 ( s, 1H), 7.43(t, J=8.0Hz, 1H), 7.33(d, J=12.0Hz, 1H), 7.26(t, J=8.0Hz, 1H), 7.04-7.01(m, 1H), 6.94-6.89(m, 2H), 6.83(d, J=8.0Hz, 1H), 5.88-5.80(m, 1H), 5.72(s, 1H), 3.95(t, J=12.0Hz, 2H), 3.57 (s, 2H), 3.33 (s, 3H), 3.01 (s, 3H), 2.81 (s, 3H), 2.30 (s, 3H), 1.62 (d, J=8.0Hz, 3H); ESI-MS ( m/z): 568.6 [M+H] + .
实施例59Example 59
(R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- Preparation of methylquinazolin-6-yl (methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000160
Figure PCTCN2022101219-appb-000160
制备方法参考实施例58相应步骤，得(R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率83.8％； 1H NMR(400MHz，DMSO-d 6)δ8.22(d，J＝8.0Hz，1H)，8.15(s，1H)，7.94(s，1H)，7.74(s，1H)，7.67(t，J＝8.0Hz，1H)，7.44-7.39(m，2H)，7.35(d，J＝8.0Hz，1H)，7.26(t，J＝8.0Hz，1H)，7.13-7.10(q，J＝4.0Hz，1H)，5.87-5.80(m，1H)，5.72(s，1H)，3.95(t，J＝12.0Hz，2H)，3.86(s，3H)，3.60(s，2H)，3.36(s，3H)，3.03(s，3H)，2.81(s，3H)，2.32(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：583.6[M+H] +。 The preparation method refers to the corresponding steps in Example 58 to obtain (R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorobenzene Base) ethyl) amino) -2-methylquinazolin-6-yl (methyl) amino) -2-methoxypyridin-3-yl) -N,N-dimethylacetamide formate , yield 83.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.22(d, J=8.0Hz, 1H), 8.15(s, 1H), 7.94(s, 1H), 7.74(s, 1H ), 7.67(t, J=8.0Hz, 1H), 7.44-7.39(m, 2H), 7.35(d, J=8.0Hz, 1H), 7.26(t, J=8.0Hz, 1H), 7.13-7.10 (q, J=4.0Hz, 1H), 5.87-5.80(m, 1H), 5.72(s, 1H), 3.95(t, J=12.0Hz, 2H), 3.86(s, 3H), 3.60(s, 2H), 3.36(s, 3H), 3.03(s, 3H), 2.81(s, 3H), 2.32(s, 3H), 1.62(d, J=8.0Hz, 3H); ESI-MS (m/z ): 583.6[M+H] + .
实施例60Example 60
(R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐制备(R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)-2-methyl Preparation of quinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000161
Figure PCTCN2022101219-appb-000161
将(R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺(20mg，0.034mmol)置于反应瓶中，0℃搅拌条件下加入HBr的水溶液(5mL，24％)，加毕，升温至90℃搅拌反应1h。反应结束后，加水(25ml)淬灭反应，用乙酸乙酯萃取(20mL×3)， 合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压过滤，有机相减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(5-(4-(4-(1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率25.3％； 1H NMR(400MHz，CD 3OD)δ8.54(s，1H)，7.60-7.53(m，2H)，7.49-7.42(m，3H)，7.37(s，1H)，7.20(t，J＝8.0Hz，1H)，5.95-5.89(m，1H)，5.18(s，1H)，4.02(t，J＝12.0Hz，2H)，3.62(s，2H)，3.38(s，3H)，3.17(s，3H)，2.97(s，3H)，2.45(s，3H)，1.70(d，J＝8.0Hz，3H)；ESI-MS(m/z)：569.6[M+H] +。 (R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2 -Methylquinazolin-6-yl (methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide (20mg, 0.034mmol) was placed in a reaction flask, Aqueous HBr solution (5 mL, 24%) was added with stirring at 0°C. After the addition was complete, the temperature was raised to 90°C and stirred for 1 h. After the reaction, add water (25ml) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter under reduced pressure, and decompress the organic phase Concentration and the resulting crude product was purified by Prep-HPLC (Method 2) to give (R)-2-(5-(4-(4-(1-(3-(1,1-difluoro-2-hydroxyethyl) -2-fluorophenyl)ethyl)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide acid salt, yield 25.3%; 1 H NMR (400MHz, CD 3 OD) δ8.54(s, 1H), 7.60-7.53(m, 2H), 7.49-7.42(m, 3H), 7.37(s, 1H ), 7.20(t, J=8.0Hz, 1H), 5.95-5.89(m, 1H), 5.18(s, 1H), 4.02(t, J=12.0Hz, 2H), 3.62(s, 2H), 3.38 (s, 3H), 3.17 (s, 3H), 2.97 (s, 3H), 2.45 (s, 3H), 1.70 (d, J=8.0Hz, 3H); ESI-MS (m/z): 569.6[ M+H] + .
实施例61Example 61
(R)-2-(5-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylquin Preparation of oxazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000162
Figure PCTCN2022101219-appb-000162
将(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基-N，N-二甲基乙酰胺(291mg，0.500mmol)和四氢呋喃(3mL)加入反应瓶中，搅拌溶解，加入Cs 2CO 3(326mg，1.000mmol)，18-冠醚-6(66mg，0.250mmol)，氮气置换3次，升温至80℃反应过夜。反应结束后，冷却至室温，缓慢滴加水(10mL)淬灭反应，用二氯甲烷萃取(15mL×3)，合并有机相，用饱和食盐水洗(10mL×2)，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)，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基-N，N-二甲基乙酰胺甲酸盐，产率49.8％； 1H NMR(400MHz，DMSO-d 6)δ8.15(s，1H)，8.05(d，J＝8.0Hz，1H)，7.87(s，1H)，7.66(s，1H)，7.54(d，J＝8.0Hz，1H)，7.43(d，J＝8.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.27(s，1H)，7.06-7.00(m，2H)，5.75-5.68(m，1H)，4.81(t，J＝16.0Hz，2H)，3.78(s，3H)，3.52(s，2H)，3.31(s，3H)，2.95(s，3H)，2.73(s，3H)，2.24(s，3H)，1.53(d，J＝8.0Hz，3H)；ESI-MS(m/z)：563.6[M+H] +。 (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- Methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl-N,N-dimethylacetamide (291 mg, 0.500 mmol) and tetrahydrofuran (3 mL) were added to the reaction In the bottle, stir to dissolve, add Cs 2 CO 3 (326mg, 1.000mmol), 18-crown-6 (66mg, 0.250mmol), nitrogen replacement 3 times, heat up to 80°C and react overnight. After the reaction, cool to room temperature , slowly dropwise added water (10mL) to quench the reaction, extracted with dichloromethane (15mL×3), combined the organic phases, washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, leaving The product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1), and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(5-((4-( (1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)- 2-Methoxypyridin-3-yl-N,N-dimethylacetamide formate, yield 49.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.15(s, 1H), 8.05 (d, J=8.0Hz, 1H), 7.87(s, 1H), 7.66(s, 1H), 7.54(d, J=8.0Hz, 1H), 7.43(d, J=8.0Hz, 1H), 7.33 (d, J=8.0Hz, 1H), 7.27(s, 1H), 7.06-7.00(m, 2H), 5.75-5.68(m, 1H), 4.81(t, J=16.0Hz, 2H), 3.78( s, 3H), 3.52(s, 2H), 3.31(s, 3H), 2.95(s, 3H), 2.73(s, 3H), 2.24(s, 3H), 1.53(d, J=8.0Hz, 3H ); ESI-MS (m/z): 563.6 [M+H] + .
实施例62Example 62
(R)-2-(4-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Preparation of ylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000163
Figure PCTCN2022101219-appb-000163
步骤a)：(R)-6-溴-N-(1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step a): (R)-6-bromo-N-(1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2- Preparation of fluorophenyl)ethyl)-2-methylquinazolin-4-amine
将(R)-2-(3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)-2-氟苯基)-2，2-二氟乙烷-1-醇(90mg，0.204mmol)、叔丁基二甲基氯硅烷(92mg，0.613mmol)、三乙胺(103mg，1.021mmol)和二氯甲烷(5mL)加入反应瓶中，室温搅拌1h。反应结束后，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)，得(R)-6-溴-N-(1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺，产率 99.0％；ESI-MS(m/z)：505.3[M+H] +。 (R)-2-(3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)-2-fluorophenyl)-2,2-difluoro Ethan-1-ol (90mg, 0.204mmol), tert-butyldimethylsilyl chloride (92mg, 0.613mmol), triethylamine (103mg, 1.021mmol) and dichloromethane (5mL) were added to the reaction flask, room temperature Stir for 1h. After the reaction was completed, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R)-6-bromo-N-(1-(3- (2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine, Yield 99.0%; ESI-MS (m/z): 505.3 [M+H] + .
步骤b)：(R)-N 4-(1-(3-(2-(叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺的制备 Step b): (R)-N 4 -(1-(3-(2-(tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluorophenyl) Preparation of ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine
将(R)-6-溴-N-(1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(100mg，0.180mmol)、甲胺盐酸盐(122mg，1.803mmol)、碳酸铯(881mg，2.702mmol)、X-phos(17mg，0.036mmol)、Pd(dba) 2(10mg，0.018mmol)和甲苯(2ml)加入反应瓶中，氮气置换3次，110℃搅拌反应16h。结束后，将反应液冷却至室温，加入乙酸乙酯(5mL)，室温搅拌10min，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＝20/1)，得(R)-N 4-(1-(3-(2-(叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺，产率87.9％；ESI-MS(m/z)：505.3[M+H] +。 (R)-6-bromo-N-(1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluorophenyl ) ethyl)-2-methylquinazolin-4-amine (100mg, 0.180mmol), methylamine hydrochloride (122mg, 1.803mmol), cesium carbonate (881mg, 2.702mmol), X-phos (17mg, 0.036mmol), Pd(dba) 2 (10mg, 0.018mmol) and toluene (2ml) were added into the reaction flask, replaced with nitrogen three times, and stirred at 110°C for 16h. After the end, the reaction solution was cooled to room temperature, ethyl acetate (5 mL) was added, stirred at room temperature for 10 min, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/ 1), to get (R)-N 4 -(1-(3-(2-(tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluorophenyl) Ethyl)-N 6 , 2-dimethylquinazoline-4,6-diamine, yield 87.9%; ESI-MS (m/z): 505.3[M+H] + .
步骤c)：(R)-2-(4-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(4-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl )-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N- Preparation of dimethylacetamide
将(R)-N 4-(1-(3-(2-(叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(80mg，0.159mmol)、2-(4-溴-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺(62mg，0.238mmol)、碳酸铯(104mg，0.318mmol)、X-phos(16mg，0.032mmol)、Pd(dba)2(10mg，0.016mmol)和甲苯(2ml)加入反应瓶中，氮气置换3次，110℃搅拌反应16h。结束后，将反应液冷却至室温，加入乙酸乙酯(5mL)，室温搅拌10min，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＝20/1)，得(R)-2-(4-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺，产率74.1％；ESI-MS(m/z)：683.3[M+H] +。 (R)-N 4 -(1-(3-(2-(tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluorophenyl)ethyl) -N 6 ,2-Dimethylquinazolin-4,6-diamine (80mg, 0.159mmol), 2-(4-bromo-2-oxopyridin-1(2H)-yl)-N,N- Dimethylacetamide (62mg, 0.238mmol), cesium carbonate (104mg, 0.318mmol), X-phos (16mg, 0.032mmol), Pd(dba)2 (10mg, 0.016mmol) and toluene (2ml) were added to the reaction flask In the process, the nitrogen was replaced 3 times, and the reaction was stirred at 110° C. for 16 h. After the end, the reaction solution was cooled to room temperature, ethyl acetate (5 mL) was added, stirred at room temperature for 10 min, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/ 1), to get (R)-2-(4-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl )-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N- Dimethylacetamide, yield 74.1%; ESI-MS (m/z): 683.3 [M+H] + .
步骤d)：(R)-2-(4-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (R)-2-(4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino) Preparation of -2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate
将((R)-2-(4-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺(80mg，0.117mmol)和四正丁基氟化铵的四氢呋喃溶液(1mL)加入反应瓶中，室温搅拌30min。加入稀盐酸(10mL，1N)淬灭反应，用乙酸乙酯萃取(10mL×2)，合并有机相，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(R)-2-(4-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率23.4％；1H NMR(400MHz，DMSO-d6)δ12.70(s，1H)，8.73(s，1H)，8.40(s，1H)，8.13(s，1H)，7.69-7.64(m，3H)，7.42(t，J＝7.2Hz，1H)，7.28-7.21(m，2H)，5.84-5.81(m，1H)，5.70(t，J＝12.0Hz，1H)，5.66-5.63(m，1H)，5.47(d，J＝4.0Hz，1H)，4.65(s，2H)，3.98-3.89(m，2H)，3.33(s，3H)，3.02(s，3H)，2.83(s，3H)，2.41(s，3H)，1.60(d，J＝4.0Hz，3H)；ESI-MS(m/z)：569.2[M+H]+。((R)-2-(4-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)- 2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethyl Acetamide (80mg, 0.117mmol) and tetrahydrofuran solution (1mL) of tetra-n-butylammonium fluoride were added in the reaction flask, stirred at room temperature for 30min. Dilute hydrochloric acid (10mL, 1N) was added to quench the reaction, extracted with ethyl acetate ( 10mL×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 Prep-HPLC (method 2) to obtain (R)-2-(4-((4-(( 1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino) -2-oxopyridin-1(2H)-yl)-N, N-dimethylacetamide formate, yield 23.4%; 1H NMR (400MHz, DMSO-d6) δ12.70 (s, 1H), 8.73(s, 1H), 8.40(s, 1H), 8.13(s, 1H), 7.69-7.64(m, 3H), 7.42(t, J=7.2Hz, 1H), 7.28-7.21(m, 2H) , 5.84-5.81(m, 1H), 5.70(t, J=12.0Hz, 1H), 5.66-5.63(m, 1H), 5.47(d, J=4.0Hz, 1H), 4.65(s, 2H), 3.98-3.89(m, 2H), 3.33(s, 3H), 3.02(s, 3H), 2.83(s, 3H), 2.41(s, 3H), 1.60(d, J=4.0Hz, 3H); ESI - MS (m/z): 569.2 [M+H]+.
实施例63Example 63
(R)-2-(4-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-NN-二甲基乙酰胺甲酸盐的制备(R)-2-(4-((4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylquin Preparation of oxazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-NN-dimethylacetamide formate
Figure PCTCN2022101219-appb-000164
Figure PCTCN2022101219-appb-000164
步骤a)：(R)-6-溴-N-(1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)-2-甲基喹唑啉-4-胺的制备Step a): (R)-6-Bromo-N-(1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)-2-methylquinazoline Preparation of -4-amine
将(R)-2-(3-(1-(6-溴-2-甲基喹唑啉-4-基)氨基乙基)-2-氟苯基)-2，2-二氟乙烷-1-醇(480.0mg，1.100mmol)和四氢呋喃(5mL)加入反应瓶中，搅拌溶解，加入Cs 2CO 3(717.0mg，2.200mmol)、18-Crown-6(145.0mg，0.550mmol)，氮气置换3次，升温至80℃反应过夜。将反应液冷却至室温，缓慢滴加水(30mL)萃灭反应，用二氯甲烷萃取(30mL×3)，合并有机相，用饱和食盐水洗(10mL×2)，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(R)-6-溴-N-(1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)-2-甲基喹唑啉-4-胺，产率79.8％，ESI-MS(m/z)：421.0[M+H] +。 (R)-2-(3-(1-(6-bromo-2-methylquinazolin-4-yl)aminoethyl)-2-fluorophenyl)-2,2-difluoroethane -1-alcohol (480.0mg, 1.100mmol) and tetrahydrofuran (5mL) were added to the reaction flask, stirred and dissolved, Cs 2 CO 3 (717.0mg, 2.200mmol), 18-Crown-6 (145.0mg, 0.550mmol) were added, Nitrogen was replaced 3 times, and the temperature was raised to 80° C. to react overnight. The reaction liquid was cooled to room temperature, and water (30 mL) was slowly added dropwise to extract the reaction, extracted with dichloromethane (30 mL×3), the organic phases were combined, washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=100/1) to obtain (R)-6-bromo-N-(1-(3,3-difluoro -2,3-dihydrobenzofuran-7-yl)ethyl)-2-methylquinazolin-4-amine, yield 79.8%, ESI-MS (m/z): 421.0 [M+H ] + .
步骤b-c)：(R)-2-(4-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备Step b-c): (R)-2-(4-((4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2 Preparation of -methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate
制备方法参考实施例62的步骤b-c，得(R)-2-(4-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率49.0％；1H NMR(400MHz，DMSO-d6)δ12.50(s，1H)，8.41-8.37(m，2H)，8.13(s，1H)，7.66(d，J＝8.0Hz，1H)，7.61-7.56(m，2H)，7.49(d，J＝8.0Hz，1H)，7.21(d，J＝8.0Hz，1H)，7.08(d，J＝8.0Hz，1H)，5.77-5.70(m，1H)，5.62(dd，J＝8.0Hz，1H)，5.45(d，J＝4.0Hz，1H)，4.87(t，J＝16.0Hz，2H)，4.64(s，2H)，3.33(s，3H)，3.02(s，3H)，2.83(s，3H)，2.37(s，3H)，1.57(d，J＝8.0Hz，3H)；ESI-MS(m/z)：549.6[M+H] +。 The preparation method refers to step bc of Example 62 to obtain (R)-2-(4-((4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate , Yield 49.0%; 1H NMR (400MHz, DMSO-d6) δ12.50(s, 1H), 8.41-8.37(m, 2H), 8.13(s, 1H), 7.66(d, J=8.0Hz, 1H ), 7.61-7.56(m, 2H), 7.49(d, J=8.0Hz, 1H), 7.21(d, J=8.0Hz, 1H), 7.08(d, J=8.0Hz, 1H), 5.77-5.70 (m, 1H), 5.62(dd, J=8.0Hz, 1H), 5.45(d, J=4.0Hz, 1H), 4.87(t, J=16.0Hz, 2H), 4.64(s, 2H), 3.33 (s, 3H), 3.02 (s, 3H), 2.83 (s, 3H), 2.37 (s, 3H), 1.57 (d, J=8.0Hz, 3H); ESI-MS (m/z): 549.6[ M+H] + .
实施例64Example 64
(R)-2-(5-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl)ethyl)amino)-2-methylquin Preparation of oxazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000165
Figure PCTCN2022101219-appb-000165
制备方法参考实施例62的步骤c，得(R)-2-(5-((4-((1-(3，3-二氟-2，3-二氢苯并呋喃-7-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率47.6％；1H NMR(400MHz，DMSO-d6)δ8.15(s，1H)，8.13(s，1H)，7.59(t，J＝4.0Hz，3H)，7.50(d，J＝8.0Hz，1H)，7.42-7.39(m，2H)，7.14-7.07(m，2H)，6.47(d，J＝8.0Hz，1H)，5.83-5.75(m，1H)，4.88(t，J＝16.0Hz，2H)，4.79(s，2H)，3.29(s，3H)，3.04(s，3H)，2.85(s，3H)，2.32(s，3H)，1.60(d，J＝8.0Hz，3H)；ESI-MS(m/z)：549.6[M+H1 +。 The preparation method refers to step c of Example 62 to obtain (R)-2-(5-((4-((1-(3,3-difluoro-2,3-dihydrobenzofuran-7-yl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate , yield 47.6%; 1H NMR (400MHz, DMSO-d6) δ8.15(s, 1H), 8.13(s, 1H), 7.59(t, J=4.0Hz, 3H), 7.50(d, J=8.0 Hz, 1H), 7.42-7.39(m, 2H), 7.14-7.07(m, 2H), 6.47(d, J=8.0Hz, 1H), 5.83-5.75(m, 1H), 4.88(t, J= 16.0Hz, 2H), 4.79(s, 2H), 3.29(s, 3H), 3.04(s, 3H), 2.85(s, 3H), 2.32(s, 3H), 1.60(d, J=8.0Hz, 3H); ESI-MS (m/z): 549.6 [M+H1 + .
实施例65Example 65
(R)-2-(3-(1-((6-((5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙醇-1-醇甲酸盐的制备(R)-2-(3-(1-((6-((5-(2-(dimethylamino)ethyl)-6-methoxypyridin-3-yl)(methyl)amino)- Preparation of 2-methylquinazolin-4-yl))amino)ethyl)-2-fluorophenyl)-2,2-difluoroethanol-1-ol formate
Figure PCTCN2022101219-appb-000166
Figure PCTCN2022101219-appb-000166
将(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基-N，N-二甲基乙酰胺(146mg，0.250mmol)和四氢呋喃(3mL)加入反应瓶中，搅拌溶解，冷却至0℃加入四氢铝锂(18.9mg，0.500mmol)，保持0℃下搅拌反应2h。反应结束后，缓慢滴加水(10mL)淬灭反应，用二氯甲烷萃取(15mL×3)，合并有机相，用饱和食盐水(10mL×2)洗，无水硫酸钠干燥，有机相减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(3-(1-((6-((5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)-2-氟苯基)-2，2-二氟乙醇-1-醇甲酸盐，产率38.8％；1H NMR(400MHz，DMSO-d6)δ8.23(d，J＝ 8.0Hz，1H)，8.18(s，2H)，7.90(d，J＝4.0Hz，1H)，7.72(d，J＝4.0Hz，1H)，7.65(t，J＝4.0Hz，1H)，7.46-7.38(m，3H)，7.25(t，J＝8.0Hz，1H)，7.12(dd，J＝8.0Hz，1H)，5.87-5.80(m，1H)，4.94(t，J＝16.0Hz，2H)，3.88(s，3H)，3.38(s，3H)，2.68(t，J＝4.0Hz，2H)，2.52(t，J＝4.0Hz，2H)，2.31(s，3H)，2.22(s，6H)，1.60(d，J＝8.0Hz，3H)；ESI-MS(m/z)：569.6[M+H] +。 (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2- Methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl-N,N-dimethylacetamide (146 mg, 0.250 mmol) and tetrahydrofuran (3 mL) were added to the reaction In the bottle, stir to dissolve, cool to 0°C and add lithium tetrahydrogen aluminum (18.9mg, 0.500mmol), keep stirring at 0°C for 2h. After the reaction, slowly add water (10mL) dropwise to quench the reaction, and extract with dichloromethane (15mL×3), the organic phases were combined, washed with saturated brine (10mL×2), dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/ Methanol=30/1), the resulting crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(3-(1-((6-((5-(2-(dimethylamino)ethyl )-6-methoxypyridin-3-yl)(methyl)amino)-2-methylquinazolin-4-yl))amino)ethyl)-2-fluorophenyl)-2,2- Difluoroethanol-1-ol formate, yield 38.8%; 1H NMR (400MHz, DMSO-d6) δ8.23(d, J=8.0Hz, 1H), 8.18(s, 2H), 7.90(d, J=4.0Hz, 1H), 7.72(d, J=4.0Hz, 1H), 7.65(t, J=4.0Hz, 1H), 7.46-7.38(m, 3H), 7.25(t, J=8.0Hz, 1H), 7.12(dd, J=8.0Hz, 1H), 5.87-5.80(m, 1H), 4.94(t, J=16.0Hz, 2H), 3.88(s, 3H), 3.38(s, 3H), 2.68(t, J=4.0Hz, 2H), 2.52(t, J=4.0Hz, 2H), 2.31(s, 3H), 2.22(s, 6H), 1.60(d, J=8.0Hz, 3H); ESI-MS (m/z): 569.6 [M+H] + .
实施例66Example 66
2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐的制备2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000167
Figure PCTCN2022101219-appb-000167
制备方法参照实施例57的步骤c至步骤h，得2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐，产率20.1％； 1H NMR(400MHz，DMSO-d 6)δ12.66(s，1H)，8.15(s，1H)，8.13(s，1H)，7.65(s，1H)，7.63-7.58(m，2H)，7.47-7.42(m，1H)，7.41-7.33(m，2H)，7.10-7.02(m，2H)，7.02-6.96(m，1H)，6.91-6.90(m，1H)，5.73-5.66(m，1H)，5.58(s，1H)，3.87-3.80(m，2H)，3.76(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.78(s，3H)，2.35(s，3H)，1.63(d，J＝7.2Hz，3H)；ESI-MS(m/z)：564.2[M+H] +。 The preparation method refers to step c to step h of Example 57 to obtain 2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) Amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide formate, yield 20.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.66(s, 1H), 8.15(s, 1H), 8.13(s, 1H), 7.65(s, 1H), 7.63-7.58(m, 2H), 7.47 -7.42(m, 1H), 7.41-7.33(m, 2H), 7.10-7.02(m, 2H), 7.02-6.96(m, 1H), 6.91-6.90(m, 1H), 5.73-5.66(m, 1H), 5.58(s, 1H), 3.87-3.80(m, 2H), 3.76(s, 3H), 3.57(s, 2H), 3.33(s, 3H), 2.99(s, 3H), 2.78(s , 3H), 2.35 (s, 3H), 1.63 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 564.2 [M+H] + .
实施例67Example 67
2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺盐酸盐的制备2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide hydrochloride
Figure PCTCN2022101219-appb-000168
Figure PCTCN2022101219-appb-000168
制备方法参考实施例58，经Pre-HPLC(方法1)纯化，得2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺盐酸盐，产率55.4％； 1H NMR(400MHz，DMSO-d 6)δ14.09(s，1H)，9.89(s，1H)，9.72(s，1H)，7.71(m，1H)，7.68(s，1H)，7.64(d，J＝8.0Hz，1H)，7.53-7.43(m，3H)，7.18(s，1H)，7.00-6.93(m，2H)，6.89(d，J＝8.4Hz，1H)，5.88(s，1H)，5.63(s，1H)，3.91-3.83(m，2H)，3.59(s，2H)，3.35(s，3H)，3.03(s，3H)，2.82(s，3H)，2.56(s，3H)，1.73(d，J＝7.2Hz，3H)；ESI-MS(m/z)：550.3[M+H] +。 The preparation method refers to Example 58 and is purified by Pre-HPLC (Method 1) to obtain 2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl) ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxyl phenyl) -N, N-dimethylacetamide hydrochloride, yield 55.4% ; 1 H NMR (400MHz, DMSO-d 6 ) δ14.09(s, 1H), 9.89(s, 1H), 9.72(s, 1H), 7.71(m, 1H), 7.68(s, 1H), 7.64 (d, J=8.0Hz, 1H), 7.53-7.43(m, 3H), 7.18(s, 1H), 7.00-6.93(m, 2H), 6.89(d, J=8.4Hz, 1H), 5.88( s, 1H), 5.63(s, 1H), 3.91-3.83(m, 2H), 3.59(s, 2H), 3.35(s, 3H), 3.03(s, 3H), 2.82(s, 3H), 2.56 (s, 3H), 1.73 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 550.3 [M+H] + .
实施例68Example 68
(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinoline- Preparation of 6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000169
Figure PCTCN2022101219-appb-000169
步骤a)：(R)-2-(3-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉)-4-基)氨基)乙基)苯基)-2，2-二氟乙酸乙酯的制备Step a): (R)-2-(3-(1-((6-((5-(2-(dimethylamino)-2-oxyethyl))-6-methoxypyridin-3-yl ) (methyl) amino) -2-methylquinazolin) -4-yl) amino) ethyl) phenyl) -2, the preparation of ethyl 2-difluoroacetate
将乙基(R)-2-(3-(1-((6-溴-2-甲基-哌啶-4-基)氨基)乙基)苯基)-2，2-二氟乙酸酯(150mg，0.323mmol)、2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(60mg，0.269mmol)、Cs 2CO 3(175mg，0.538mmol)、Pd(dba) 2(31mg，0.054mmol)、X-phos(52mg，0.108mmol)和甲苯(6mL)依次加入反应瓶中，氮气置换三次，升温至105℃搅拌反应3h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，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，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(3-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉)-4-基)氨基)乙基)苯基)-2，2-二氟乙酸乙酯，产率84.0％；ESI-MS(m/z)：607.3[M+H] +。 Ethyl (R)-2-(3-(1-((6-bromo-2-methyl-piperidin-4-yl)amino)ethyl)phenyl)-2,2-difluoroacetic acid Ester (150 mg, 0.323 mmol), 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (60 mg, 0.269 mmol), Cs 2 CO 3 (175mg, 0.538mmol), Pd(dba) 2 (31mg, 0.054mmol), X-phos (52mg, 0.108mmol) and toluene (6mL) were sequentially added to the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 3h . After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The product was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(3-(1-((6-((5-(2-(dimethyl Amino)-2-oxyethyl)-6-methoxypyridin-3-yl)(methyl)amino)-2-methylquinazolin)-4-yl)amino)ethyl)phenyl)- Ethyl 2,2-difluoroacetate, yield 84.0%; ESI-MS (m/z): 607.3 [M+H] + .
步骤b)：(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备Step b): (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methanol Preparation of quinolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
将(R)-2-(3-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉)-4-基)氨基)乙基)苯基)-2，2-二氟乙酸乙酯(200mg，0.330mmol)溶解在THF(10mL)中，加入硼氢化钠(25mg，0.659mmol)，室温搅拌反应16h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，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，残余物经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率90.0％； 1H NMR(400MHz，DMSO-d 6)δ12.72(s，1H)，8.13(s，2H)，7.94(s，1H)，7.70(s，1H)，7.65(s，1H)，7.60(s，1H)，7.46-7.34(m，4H)，7.10(d，J＝8.0Hz，1H)，5.75-5.66(m，1H)，5.60(t，J＝8.0Hz，1H)，3.88-3.79(m，5H)，3.59(s，2H)，3.36(s，3H)，3.02(s，3H)，2.80(s，3H)，2.36(s，3H)，1.63(d，J＝8.0Hz，3H)；ESI-MS(m/z)：565.3[M+H] +。 (R)-2-(3-(1-((6-((5-(2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)(methyl yl)amino)-2-methylquinazolin)-4-yl)amino)ethyl)phenyl)-2,2-difluoroacetic acid ethyl ester (200 mg, 0.330 mmol) was dissolved in THF (10 mL), Sodium borohydride (25mg, 0.659mmol) was added, and the reaction was stirred at room temperature for 16h. After the reaction was completed, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×2), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The material was purified by Prep-HPLC (method 2) to give (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl) Base)amino)-2-methylquinolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate, yield 90.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.72(s, 1H), 8.13(s, 2H), 7.94(s, 1H), 7.70(s, 1H), 7.65(s, 1H) , 7.60(s, 1H), 7.46-7.34(m, 4H), 7.10(d, J=8.0Hz, 1H), 5.75-5.66(m, 1H), 5.60(t, J=8.0Hz, 1H), 3.88-3.79(m, 5H), 3.59(s, 2H), 3.36(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.36(s, 3H), 1.63(d, J= 8.0 Hz, 3H); ESI-MS (m/z): 565.3 [M+H] + .
实施例69Example 69
(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000170
Figure PCTCN2022101219-appb-000170
制备方法参考实施例38，经Pre-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率54.0％； 1H NMR(400MHz，CD 3OD)δ8.54(s，1H)，7.62(s，1H)，7.57-7.50(m，3H)，7.42-7.36(m，4H)，7.33(s，1H)，5.76-5.71(m，1H)，3.86(t，J＝16.0Hz，2H)，3.56(s，2H)，3.34(s，3H)，3.14(s，3H)，2.93(s，3H)，2.45(s，3H)，1.67(d，J＝8.0Hz，3H)；ESI-MS(m/z)：551.4[M+H] +。 The preparation method refers to Example 38, and is purified by Pre-HPLC (method 2) to obtain (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl Base) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -N,N-dimethylacetamide acid salt, yield 54.0%; 1 H NMR (400MHz, CD 3 OD) δ8.54(s, 1H), 7.62(s, 1H), 7.57-7.50(m, 3H), 7.42-7.36(m, 4H ), 7.33(s, 1H), 5.76-5.71(m, 1H), 3.86(t, J=16.0Hz, 2H), 3.56(s, 2H), 3.34(s, 3H), 3.14(s, 3H) , 2.93 (s, 3H), 2.45 (s, 3H), 1.67 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 551.4 [M+H] + .
实施例70Example 70
(R)-2-(3-(1-((6-((5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)苯基)-2，2-二氟乙醇-1-醇的制备(R)-2-(3-(1-((6-((5-(2-(dimethylamino)ethyl)-6-methoxypyridin-3-yl)(methyl)amino)- Preparation of 2-methylquinazolin-4-yl))amino)ethyl)phenyl)-2,2-difluoroethanol-1-ol
Figure PCTCN2022101219-appb-000171
Figure PCTCN2022101219-appb-000171
将(R)-2-(3-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉)-4-基)氨基)乙基)苯基)-2，2-二氟乙酸乙酯(100.0mg，0.165mmol)溶解在THF(10mL)中，加入氢化铝锂(31.3mg，0.825mmol)，室温搅拌30min。加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，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3)纯化，得(R)-2-(3-(1-((6-((5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基))氨基)乙基)苯基)-2，2-二氟乙醇-1-醇，产率90.0％； 1H NMR(400MHz，DMSO-d 6)δ8.19(s，1H)，8.16(s，1H)，7.88(s，1H)，7.68(s，1H)，7.65(s，1H)，7.59(d，J＝8.0Hz，1H)，7.46-7.42(m，2H)，7.39-7.36(m，2H)，7.09(d，J＝8.0Hz，1H)，5.73-5.66(m，1H)，3.88(s，3H)，3.83(t，J＝12.0Hz，2H)，3.35(m，3H)，2.67-2.64(m，2H)，2.49(t，J＝12.0Hz，2H)，2.35(s，3H)，2.19(s，6H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：551.5[M+H] +。 (R)-2-(3-(1-((6-((5-(2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)(methyl yl)amino)-2-methylquinazolin)-4-yl)amino)ethyl)phenyl)-2,2-difluoroacetic acid ethyl ester (100.0 mg, 0.165 mmol) was dissolved in THF (10 mL) , add lithium aluminum hydride (31.3 mg, 0.825 mmol), and stir at room temperature for 30 min. Add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purification by HPLC (Method 3) afforded (R)-2-(3-(1-((6-((5-(2-(dimethylamino)ethyl)-6-methoxypyridin-3-yl )(methyl)amino)-2-methylquinazolin-4-yl))amino)ethyl)phenyl)-2,2-difluoroethanol-1-ol, yield 90.0%; 1 H NMR (400MHz, DMSO-d 6 )δ8.19(s, 1H), 8.16(s, 1H), 7.88(s, 1H), 7.68(s, 1H), 7.65(s, 1H), 7.59(d, J =8.0Hz, 1H), 7.46-7.42(m, 2H), 7.39-7.36(m, 2H), 7.09(d, J=8.0Hz, 1H), 5.73-5.66(m, 1H), 3.88(s, 3H), 3.83(t, J=12.0Hz, 2H), 3.35(m, 3H), 2.67-2.64(m, 2H), 2.49(t, J=12.0Hz, 2H), 2.35(s, 3H), 2.19 (s, 6H), 1.62 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 551.5 [M+H] + .
实施例71Example 71
(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙腈甲酸盐的制备(R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxypyridin-3-yl)acetonitrile formate
Figure PCTCN2022101219-appb-000172
Figure PCTCN2022101219-appb-000172
步骤a)：(R)-2-(3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2，2-二氟乙烷-1-醇的制备Step a): (R)-2-(3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethyl Preparation of alkan-1-ols
将(R)-2-(3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2，2-二氟乙酸乙酯(300mg，0.648mmol)、THF(5mL)和水(0.1mL)加入反应瓶中，再加入硼氢化钠(54mg，1.296mmol)，室温搅拌1h，加入水(5mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，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＝3/1)，得(R)-2-(3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2，2-二氟乙烷-1-醇，产率50.6％；ESI-MS(m/z)：422.1[M+H] +。 (R)-2-(3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroacetic acid ethyl ester ( 300mg, 0.648mmol), THF (5mL) and water (0.1mL) were added to the reaction flask, then sodium borohydride (54mg, 1.296mmol) was added, stirred at room temperature for 1h, water (5mL) was added to quench the reaction, and ethyl acetate Extract (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain (R)-2-(3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethane-1- Alcohol, yield 50.6%; ESI-MS (m/z): 422.1 [M+H] + .
步骤b)：(R)-6-溴-N-(1-(3-(2-((叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step b): (R)-6-bromo-N-(1-(3-(2-((tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl The preparation of )-2-methylquinazolin-4-amine
将(R)-2-(3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)苯基)-2，2-二氟乙烷-1-醇(150mg，0.355mmol)、三乙胺(173mg，0.666mmol)、叔丁基二甲基氯硅烷(290mg，0.888mmol)、4-二甲氨基吡啶(4.3mg，0.035mmol)和二氯甲烷(5mL)加入反应瓶中，室温搅拌5h。将反应液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)，得(R)-6-溴-N-(1-(3-(2-((叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)-2-甲基喹唑啉-4-胺，产率97.6％；ESI-MS(m/z)：536.2[M+H] +。 (R)-2-(3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)phenyl)-2,2-difluoroethane-1 -alcohol (150mg, 0.355mmol), triethylamine (173mg, 0.666mmol), tert-butyldimethylsilyl chloride (290mg, 0.888mmol), 4-dimethylaminopyridine (4.3mg, 0.035mmol) and dichloro Methane (5 mL) was added into the reaction flask and stirred at room temperature for 5 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R)-6-bromo-N-(1-(3-( 2-((tert-Butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)-2-methylquinazolin-4-amine, yield 97.6%; ESI- MS (m/z): 536.2 [M+H] + .
步骤c)：(R)-N 4-(1-(3-(2-(叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺的制备 Step c): (R)-N 4 -(1-(3-(2-(tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)-N 6 , the preparation of 2-dimethylquinazoline-4,6-diamine
将(R)-6-溴-N-(1-(3-(2-((叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)-2-甲基喹唑啉-4-胺(190mg，0.354mmol)、甲胺盐酸盐(239mg，3.541mmol)、碳酸铯(1.7g，5.312mmol)、X-phos(34mg，0.071mmol)、Pd(dba) 2(22mg，0.035mmol)和甲苯(10ml)加入恒容反应器中，氮气鼓吹2min后，升温120℃搅拌16h。将反应液降至室温，加入乙酸乙酯(20mL)室温搅拌10min，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＝20/1)，得(R)-N 4-(1-(3-(2-(叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺，产率81.9％；ESI-MS(m/z)：487.3[M+H] +。 (R)-6-bromo-N-(1-(3-(2-((tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)-2 -Methylquinazolin-4-amine (190mg, 0.354mmol), methylamine hydrochloride (239mg, 3.541mmol), cesium carbonate (1.7g, 5.312mmol), X-phos (34mg, 0.071mmol), Pd (dba) 2 (22mg, 0.035mmol) and toluene (10ml) were added to a constant volume reactor, and after blowing nitrogen for 2min, the temperature was raised to 120°C and stirred for 16h. The reaction solution was lowered to room temperature, and ethyl acetate (20mL) was added and stirred at room temperature for 10min , filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-N 4 -(1-(3-(2-( tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine, yield 81.9% ; ESI-MS (m/z): 487.3 [M+H] + .
步骤d)：(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酸乙酯的制备Step d): (R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl () phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) preparation of ethyl acetate
将(R)-N 4-(1-(3-(2-(叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(100mg，0.205mmol)，2-(5-溴-2-甲氧基吡啶-3-基)乙酸乙酯(86mg，0.308mmol)、碳酸铯(135mg，0.411mmol)、X-phos(20mg，0.041mmol)、Pd(dba) 2(12.1mg，0.021mmol)和甲苯(10ml)加入反应瓶中，氮气置换3次，升温100℃搅拌4h。反应结束后，冷却至室温，加入乙酸乙酯(20mL)室温搅拌10min，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＝20/1)，得(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酸乙酯，产率71.6％；ESI-MS(m/z)：680.3[M+H] +。 (R)-N 4 -(1-(3-(2-(tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)-N 6 , 2- Dimethylquinazoline-4,6-diamine (100mg, 0.205mmol), ethyl 2-(5-bromo-2-methoxypyridin-3-yl)acetate (86mg, 0.308mmol), cesium carbonate (135mg, 0.411mmol), X-phos (20mg, 0.041mmol), Pd(dba) 2 (12.1mg, 0.021mmol) and toluene (10ml) were added into the reaction flask, replaced with nitrogen three times, and stirred at 100°C for 4h. After the reaction, cool to room temperature, add ethyl acetate (20 mL) and stir at room temperature for 10 min, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1), Get (R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)phenyl ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) ethyl acetate, yield 71.6%; ESI-MS ( m/z): 680.3 [M+H] + .
步骤e)：(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酸的制备Step e): (R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl ) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetic acid preparation
将(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酸乙酯(100mg，0.147mmol)，THF(2mL)、甲醇(2mL)、和水(4mL)加入反应瓶中，再加入氢氧化锂一水合物(31mg，0.735mmol)室温搅拌2h，用1N的盐酸水溶液调节pH＝5～6，加入乙酸乙酯萃取(20mL×2)，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：二氯甲烷/甲醇＝20/1)，得(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酸，产率61.1％；ESI-MS(m/z)：652.3[M+H] +。 (R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)phenyl )ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)ethyl acetate (100mg, 0.147mmol), THF (2mL ), methanol (2mL), and water (4mL) were added to the reaction flask, then lithium hydroxide monohydrate (31mg, 0.735mmol) was added and stirred at room temperature for 2h, the pH was adjusted to 5-6 with 1N hydrochloric acid aqueous solution, and ethyl acetate was added Ester extraction (20mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain ( R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)phenyl)ethyl base)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)acetic acid, yield 61.1%; ESI-MS (m/z) : 652.3[M+H] + .
步骤f)：(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酰胺的制备Step f): (R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyloxy)-1,1-difluoroethyl)benzene Preparation of base) ethyl) amino)-2-methylquinazolin-6-yl) (methyl) amino)-2-methoxypyridin-3-yl) acetamide
将(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酸(80mg，0.123mmol)，2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸酯(70mg，0.184mmol)，N，N-二异丙基乙胺(32mg，0.246mmol)，1mol/L氨甲醇溶液(0.8mL)和N，N-二甲基甲酰胺(2mL)加入反应瓶中，室温搅拌3h，再加入水(5mL)和乙酸乙酯(10mL)萃取，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：二氯甲烷/甲醇＝20/1)，得(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酰胺，产率99.9％；ESI-MS(m/z)：651.3[M+H] +。 (R)-2-(5-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)phenyl ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) acetic acid (80mg, 0.123mmol), 2-(7- Azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (70mg, 0.184mmol), N,N-diisopropylethylamine (32mg, 0.246mmol) , 1mol/L ammonia methanol solution (0.8mL) and N,N-dimethylformamide (2mL) were added to the reaction flask, stirred at room temperature for 3h, then added water (5mL) and ethyl acetate (10mL) for extraction, and the organic phase Dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(5-((4 -((1-(3-(2-((tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquinazoline- 6-yl)(methyl)amino)-2-methoxypyridin-3-yl)acetamide, yield 99.9%; ESI-MS (m/z): 651.3 [M+H] + .
步骤g)：(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙腈甲酸盐的制备Step g): (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methanol Preparation of quinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)acetonitrile formate
将N，N-二甲基甲酰胺(3mL)加入反应瓶中，冰浴下搅拌下加入二氯亚砜(0.5mL)，维持冰浴搅拌30min，滴加(R)-2-(5-((4-((1-(3-(2-((叔丁基二甲基硅氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙酰胺(60mg，0.092mmol)的N，N-二甲基甲酰胺(1mL)溶液，搅拌1h，加水(5mL)淬灭反应，再加入二氯甲烷(20mL)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)乙腈甲酸盐，产率37.8％； 1H NMR(400MHz，DMSO-d 6)δ8.31(s，1H)，8.13(s，1H)，8.03(s，1H)，7.78(s，1H)，7.65(s，1H)，7.60-7.59(m，2H)，7.46-7.42(m，2H)，7.38(d，J＝8.0Hz，1H)，7.18(d，J＝8.0Hz，1H)，5.74-5.67(m，1H)，5.60(t，J＝12.0Hz，1H)，3.93(s，3H)，3.88-3.79(m，4H)，3.37(s，3H)，2.37(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：519.3[M+H] +。 Add N,N-dimethylformamide (3mL) into the reaction flask, add thionyl chloride (0.5mL) while stirring in ice bath, keep stirring in ice bath for 30min, drop (R)-2-(5- ((4-((1-(3-(2-((tert-butyldimethylsilyloxy)-1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquin A solution of oxazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)acetamide (60 mg, 0.092 mmol) in N,N-dimethylformamide (1 mL) was stirred for 1 h , add water (5mL) to quench the reaction, then add dichloromethane (20mL) for extraction, the organic phase is dried over anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by Prep-HPLC (method 2) to obtain (R) -2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazoline-6- yl)(methyl)amino)-2-methoxypyridin-3-yl)acetonitrile formate, yield 37.8%; 1 H NMR (400MHz, DMSO-d 6 )δ8.31(s, 1H), 8.13(s, 1H), 8.03(s, 1H), 7.78(s, 1H), 7.65(s, 1H), 7.60-7.59(m, 2H), 7.46-7.42(m, 2H), 7.38(d, J=8.0Hz, 1H), 7.18(d, J=8.0Hz, 1H), 5.74-5.67(m, 1H), 5.60(t, J=12.0Hz, 1H), 3.93(s, 3H), 3.88- 3.79 (m, 4H), 3.37 (s, 3H), 2.37 (s, 3H), 1.62 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 519.3 [M+H] + .
实施例72Example 72
(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-methylphenyl)ethyl)amino)-2- Preparation of methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000173
Figure PCTCN2022101219-appb-000173
制备方法参考实施例57的步骤g和步骤h，得(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率90.0％； 1H NMR(400MHz，DMSO-d 6)δ8.26(s，1H)，8.16(s，1H)，7.93(s，1H)，7.73(s，1H)，7.67(s，1H)，7.37(d，J＝8.0Hz，1H)，7.34-7.32(m，2H)，7.25(t，J＝8.0Hz，1H)，7.09(d，J＝8.0Hz，1H)，5.82-5.75(m，1H)，5.65(s，1H)，3.94-3.87(m，2H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.60(s，3H)，2.31(s，3H)，1.55(d，J＝8.0Hz，3H)；ESI-MS(m/z)：579.3[M+H] +。 The preparation method refers to step g and step h of Example 57 to obtain (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2 -Methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethyl Acetamide formate, yield 90.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.26(s, 1H), 8.16(s, 1H), 7.93(s, 1H), 7.73(s, 1H ), 7.67(s, 1H), 7.37(d, J=8.0Hz, 1H), 7.34-7.32(m, 2H), 7.25(t, J=8.0Hz, 1H), 7.09(d, J=8.0Hz , 1H), 5.82-5.75(m, 1H), 5.65(s, 1H), 3.94-3.87(m, 2H), 3.85(s, 3H), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.60(s, 3H), 2.31(s, 3H), 1.55(d, J=8.0Hz, 3H); ESI-MS(m/z): 579.3 [M+H] + .
实施例73Example 73
(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-methylphenyl)ethyl)amino)-2- Preparation of methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000174
Figure PCTCN2022101219-appb-000174
制备方法参考实施例38，经Pre-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(1，1-二氟-2-羟乙基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率46.0％； 1H NMR(400MHz，DMSO-d 6)δ11.61(s，1H)，8.22(d，J＝8.0Hz，1H)，8.14(s，1H)，7.66(d，J＝8.0Hz，1H)，7.55(s，1H)，7.37(d，J＝12.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.26-7.22(m，2H)，7.18(s，1H)，7.05(d，J＝8.0Hz，1H)，5.82-5.75(m，1H)，5.65(s，1H)，3.90(t，J＝12.0Hz，2H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.79(s，3H)，2.60(s，3H)，2.31(s，3H)，1.55(d，J＝8.0Hz，3H)；ESI-MS(m/z)：565.3[M+H] +。 The preparation method refers to Example 38, and is purified by Pre-HPLC (method 2) to obtain (R)-2-(5-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl Base)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-two Methylacetamide formate, yield 46.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.61(s, 1H), 8.22(d, J=8.0Hz, 1H), 8.14(s, 1H ), 7.66(d, J=8.0Hz, 1H), 7.55(s, 1H), 7.37(d, J=12.0Hz, 1H), 7.33(d, J=8.0Hz, 1H), 7.26-7.22(m , 2H), 7.18(s, 1H), 7.05(d, J=8.0Hz, 1H), 5.82-5.75(m, 1H), 5.65(s, 1H), 3.90(t, J=12.0Hz, 2H) , 3.42(s, 2H), 3.28(s, 3H), 3.01(s, 3H), 2.79(s, 3H), 2.60(s, 3H), 2.31(s, 3H), 1.55(d, J=8.0 Hz, 3H); ESI-MS (m/z): 565.3 [M+H] + .
实施例74Example 74
(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(6-methylpyridin-2-yl)ethyl)amino)quinazoline- Preparation of 6-yl)amino)phenyl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000175
Figure PCTCN2022101219-appb-000175
步骤a)：(R，E)-2-甲基-N-(1-(6-甲基吡啶-2-基)亚乙基)丙烷-2-亚磺酰胺的制备Step a): Preparation of (R,E)-2-methyl-N-(1-(6-methylpyridin-2-yl)ethylidene)propane-2-sulfinamide
将1-(6-甲基吡啶-2-基)-乙-1-酮(5.0g，0.037mol)、(R)-叔丁基亚磺酰胺(9.0g，0.074mol)、钛酸四乙酯(25.3g，0.111mol)和THF(100mL)加入反应瓶中，升温至回流搅拌3h。反应结束后，冷却至室温，加水(100mL)和乙酸乙酯(100ml)稀释，室温搅拌10min，过滤，滤液分液，有机相用饱和食盐水(50ml)洗涤，无水硫酸钠干燥，加压抽滤，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)，得(R，E)-2-甲基-N-(1-(6-甲基吡啶-2-基)亚乙基)丙烷-2-亚磺酰胺，产率62.4％；ESI-MS(m/z)：239.1[M+H] +。 1-(6-methylpyridin-2-yl)-ethan-1-one (5.0g, 0.037mol), (R)-tert-butylsulfinamide (9.0g, 0.074mol), tetraethyl titanate Ester (25.3 g, 0.111 mol) and THF (100 mL) were added into the reaction flask, heated to reflux and stirred for 3 h. After the reaction, cool to room temperature, dilute with water (100mL) and ethyl acetate (100ml), stir at room temperature for 10min, filter, separate the filtrate, wash the organic phase with saturated brine (50ml), dry over anhydrous sodium sulfate, pressurize Suction filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R,E)-2-methyl-N-(1- (6-methylpyridin-2-yl)ethylene)propane-2-sulfinamide, yield 62.4%; ESI-MS (m/z): 239.1 [M+H] + .
步骤b)：(R)-2-甲基-N-((R)-1-(6-甲基吡啶-2-基)乙基)丙烷-2-亚磺酰胺的制备Step b): Preparation of (R)-2-methyl-N-((R)-1-(6-methylpyridin-2-yl)ethyl)propane-2-sulfinamide
将(R，E)-2-甲基-N-(1-(6-甲基吡啶-2-基)亚乙基)丙烷-2-亚磺酰胺(5.0g，0.021mol)和THF(100mL)水(2ml)加入反应瓶中，搅拌溶解，再降温至-78℃搅拌10分钟。分批加入硼氢化钠(1.2g，0.032mol)，-78℃搅拌1h后，缓慢升至室温继续搅拌30min。加水(50ml)淬灭反应，以乙酸乙酯(50ml)萃取，有机相用饱和食盐水(50ml)洗涤，无水硫酸钠干燥，加压抽滤，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)，得(R)-2-甲基-N-((R)-1-(6-甲基吡啶-2-基)乙基)丙烷-2-亚磺酰胺3.4g，产率66.7％；ESI-MS(m/z)：241.1[M+H] +。 (R,E)-2-methyl-N-(1-(6-methylpyridin-2-yl)ethylidene)propane-2-sulfinamide (5.0g, 0.021mol) and THF (100mL ) water (2ml) was added into the reaction flask, stirred to dissolve, then cooled to -78°C and stirred for 10 minutes. Add sodium borohydride (1.2 g, 0.032 mol) in batches, stir at -78°C for 1 h, then slowly warm to room temperature and continue stirring for 30 min. Add water (50ml) to quench the reaction, extract with ethyl acetate (50ml), wash the organic phase with saturated brine (50ml), dry over anhydrous sodium sulfate, filter under pressure, concentrate the filtrate under reduced pressure, and pass the residue through a silica gel column layer Analysis and purification (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R)-2-methyl-N-((R)-1-(6-methylpyridin-2-yl)ethyl 3.4 g of propane-2-sulfinamide, yield 66.7%; ESI-MS (m/z): 241.1 [M+H] + .
步骤c)：(R)-1-(6-甲基吡啶-2-基)乙烷-1-胺的制备Step c): Preparation of (R)-1-(6-methylpyridin-2-yl)ethan-1-amine
将(R)-2-甲基-N-((R)-1-(6-甲基吡啶-2-基)乙基)丙烷-2-亚磺酰胺(2.4g，0.010m0l)和THF(10ml)加入反应瓶中，搅拌溶解，再加入氯化氢1，4-二氧六环溶液(30mL，4M)，室温搅拌3h。将反应液减压浓缩，再加入乙酸乙酯(10mL)和石油醚(100mL)室温打浆30min，过滤，所得固体减压干燥得(R)-1-(6-甲基吡啶-2-基)乙烷-1-胺，产率95.6％；ESI-MS(m/z)：137.1[M+H] +。 (R)-2-Methyl-N-((R)-1-(6-methylpyridin-2-yl)ethyl)propane-2-sulfinamide (2.4 g, 0.010 mol) and THF ( 10ml) into the reaction flask, stirred to dissolve, then added hydrogen chloride 1,4-dioxane solution (30mL, 4M), stirred at room temperature for 3h. Concentrate the reaction solution under reduced pressure, then add ethyl acetate (10 mL) and petroleum ether (100 mL) to make slurry at room temperature for 30 min, filter, and dry the obtained solid under reduced pressure to obtain (R)-1-(6-methylpyridin-2-yl) Ethane-1-amine, yield 95.6%; ESI-MS (m/z): 137.1 [M+H] + .
步骤d)：(R)-6-溴-2-甲基-N-(1-(6-甲基吡啶-2-基)乙基)喹唑啉-4-胺的制备Step d): Preparation of (R)-6-bromo-2-methyl-N-(1-(6-methylpyridin-2-yl)ethyl)quinazolin-4-amine
将(R)-1-(6-甲基吡啶-2-基)乙烷-1-胺(100mg，0.734mmol)、6-溴-4-氯-2-甲基喹唑啉(227mg，0.881mmol)溶于DMF(2mL)中，加入DIPEA(286mg，2.203mmol)，升温80℃搅拌3h。反应结束后，将反应液冷却至室温，加水(2mL)和乙酸乙酯(4mL)萃取，有机相用饱和食盐水(5mL)洗涤，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)，得(R)-6-溴-2-甲基-N-(1-(6-甲基吡啶-2-基)乙基)喹唑啉-4-胺，产率57.2％；ESI-MS(m/z)：357.0[M+H] +。 (R)-1-(6-methylpyridin-2-yl)ethane-1-amine (100mg, 0.734mmol), 6-bromo-4-chloro-2-methylquinazoline (227mg, 0.881 mmol) was dissolved in DMF (2 mL), DIPEA (286 mg, 2.203 mmol) was added, and the temperature was raised to 80° C. and stirred for 3 h. After the reaction, the reaction liquid was cooled to room temperature, added water (2 mL) and ethyl acetate (4 mL) for extraction, the organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue Purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=3/1) to obtain (R)-6-bromo-2-methyl-N-(1-(6-methylpyridine-2 -yl)ethyl)quinazolin-4-amine, yield 57.2%; ESI-MS (m/z): 357.0 [M+H] + .
步骤e)：(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step e): (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(6-methylpyridin-2-yl)ethyl)amino) Preparation of quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide formate
将(R)-6-溴-2-甲基-N-(1-(6-甲基吡啶-2-基)乙基)喹唑啉-4-胺(55mg，0.154mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-NN-二甲基乙酰胺盐酸盐(52mg，0.200mmol)、碳酸铯(101mg，0.308mmol)、X-phos(15mg，0.031mmol)、Pd(dba) 2(9mg，0.015mmol)和甲苯(2ml)加入反应瓶中，氮气置换3次，升温回流搅拌16h。反应结束后，冷却至至室温，加入乙酸乙酯(5mL)室温搅拌10min，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＝20/1)，所得粗品再经Prep-HPLC(方法2)纯化，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺甲酸盐，产率13.4％； 1H NMR(400MHz，DMSO-d 6)δ8.16(s，1H)，8.14(s，1H)，8.13(s，1H)，7.64-7.61(m，2H)，7.37(d，J＝12.0Hz，1H)，7.25(d，J＝8.0Hz，1H)，7.12-7.05(m，3H)，7.00(d，J＝8.0Hz，1H)，6.93(s，1H)，5.66-5.59(m，1H)，3.78(s，3H)，3.58(s，2H)，3.34(s，3H)，2.99(s，3H)，2.79(s，3H)，2.48(s，3H)，2.34(s，3H)，1.62(d，J＝8.0Hz，3H)；ESI-MS(m/z)：499.2[M+H] +。 (R)-6-bromo-2-methyl-N-(1-(6-methylpyridin-2-yl)ethyl)quinazolin-4-amine (55mg, 0.154mmol), 2-( 2-methoxy-5-(methylamino)phenyl)-NN-dimethylacetamide hydrochloride (52mg, 0.200mmol), cesium carbonate (101mg, 0.308mmol), X-phos (15mg, 0.031mmol ), Pd(dba) 2 (9mg, 0.015mmol) and toluene (2ml) were added into the reaction flask, replaced with nitrogen for 3 times, and stirred at reflux for 16h. After the reaction, cool to room temperature, add ethyl acetate (5 mL) and stir at room temperature for 10 min, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) , the resulting crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(6-methyl Pyridin-2-yl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide formate, yield 13.4%; 1 H NMR (400MHz, DMSO -d 6 )δ8.16(s, 1H), 8.14(s, 1H), 8.13(s, 1H), 7.64-7.61(m, 2H), 7.37(d, J=12.0Hz, 1H), 7.25( d, J=8.0Hz, 1H), 7.12-7.05(m, 3H), 7.00(d, J=8.0Hz, 1H), 6.93(s, 1H), 5.66-5.59(m, 1H), 3.78(s , 3H), 3.58(s, 2H), 3.34(s, 3H), 2.99(s, 3H), 2.79(s, 3H), 2.48(s, 3H), 2.34(s, 3H), 1.62(d, J = 8.0 Hz, 3H); ESI-MS (m/z): 499.2 [M+H] + .
实施例75Example 75
(R)-2-(5-(4-(1-(5-氨基吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-(4-(1-(5-aminopyridin-3-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)- Preparation of 2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000176
Figure PCTCN2022101219-appb-000176
步骤a)：1-(5-硝基吡啶-3-基)乙基-1-酮的制备Step a): Preparation of 1-(5-nitropyridin-3-yl)ethyl-1-one
将3-溴-5-硝基吡啶(1.725g，8.498mmol)、三丁基(1-乙氧基乙烯基)锡烷(3.989g，11.047mmol)、Pd(PPh 3)Cl 2(298mg，0.425mmol)、三乙胺(1.716g，16.996mmol)和1，4-二氧六环(30mL)加入到反应瓶中，氮气置换三次，升温至90℃搅拌反应16h。反应结束后，将反应液冷却至室温，加入2N的稀盐酸调至pH＝2-3，室温搅拌1h，浓缩除去溶剂，将饱和碳酸氢钠水溶液加入混合物中，用乙酸乙酯萃取(50mL×3)，合并有机相，以饱和食盐水(150mL)洗涤，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)，得1-(5-硝基吡啶-3-基)乙基-1-酮，产率42.0％；ESI-MS(m/z)：167.1[M+H] +。 3-Bromo-5-nitropyridine (1.725g, 8.498mmol), tributyl(1-ethoxyvinyl)stannane (3.989g, 11.047mmol), Pd(PPh 3 )Cl 2 (298mg, 0.425mmol), triethylamine (1.716g, 16.996mmol) and 1,4-dioxane (30mL) were added into the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred for 16h. After the reaction, the reaction liquid was cooled to room temperature, 2N dilute hydrochloric acid was added to adjust the pH to 2-3, stirred at room temperature for 1 h, concentrated to remove the solvent, saturated aqueous sodium bicarbonate was added to the mixture, and extracted with ethyl acetate (50 mL× 3), the organic phases were combined, washed with saturated brine (150 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10 /1) to obtain 1-(5-nitropyridin-3-yl)ethyl-1-one with a yield of 42.0%; ESI-MS (m/z): 167.1 [M+H] + .
步骤b)：(R，E)-2-甲基-N-(1-(5-硝基吡啶-3-基)亚乙基)丙烷-2-亚磺酰胺的制备Step b): Preparation of (R,E)-2-methyl-N-(1-(5-nitropyridin-3-yl)ethylidene)propane-2-sulfinamide
将1-(5-硝基吡啶-3-基)乙基-1-酮(630mg，3.800mmol)和(R)-(+)-叔丁基亚磺酰胺(0.69g，5.700mmol)和THF(15mL)加入反应瓶中，搅拌溶解，室温下加入钛酸四乙酯(2.665g，7.600mmol，65％)，加毕升温至80℃搅拌3h。反应结束后，冷却至室温，加水(20mL)，析出大量固体，过滤，滤饼用乙酸乙酯(50mL)洗涤，滤液以乙酸乙酯萃取(50mL×3)，合并有机相，以饱和食盐水(20mL)洗涤，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)，得(R，E)-2-甲基-N-(1-(5-硝基吡啶-3-基)亚乙基)丙烷-2-亚磺酰胺，产率99.0％；ESI-MS(m/z)：270.3[M+H] +。 1-(5-nitropyridin-3-yl)ethyl-1-one (630mg, 3.800mmol) and (R)-(+)-tert-butylsulfinamide (0.69g, 5.700mmol) and THF (15 mL) was added to the reaction flask, stirred to dissolve, and tetraethyl titanate (2.665 g, 7.600 mmol, 65%) was added at room temperature, and the temperature was raised to 80° C. and stirred for 3 h after the addition. After the reaction, cool to room temperature, add water (20mL), precipitate a large amount of solid, filter, wash the filter cake with ethyl acetate (50mL), extract the filtrate with ethyl acetate (50mL×3), combine the organic phases, and wash with saturated brine (20mL) was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=5/1) to obtain (R, E)- 2-Methyl-N-(1-(5-nitropyridin-3-yl)ethylidene)propane-2-sulfinamide, yield 99.0%; ESI-MS (m/z): 270.3 [M +H] + .
步骤c)：(R)-2-甲基-N-((R)-1-(5-硝基吡啶-3-基)乙基)丙烷-2-亚磺酰胺的制备Step c): Preparation of (R)-2-methyl-N-((R)-1-(5-nitropyridin-3-yl)ethyl)propane-2-sulfinamide
将(R)-2-甲基-N-(1-(5-硝基吡啶-3-基)亚乙基)丙烷-2-亚磺酰胺(942mg，3.500mmol)和THF(15mL)加入反应瓶中，搅拌溶解，在-78℃搅拌条件下，缓慢加入DIBAL-H的THF溶液(1M，10.5mL，10.500mmol)，维持-78℃反应1小时。反应结束后，自然升温至室温，加入饱和食盐水(50mL)淬灭反应，析出大量固体，过滤，滤饼用乙酸乙酯(50mL)洗涤，滤液以乙酸乙酯萃取(50mL×3)，合并有机相，以饱和食盐水(50mL)洗涤，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＝2/1)，得(R)-2-甲基-N-((R)-1-(5-硝基吡啶-3-基)乙基)丙烷-2-亚磺酰胺，产率90.0％；ESI-MS(m/z)：272.3[M+H] +。 (R)-2-Methyl-N-(1-(5-nitropyridin-3-yl)ethylidene)propane-2-sulfinamide (942 mg, 3.500 mmol) and THF (15 mL) were added to the reaction Stir to dissolve in the bottle, slowly add DIBAL-H solution in THF (1M, 10.5mL, 10.500mmol) with stirring at -78°C, and maintain -78°C for 1 hour. After the reaction, the temperature was naturally raised to room temperature, and saturated brine (50 mL) was added to quench the reaction, and a large amount of solid was precipitated, filtered, the filter cake was washed with ethyl acetate (50 mL), the filtrate was extracted with ethyl acetate (50 mL×3), and the combined The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=2/1), (R)-2-methyl-N-((R)-1-(5-nitropyridin-3-yl)ethyl)propane-2-sulfinamide was obtained with a yield of 90.0%; ESI-MS ( m/z): 272.3 [M+H] + .
步骤d)：(R)-1-(5-硝基吡啶-3-基)乙基-1-胺盐酸盐的制备Step d): Preparation of (R)-1-(5-nitropyridin-3-yl)ethyl-1-amine hydrochloride
将(R)-2-甲基-N-((R)-1-(5-硝基吡啶-3-基)乙基)丙烷-2-亚磺酰胺(854mg，3.150mmol)和THF(5mL)加入反应瓶中，搅拌溶解，在0℃搅拌条件下，缓慢加入氯化氢二氧六环溶液(4M，10mL)，加毕，自然升温至室温反应1h。反应完毕，减压浓缩，残余物用少量乙酸乙酯溶解，搅拌下分批加入大量石油醚析出大量白色沉淀，过滤，石油醚洗涤，得(R)-1-(5-硝基吡啶-3-基)乙基-1-胺盐酸盐，产率95.5％；ESI-MS(m/z)：168.1[M+H] +。 (R)-2-Methyl-N-((R)-1-(5-nitropyridin-3-yl)ethyl)propane-2-sulfinamide (854mg, 3.150mmol) and THF (5mL ) into the reaction flask, stirred to dissolve, and slowly added hydrogen chloride dioxane solution (4M, 10mL) under stirring condition at 0°C. After completion of the reaction, concentrate under reduced pressure, dissolve the residue with a small amount of ethyl acetate, add a large amount of petroleum ether in batches under stirring to precipitate a large amount of white precipitate, filter, and wash with petroleum ether to obtain (R)-1-(5-nitropyridine-3 -yl)ethyl-1-amine hydrochloride, yield 95.5%; ESI-MS (m/z): 168.1 [M+H] + .
步骤e)：(R)-6-溴-2-甲基-N-(1-(5-硝基吡啶-3-基)乙基)喹唑啉-4-胺的制备Step e): Preparation of (R)-6-bromo-2-methyl-N-(1-(5-nitropyridin-3-yl)ethyl)quinazolin-4-amine
将6-溴-4-氯-2-甲基喹唑啉(200mg，0.733mmol)、(R)-1-(5-硝基吡啶-3-基)乙基-1-胺盐酸盐(150mg，0.733mmol)和DIPEA(283mg，2.198mmol)溶解在DMSO(5mL)中，将反应液加热至80℃搅拌1h，反应结束后，将反应液冷却至室温，加入水(50mL)萃灭，用乙酸乙酯萃取(30mL×3)，合并有机相，以饱和食盐水(50mL)洗涤，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＝2/1)，得(R)-6-溴-2-甲基-N-(1-(5-硝基吡啶-3-基)乙基)喹唑啉-4-胺，产率92.3％；ESI-MS(m/z)：389.2[M+H] +。 6-bromo-4-chloro-2-methylquinazoline (200mg, 0.733mmol), (R)-1-(5-nitropyridin-3-yl)ethyl-1-amine hydrochloride ( 150mg, 0.733mmol) and DIPEA (283mg, 2.198mmol) were dissolved in DMSO (5mL), and the reaction solution was heated to 80°C and stirred for 1h. After the reaction was completed, the reaction solution was cooled to room temperature and quenched by adding water (50mL). Extracted with ethyl acetate (30mL×3), combined the organic phases, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate=2/1), (R)-6-bromo-2-methyl-N-(1-(5-nitropyridin-3-yl)ethyl)quinazoline-4 -Amine, yield 92.3%; ESI-MS (m/z): 389.2 [M+H] + .
步骤f)：(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-硝基吡啶-3-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备Step f): (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(5-nitropyridin-3-yl)ethyl)amino) Preparation of quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide
将(R)-6-溴-2-甲基-N-(1-(5-硝基吡啶-3-基)乙基)喹唑啉-4-胺(120mg，0.310mmol)、2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(70mg，0.310mmol)、Cs 2CO 3(203mg，0.620mmol)、X-Phos(30mg，0.062mmol)、Pd(dba) 2(18mg，0.003mmol)和甲苯(7mL)加入到反应瓶中，氮气置换三次，升温至90℃搅拌反应16h。反应结束后，加水(25mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水(30mL)洗涤，无水硫酸钠干燥，减压过滤，有机相减压浓缩干，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝30/1)，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-硝基吡啶-3-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺，产率60.9％；ESI-MS(m/z)：531.6[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(5-nitropyridin-3-yl)ethyl)quinazolin-4-amine (120mg, 0.310mmol), 2-( 2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (70 mg, 0.310 mmol), Cs 2 CO 3 (203 mg, 0.620 mmol), X-Phos ( 30mg, 0.062mmol), Pd(dba) 2 (18mg, 0.003mmol) and toluene (7mL) were added into the reaction flask, replaced with nitrogen three times, heated to 90°C and stirred for 16h. After the reaction, add water (25mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter under reduced pressure, and depressurize the organic phase Concentrate to dryness, and the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol=30/1) to obtain (R)-2-(2-methoxy-5-(methyl(2-methanol) Base-4-((1-(5-nitropyridin-3-yl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide , yield 60.9%; ESI-MS (m/z): 531.6 [M+H] + .
步骤g)：(R)-2-(5-(4-(1-(5-氨基吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备Step g): (R)-2-(5-(4-(1-(5-aminopyridin-3-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl )amino)-2-methoxypyridin-3-yl)-N, the preparation of N-dimethylacetamide formate
将(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-硝基吡啶-3-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺(143mg，0.270mmol)溶于甲醇(2mL)中，加入铁粉(75mg，1.350mmol)和饱和氯化铵水溶液(2mL)，将反应液升温至回流反应1h，待反应液冷却至室温后，加入乙酸乙酯(10mL)和水(10mL)，抽滤，滤液分液，水相用乙酸乙酯萃取(20mL×2)，合并有机相，以饱和食盐水(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(R)-2-(5-(4-(1-(5-氨基吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率48.5％；1H NMR(400MHz，DMSO-d6)δ8.16(s，1H)，8.11(d，J＝8.0Hz，1H)，7.94(s，1H)，7.87(s，1H)，7.79(s，1H)，7.70(s，1H)，7.40(d，J＝8.0Hz，1H)，7.33(s，1H)，7.11(d，J＝8.0Hz，1H)，6.95(s，1H)，5.63-5.56(m，1H)，5.25(s，2H)，3.85(s，3H)，3.59(s，2H)，3.35(s，3H)，3.02(s，3H)，2.80(s，3H)，2.37(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：501.6[M+H] +。 (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(5-nitropyridin-3-yl)ethyl)amino)quinazoline -6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide (143 mg, 0.270 mmol) was dissolved in methanol (2 mL), iron powder (75 mg, 1.350 mmol) was added and saturated chloride Ammonium aqueous solution (2mL), the reaction solution was heated to reflux for 1h, after the reaction solution was cooled to room temperature, ethyl acetate (10mL) and water (10mL) were added, suction filtered, the filtrate was separated, and the aqueous phase was extracted with ethyl acetate (20mL×2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2 -(5-(4-(1-(5-aminopyridin-3-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxy Pyridin-3-yl)-N,N-dimethylacetamide formate, yield 48.5%; 1H NMR (400MHz, DMSO-d6) δ8.16(s, 1H), 8.11(d, J=8.0 Hz, 1H), 7.94(s, 1H), 7.87(s, 1H), 7.79(s, 1H), 7.70(s, 1H), 7.40(d, J=8.0Hz, 1H), 7.33(s, 1H ), 7.11(d, J=8.0Hz, 1H), 6.95(s, 1H), 5.63-5.56(m, 1H), 5.25(s, 2H), 3.85(s, 3H), 3.59(s, 2H) , 3.35(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.37(s, 3H), 1.58(d, J=8.0Hz, 3H); ESI-MS(m/z): 501.6[M+H] + .
实施例76Example 76
(R)-2-(5-((4-((1-(5-氨基吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲 基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(5-aminopyridin-3-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino )-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000177
Figure PCTCN2022101219-appb-000177
制备方法参考实施例75的步骤f和步骤g，得(R)-2-(5-((4-((1-(5-氨基吡啶-3-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺甲酸盐，产率39.8％； 1H NMR(400MHz，DMSO-d 6)δ8.16(s，1H)，8.09(d，J＝8.0Hz，1H)，7.87(s，1H)，7.78(s，1H)，7.63(s，1H)，7.35(d，J＝12.0Hz，1H)，7.09-7.03(m，2H)，6.99(d，J＝8.0Hz，1H)，6.95(s，1H)，6.90(s，1H)，5.63-5.56(m，1H)，5.25(s，2H)，3.77(s，3H)，3.57(s，2H)，3.33(s，3H)，2.99(s，3H)，2.79(s，3H)，2.36(s，3H)，1.58(d，J＝8.0Hz，3H)；ESI-MS(m/z)：500.6[M+H] +。 The preparation method refers to step f and step g of Example 75 to obtain (R)-2-(5-((4-((1-(5-aminopyridin-3-yl)ethyl)amino)-2-methyl ylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide formate, yield 39.8%; 1 H NMR (400MHz, DMSO -d 6 )δ8.16(s, 1H), 8.09(d, J=8.0Hz, 1H), 7.87(s, 1H), 7.78(s, 1H), 7.63(s, 1H), 7.35(d, J=12.0Hz, 1H), 7.09-7.03(m, 2H), 6.99(d, J=8.0Hz, 1H), 6.95(s, 1H), 6.90(s, 1H), 5.63-5.56(m, 1H ), 5.25(s, 2H), 3.77(s, 3H), 3.57(s, 2H), 3.33(s, 3H), 2.99(s, 3H), 2.79(s, 3H), 2.36(s, 3H) , 1.58 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 500.6 [M+H] + .
实施例77Example 77
(R)-2-(5-((4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Base) amino)-2-methoxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000178
Figure PCTCN2022101219-appb-000178
步骤a)：3-乙酰基-2-甲基苄腈的制备Step a): Preparation of 3-acetyl-2-methylbenzonitrile
将3-溴-2-甲基苄腈(3.0g，15.302mmol)、三丁基(1-乙氧基乙烯基)锡烷(7.2g，19.893mmol)、Pd(PPh 3) 2Cl 2(537.0mg，0.765mmol)、三乙胺(3.1g，30.604mmol)加入1，4-二氧六环(45mL)中，升温至100℃下搅拌反应2h。冷却至室温，加入乙酸乙酯(80mL)和氟化钾水溶液(5g/50mL)，搅拌30min，过滤，滤饼用乙酸乙酯(20mL×2)淋洗，合并滤液，分液，饱和食盐水(30mL)洗涤，有机相加入氯化氢乙酸乙酯溶液(30mL，4M)室温搅拌30min，加饱和碳酸氢钠水溶液将反应液pH值调至中性，分液，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：乙酸乙酯/石油醚＝1/10)，得3-乙酰基-2-甲基苄腈，产率66％；1H NMR(400MHz，DMSO-d6)δ8.06(d，J＝8.0Hz，1H)，7.94(d，J＝8.0Hz，1H)，7.52(t，J＝8.0Hz，1H)，2.58(s，3H)，2.56(s，3H)。 3-Bromo-2-methylbenzonitrile (3.0 g, 15.302 mmol), tributyl(1-ethoxyvinyl) stannane (7.2 g, 19.893 mmol), Pd(PPh 3 ) 2 Cl 2 ( 537.0mg, 0.765mmol), triethylamine (3.1g, 30.604mmol) were added to 1,4-dioxane (45mL), heated to 100°C and stirred for 2h. Cool to room temperature, add ethyl acetate (80mL) and potassium fluoride aqueous solution (5g/50mL), stir for 30min, filter, rinse the filter cake with ethyl acetate (20mL×2), combine the filtrates, separate the liquids, and saturated saline (30mL) was washed, the organic phase was added with ethyl chloride hydrogen acetate solution (30mL, 4M) and stirred at room temperature for 30min, and saturated aqueous sodium bicarbonate solution was added to adjust the pH value of the reaction solution to neutrality, and the liquid was separated, and the organic phase was washed with saturated brine (30mL) 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=1/10) to obtain 3-acetyl-2-methyl Benzonitrile, yield 66%; 1H NMR (400MHz, DMSO-d6) δ8.06(d, J=8.0Hz, 1H), 7.94(d, J=8.0Hz, 1H), 7.52(t, J=8.0 Hz, 1H), 2.58(s, 3H), 2.56(s, 3H).
步骤b)：N-(1-(3-氰基-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step b): Preparation of N-(1-(3-cyano-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide
将3-乙酰基-2-甲基苄腈(1.6g，10.051mmol)，(R)-(+)-叔丁基亚磺酰胺(1.46g，12.061mmol)，钛酸四乙酯(4.6g，13.066mmol，65％)和THF(25mL)加入反应瓶中，80℃反应2h。反应结束后，冷却至室温，加入乙酸乙酯(30mL)和水(30mL)，搅拌10min，过滤，滤饼用乙酸乙酯(10mL×2)洗涤，合并滤液，分液，水相用乙酸乙酯(20mL)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，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/5)，得N-(1-(3-氰基-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺，产率64％；ESI-MS(m/z)：263.2[M+H] +。 3-acetyl-2-methylbenzonitrile (1.6g, 10.051mmol), (R)-(+)-tert-butylsulfinamide (1.46g, 12.061mmol), tetraethyl titanate (4.6g , 13.066mmol, 65%) and THF (25mL) were added to the reaction flask, and reacted at 80°C for 2h. After the reaction, cool to room temperature, add ethyl acetate (30mL) and water (30mL), stir for 10min, filter, wash the filter cake with ethyl acetate (10mL×2), combine the filtrates, separate the liquids, and wash the water phase with ethyl acetate Esters (20 mL) were extracted, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum Ether=1/5), N-(1-(3-cyano-2-methylphenyl) ethylidene)-2-methylpropane-2-sulfinamide, yield 64%; ESI- MS (m/z): 263.2 [M+H] + .
步骤c)：N-((R)-1-(3-氰基-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step c): Preparation of N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide
将N-(1-(3-氰基-2-甲基苯基)亚乙基)-2-甲基丙烷-2-亚磺酰胺(1.7g，6.479mmol)和四氢呋喃/水混合液(18mL，v/v＝8/1)加入反应瓶中，-78℃搅拌下，加入NaBH4(615.4mg，16.196mmol)，并在-78℃下反应1h，加水(10mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，合并有机相，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/3)，得N-((R)-1-(3-氰基-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺，产率25％；ESI-MS(m/z)：265.1[M+H] +。 N-(1-(3-cyano-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (1.7g, 6.479mmol) and tetrahydrofuran/water mixture (18mL , v/v=8/1) into the reaction flask, under stirring at -78°C, NaBH4 (615.4mg, 16.196mmol) was added, and reacted at -78°C for 1h, adding water (10mL) to quench the reaction, and using ethyl acetate Ester extraction (20mL×2), the organic phases were combined, washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/ Petroleum ether=1/3), N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide was obtained, yield 25 %; ESI-MS (m/z): 265.1 [M+H] + .
步骤d)：(R)-3-(1-氨基乙基)-2-甲基苄腈盐酸盐的制备Step d): Preparation of (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride
将N-((R)-1-(3-氰基-2-甲基苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(400.0mg，1.513mmol)溶于乙酸乙酯(3.5 mL)中，加入氯化氢二氧六环溶液(4M，3.5mL)，室温反应2h。将反应液减压浓缩干，所得粗品直接进行下一步反应。Dissolve N-((R)-1-(3-cyano-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (400.0 mg, 1.513 mmol) in ethyl acetate (3.5 mL), add hydrogen chloride dioxane solution (4M, 3.5 mL), react at room temperature for 2 h. The reaction solution was concentrated to dryness under reduced pressure, and the obtained crude product was directly subjected to the next reaction.
步骤e)：(R)-3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苄腈的制备Step e): Preparation of (R)-3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile
将6-溴-4-氯-2-甲基喹唑啉(428.5mg，1.664mmol)，(R)-3-(1-氨基乙基)-2-甲基苄腈盐酸盐(298.0mg，1.513mmol)，DIPEA(585.5mg，4.539mmol)和DMF(10mL)加入反应瓶中，80℃搅拌1h。反应结束后，冷却至室温，搅拌条件下逐滴加入到冰水混合物中(50mL)，室温搅拌30min，过滤，滤饼用水淋洗(10mL×2)，干燥滤饼，得(R)-3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苄腈，产率93％；ESI-MS(m/z)：381.0[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (428.5mg, 1.664mmol), (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride (298.0mg , 1.513mmol), DIPEA (585.5mg, 4.539mmol) and DMF (10mL) were added into the reaction flask and stirred at 80°C for 1h. After the reaction, cool to room temperature, add dropwise to ice-water mixture (50mL) with stirring, stir at room temperature for 30min, filter, rinse the filter cake with water (10mL×2), dry the filter cake to obtain (R)-3 -(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile, yield 93%; ESI-MS (m/z): 381.0 [M+H] + .
步骤f)：(R)-2-(5-((4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step f): (R)-2-(5-((4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-methoxypyridin-3-yl) -N, the preparation of N-dimethylacetamide
将(R)-3-(1-((6-溴-2-甲基喹唑啉-4-基)氨基)乙基)-2-甲基苄腈(200.0mg，0.525mmol)，2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(128.8mg，0.577mmol)，Cs 2CO 3(513.4mg，1.575mmol)，X-Phos(25.1mg，0.053mmol)，Pd(dba) 2(15.0mg，0.026mmol)和甲苯(4mL)加入到反应瓶中，氮气置换三次，110℃搅拌反应2h。将反应液降至室温，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/10)，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺32％； 1H NMR(400MHz，DMSO-d 6)δ8.28(d，J＝6.8Hz，1H)，7.93(s，1H)，7.82(d，J＝8.0Hz，1H)，7.71(s，1H)，7.63(d，J＝7.6Hz，1H)，7.39-7.33(m，3H)，7.09(d，J＝9.2Hz，1H)，5.70-5.63(m，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.73(s，3H)，2.31(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：524.5[M+H] +。 (R)-3-(1-((6-bromo-2-methylquinazolin-4-yl)amino)ethyl)-2-methylbenzonitrile (200.0mg, 0.525mmol), 2- (2-Methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (128.8 mg, 0.577 mmol), Cs 2 CO 3 (513.4 mg, 1.575 mmol), X -Phos (25.1mg, 0.053mmol), Pd(dba) 2 (15.0mg, 0.026mmol) and toluene (4mL) were added to the reaction flask, replaced with nitrogen three times, and stirred at 110°C for 2h. The reaction solution was lowered to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/10), and the obtained crude product was purified by Prep-HPLC (method 3) to obtain (R )-2-(5-((4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl) Amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide 32%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.28 (d, J=6.8Hz, 1H ), 7.93(s, 1H), 7.82(d, J=8.0Hz, 1H), 7.71(s, 1H), 7.63(d, J=7.6Hz, 1H), 7.39-7.33(m, 3H), 7.09 (d, J=9.2Hz, 1H), 5.70-5.63(m, 1H), 3.85(s, 3H), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80( s, 3H), 2.73 (s, 3H), 2.31 (s, 3H), 1.56 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 524.5 [M+H] + .
实施例78Example 78
(R)-2-(5-((4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Base) amino)-2-hydroxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000179
Figure PCTCN2022101219-appb-000179
制备方法参考实施例38，得(R)-2-(5-((4-((1-(3-氰基-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率32％； 1H NMR(400MHz，DMSO-d 6)δ11.58(brs，1H)，8.22(d，J＝6.8Hz，1H)，7.81(d，J＝8.0Hz，1H)，7.62(d，J＝7.6Hz，1H)，7.53(s，1H)，7.39-7.34(m，2H)，7.25(s，1H)，7.16(s，1H)，7.06(d，J＝9.2Hz，1H)，5.70-5.63(m，1H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.78(s，3H)，2.73(s，3H)，2.30(s，3H)，1.56(d，J＝7.2Hz，3H)；ESI-MS(m/z)：510.5[M+H] +。 The preparation method refers to Example 38 to obtain (R)-2-(5-((4-((1-(3-cyano-2-methylphenyl)ethyl)amino)-2-methylquinazole Lin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 32%; 1 H NMR (400MHz, DMSO-d 6 )δ11 .58(brs, 1H), 8.22(d, J=6.8Hz, 1H), 7.81(d, J=8.0Hz, 1H), 7.62(d, J=7.6Hz, 1H), 7.53(s, 1H) , 7.39-7.34(m, 2H), 7.25(s, 1H), 7.16(s, 1H), 7.06(d, J=9.2Hz, 1H), 5.70-5.63(m, 1H), 3.42(s, 2H ), 3.28(s, 3H), 3.01(s, 3H), 2.78(s, 3H), 2.73(s, 3H), 2.30(s, 3H), 1.56(d, J=7.2Hz, 3H); ESI - MS (m/z): 510.5 [M+H] + .
实施例79Example 79
(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl) Preparation of amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000180
Figure PCTCN2022101219-appb-000180
制备方法参考实施例77，经Pre-HPLC(方法2)纯化，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率49.2％； 1H NMR (400MHz，DMSO-d 6)δ12.74(s，1H)，8.31(d，J＝7.2Hz，1H)，8.14(s，1H)，7.94(s，1H)，7.81(d，J＝7.6Hz，1H)，7.72(s，1H)，7.53(d，J＝7.2Hz，1H)，7.40-7.31(m，3H)，7.09(d，J＝9.2Hz，1H)，5.75(s，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.64(s，3H)，2.30(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：567.2[M+H] +。 The preparation method refers to Example 77, and is purified by Pre-HPLC (method 2) to obtain (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(2 -methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide formate, Yield 49.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.74(s, 1H), 8.31(d, J=7.2Hz, 1H), 8.14(s, 1H), 7.94(s, 1H) , 7.81(d, J=7.6Hz, 1H), 7.72(s, 1H), 7.53(d, J=7.2Hz, 1H), 7.40-7.31(m, 3H), 7.09(d, J=9.2Hz, 1H), 5.75(s, 1H), 3.85(s, 3H), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.64(s, 3H ), 2.30 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 567.2 [M+H] + .
实施例80Example 80
(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(2-Hydroxy-5-(methyl(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)amino) Preparation of quinazoline-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000181
Figure PCTCN2022101219-appb-000181
制备方法参考实施例38，经Pre-HPLC(方法2)纯化，得(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率66.7％； 1H NMR(400MHz，DMSO-d 6)δ12.64(s，1H)，11.64(s，1H)，8.41(d，J＝7.2Hz，1H)，8.14(s，1H)，7.81(d，J＝7.6Hz，1H)，7.58-7.51(m，2H)，7.41-7.33(m，2H)，7.27(s，1H)，7.19(s，1H)，7.08(d，J＝9.2Hz，1H)，5.76(s，1H)，3.42(s，2H)，3.29(s，3H)，3.01(s，3H)，2.79(s，3H)，2.64(s，3H)，2.30(s，3H)，1.59(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.4[M+H] +。 The preparation method refers to Example 38, and is purified by Pre-HPLC (method 2) to obtain (R)-2-(2-hydroxyl-5-(methyl(2-methyl-4-((1-(2-methyl Base-3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide formate, yield 66.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.64(s, 1H), 11.64(s, 1H), 8.41(d, J=7.2Hz, 1H), 8.14(s, 1H), 7.81 (d, J=7.6Hz, 1H), 7.58-7.51(m, 2H), 7.41-7.33(m, 2H), 7.27(s, 1H), 7.19(s, 1H), 7.08(d, J=9.2 Hz, 1H), 5.76(s, 1H), 3.42(s, 2H), 3.29(s, 3H), 3.01(s, 3H), 2.79(s, 3H), 2.64(s, 3H), 2.30(s , 3H), 1.59 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 553.4 [M+H] + .
实施例81Example 81
(R)-2-(5-((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000182
Figure PCTCN2022101219-appb-000182
步骤a)：2-氟-N-甲氧基-N-甲基-3-(三氟甲基)苯甲酰胺的制备Step a): Preparation of 2-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide
将2-氟-3-(三氟甲基)苯甲酸(5.0g，24.035mmol)、二甲羟胺盐酸盐(2.8g，28.841mmol)、HATU(13.5g，35.527mmol)、DIPEA(9.3g，71.925mmol)和二氯甲烷(100mL)加入反应瓶中，室温搅拌1h。反应结束后，加水(150mL)淬灭反应，以二氯甲烷(150mL×3)萃取，合并有机相，依次用水(200mL×2)，饱和食盐水(200mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得2-氟-N-甲氧基-N-甲基-3-(三氟甲基)苯甲酰胺；收率87.0％；ESI-MS(m/z)：252.0[M+H] +。 2-fluoro-3-(trifluoromethyl)benzoic acid (5.0g, 24.035mmol), dimethylhydroxylamine hydrochloride (2.8g, 28.841mmol), HATU (13.5g, 35.527mmol), DIPEA (9.3g , 71.925mmol) and dichloromethane (100mL) were added to the reaction flask, stirred at room temperature for 1h. After the reaction, add water (150mL) to quench the reaction, extract with dichloromethane (150mL×3), combine the organic phases, wash with water (200mL×2), saturated brine (200mL) successively, dry over anhydrous sodium sulfate, filter , the filtrate was concentrated under reduced pressure to give 2-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide; yield 87.0%; ESI-MS (m/z): 252.0 [M +H] + .
步骤b)：2-氟-3-(三氟甲基)苯乙酮的制备Step b): Preparation of 2-fluoro-3-(trifluoromethyl)acetophenone
将2-氟-N-甲氧基-N-甲基-3-(三氟甲基)苯甲酰胺(6.3g，25.099mmol)溶于四氢呋喃(60mL)中，冰浴下滴加入甲基溴溴化镁(16.7mL，50.199mmol，3M)，滴加完毕后，升温至室温搅拌1h。反应结束后，将反应液滴加到冰水混合物(100mL)中淬灭，以乙酸乙酯萃取(100mL×3)，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，残余物经硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)，得2-氟-3-(三氟甲基)苯乙酮；收率79.4％。Dissolve 2-fluoro-N-methoxy-N-methyl-3-(trifluoromethyl)benzamide (6.3g, 25.099mmol) in tetrahydrofuran (60mL), and add methyl bromide dropwise under ice-cooling Magnesium bromide (16.7mL, 50.199mmol, 3M), after the dropwise addition, warmed up to room temperature and stirred for 1h. After the reaction was completed, the reaction solution was added dropwise to an ice-water mixture (100 mL) to quench, extracted with ethyl acetate (100 mL×3), the organic phases were combined, washed with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=10/1) to obtain 2-fluoro-3-(trifluoromethyl)acetophenone; the yield was 79.4%.
步骤c-g)：(R)-2-(5-((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Steps c-g): (R)-2-(5-((4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
制备方法参考实施例77的步骤b至步骤f，得(R)-2-(5-((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率44.7％； 1H NMR(400MHz，DMSO-d 6) δ8.25(s，1H)，7.94(d，J＝2.8Hz，1H)，7.82(t，J＝7.2Hz，1H)，7.72(d，J＝2.4Hz，1H)，7.63(t，J＝7.2Hz，1H)，7.41-7.33(m，3H)，7.11(m，1H)，5.79(q，J＝7.2Hz，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.28(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：571.2[M+H] +。 The preparation method refers to step b to step f of Example 77 to obtain (R)-2-(5-((4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl) Amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 44.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.25(s, 1H), 7.94(d, J=2.8Hz, 1H), 7.82(t, J=7.2Hz, 1H), 7.72(d, J=2.4 Hz, 1H), 7.63(t, J=7.2Hz, 1H), 7.41-7.33(m, 3H), 7.11(m, 1H), 5.79(q, J=7.2Hz, 1H), 3.85(s, 3H ), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.28(s, 3H), 1.64(d, J=7.2Hz, 3H); ESI - MS (m/z): 571.2 [M+H] + .
实施例82Example 82
(R)-2-(5-((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000183
Figure PCTCN2022101219-appb-000183
制备方法参考实施例38，得(R)-2-(5-((4-((1-(2-氟-3-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率37.6％； 1H NMR(400MHz，DMSO-d 6)δ11.59(s，1H)，8.20(d，J＝7.2Hz，1H)，7.81(t，J＝6.8Hz，1H)，7.63(t，J＝7.2Hz，1H)，7.54(d，J＝2.4Hz，1H)，7.39(d，J＝9.2Hz，1H)，7.35(t，J＝7.6Hz，1H)，7.26(d，J＝2.8Hz，1H)，7.19(d，J＝2.8Hz，1H)，7.08(d J＝9.2，1H)，5.78(m，1H)，3.42(s，2H)，3.29(s，3H)，3.01(s，3H)，2.78(s，3H)，2.27(s，3H)，1.64(d，J＝7.2Hz，3H)；ESI-MS(m/z)：557.2[M+H] +。 The preparation method refers to Example 38 to obtain (R)-2-(5-((4-((1-(2-fluoro-3-(trifluoromethyl)phenyl)ethyl)amino)-2-methano ylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, yield 37.6%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.59(s, 1H), 8.20(d, J=7.2Hz, 1H), 7.81(t, J=6.8Hz, 1H), 7.63(t, J=7.2Hz, 1H), 7.54(d , J=2.4Hz, 1H), 7.39(d, J=9.2Hz, 1H), 7.35(t, J=7.6Hz, 1H), 7.26(d, J=2.8Hz, 1H), 7.19(d, J =2.8Hz, 1H), 7.08(dJ=9.2, 1H), 5.78(m, 1H), 3.42(s, 2H), 3.29(s, 3H), 3.01(s, 3H), 2.78(s, 3H ), 2.27 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 557.2 [M+H] + .
实施例83Example 83
2-(5-((4-((1-(1，1-二氟-2，3-二氢-1H-茚-4-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-NN-二甲基乙酰胺甲酸盐的制备2-(5-((4-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-2-methylquinazoline- Preparation of 6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-NN-dimethylacetamide formate
Figure PCTCN2022101219-appb-000184
Figure PCTCN2022101219-appb-000184
制备方法参考实施例77，经Pre-HPLC(方法2)纯化，得2-(5-((4-((1-(1，1-二氟-2，3-二氢-1H-茚-4-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率24.2％； 1H NMR(400MHz，DMSO-d 6)δ12.75(s，1H)，8.23(d，J＝7.2Hz，1H)，8.14(s，1H)，7.93(s，1H)，7.70(s，1H)，7.67(d，J＝8.0Hz，1H)，7.40-7.36(m，3H)，7.33(s，1H)，7.09(d，J＝9.2Hz，1H)，5.62-5.55(m，1H)，3.84(s，3H)，3.59(s，2H)，3.37(s，3H)，3.18-3.11(m，2H)，3.02(s，3H)，2.80(s，3H)，2.69-2.58(m，2H)，2.32(s，3H)，1.60(d，J＝6.8Hz，3H)；ESI-MS(m/z)：561.2[M+H] +。 The preparation method refers to Example 77, which is purified by Pre-HPLC (method 2) to obtain 2-(5-((4-((1-(1,1-difluoro-2,3-dihydro-1H-indene- 4-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide Formate salt, yield 24.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.75(s, 1H), 8.23(d, J=7.2Hz, 1H), 8.14(s, 1H), 7.93( s, 1H), 7.70(s, 1H), 7.67(d, J=8.0Hz, 1H), 7.40-7.36(m, 3H), 7.33(s, 1H), 7.09(d, J=9.2Hz, 1H ), 5.62-5.55(m, 1H), 3.84(s, 3H), 3.59(s, 2H), 3.37(s, 3H), 3.18-3.11(m, 2H), 3.02(s, 3H), 2.80( s, 3H), 2.69-2.58 (m, 2H), 2.32 (s, 3H), 1.60 (d, J=6.8Hz, 3H); ESI-MS (m/z): 561.2 [M+H] + .
实施例84Example 84
(R)-2-(5-((4-((1-(1，1-二氟-2，3-二氢-1H-茚-4-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐的制备(R)-2-(5-((4-((1-(1,1-difluoro-2,3-dihydro-1H-inden-4-yl)ethyl)amino)-2-methyl Preparation of quinazoline-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide hydrochloride
Figure PCTCN2022101219-appb-000185
Figure PCTCN2022101219-appb-000185
制备方法参考实施例33，经Pre-HPLC(方法1)纯化，得(R)-2-(5-((4-((1-(1，1-二氟-2，3-二氢-1H-茚-4-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐，产率8.5％； 1H NMR(400MHz，DMSO-d 6)δ14.22(s，1H)，11.73(s，1H)，10.08(d，J＝6.4Hz，1H)，7.80(s，1H)，7.75(d，J＝6.4Hz，1H)，7.56(d，J＝9.2Hz，1H)，7.51-7.41(m，2H)，7.36(s，1H)，7.26(d，J＝9.2Hz，1H)，7.20(s，1H)，5.79(m，1H)，3.43(s，2H)，3.33(s，3H)，3.28-3.11(m，2H)，3.03(s，3H)，2.80(s，3H)，2.70-2.59(m，2H)，2.54(s，3H)，1.71(d，J＝7.2Hz，3H)；ESI-MS(m/z)：547.0[M+H] +。 The preparation method refers to Example 33 and is purified by Pre-HPLC (method 1) to obtain (R)-2-(5-((4-((1-(1,1-difluoro-2,3-dihydro- 1H-inden-4-yl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethyl Acetamide hydrochloride, yield 8.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ14.22(s, 1H), 11.73(s, 1H), 10.08(d, J=6.4Hz, 1H), 7.80(s, 1H), 7.75(d, J=6.4Hz, 1H), 7.56(d, J=9.2Hz, 1H), 7.51-7.41(m, 2H), 7.36(s, 1H), 7.26(d , J=9.2Hz, 1H), 7.20(s, 1H), 5.79(m, 1H), 3.43(s, 2H), 3.33(s, 3H), 3.28-3.11(m, 2H), 3.03(s, 3H), 2.80(s, 3H), 2.70-2.59(m, 2H), 2.54(s, 3H), 1.71(d, J=7.2Hz, 3H); ESI-MS (m/z): 547.0 [M +H] + .
实施例85Example 85
(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-oxopyridin-1 (2H)-yl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000186
Figure PCTCN2022101219-appb-000186
步骤a)：(R)-N 6-2-二甲基-N 4-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4，6-二胺的制备 Step a): (R)-N 6 -2-dimethyl-N 4 -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazoline-4,6 - Preparation of diamines
将(R)-6-溴-2-甲基-N-(1-(3-硝基-5-)三氟甲基)苯基)乙基)喹唑啉-4-胺(200mg，0.439mmol)、甲胺盐酸盐(296mg，4.390mmol)、碳酸铯(2148mg，6.591mmol)、X-phos(42mg，0.088mmol)、Pd(dba) 2(29mg，0.052mmol)和甲苯(10ml)加入反应瓶中，氮气鼓吹3min后，升温至120℃搅拌16h。反应结束后，冷却至室温，加入乙酸乙酯(5mL)室温搅拌10min，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＝20/1)，得(R)-N 6-2-二甲基-N 4-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4，6-二胺，产率73.0％；ESI-MS(m/z)：406.1[M+H] +。 (R)-6-Bromo-2-methyl-N-(1-(3-nitro-5-)trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (200mg, 0.439 mmol), methylamine hydrochloride (296mg, 4.390mmol), cesium carbonate (2148mg, 6.591mmol), X-phos (42mg, 0.088mmol), Pd(dba) 2 (29mg, 0.052mmol) and toluene (10ml) Add it into the reaction flask, blow nitrogen gas for 3 minutes, then raise the temperature to 120°C and stir for 16 hours. After the reaction, cool to room temperature, add ethyl acetate (5 mL) and stir at room temperature for 10 min, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1), Obtain (R)-N 6 -2-dimethyl-N 4 -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazoline-4,6-diamine , yield 73.0%; ESI-MS (m/z): 406.1 [M+H] + .
步骤b)：(R)-N，N-二甲基-2-(4-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-氧代吡啶-1(2H)-基)乙酰胺的制备Step b): (R)-N,N-dimethyl-2-(4-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl) Preparation of phenyl)ethyl)amino)quinazolin-6-yl)amino)-2-oxopyridin-1(2H)-yl)acetamide
将(R)-N 6-2-二甲基-N 4-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4，6-二胺(120mg，0.296mmol)、2-(4-溴-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺(115mg，0.444mmol)、碳酸铯(193mg，0，592mmol)、X-phos(28mg，0.059mmol)、Pd(dba) 2(17mg，0.030mmol)和甲苯(2ml)加入反应瓶中，氮气置换3次后，升温回流搅拌16h。将反应液降至室温，加入乙酸乙酯(10mL)室温搅拌10min，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＝20/1)，得(R)-N，N-二甲基-2-(4-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-氧代吡啶-1(2H)-基)乙酰胺，产率26.2％；ESI-MS(m/z)：584.2[M+H] +。 (R)-N 6 -2-dimethyl-N 4 -(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazoline-4,6-diamine (120mg, 0.296mmol), 2-(4-bromo-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide (115mg, 0.444mmol), cesium carbonate (193mg, 0 , 592mmol), X-phos (28mg, 0.059mmol), Pd(dba) 2 (17mg, 0.030mmol) and toluene (2ml) were added into the reaction flask, replaced with nitrogen for 3 times, and stirred at reflux for 16h. The reaction solution was lowered to room temperature, added ethyl acetate (10 mL) and stirred at room temperature for 10 min, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-N, N-dimethyl-2-(4-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) phenyl) ethyl Base) amino) quinazoline-6-yl) amino)-2-oxopyridin-1 (2H)-yl) acetamide, yield 26.2%; ESI-MS (m/z): 584.2 [M+H ] + .
步骤c)：(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备Step c): (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate
将(R)-N，N-二甲基-2-(4-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-2-氧代吡啶-1(2H)-基)乙酰胺(45mg，0.077mmol)、铁粉(150mg)、饱和氯化铵水溶液(5mL)和甲醇(5mL)加入反应瓶中，100℃搅拌1h。反应结束后，冷却至室温，过滤，滤饼用甲醇淋洗，合并滤液，减压浓缩去除甲醇后加水稀释，用二氯甲烷萃取(10mL×2)，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(R)-2-(4-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率25.1％； 1H NMR(400MHz，DMSO-d 6)δ8.36(d，J＝8.0Hz，1H)，8.33(s，1H)，8.17(s，2H)，7.66(d，J＝8.0Hz，1H)，7.60-7.57(m，1H)，7.20(d，J＝8.0Hz，1H)，6.90(s，1H)，6.86(s，1H)，6.70(s，1H)，5.63-5.61(m，1H)，5.58-5.52(m，3H)，5.45(s，1H)，4.64(s，2H)，3.32(s，3H)，3.03(s，3H)，2.83(s，3H)，2.42(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：554.3[M+H] +。 (R)-N, N-dimethyl-2-(4-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl) Ethyl)amino)quinazolin-6-yl)amino)-2-oxopyridin-1(2H)-yl)acetamide (45mg, 0.077mmol), iron powder (150mg), saturated aqueous ammonium chloride ( 5mL) and methanol (5mL) were added into the reaction flask, stirred at 100°C for 1h. After the reaction, cool to room temperature, filter, rinse the filter cake with methanol, combine the filtrate, concentrate under reduced pressure to remove methanol, dilute with water, extract with dichloromethane (10mL×2), combine the organic phases, and dry over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(4-((4-((1-(3-amino-5-(trifluoromethyl) Phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylethyl Amide formate, yield 25.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.36(d, J=8.0Hz, 1H), 8.33(s, 1H), 8.17(s, 2H), 7.66 (d, J=8.0Hz, 1H), 7.60-7.57(m, 1H), 7.20(d, J=8.0Hz, 1H), 6.90(s, 1H), 6.86(s, 1H), 6.70(s, 1H), 5.63-5.61(m, 1H), 5.58-5.52(m, 3H), 5.45(s, 1H), 4.64(s, 2H), 3.32(s, 3H), 3.03(s, 3H), 2.83 (s, 3H), 2.42 (s, 3H), 1.54 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 554.3 [M+H] + .
实施例86Example 86
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羰基吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-carbonylpyridin-1 (2H)-yl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000187
Figure PCTCN2022101219-appb-000187
制备方法参考实施例85，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羰基吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率90.7％； 1H NMR(400MHz，DMSO-d 6)δ8.26(s，1H)，8.13(s，1H)，7.59(s，1H)，7.56(s，1H)，7.43-7.38(m，2H)，7.12(d，J＝9.2Hz，1H)，6.90(s，1H)，6.87(s，1H)，6.71(s，1H)，6.46(d，J＝9.6Hz，1H)，5.66-5.58(m，1H)，5.54(s，2H)，4.78(s，2H)，3.27(s，3H)，3.04(s，3H)，2.85(s，3H)，2.38(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：554.6[M+H] +。 The preparation method refers to Example 85 to obtain (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methano ylquinazolin-6-yl)(methyl)amino)-2-carbonylpyridin-1(2H)-yl)-N,N-dimethylacetamide formate, yield 90.7%; 1 H NMR (400MHz, DMSO-d 6 )δ8.26(s, 1H), 8.13(s, 1H), 7.59(s, 1H), 7.56(s, 1H), 7.43-7.38(m, 2H), 7.12(d , J=9.2Hz, 1H), 6.90(s, 1H), 6.87(s, 1H), 6.71(s, 1H), 6.46(d, J=9.6Hz, 1H), 5.66-5.58(m, 1H) , 5.54(s, 2H), 4.78(s, 2H), 3.27(s, 3H), 3.04(s, 3H), 2.85(s, 3H), 2.38(s, 3H), 1.58(d, J=7.2 Hz, 3H); ESI-MS (m/z): 554.6 [M+H] + .
实施例87Example 87
(R)-N 4-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-N 6，2-二甲基喹唑啉-4，6-二胺甲酸盐的制备 (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N 6 -(5-(2-(dimethylamino)ethyl)-6- Preparation of methoxypyridin-3-yl)-N 6 ,2-dimethylquinazoline-4,6-diamine formate
Figure PCTCN2022101219-appb-000188
Figure PCTCN2022101219-appb-000188
将(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺(300mg，0.502mmol)和THF(5ml)加入反应瓶中，分批加入四氢铝锂(95mg，2.510mmol)，室温搅拌16h。反应结束后，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×2)，合并有机相，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(R)-N 4-(1-(3-氨基-5-(三氟甲基)苯基)乙基)-N6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-N6，2-二甲基喹唑啉-4，6-二胺甲酸盐，产率28.6％；1H NMR(400MHz，DMSO-d6)δ8.17(s，2H)，8.13(d，J＝8.0Hz，2H)，7.88(s，1H)，7.68(s，1H)，7.44(s，1H)，7.39(d，J＝8.0Hz，1H)，6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.61-5.58(m，1H)，5.53(s，1H)，3.88(s，3H)，3.35(s，3H)，2.67-2.63(m，2H)，2.47-2.45(m，2H)，2.36(s，3H)，2.18(s，6H)，1.57(d，J＝8.0Hz，3H)；ESI-MS(m/z)：554.2[M+H] +。 (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl )amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide (300mg, 0.502mmol) and THF (5ml) were added to the reaction flask, and tetrahydro Aluminum lithium (95mg, 2.510mmol), stirred at room temperature for 16h. After the reaction, add water (20mL) to quench the reaction, extract with ethyl acetate (20mL×2), combine the organic phases, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is subjected to Prep-HPLC (method 2) Purify to give (R)-N 4 -(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-N6-(5-(2-(dimethylamino)ethyl)- 6-methoxypyridin-3-yl)-N6,2-dimethylquinazoline-4,6-diamine formate, yield 28.6%; 1H NMR (400MHz, DMSO-d6) δ8.17 (s, 2H), 8.13(d, J=8.0Hz, 2H), 7.88(s, 1H), 7.68(s, 1H), 7.44(s, 1H), 7.39(d, J=8.0Hz, 1H) , 6.90(s, 1H), 6.87(s, 1H), 6.70(s, 1H), 5.61-5.58(m, 1H), 5.53(s, 1H), 3.88(s, 3H), 3.35(s, 3H ), 2.67-2.63 (m, 2H), 2.47-2.45 (m, 2H), 2.36 (s, 3H), 2.18 (s, 6H), 1.57 (d, J=8.0Hz, 3H); ESI-MS ( m/z): 554.2 [M+H] + .
实施例88Example 88
(R)-5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-(2-(二甲氨基)乙基)吡啶-2-醇甲酸盐的制备(R)-5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Preparation of base) amino)-3-(2-(dimethylamino) ethyl) pyridin-2-ol formate
Figure PCTCN2022101219-appb-000189
Figure PCTCN2022101219-appb-000189
制备方法参考实施例38，经Pre-HPLC(方法2)纯化，得(R)-5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-(2-(二甲氨基)乙基)吡啶-2-醇甲酸盐，产率44.2％； 1H NMR(400MHz，DMSO-d 6)δ8.18(s，2H)，8.09(d，J＝8.0Hz，1H)，7.52(d，J＝4.0Hz，1H)，7.39(d，J＝12.0Hz，1H)，7.26(s，1H)，7.21(s，1H)，7.06(s，1H)，6.90(s，1H)，6.87(s，1H)，6.70(s，1H)，5.63-5.56(m，2H)，5.53(s，1H)，3.25(s，3H)，2.54-2.52(m，4H)，2.35(s，3H)，2.23(s，6H)，1.57(d，J＝4.0Hz，3H)；ESI-MS(m/z)：540.3[M+H] +。 The preparation method refers to Example 38 and is purified by Pre-HPLC (method 2) to obtain (R)-5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl) )amino)-2-methylquinazolin-6-yl)(methyl)amino)-3-(2-(dimethylamino)ethyl)pyridin-2-ol formate, yield 44.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.18(s, 2H), 8.09(d, J=8.0Hz, 1H), 7.52(d, J=4.0Hz, 1H), 7.39(d, J= 12.0Hz, 1H), 7.26(s, 1H), 7.21(s, 1H), 7.06(s, 1H), 6.90(s, 1H), 6.87(s, 1H), 6.70(s, 1H), 5.63- 5.56(m, 2H), 5.53(s, 1H), 3.25(s, 3H), 2.54-2.52(m, 4H), 2.35(s, 3H), 2.23(s, 6H), 1.57(d, J= 4.0 Hz, 3H); ESI-MS (m/z): 540.3 [M+H] + .
实施例89Example 89
(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(6-methylpyridin-2-yl)ethyl)amino)quinazoline- Preparation of 6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000190
Figure PCTCN2022101219-appb-000190
制备方法参考实施例35，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺，产率64.2％； 1H NMR(400MHz，DMSO-d 6)δ8.17(d，J＝8.0Hz，1H)，7.95(s，1H)，7.69(s，1H)，7.62(m，1H)，7.41(d，J＝7.6Hz，1H)，7.36(s，1H)，7.25(d，J＝8.4Hz，1H)，7.14-7.10(m，2H)，5.66-5.59(m，1H)，3.85(s，3H)，3.60(s，2H)，3.37(s，3H)，3.02(s，3H)，2.80(s，3H)，2.48(s，3H)，2.34(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：500.0[M+H] +。 The preparation method refers to Example 35 to obtain (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(6-methylpyridin-2-yl)ethyl) yl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide, yield 64.2%; 1 H NMR (400MHz, DMSO-d 6 )δ8.17 (d, J=8.0Hz, 1H), 7.95(s, 1H), 7.69(s, 1H), 7.62(m, 1H), 7.41(d, J=7.6Hz, 1H), 7.36(s, 1H) , 7.25(d, J=8.4Hz, 1H), 7.14-7.10(m, 2H), 5.66-5.59(m, 1H), 3.85(s, 3H), 3.60(s, 2H), 3.37(s, 3H ), 3.02(s, 3H), 2.80(s, 3H), 2.48(s, 3H), 2.34(s, 3H), 1.61(d, J=7.2Hz, 3H); ESI-MS(m/z) : 500.0[M+H] + .
实施例90Example 90
(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(2-Hydroxy-5-(methyl(2-methyl-4-((1-(6-methylpyridin-2-yl)ethyl)amino)quinazoline-6- Base) amino) pyridin-3-yl) -N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000191
Figure PCTCN2022101219-appb-000191
制备方法参考实施例38，得(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(6-甲基吡啶-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺，产率37.8％；1H NMR(400MHz，DMSO-d6)δ11.61(s，1H)，8.13(d，J＝8.0Hz，1H)，7.62(t，J＝16.0Hz，1H)，7.52(s，1H)，7.41(d，J＝8.0Hz，1H)，7.2-7.23(m，2H)，7.20(s，1H)，7.12-7.08(m，2H)，5.64-5.59(m，1H)，3.57(s，2H)，3.27(s，3H)，3.01(s，3H)，2.80(s，3H)，2.48(s，3H)，2.33(s，3H)，1.62(d，J＝4.0Hz，3H)；ESI-MS(m/z)：486.0[M+H] +。 The preparation method refers to Example 38 to obtain (R)-2-(2-hydroxy-5-(methyl(2-methyl-4-((1-(6-methylpyridin-2-yl)ethyl) Amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-dimethylacetamide, yield 37.8%; 1H NMR (400MHz, DMSO-d6)δ11.61(s, 1H ), 8.13(d, J=8.0Hz, 1H), 7.62(t, J=16.0Hz, 1H), 7.52(s, 1H), 7.41(d, J=8.0Hz, 1H), 7.2-7.23(m , 2H), 7.20(s, 1H), 7.12-7.08(m, 2H), 5.64-5.59(m, 1H), 3.57(s, 2H), 3.27(s, 3H), 3.01(s, 3H), 2.80 (s, 3H), 2.48 (s, 3H), 2.33 (s, 3H), 1.62 (d, J = 4.0 Hz, 3H); ESI-MS (m/z): 486.0 [M+H] + .
实施例91Example 91
(R)-2-(4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-oxopyridin-1 (2H)-yl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000192
Figure PCTCN2022101219-appb-000192
步骤a)：(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺的制备将(R)-6-溴-N-(1-(3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(360mg，0.878mmol)、甲胺盐酸盐(590mg，8.780mmol)、碳酸铯(4.30g，13.171mmol)、X-phos(84mg，0.176mmol)、Pd(dba) 2(50mg，0.088mmol)和甲苯(2ml)加入反应瓶中，氮气置换3次，升温至回流搅拌16h。反应结束后，冷却至室温，加入乙酸乙酯(5mL)室温搅拌10min，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＝20/1)，得(R)-N4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N6，2-二甲基喹唑啉-4，6-二胺，产率50.6％；ESI-MS(m/z)：361.2[M+H] +。 Step a): (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6- The preparation of diamine will (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl) ethyl)-2-methylquinazolin-4-amine ( 360mg, 0.878mmol), methylamine hydrochloride (590mg, 8.780mmol), cesium carbonate (4.30g, 13.171mmol), X-phos (84mg, 0.176mmol), Pd (dba) 2 (50mg, 0.088mmol) and Add toluene (2ml) into the reaction flask, replace with nitrogen three times, heat up to reflux and stir for 16h. After the reaction, cool to room temperature, add ethyl acetate (5 mL) and stir at room temperature for 10 min, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: dichloromethane/methanol=20/1), Obtain (R)-N4-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N6,2-dimethylquinazoline-4,6-diamine, yield 50.6%; ESI-MS (m/z): 361.2 [M+H] + .
步骤b)：(R)-2-(4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐的制备Step b): (R)-2-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate
将(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺、(160mg，0.444mmol)、2-(4-溴-2-氧吡啶-1(2H)-基)-N，N-二甲基乙酰胺(173mg，0.666mmol)、碳酸铯(290mg，0.888mmol)、X-phos(42mg，0.088mmol)、双(二亚苄基丙酮)钯(25mg，0.044mmol)和甲苯(2mL)加入反应瓶中，氮气 置换3次，升温至回流搅拌16h。将反应液降至室温，加入乙酸乙酯(10mL)室温搅拌10min，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＝20/1)，所得粗品经Prep-HPLC(方法2)，纯化，得(R)-2-(4-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺甲酸盐，产率21.0％； 1H NMR(400MHz，DMSO-d 6)δ12.72(s，1H)，8.48(d，J＝8.0Hz，1H)，8.36(s，1H)，8.14(s，1H)，7.70-7.65(m，2H)，7.61-7.59(m，1H)，7.50(t，J＝12.0Hz，1H)，7.38-7.10(m，1H)，7.29(s，1H)，7.23(d，J＝8.0Hz，1H)，5.80(s，1H)，5.63(s，1H)，5.46(d，J＝4.0Hz，1H)，4.65(s，2H)，3.33(s，3H)，3.03(s，3H)，2.84(s，3H)，2.37(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：539.1[M+H] +。 (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine, (160mg, 0.444mmol), 2-(4-bromo-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide (173mg, 0.666mmol), cesium carbonate (290mg, 0.888mmol ), X-phos (42mg, 0.088mmol), bis(dibenzylideneacetone)palladium (25mg, 0.044mmol) and toluene (2mL) were added into the reaction flask, replaced with nitrogen three times, heated to reflux and stirred for 16h. The reaction solution was lowered to room temperature, added ethyl acetate (10 mL) and stirred at room temperature for 10 min, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain The crude product was purified by Prep-HPLC (method 2) to give (R)-2-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino )-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide formate, yield 21.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.72(s, 1H), 8.48(d, J=8.0Hz, 1H), 8.36(s, 1H), 8.14(s, 1H), 7.70 -7.65(m, 2H), 7.61-7.59(m, 1H), 7.50(t, J=12.0Hz, 1H), 7.38-7.10(m, 1H), 7.29(s, 1H), 7.23(d, J =8.0Hz, 1H), 5.80(s, 1H), 5.63(s, 1H), 5.46(d, J=4.0Hz, 1H), 4.65(s, 2H), 3.33(s, 3H), 3.03(s , 3H), 2.84 (s, 3H), 2.37 (s, 3H), 1.59 (d, J=8.0Hz, 3H); ESI-MS (m/z): 539.1 [M+H] + .
实施例92Example 92
(R)-2-(3-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-6-carbonyl pyridazin-1 (6H)-yl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000193
Figure PCTCN2022101219-appb-000193
步骤a)：2-(3-溴-6-羰基哒嗪-1(6H)-基)乙酸乙酯Step a): Ethyl 2-(3-bromo-6-carbonylpyridazin-1(6H)-yl)acetate
将6-溴哒嗪-3(2H)-酮(5.0g，28.573mmol)、2-溴乙酸乙酯(5.2g，31.437mmol)和DMF(5mL)依次加入反应瓶中，降温至0℃后再加入无水碳酸钾(4.7g，34.296mmol)，0℃下搅拌反应1.5h。将反应液过滤，滤饼用乙酸乙酯淋洗(30mL×3)，滤液用饱和食盐水洗涤(50mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，得2-(3-溴-6-羰基哒嗪-1(6H)-基)乙酸乙酯，产率95.2％；ESI-MS(m/z)：262.1[M+H] +。 Add 6-bromopyridazin-3(2H)-one (5.0g, 28.573mmol), ethyl 2-bromoacetate (5.2g, 31.437mmol) and DMF (5mL) into the reaction flask in turn, after cooling to 0°C Then anhydrous potassium carbonate (4.7 g, 34.296 mmol) was added, and the reaction was stirred at 0° C. for 1.5 h. The reaction solution was filtered, the filter cake was rinsed with ethyl acetate (30mL×3), the filtrate was washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2-(3- Bromo-6-carbonylpyridazin-1(6H)-yl) ethyl acetate, yield 95.2%; ESI-MS (m/z): 262.1 [M+H] + .
步骤b)：2-(3-溴-6-羰基哒嗪-1(6H)-基)乙酸的制备Step b): Preparation of 2-(3-bromo-6-carbonylpyridazin-1(6H)-yl)acetic acid
将2-(3-溴-6-羰基哒嗪-1(6H)-基)乙酸乙酯(1.0g，3.830mmol)溶于THF(10mL)和甲醇(2mL)的混合溶剂中，加入氢氧化锂水溶液(4.5mL，3mol/L)，25℃搅拌反应1h。减压浓缩，残余物用15％的盐酸调至pH＝2.0，室温搅拌10min后过滤，滤饼水洗(20mL×2)、真空干燥后得2-(3-溴-6-羰基哒嗪-1(6H)-基)乙酸，产率72.4°％；ESI-MS(m/z)：234.0[M+H] +。 Dissolve ethyl 2-(3-bromo-6-carbonylpyridazin-1(6H)-yl)acetate (1.0g, 3.830mmol) in a mixed solvent of THF (10mL) and methanol (2mL), add hydroxide Aqueous lithium solution (4.5 mL, 3 mol/L) was stirred at 25°C for 1 h. Concentrate under reduced pressure, adjust the residue to pH=2.0 with 15% hydrochloric acid, stir at room temperature for 10 minutes, filter, wash the filter cake with water (20mL×2), and dry in vacuo to obtain 2-(3-bromo-6-carbonylpyridazine-1 (6H)-yl)acetic acid, yield 72.4°%; ESI-MS (m/z): 234.0[M+H] + .
步骤c)：2-(3-溴-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备Step c): Preparation of 2-(3-bromo-6-carbonylpyridazin-1(6H)-yl)-N,N-dimethylacetamide
将2-(3-溴-6-羰基哒嗪-1(6H)-基)乙酸(640.0mg，2.746mmol)、二甲胺盐酸盐(335.9mg，4.120mmol)、2-(3H-[1，2，3]三氮唑[4，5-b]吡啶-3-基)-1，1，3，3-四甲基脲六氟磷酸盐(1.6g，4.120mmol)，DIPEA(887.2mg，6.865mmol)和二氯甲烷(10mL)依次加入反应瓶中，25℃下搅拌反应30min。加水(20mL)淬灭反应，分液，有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤，将滤液减压浓缩，得2-(3-溴-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺，产率91.3％；ESI-MS(m/z)：261.1[M+H] +。 2-(3-Bromo-6-carbonylpyridazin-1(6H)-yl)acetic acid (640.0mg, 2.746mmol), dimethylamine hydrochloride (335.9mg, 4.120mmol), 2-(3H-[ 1,2,3]triazol[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1.6g, 4.120mmol), DIPEA (887.2 mg, 6.865mmol) and dichloromethane (10mL) were sequentially added into the reaction flask, and the reaction was stirred at 25°C for 30min. Add water (20mL) to quench the reaction, separate the layers, wash the organic phase with saturated brine (20mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 2-(3-bromo-6-carbonylpyridine Azin-1(6H)-yl)-N,N-dimethylacetamide, yield 91.3%; ESI-MS (m/z): 261.1[M+H] + .
步骤d)：(R)-2-(3-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐的制备Step d): (R)-2-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-6-carbonylpyridazin-1(6H)-yl)-N,N-dimethylacetamide formate
将(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(100.0mg，0.277mmol)，2-(3-溴-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺(108.2mg，0.416mmol)，X-Phos(52.8mg，0.111mmol)，Cs 2CO 3(241.4mg，0.741mmol)，Pd(dba) 2(42.6mg，0.074mmol)和甲苯(5mL)依次加入反应瓶中，氮气置换三次，升温至105℃反应5h。反应结束后，冷却至室温，加水淬灭反应(30mL)，用乙酸乙酯萃取(30mL×2)，合并有机相，用饱和食盐水洗涤(30mL)，有机相减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(3-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐，产率42.4％； 1H NMR(400MHz，DMSO-d 6)δ8.40(d，J＝7.6Hz，1H)，8.22(s，1H)，8.13(s，1H)，7.67(t，J＝7.2Hz，1H)，7.62-7.56(m，2H)，7.49(t，J＝6.8Hz，1H)，7.28(t，J＝8.0Hz，1H)，7.23(s，1H)，7.09(d，J＝10.0Hz，1H)，6.79(d，J＝10.0Hz，1H)，5.84-5.76(m，1H)，4.82(s，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.34(s，3H)，1.59(d，J＝7.2Hz，3H)；ESI-MS(m/z)：540.6[M+H] +。 (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine ( 100.0mg, 0.277mmol), 2-(3-bromo-6-carbonylpyridazin-1(6H)-yl)-N,N-dimethylacetamide (108.2mg, 0.416mmol), X-Phos (52.8 mg, 0.111mmol), Cs 2 CO 3 (241.4mg, 0.741mmol), Pd(dba) 2 (42.6mg, 0.074mmol) and toluene (5mL) were sequentially added to the reaction flask, replaced with nitrogen three times, and heated to 105°C for reaction 5h. After the reaction, cool to room temperature, add water to quench the reaction (30mL), extract with ethyl acetate (30mL×2), combine the organic phases, wash with saturated brine (30mL), and concentrate the organic phases under reduced pressure. - HPLC (method 2) purification to give (R)-2-(3-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- Methylquinazolin-6-yl)(methyl)amino)-6-carbonylpyridazin-1(6H)-yl)-N,N-dimethylacetamide formate, yield 42.4%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.40(d, J=7.6Hz, 1H), 8.22(s, 1H), 8.13(s, 1H), 7.67(t, J=7.2Hz, 1H), 7.62-7.56(m, 2H), 7.49(t, J=6.8Hz, 1H), 7.28(t, J=8.0Hz, 1H), 7.23(s, 1H), 7.09(d, J=10.0Hz, 1H ), 6.79(d, J=10.0Hz, 1H), 5.84-5.76(m, 1H), 4.82(s, 2H), 3.33(s, 3H), 3.04(s, 3H), 2.86(s, 3H) , 2.34 (s, 3H), 1.59 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 540.6 [M+H] + .
实施例93Example 93
(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-6-carbonyl pyridazin-1 (6H)-yl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000194
Figure PCTCN2022101219-appb-000194
制备方法参考实施例85，得(R)-2-(3-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-羰基哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐，产率92.8％； 1H NMR(400MHz，DMSO-d 6)δ12.63(s，1H)，8.31(d，J＝8.0Hz，1H)，8.19(s，1H)，8.13(s，1H)，7.61-7.55(m，2H)，7.08(d，J＝9.6Hz，1H)，6.89(s，1H)，6.85(s，1H)，6.77(d，J＝10.0，1H)，6.70(s，1H)，5.60-5.54(m，1H)，5.52(s，2H)，4.82(s，2H)，3.32(s，3H)，3.04(s，3H)，2.86(s，3H)，2.40(s，3H)，1.54(d，J＝7.2Hz，3H)；ESI-MS(m/z)：555.6[M+H] +。 The preparation method refers to Example 85 to obtain (R)-2-(3-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methyl Quinazolin-6-yl)(methyl)amino)-6-carbonylpyridazin-1(6H)-yl)-N,N-dimethylacetamide formate, yield 92.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.63(s, 1H), 8.31(d, J=8.0Hz, 1H), 8.19(s, 1H), 8.13(s, 1H), 7.61-7.55(m, 2H), 7.08(d, J=9.6Hz, 1H), 6.89(s, 1H), 6.85(s, 1H), 6.77(d, J=10.0, 1H), 6.70(s, 1H), 5.60-5.54 (m, 1H), 5.52(s, 2H), 4.82(s, 2H), 3.32(s, 3H), 3.04(s, 3H), 2.86(s, 3H), 2.40(s, 3H), 1.54( d, J = 7.2 Hz, 3H); ESI-MS (m/z): 555.6 [M+H] + .
实施例94Example 94
(R)-2-(3-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(3-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000195
Figure PCTCN2022101219-appb-000195
步骤a)：(R)-2-(3-((4-((1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备Step a): (R)-2-(3-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethane Base) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -6-oxopyridazin-1 (6H) -yl) -N,N-two Preparation of methylacetamide
将(R)-N 4-(1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(70.0mg，0.144mmol)，2-(3-溴-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺(56mg，0.216mmol)，Cs 2CO 3(140mg，0.432mmol)，Pd(dba) 2(33mg，0.058mmol)，X-phos(55mg，0.115mmol)和甲苯(5mL)依次加入反应瓶中，氮气置换三次，升温至105℃搅拌反应16h。反应结束后，冷却至室温，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，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，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)得到(R)-2-(3-((4-((1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺，产率84.0％；ESI-MS(m/z)：666.4[M+H] +。 (R)-N 4 -(1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)phenyl)ethyl)-N 6,2-Dimethylquinazoline-4,6-diamine (70.0mg, 0.144mmol), 2-(3-bromo- 6 -oxopyridazin-1(6H)-yl)-N,N - Dimethylacetamide ( 56mg, 0.216mmol), Cs2CO3 (140mg, 0.432mmol), Pd(dba) 2 (33mg, 0.058mmol), X-phos (55mg, 0.115mmol) and toluene (5mL) They were added to the reaction flask in turn, replaced with nitrogen three times, and heated to 105° C. and stirred for 16 hours. After the reaction, cool to room temperature, add water (20mL) to quench the reaction, extract with ethyl acetate (20mL×3), combine the organic phases, wash with saturated brine (20mL), dry over anhydrous sodium sulfate, filter, and the filtrate Concentrate under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(3-((4-((1-(3-(2- ((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl) Amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide, yield 84.0%; ESI-MS (m/z): 666.4[M+H] + .
步骤b)：(R)-2-(3-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐的制备Step b): (R)-2-(3-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methanol Preparation of ylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide formate
将(R)-2-(3-((4-((1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺(84mg，0.126mmol)溶解在THF(5mL)中，加入四丁基氟化铵(42mg，0.152mmol)，室温搅拌2h。将反应液减压浓缩，所得粗品经Prep-HPLC(方法2)纯化，得(R)-2-(3-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺甲酸盐，产率35.0％； 1H NMR(400MHz，DMSO-d 6)δ8.38(d，J＝8.0Hz，1H)，8.18(s，1H)，8.13(s，1H)，7.63(s，1H)，7.61-7.55(m，3H)，7.45-7.36(m，2H)，7.07(d，J＝12.0Hz，1H)，6.77(d，J＝12.0Hz，1H)，5.70-5.62(m，1H)，5.59(t，J＝8.0Hz，1H)，4.82(s，2H)，3.87-3.78(s，2H)，3.32(s，3H)，3.04(s，3H)，2.86(s，3H)，2.40(s，3H)，1.59(d，J＝8.0Hz，3H)；ESI-MS(m/z)：552.1[M+H] +。 (R)-2-(3-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)benzene Base) ethyl) amino)-2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylethyl Amide (84mg, 0.126mmol) was dissolved in THF (5mL), tetrabutylammonium fluoride (42mg, 0.152mmol) was added, and stirred at room temperature for 2h. The reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 2) to obtain (R)-2-(3-((4-((1-(3-(1,1-difluoro-2- Hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N - Dimethylacetamide formate, yield 35.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.38 (d, J=8.0Hz, 1H), 8.18(s, 1H), 8.13(s , 1H), 7.63(s, 1H), 7.61-7.55(m, 3H), 7.45-7.36(m, 2H), 7.07(d, J=12.0Hz, 1H), 6.77(d, J=12.0Hz, 1H), 5.70-5.62(m, 1H), 5.59(t, J=8.0Hz, 1H), 4.82(s, 2H), 3.87-3.78(s, 2H), 3.32(s, 3H), 3.04(s , 3H), 2.86 (s, 3H), 2.40 (s, 3H), 1.59 (d, J=8.0Hz, 3H); ESI-MS (m/z): 552.1 [M+H] + .
实施例95Example 95
(R)-2-(4-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺的制备(R)-2-(4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)phenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-oxopyridin-1(2H)-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000196
Figure PCTCN2022101219-appb-000196
制备方法参考实施例91，经Prep-HPLC(方法3)纯化，得(R)-2-(4-((4-((1-(3-(1，1-二氟-2-羟乙基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶-1(2H)-基)-N，N-二甲基乙酰胺，产率11.5％； 1H NMR(400MHz，DMSO-d 6)δ7.95(d，J＝8.0Hz，1H)，7.75(s，1H)，7.65-7.61(m，1H)，7.48(s，2H)，7.34(t，J＝7.6Hz，2H)，7.09(d，J＝8.8Hz，1H)，7.04(s，1H)，5.96-5.90(m，2H)，5.84-5.81(m，1H)，5.72-5.64(m，1H)，4.68-4.57(m，4H)，3.02(s，3H)，2.83(s，3H)，2.81(d，J＝4.8Hz，3H)，2.31(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：551.2[M+H] +。 The preparation method refers to Example 91, and is purified by Prep-HPLC (method 3) to obtain (R)-2-(4-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl Base) phenyl) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-oxopyridin-1 (2H) -yl) -N, N-dimethyl Acetamide, yield 11.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ7.95 (d, J=8.0Hz, 1H), 7.75 (s, 1H), 7.65-7.61 (m, 1H), 7.48(s, 2H), 7.34(t, J=7.6Hz, 2H), 7.09(d, J=8.8Hz, 1H), 7.04(s, 1H), 5.96-5.90(m, 2H), 5.84-5.81 (m, 1H), 5.72-5.64(m, 1H), 4.68-4.57(m, 4H), 3.02(s, 3H), 2.83(s, 3H), 2.81(d, J=4.8Hz, 3H), 2.31 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 551.2 [M+H] + .
实施例96Example 96
(R)-2-(5-((4-((1-(4-(二氟甲基)-1H-吲哚-6-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(4-(difluoromethyl)-1H-indol-6-yl)ethyl)amino)-2-methylquinazoline- Preparation of 6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000197
Figure PCTCN2022101219-appb-000197
步骤a)：2-甲基-3-硝基苯甲醛的制备Step a): Preparation of 2-methyl-3-nitrobenzaldehyde
将2-甲基-3-硝基苯甲醇(5.0g，29.911mmol)和二氯甲烷(50mL)加入反应瓶中，0℃分批加入戴斯-马丁试剂(15.22g，35.894mmol)，室温反应15min。过滤，滤液减压浓缩，加乙酸乙酯(50mL)稀释，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)，得2-甲基-3-硝基苯甲醛，产率97.5％。2-Methyl-3-nitrobenzyl alcohol (5.0g, 29.911mmol) and dichloromethane (50mL) were added to the reaction flask, and Dess-Martin reagent (15.22g, 35.894mmol) was added in batches at 0°C. React for 15 minutes. Filtration, the filtrate was concentrated under reduced pressure, diluted with ethyl acetate (50 mL), filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/10) to obtain 2 -Methyl-3-nitrobenzaldehyde, yield 97.5%.
步骤b)：5-溴-2-甲基-3-硝基苯甲醛的制备Step b): Preparation of 5-bromo-2-methyl-3-nitrobenzaldehyde
将2-甲基-3-硝基苯甲醛(4.82g，29.179mmol)、NBS(6.23g，35.015mmol)、浓硫酸(15mL)和三氟乙酸(50mL)加入反应瓶中，60℃反应3h。冷却至室温，减压浓缩，加入甲基叔丁基醚(200mL)、饱和硫代硫酸钠水溶液(200mL)和饱和碳酸氢钠水溶液调至至pH＝7，室温搅拌1h，分液，水相用甲基叔丁基醚(100mL)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：乙酸乙酯/石油醚＝1/15)，得5-溴-2-甲基-3-硝基苯甲醛，产率47.9％； 1H NMR(400MHz，DMSO-d 6)δ10.25(s，1H)，8.42(s，1H)，8.25(s，1H)，2.60(s，3H)。 Add 2-methyl-3-nitrobenzaldehyde (4.82g, 29.179mmol), NBS (6.23g, 35.015mmol), concentrated sulfuric acid (15mL) and trifluoroacetic acid (50mL) into the reaction flask, and react at 60°C for 3h . Cool to room temperature, concentrate under reduced pressure, add methyl tert-butyl ether (200 mL), saturated aqueous sodium thiosulfate (200 mL) and saturated aqueous sodium bicarbonate to adjust to pH = 7, stir at room temperature for 1 h, separate liquids, and aqueous phase Extract with methyl tert-butyl ether (100 mL), combine the organic phases, wash with saturated brine (100 mL), 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=1/15) to obtain 5-bromo-2-methyl-3-nitrobenzaldehyde with a yield of 47.9%; 1 H NMR (400MHz, DMSO-d 6 ) δ10.25( s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 2.60 (s, 3H).
步骤c)：5-溴-1-(二氟甲基)-2-甲基-3-硝基苯的制备Step c): Preparation of 5-bromo-1-(difluoromethyl)-2-methyl-3-nitrobenzene
将5-溴-2-甲基-3-硝基苯甲醛(3.41g，13.981mmol)和二氯甲烷(34mL)加入反应瓶中，0℃加DAST(3.38g，20.972mmol)，室温反应0.5h。加入饱和硫代硫酸钠水溶液(50mL)、用饱和碳酸氢钠溶液调至 pH＝6，加入二氯甲烷(50mL)，分液，水相用二氯甲烷(50mL)萃取，合并有机相，用饱和食盐水(50mL×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：乙酸乙酯/石油醚＝1/20)，得5-溴-1-(二氟甲基)-2-甲基-3-硝基苯，产率90.2％。Add 5-bromo-2-methyl-3-nitrobenzaldehyde (3.41g, 13.981mmol) and dichloromethane (34mL) into the reaction flask, add DAST (3.38g, 20.972mmol) at 0°C, and react at room temperature for 0.5 h. Add saturated aqueous sodium thiosulfate (50 mL), adjust to pH=6 with saturated sodium bicarbonate solution, add dichloromethane (50 mL), separate the layers, extract the aqueous phase with dichloromethane (50 mL), combine the organic phases, and use Wash with saturated brine (50mL×2), 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=1/20) to obtain 5 -Bromo-1-(difluoromethyl)-2-methyl-3-nitrobenzene, yield 90.2%.
步骤d)：2-(4-溴-2-(二氟甲基)-6-硝基苯基)-N，N-二甲基乙烯基-1-胺的制备Step d): Preparation of 2-(4-bromo-2-(difluoromethyl)-6-nitrophenyl)-N,N-dimethylvinyl-1-amine
将5-溴-1-(二氟甲基)-2-甲基-3-硝基苯(3.35g，12.607mmol)、DMF-DMA(3.0g，25.214mmol)和DMF(33mL)加入反应瓶中，140℃反应1h。冷却至室温，加入饱和食盐水(100mL)，以乙酸乙酯(50mL×2)萃取，合并有机相，饱和食盐水(50mL×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：乙酸乙酯/石油醚＝1/10)，得2-(4-溴-2-(二氟甲基)-6-硝基苯基)-N，N-二甲基乙烯基-1-胺，产率69.5％。5-Bromo-1-(difluoromethyl)-2-methyl-3-nitrobenzene (3.35 g, 12.607 mmol), DMF-DMA (3.0 g, 25.214 mmol) and DMF (33 mL) were added to the reaction flask , react at 140°C for 1h. Cool to room temperature, add saturated brine (100 mL), extract with ethyl acetate (50 mL×2), combine the organic phases, wash with saturated brine (50 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: ethyl acetate/petroleum ether = 1/10) to obtain 2-(4-bromo-2-(difluoromethyl)-6-nitrophenyl)- N,N-Dimethylvinyl-1-amine, yield 69.5%.
步骤e)：6-溴-4-(二氟甲基)-1H-吲哚的制备Step e): Preparation of 6-bromo-4-(difluoromethyl)-1H-indole
将2-(4-溴-2-(二氟甲基)-6-硝基苯基)-N，N-二甲基乙烯基-1-胺(2.01g，6.275mmol)、铁粉(1.05g，18.825mmol)和乙酸(20mL)加入反应瓶中，氮气保护下90℃搅拌1h。冷却至室温，加入乙酸乙酯(50mL)，过滤，滤饼用乙酸乙酯(20mL×2)淋洗，合并滤液，减压浓缩，加饱和碳酸氢钠水溶液(100mL)和乙酸乙酯(100mL)稀释，分液，水相用乙酸乙酯(50mL)萃取，合并有机相，饱和食盐水(50mL×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：乙酸乙酯/石油醚＝1/20)，得6-溴-4-(二氟甲基)-1H-吲哚，产率54.0％。2-(4-Bromo-2-(difluoromethyl)-6-nitrophenyl)-N,N-dimethylvinyl-1-amine (2.01g, 6.275mmol), iron powder (1.05 g, 18.825mmol) and acetic acid (20mL) were added into the reaction flask, stirred at 90°C for 1h under nitrogen protection. Cool to room temperature, add ethyl acetate (50mL), filter, filter cake with ethyl acetate (20mL×2), combine the filtrate, concentrate under reduced pressure, add saturated aqueous sodium bicarbonate (100mL) and ethyl acetate (100mL ), separated, and the aqueous phase was extracted with ethyl acetate (50mL), the organic phases were combined, washed with saturated brine (50mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was passed through a silica gel column layer Analysis and purification (eluent: ethyl acetate/petroleum ether=1/20) gave 6-bromo-4-(difluoromethyl)-1H-indole with a yield of 54.0%.
步骤f)：6-溴-4-(二氟甲基)-1H-吲哚-1-甲酸苄酯的制备Step f): Preparation of benzyl 6-bromo-4-(difluoromethyl)-1H-indole-1-carboxylate
将6-溴-4-(二氟甲基)-1H-吲哚(814mg，3.308mmol)、4-二甲氨基吡啶(40mg，0.331mmol)、三乙胺(502mg，4.962mmol)和二氯甲烷(8mL)加入到反应瓶中，0℃滴加氯甲酸苄酯(677mg，3.970mmol)，室温反应0.5h。加饱和碳酸氢钠(30mL)和二氯甲烷(30mL)搅拌混匀，分液，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：乙酸乙酯/石油醚＝1/20)，得6-溴-4-(二氟甲基)-1H-吲哚-1-甲酸苄酯，产率54.1％； 1H NMR(400MHz，DMSO-d 6)δ8.45(s，1H)，7.95-7.94(m，1H)，7.71(s，1H)，7.60(d，J＝7.2Hz，2H)7.51-7.24(m，4H)，6.96-6.91(m，1H)，5.55(s，2H)。 6-Bromo-4-(difluoromethyl)-1H-indole (814mg, 3.308mmol), 4-dimethylaminopyridine (40mg, 0.331mmol), triethylamine (502mg, 4.962mmol) and dichloro Methane (8 mL) was added to the reaction flask, benzyl chloroformate (677 mg, 3.970 mmol) was added dropwise at 0°C, and reacted at room temperature for 0.5 h. Add saturated sodium bicarbonate (30mL) and dichloromethane (30mL), stir and mix, separate the liquids, wash the organic phase with saturated brine (30mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purified by column chromatography (eluent: ethyl acetate/petroleum ether=1/20) to obtain benzyl 6-bromo-4-(difluoromethyl)-1H-indole-1-carboxylate with a yield of 54.1% ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.45(s, 1H), 7.95-7.94(m, 1H), 7.71(s, 1H), 7.60(d, J=7.2Hz, 2H) 7.51- 7.24 (m, 4H), 6.96-6.91 (m, 1H), 5.55 (s, 2H).
步骤g)：6-乙酰基-4-(二氟甲基)-1H-吲哚-1-甲酸苄酯的制备Step g): Preparation of benzyl 6-acetyl-4-(difluoromethyl)-1H-indole-1-carboxylate
将6-溴-4-(二氟甲基)-1H-吲哚-1-甲酸苄酯(681mg，1.791mmol)、三丁基(1-乙氧基乙烯基)锡烷(776mg，2.149mmol)、Pd(PPh 3) 2Cl 2(63mg，0.089mmol)、三乙胺(453mg，4.477mmol)加入1，4-二氧六环(7mL)中，维持100℃下搅拌反应2h。冷却至室温，加入乙酸乙酯(50mL)、氟化钾(1g，17.21mmol)和水(10mL)，搅拌30min，过滤，滤饼用乙酸乙酯(20mL×2)淋洗，滤液分液，饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩干，残余物用乙酸乙酯(50mL)溶解，加入氯化氢乙酸乙酯溶液(10mL，4M)室温搅拌10min，加饱和碳酸氢钠水溶液将反应液将pH调至中性，分液，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：乙酸乙酯/石油醚＝1/10)，得6-乙酰基-4-(二氟甲基)-1H-吲哚-1-甲酸苄酯，产率99.2％；ESI-MS(m/z)：344.0[M+H] +。 Benzyl 6-bromo-4-(difluoromethyl)-1H-indole-1-carboxylate (681mg, 1.791mmol), tributyl(1-ethoxyvinyl)stannane (776mg, 2.149mmol ), Pd(PPh 3 ) 2 Cl 2 (63mg, 0.089mmol), and triethylamine (453mg, 4.477mmol) were added to 1,4-dioxane (7mL), and the reaction was stirred at 100°C for 2h. Cool to room temperature, add ethyl acetate (50 mL), potassium fluoride (1 g, 17.21 mmol) and water (10 mL), stir for 30 min, filter, filter cake with ethyl acetate (20 mL×2), and separate the filtrate. Wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate to dryness under reduced pressure, dissolve the residue in ethyl acetate (50 mL), add hydrogen chloride ethyl acetate solution (10 mL, 4M) and stir at room temperature for 10 min, add saturation The pH of the reaction solution was adjusted to neutral with aqueous sodium bicarbonate solution, and the layers were separated. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography ( Eluent: ethyl acetate/petroleum ether=1/10) to obtain benzyl 6-acetyl-4-(difluoromethyl)-1H-indole-1-carboxylate with a yield of 99.2%; ESI-MS (m/z): 344.0 [M+H] + .
步骤h)：6-(1-(((R)-叔丁基亚磺酰基)亚氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯的制备Step h): Preparation of ethyl 6-(1-(((R)-tert-butylsulfinyl)imino)ethyl)-4-(difluoromethyl)-1H-indole-1-carboxylate
将6-乙酰基-4-(二氟甲基)-1H-吲哚-1-甲酸苄酯(610mg，1.777mmol)、(R)-(+)-叔丁基亚磺酰胺(360mg，2.971mmol)、钛酸四乙酯(2.09g，5.943mmol，65％)和THF(7mL)加入反应瓶中，80℃反应1h。将反应液冷却至室温，加入乙酸乙酯(50mL)和水(50mL)，室温搅拌10min，过滤，滤饼用乙酸乙酯(20mL×2)淋洗，合并滤液，分液，水相用乙酸乙酯(30mL)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，所得粗品经硅胶柱层析纯化(洗脱剂：乙酸乙酯/石油醚＝1/5)，得6-(1-(((R)-叔丁基亚磺酰基)亚氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-羧酸乙酯，产率49.3％； 1H NMR(400MHz，DMSO-d 6)δ8.88(s，1H)，8.09-8.01(m，2H)，7.55-7.28(m，1H)，6.95-6.94(m，1H)，4.53-4.47(m，2H)，2.82(s，3H)，1.45-1.40(m，3H)，1.26(s，9H)；ESI-MS(m/z)：385.1[M+H] +。 Benzyl 6-acetyl-4-(difluoromethyl)-1H-indole-1-carboxylate (610 mg, 1.777 mmol), (R)-(+)-tert-butylsulfinamide (360 mg, 2.971 mmol), tetraethyl titanate (2.09 g, 5.943 mmol, 65%) and THF (7 mL) were added into the reaction flask, and reacted at 80° C. for 1 h. Cool the reaction solution to room temperature, add ethyl acetate (50mL) and water (50mL), stir at room temperature for 10min, filter, filter the cake with ethyl acetate (20mL×2), combine the filtrates, separate the layers, and wash the aqueous phase with acetic acid Ethyl ester (30 mL) was extracted, the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/ Petroleum ether=1/5), 6-(1-(((R)-tert-butylsulfinyl)imino)ethyl)-4-(difluoromethyl)-1H-indole-1- Ethyl carboxylate, yield 49.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.88(s, 1H), 8.09-8.01(m, 2H), 7.55-7.28(m, 1H), 6.95- 6.94(m, 1H), 4.53-4.47(m, 2H), 2.82(s, 3H), 1.45-1.40(m, 3H), 1.26(s, 9H); ESI-MS(m/z): 385.1[ M+H] + .
步骤i)：(R)-6-(1-(((R)-叔丁基亚磺酰基)氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯的制备Step i): (R)-6-(1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-(difluoromethyl)-1H-indole-1-carboxylic acid ethyl Preparation of esters
将6-(1-(((R)-叔丁基亚磺酰基)亚氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯(317mg，0.825mmol)和THF/水混合液(4.5mL，v/v＝8/1)加入反应瓶中，-78℃搅拌下，加入NaBH4(62mg，1.649mmol)，室温反应0.5h。加水(10mL)淬灭反应，用乙酸乙酯萃取(15mL×2)，合并有机相，饱和食盐水(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：乙酸乙酯/石油醚＝1/3)，得(R)-6-(1-(((R)-叔丁基亚磺酰基)氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-羧酸乙酯，产率78.1％；ESI-MS(m/z)：387.1[M+H] +。 Ethyl 6-(1-(((R)-tert-butylsulfinyl)imino)ethyl)-4-(difluoromethyl)-1H-indole-1-carboxylate (317mg, 0.825mmol ) and THF/water mixture (4.5mL, v/v=8/1) were added to the reaction flask, and NaBH4 (62mg, 1.649mmol) was added under stirring at -78°C, and reacted at room temperature for 0.5h. Add water (10 mL) to quench the reaction, extract with ethyl acetate (15 mL×2), combine the organic phases, wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Analysis and purification (eluent: ethyl acetate/petroleum ether = 1/3) to obtain (R)-6-(1-(((R)-tert-butylsulfinyl)amino)ethyl)-4- Ethyl (difluoromethyl)-1H-indole-1-carboxylate, yield 78.1%; ESI-MS (m/z): 387.1 [M+H] + .
步骤j)：(R)-6-(1-氨基乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯盐酸盐的制备Step j): Preparation of (R)-6-(1-aminoethyl)-4-(difluoromethyl)-1H-indole-1-carboxylic acid ethyl ester hydrochloride
将(R)-6-(1-(((R)-叔丁基亚磺酰基)氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯(145mg，0.375mmol)溶于乙酸乙酯(3.5mL)中，加入盐酸乙酸乙酯溶液(4M，0.5mL)，室温反应3h，减压浓缩干，所得粗 品直接进行下一步反应。Ethyl (R)-6-(1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-(difluoromethyl)-1H-indole-1-carboxylate (145mg , 0.375mmol) was dissolved in ethyl acetate (3.5mL), ethyl acetate hydrochloride solution (4M, 0.5mL) was added, reacted at room temperature for 3h, concentrated to dryness under reduced pressure, and the obtained crude product was directly subjected to the next reaction.
步骤k)：(R)-6-(1-((6-溴-2甲基喹唑啉-4基)氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯的制备Step k): (R)-6-(1-((6-bromo-2methylquinazolin-4yl)amino)ethyl)-4-(difluoromethyl)-1H-indole-1 - Preparation of ethyl formate
将6-溴-4-氯-2-甲基喹唑啉(89mg，0.345mmol)、(R)-6-(1-氨基乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯盐酸盐(110mg，0.345mmol)、DIPEA(134mg，1.035mmol)和DMF(2mL)加入反应瓶中，氮气保护下80℃搅拌1h。反应结束后，冷却至室温，加饱和食盐水(15mL)淬灭反应，乙酸乙酯萃取(20mL×2)，合并有机相，饱和食盐水(15mL×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：乙酸乙酯/石油醚＝1/1)，得(R)-6-(1-((6-溴-2甲基喹唑啉-4基)氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯，产率75.4％；ESI-MS(m/z)：503.1[M+H] +。 6-Bromo-4-chloro-2-methylquinazoline (89mg, 0.345mmol), (R)-6-(1-aminoethyl)-4-(difluoromethyl)-1H-indole -1-Ethyl formate hydrochloride (110mg, 0.345mmol), DIPEA (134mg, 1.035mmol) and DMF (2mL) were added to the reaction flask, stirred at 80°C for 1h under nitrogen protection. After the reaction, cool to room temperature, add saturated brine (15mL) to quench the reaction, extract with ethyl acetate (20mL×2), combine the organic phases, wash with saturated brine (15mL×3), dry over anhydrous sodium sulfate, filter , the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate/petroleum ether=1/1) to obtain (R)-6-(1-((6-bromo-2methyl Quinazoline-4 yl)amino)ethyl)-4-(difluoromethyl)-1H-indole-1-carboxylic acid ethyl ester, yield 75.4%; ESI-MS (m/z): 503.1 [M +H] + .
步骤l)：(R)-(4-(二氟甲基)-6-(1-((6-((5-(2-(二甲基氨基)-2-氧代乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基-1H-吲哚-1-甲酸乙酯制备Step l): (R)-(4-(difluoromethyl)-6-(1-((6-((5-(2-(dimethylamino)-2-oxoethyl))-6 Preparation of -methoxypyridin-3-yl)(methyl)amino)-2-methylquinazolin-4-yl)amino)ethyl-1H-indole-1-carboxylate
将(R)-6-(1-((6-溴-2甲基喹唑啉-4基)氨基)乙基)-4-(二氟甲基)-1H-吲哚-1-甲酸乙酯(130mg，0.258mmol)、2-(2-甲氧基-5-(甲氨基)苯基)-N，N-二甲基乙酰胺盐酸盐(58mg，0.258mmol)、Cs 2CO 3(168mg，0.516mmol)、X-Phos(49mg，0.103mmol)、Pd(dba) 2(29mg，0.052mmol)和甲苯(2mL)加入到反应瓶中，氮气置换三次，90℃搅拌反应1h。反应结束后，冷却至室温，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＝1/10)，得(R)-(4-(二氟甲基)-6-(1-((6-((5-(2-(二甲基氨基)-2-氧代乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基-1H-吲哚-1-甲酸乙酯，产率91.9％；ESI-MS(m/z)：646.2[M+H] +。 (R)-6-(1-((6-bromo-2methylquinazolin-4 base)amino)ethyl)-4-(difluoromethyl)-1H-indole-1-carboxylic acid ethyl Ester (130mg, 0.258mmol), 2-(2-methoxy-5-(methylamino)phenyl)-N,N-dimethylacetamide hydrochloride (58mg, 0.258mmol), Cs 2 CO 3 (168mg, 0.516mmol), X-Phos (49mg, 0.103mmol), Pd(dba) 2 (29mg, 0.052mmol) and toluene (2mL) were added to the reaction flask, replaced with nitrogen three times, and stirred at 90°C for 1h. After the reaction, cool to room temperature and concentrate under reduced pressure. The obtained crude product is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/10) to obtain (R)-(4-(difluoromethyl) -6-(1-((6-((5-(2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)(methyl)amino)- Ethyl 2-methylquinazolin-4-yl)amino)ethyl-1H-indole-1-carboxylate, yield 91.9%; ESI-MS (m/z): 646.2 [M+H] + .
步骤m)：(R)-2-(5-((4-((1-(4-(二氟甲基)-1H-吲哚-6-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备Step m): (R)-2-(5-((4-((1-(4-(difluoromethyl)-1H-indol-6-yl)ethyl)amino)-2-methyl Preparation of quinazoline-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate
将(R)-(4-(二氟甲基)-6-(1-((6-((5-(2-(二甲基氨基)-2-氧代乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基-1H-吲哚-1-甲酸乙酯(153mg，0.237mmol)、一水合氢氧化锂(40mg，0.948mmol)、THF(3mL)和水(1mL)加入到反应瓶中，升温至回流搅拌反应1h。反应结束后，冷却至室温，用1N的盐酸将反应液调至pH＝2～3，用乙酸乙酯萃取(20mL×2)，合并有机相，用饱和食盐水(15mL)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(R)-2-(5-((4-((1-(4-(二氟甲基)-1H-吲哚-6-基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率33.7％； 1H NMR(400MHz，DMSO-d 6)δ12.64(s，1H)，11.32(s，1H)，8.20(d，J＝8.0Hz，1H)，8.14(s，1H)，7.93(s，1H)，7.73(s，1H)，7.63(s，1H)，7.44-7.33(m，4H)，7.32-7.12(m，1H)，7.10-7.08(m，1H)，6.53(s，1H)，5.83-5.79(m，1H)，3.84(s，3H)，3.58(s，2H)，3.36(s，3H)，3.01(s，3H)，2.79(s，3H)，2.36(s，3H)，1.67(d，J＝7.2Hz，3H)；ESI-MS(m/z)：574.2[M+H] +。 (R)-(4-(Difluoromethyl)-6-(1-((6-((5-(2-(Dimethylamino)-2-oxoethyl)-6-methoxy Pyridin-3-yl)(methyl)amino)-2-methylquinazolin-4-yl)amino)ethyl-1H-indole-1-carboxylic acid ethyl ester (153mg, 0.237mmol), monohydrate Lithium hydroxide (40mg, 0.948mmol), THF (3mL) and water (1mL) were added in the reaction flask, heated to reflux and stirred for 1h. After the reaction was completed, cooled to room temperature, and the reaction solution was adjusted to pH with 1N hydrochloric acid =2～3, extracted with ethyl acetate (20mL×2), combined the organic phases, washed with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was subjected to Prep-HPLC (Method 2) Purify to get (R)-2-(5-((4-((1-(4-(difluoromethyl)-1H-indol-6-yl)ethyl)amino)-2-methyl ylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide formate, yield 33.7%; 1 H NMR ( 400MHz, DMSO-d 6 )δ12.64(s, 1H), 11.32(s, 1H), 8.20(d, J=8.0Hz, 1H), 8.14(s, 1H), 7.93(s, 1H), 7.73 (s, 1H), 7.63 (s, 1H), 7.44-7.33 (m, 4H), 7.32-7.12 (m, 1H), 7.10-7.08 (m, 1H), 6.53 (s, 1H), 5.83-5.79 (m, 1H), 3.84(s, 3H), 3.58(s, 2H), 3.36(s, 3H), 3.01(s, 3H), 2.79(s, 3H), 2.36(s, 3H), 1.67( d, J = 7.2 Hz, 3H); ESI-MS (m/z): 574.2 [M+H] + .
实施例97Example 97
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟-5-羟基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluoro-5-hydroxyphenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000198
Figure PCTCN2022101219-appb-000198
步骤a)：3-溴-2-氟-5-碘苯甲酸的制备Step a): Preparation of 3-bromo-2-fluoro-5-iodobenzoic acid
将3-溴-2-氟苯甲酸(7.0g，0.032mol)和浓硫酸(50mL)加入反应瓶中，冰浴下搅拌，分批次加入N-碘代丁二酰亚胺(7.6g，0.034mol)，加毕，自然升温至室温搅拌2h，将反应液倒入冰水(100mL)中，室温搅拌30min，过滤，滤饼加饱和硫代硫酸钠水溶液(50mL)室温搅拌30min，过滤，滤饼用适量水淋洗，真空干燥，得3-溴-2-氟-5-碘苯甲酸，产率99.4％。Add 3-bromo-2-fluorobenzoic acid (7.0g, 0.032mol) and concentrated sulfuric acid (50mL) into the reaction flask, stir under ice bath, add N-iodosuccinimide (7.6g, 0.034mol), after the addition, the temperature was naturally raised to room temperature and stirred for 2h, the reaction solution was poured into ice water (100mL), stirred at room temperature for 30min, filtered, and the filter cake was stirred with saturated aqueous sodium thiosulfate (50mL) at room temperature for 30min, filtered, The filter cake was rinsed with an appropriate amount of water and dried under vacuum to obtain 3-bromo-2-fluoro-5-iodobenzoic acid with a yield of 99.4%.
步骤b)：3-溴-2-氟-5-羟基苯甲酸的制备Step b): Preparation of 3-bromo-2-fluoro-5-hydroxybenzoic acid
将3-溴-2-氟-5-碘苯甲酸(150.0mg，0.355mmol)、氢氧化钠(6.4g，0.164mol)，氧化亚铜(665.3mg，4.633mmol)和水(110mL)加入反应瓶中，100℃搅拌反应16h。反应结束后，冷却至室温，用1N的盐酸水溶液调节pH＝1～2，过滤，滤液用乙酸乙酯(100mL)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，残余物加入石油醚(100mL)室温搅拌30min，过滤，滤饼真空干燥，得3-溴-2-氟-5-羟基苯甲酸，产率69.3％。3-Bromo-2-fluoro-5-iodobenzoic acid (150.0 mg, 0.355 mmol), sodium hydroxide (6.4 g, 0.164 mol), cuprous oxide (665.3 mg, 4.633 mmol) and water (110 mL) were added to the reaction In the bottle, the reaction was stirred at 100°C for 16h. After the reaction, cool to room temperature, adjust pH=1~2 with 1N hydrochloric acid aqueous solution, filter, extract the filtrate with ethyl acetate (100 mL), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and add the residue to Petroleum ether (100 mL) was stirred at room temperature for 30 min, filtered, and the filter cake was vacuum-dried to obtain 3-bromo-2-fluoro-5-hydroxybenzoic acid with a yield of 69.3%.
步骤c)：3-溴-5-((叔丁基二甲基硅)氧基)-2-氟苯甲酸的制备Step c): Preparation of 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzoic acid
将3-溴-2-氟-5-羟基苯甲酸(5.2g，0.022mol)，三乙胺(5.6g，0.055mol)，叔丁基二甲基氯硅烷(5.0g，0.033mol)和二氯甲烷(100mL)加入反应瓶中，室温搅拌2h，加入1N的盐酸水溶液(50mL)，分液，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＝50/1)，得3-溴-5-((叔丁基二甲基硅)氧基)-2-氟苯甲酸，产率64.9％。3-bromo-2-fluoro-5-hydroxybenzoic acid (5.2g, 0.022mol), triethylamine (5.6g, 0.055mol), tert-butyldimethylsilyl chloride (5.0g, 0.033mol) and di Chloromethane (100 mL) was added to the reaction flask, stirred at room temperature for 2 h, 1N aqueous hydrochloric acid solution (50 mL) was added, the layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( Eluent: petroleum ether/ethyl acetate=50/1) to obtain 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzoic acid with a yield of 64.9%.
步骤d)：3-溴-5-((叔丁基二甲基硅基)氧基)-2-氟苯甲酸甲酯的制备Step d): Preparation of methyl 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzoate
将3-溴-5-((叔丁基二甲基硅)氧基)-2-氟苯甲酸(4.6g，0.013mol)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(3.3g，0.017mol)，4-二甲氨基吡啶(3.2g，0.026mol)，甲醇(5mL)和二氯甲烷(50mL)加入反应瓶中，氮气置换3次，室温搅拌反应2h，加水(50mL)稀释搅拌，分液，有机相依次用1N的盐酸水溶液(50mL)、水(50mL)洗涤，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)，得3-溴-5-((叔丁基二甲基硅基)氧基)-2-氟苯甲酸甲酯，产率71.6％。3-Bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzoic acid (4.6g, 0.013mol), 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide hydrochloride (3.3g, 0.017mol), 4-dimethylaminopyridine (3.2g, 0.026mol), methanol (5mL) and dichloromethane (50mL) were added to the reaction flask, and nitrogen was replaced 3 times. Stir the reaction at room temperature for 2 h, add water (50 mL) to dilute and stir, separate the liquids, wash the organic phase with 1N aqueous hydrochloric acid (50 mL) and water (50 mL) successively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and wash the residue through silica gel Purified by column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain methyl 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzoate , yield 71.6%.
步骤e)：3-溴-5-((叔丁基二甲基硅氧基)-2-氟苯基)甲醇的制备Step e): Preparation of 3-bromo-5-((tert-butyldimethylsilyloxy)-2-fluorophenyl)methanol
将3-溴-5-((叔丁基二甲基硅基)氧基)-2-氟苯甲酸甲酯(2.1g，0.005mol)和THF(25mL)加入反应瓶中，再分批次加入四氢铝锂(0.6g，0.016mol)，室温搅拌1h。加入饱和氯化铵溶液(20mL)和二氯甲烷(20mL)，搅拌10min淬灭反应。过滤，滤饼用二氯甲烷淋洗，滤液分液，有机相以无水硫酸钠干燥，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)，得3-溴-5-((叔丁基二甲基硅氧基)-2-氟苯基)甲醇，产率51.6％。Add 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzoic acid methyl ester (2.1 g, 0.005 mol) and THF (25 mL) into the reaction flask, and then batch Lithium aluminum hydride (0.6 g, 0.016 mol) was added and stirred at room temperature for 1 h. Add saturated ammonium chloride solution (20 mL) and dichloromethane (20 mL), and stir for 10 min to quench the reaction. Filtration, the filter cake was rinsed with dichloromethane, the filtrate was separated, the organic phase was dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate =10/1) to obtain 3-bromo-5-((tert-butyldimethylsilyloxy)-2-fluorophenyl)methanol with a yield of 51.6%.
步骤f)：3-溴-5-((叔丁基二甲基硅)氧基)-2-氟苯甲醛的制备Step f): Preparation of 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzaldehyde
将3-溴-5-((叔丁基二甲基硅氧基)-2-氟苯基)甲醇(2.1g，0.006mol)、戴斯马丁氧化剂(4.0g，0.009mol)和二氯甲烷(20mL)加入反应瓶中，室温搅拌1h，过滤，滤液用饱和碳酸氢钠水溶液(20mL)洗涤，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＝20/1)，得3-溴-5-((叔丁基二甲基硅)氧基)-2-氟苯甲醛，产率47.6％。3-Bromo-5-((tert-butyldimethylsilyloxy)-2-fluorophenyl)methanol (2.1 g, 0.006 mol), Dess Martin oxidizer (4.0 g, 0.009 mol) and dichloromethane (20mL) was added to the reaction flask, stirred at room temperature for 1h, filtered, the filtrate was washed with saturated aqueous sodium bicarbonate (20mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography ( Eluent: petroleum ether/ethyl acetate=20/1) to obtain 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzaldehyde with a yield of 47.6%.
步骤g)：(3-溴-5-(二氟甲基)-4-氟苯氧基)(叔丁基)二甲基硅烷的制备Step g): Preparation of (3-bromo-5-(difluoromethyl)-4-fluorophenoxy)(tert-butyl)dimethylsilane
将3-溴-5-((叔丁基二甲基硅)氧基)-2-氟苯甲醛(1.5g，0.005mol)和二氯甲烷(15mL)加入反应瓶中，冰浴搅拌条件下滴加二乙胺基三氟化硫(1.5g，0.010mol)，加毕，冰浴下搅拌反应30min，升温至室温搅拌2h。反应结束后，缓慢滴加饱和碳酸氢钠水溶液(5mL)淬灭反应，加入二氯甲烷(20mL)萃取，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＝50/1)，得(3-溴-5-(二氟甲基)-4-氟苯氧基)(叔丁基)二甲基硅烷，产率42.7％。Add 3-bromo-5-((tert-butyldimethylsilyl)oxy)-2-fluorobenzaldehyde (1.5g, 0.005mol) and dichloromethane (15mL) into the reaction flask, and stir in the ice bath Diethylaminosulfur trifluoride (1.5 g, 0.010 mol) was added dropwise. After the addition was complete, the reaction was stirred for 30 min in an ice bath, then warmed up to room temperature and stirred for 2 h. After the reaction was completed, slowly add saturated aqueous sodium bicarbonate (5 mL) dropwise to quench the reaction, add dichloromethane (20 mL) for extraction, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography Purify (eluent: petroleum ether/ethyl acetate=50/1) to obtain (3-bromo-5-(difluoromethyl)-4-fluorophenoxy)(tert-butyl)dimethylsilane, Yield 42.7%.
步骤h)：1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙烷-1-酮的制备Step h): Preparation of 1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethan-1-one
将(3-溴-5-(二氟甲基)-4-氟苯氧基)(叔丁基)二甲基硅烷(500mg，1.408mmol)、三乙胺(285mg，2.817mmol)、三正丁基(乙烯基)锡(670mg，1.831mmol)、双(三苯基膦)二氯化钯(II)(100mg，0.141mmol)和1，4-二氧六环(10mL)加入反应瓶中，氮气置换3次，升温至100℃搅拌3h，反应结束后，冷却至室温，加入饱和氟化钾饱和水溶液(20mL)，室温搅拌10min，过滤，滤饼用乙酸乙酯(20mL)淋洗，滤液再用乙酸乙酯(20mL)萃取，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，残余物加入乙酸乙酯(5mL)溶解，加入氯化氢的乙酸乙酯溶液(10mL，4M)，室温搅拌10min，加入水(10mL)分液，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＝50/1)，得1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙烷-1-酮，产率45.1％。(3-Bromo-5-(difluoromethyl)-4-fluorophenoxy)(tert-butyl)dimethylsilane (500mg, 1.408mmol), triethylamine (285mg, 2.817mmol), tri-n- Butyl(vinyl)tin (670 mg, 1.831 mmol), bis(triphenylphosphine)palladium(II) chloride (100 mg, 0.141 mmol) and 1,4-dioxane (10 mL) were added to the reaction flask , replaced with nitrogen for 3 times, heated to 100°C and stirred for 3 hours. After the reaction, cooled to room temperature, added saturated potassium fluoride aqueous solution (20mL), stirred at room temperature for 10min, filtered, and the filter cake was rinsed with ethyl acetate (20mL). The filtrate was extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (5 mL), and hydrogen chloride in ethyl acetate (10 mL, 4M) was added. Stir at room temperature for 10 min, add water (10 mL) for separation, dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=50/1 ) to obtain 1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethan-1-one with a yield of 45.1%.
步骤i)：(R，Z)-N-(1-(5-(叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-磺酰胺 的制备Step i): (R, Z)-N-(1-(5-(tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethylene )-2-methylpropane-2-sulfonamide preparation
将1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙烷-1-酮(350mg，1.099mmol)、(R)-叔丁基亚磺酰胺(160mg，1.322mmol)、钛酸四乙酯(380mg，1.667mmol)和四氢呋喃(4mL)加入反应瓶中，氮气保护下升温至80℃搅拌反应3h。反应结束后冷却至室温，加水(10mL)和乙酸乙酯(10ml)室温搅拌10min，过滤，分取有机相，用饱和食盐水(5mL)洗涤，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)，得(R，Z)-N-(1-(5-(叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-磺酰胺，产率36.8％；ESI-MS(m/z)：422.2[M+H] +。 1-(5-((tert-Butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethan-1-one (350 mg, 1.099 mmol), ( R)-tert-butylsulfinamide (160mg, 1.322mmol), tetraethyl titanate (380mg, 1.667mmol) and tetrahydrofuran (4mL) were added to the reaction flask, heated to 80°C under nitrogen protection and stirred for 3h. After the reaction, cool to room temperature, add water (10mL) and ethyl acetate (10ml) and stir at room temperature for 10min, filter, separate the organic phase, wash with saturated brine (5mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure , the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1) to obtain (R, Z)-N-(1-(5-(tert-butyldimethylsilyl )oxy)-3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfonamide, yield 36.8%; ESI-MS (m/z): 422.2[M+H] + .
步骤j)：(R)-N-((R)-1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺的制备Step j): (R)-N-((R)-1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl) Preparation of ethyl)-2-methylpropane-2-sulfinamide
将(R，Z)-N-(1-(5-(叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)亚乙基)-2-甲基丙烷-2-磺酰胺(120mg，0.285mmol)、THF(2mL)和水(0.1mL)加入反应瓶中，再加入硼氢化钠(17mg，0.428mmol)，-78℃下搅拌反应1h，升温至室温搅拌反应30min，加水(10mL)和乙酸乙酯(20mL)萃取，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)，得(R)-N-((R)-1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺，产率72.5％；ESI-MS(m/z)：424.2[M+H] +。 (R, Z)-N-(1-(5-(tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethylene)-2 -Methylpropane-2-sulfonamide (120mg, 0.285mmol), THF (2mL) and water (0.1mL) were added to the reaction flask, then sodium borohydride (17mg, 0.428mmol) was added, and the reaction was stirred at -78°C for 1h , warmed up to room temperature and stirred for 30 min, added water (10 mL) and ethyl acetate (20 mL) for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10/1), to get (R)-N-((R)-1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl )-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide, yield 72.5%; ESI-MS (m/z): 424.2[M+H] + .
步骤k)：(R)-1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙烷-1-胺的制备Step k): (R)-1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine preparation
将(R)-N-((R)-1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基丙烷-2-亚磺酰胺(87mg，0.206mmol)和THF(1mL)加入反应瓶中，再加入氯化氢的1，4-二氧六环溶液(2mL，4N)，室温搅拌反应1h，减压浓缩得(R)-1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙烷-1-胺，无需纯化直接用于下一步反应。ESI-MS(m/z)：320.2[M+H] +。 (R)-N-((R)-1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethyl) -2-Methylpropane-2-sulfinamide (87mg, 0.206mmol) and THF (1mL) were added to the reaction flask, then hydrogen chloride in 1,4-dioxane solution (2mL, 4N) was added, and the reaction was stirred at room temperature 1h, concentrated under reduced pressure to give (R)-1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethane-1- The amine was directly used in the next reaction without further purification. ESI-MS (m/z): 320.2 [M+H] + .
步骤l)：(R)-6-溴-N-(1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺的制备Step l): (R)-6-bromo-N-(1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl) Preparation of ethyl)-2-methylquinazolin-4-amine
将(R)-1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙烷-1-胺(80mg，0.225mmol)、6-溴-4-氯-2-甲基喹唑啉(87mg，0.337mmol)、DIPEA(232mg，1.798mmol)和N，N-二甲基甲酰胺(2mL)加入反应瓶中，升温80℃搅拌1h，将反应液降至室温，加入水(10mL)和乙酸乙酯(20mL)搅拌分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)，得(R)-6-溴-N-(1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺，产率82.5％；ESI-MS(m/z)：540.1[M+H] + (R)-1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethan-1-amine (80mg, 0.225 mmol), 6-bromo-4-chloro-2-methylquinazoline (87mg, 0.337mmol), DIPEA (232mg, 1.798mmol) and N,N-dimethylformamide (2mL) were added to the reaction flask, Raise the temperature to 80°C and stir for 1 h, then lower the reaction solution to room temperature, add water (10 mL) and ethyl acetate (20 mL) to stir and separate the liquids, dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue through a silica gel column Chromatographic purification (eluent: petroleum ether/ethyl acetate=5/1) to obtain (R)-6-bromo-N-(1-(5-((tert-butyldimethylsilyl)oxy) )-3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine, yield 82.5%; ESI-MS (m/z): 540.1 [M +H] +
步骤m)：(R)-2-(5-((4-((1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step m): (R)-2-(5-((4-((1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2- Fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide preparation of
将(R)-6-溴-N-(1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)-2-甲基喹唑啉-4-胺(45mg，0.083mmol)、碳酸铯(55mg，0.167mmol)、X-phos(8.3mg，0.017mmol)，Pd(dba) 2(5.0mg，0.008mmol)，2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(28mg，0.125mmol)和甲苯(2mL)加入反应瓶中，氮气置换3次后，100℃搅拌3h。反应结束后，冷却至室温，减压浓缩，残余物经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-2-(5-((4-((1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率81.6％；ESI-MS(m/z)：683.3[M+H] +。 (R)-6-bromo-N-(1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethyl) -2-methylquinazolin-4-amine (45mg, 0.083mmol), cesium carbonate (55mg, 0.167mmol), X-phos (8.3mg, 0.017mmol), Pd(dba) 2 (5.0mg, 0.008mmol ), 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (28mg, 0.125mmol) and toluene (2mL) were added to the reaction flask, nitrogen After three replacements, stir at 100°C for 3h. After the reaction was completed, it was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(5-((4- ((1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline -6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 81.6%; ESI-MS (m/z): 683.3[ M+H] + .
步骤n)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟-5-羟基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备Step n): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluoro-5-hydroxyphenyl)ethyl)amino)-2-methanol Preparation of ylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide formate
将(R)-2-(5-((4-((1-(5-((叔丁基二甲基硅基)氧基)-3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺(40mg，0.059mmol)、THF(2mL)和四丁基氟化铵的THF溶液(1M，2mL)加入反应瓶中，室温搅拌30min，加入二氯甲烷(20mL)，再用1N的盐酸水溶液(10mL)洗涤，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟-5-羟基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡 啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率27.8％； 1H NMR(400MHz，DMSO-d 6)δ8.38(s，1H)，8.15(d，J＝8.0Hz，1H)，8.14(s，1H)，7.95(d，J＝4.0Hz，1H)，7.74(s，1H)，7.40(d，J＝8.0Hz，1H)，7.35(s，1H)，7.14(t，J＝56.0Hz，1H)，7.11(d，J＝8.0Hz，1H)，7.03(s，1H)，6.79(s，1H)，5.79-5.75(m，1H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.31(s，3H)，1.34-1.28(m，3H)；ESI-MS(m/z)：569.2[M+H] +。 (R)-2-(5-((4-((1-(5-((tert-butyldimethylsilyl)oxy)-3-(difluoromethyl)-2-fluorophenyl ) ethyl) amino)-2-methylquinazolin-6-yl) (methyl) amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide (40mg, 0.059mmol), THF (2mL) and THF solution of tetrabutylammonium fluoride (1M, 2mL) were added to the reaction flask, stirred at room temperature for 30min, dichloromethane (20mL) was added, and then washed with 1N aqueous hydrochloric acid solution (10mL) , the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 2) to obtain (R)-2-(5-((4-((1-(3-( Difluoromethyl)-2-fluoro-5-hydroxyphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl) -N,N-Dimethylacetamide formate, yield 27.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.38(s, 1H), 8.15(d, J=8.0Hz, 1H) , 8.14(s, 1H), 7.95(d, J=4.0Hz, 1H), 7.74(s, 1H), 7.40(d, J=8.0Hz, 1H), 7.35(s, 1H), 7.14(t, J=56.0Hz, 1H), 7.11(d, J=8.0Hz, 1H), 7.03(s, 1H), 6.79(s, 1H), 5.79-5.75(m, 1H), 3.85(s, 3H), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.31(s, 3H), 1.34-1.28(m, 3H); ESI-MS(m/ z): 569.2 [M+H] + .
实施例98Example 98
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟-5-羟基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluoro-5-hydroxyphenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000199
Figure PCTCN2022101219-appb-000199
制备方法参考实施例38，经Pre-HPLC(方法2)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟-5-羟基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺甲酸盐，产率33.6％； 1H NMR(400MHz，DMSO-d 6)δ11.63(s，1H)，9.70(s，1H)，8.13(s，2H)，7.59(s，1H)，7.42(s，1H)，7.28(s，1H)，7.19(s，1H)，7.15(t，J＝56.0Hz，1H)，7.13(s，1H)，7.01(s，1H)，6.81(s，1H)，5.80(m，1H)，3.42(s，2H)，3.31(s，3H)，3.02(s，3H)，2.79(s，3H)，2.34(s，3H)，1.60(d，J＝8.0Hz，3H)；ESI-MS(m/z)：555.2[M+H] +。 The preparation method refers to Example 38 and is purified by Pre-HPLC (method 2) to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluoromethyl)-2-fluoro-5 -Hydroxyphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide acid salt, yield 33.6%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.63(s, 1H), 9.70(s, 1H), 8.13(s, 2H), 7.59(s, 1H), 7.42 (s, 1H), 7.28(s, 1H), 7.19(s, 1H), 7.15(t, J=56.0Hz, 1H), 7.13(s, 1H), 7.01(s, 1H), 6.81(s, 1H), 5.80(m, 1H), 3.42(s, 2H), 3.31(s, 3H), 3.02(s, 3H), 2.79(s, 3H), 2.34(s, 3H), 1.60(d, J = 8.0 Hz, 3H); ESI-MS (m/z): 555.2 [M+H] + .
实施例99Example 99
(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000200
Figure PCTCN2022101219-appb-000200
步骤a)：2-溴-6-甲基-4-硝基苯胺的制备Step a): Preparation of 2-bromo-6-methyl-4-nitroaniline
将2-甲基-4-硝基苯胺(1.5g，9.859mmol)和冰乙酸(20mL)加入到反应瓶中，室温下加入溴素(1.8g，12.953mmol)，维持室温搅拌反应1.5h。将反应液倒入到冰水(100mL)中，搅拌10min，过滤，滤饼依次用水(20mL)、饱和碳酸氢钠水溶液(20mL)淋洗，真空干燥，得2-溴-6-甲基-4-硝基苯胺，产率97.0％。2-Methyl-4-nitroaniline (1.5 g, 9.859 mmol) and glacial acetic acid (20 mL) were added to the reaction flask, bromine (1.8 g, 12.953 mmol) was added at room temperature, and the reaction was maintained at room temperature for 1.5 h with stirring. The reaction solution was poured into ice water (100mL), stirred for 10min, filtered, and the filter cake was rinsed with water (20mL) and saturated aqueous sodium bicarbonate solution (20mL) successively, and dried in vacuo to obtain 2-bromo-6-methyl- 4-Nitroaniline, yield 97.0%.
步骤b)：1-(2-溴-6-甲基-4-硝基苯基)-2-重氮氟硼酸盐的制备Step b): Preparation of 1-(2-bromo-6-methyl-4-nitrophenyl)-2-diazofluoroborate
将2-溴-6-甲基-4-硝基苯胺(6.0g，26.087mmol)和氟硼酸水溶液(30mL，50％)加入反应瓶中，将反应液冷却至0-5℃，缓慢滴加亚硝酸钠(2.0g，25.986mmol)的水溶液(4.0mL)，加毕，在0-10℃反应1h。反应结束后，过滤，滤饼用氟硼酸水溶液(30mL，50％)和乙酸乙酯(10mL×2)淋洗，滤饼真空干燥，得1-(2-溴-6-甲基-4-硝基苯基)-2-重氮氟硼酸盐，产率78.6％。Add 2-bromo-6-methyl-4-nitroaniline (6.0g, 26.087mmol) and fluoroboric acid aqueous solution (30mL, 50%) into the reaction flask, cool the reaction solution to 0-5°C, and slowly add An aqueous solution (4.0 mL) of sodium nitrite (2.0 g, 25.986 mmol) was added, and reacted at 0-10° C. for 1 h. After the reaction, filter, the filter cake was rinsed with fluoroboric acid aqueous solution (30mL, 50%) and ethyl acetate (10mL×2), and the filter cake was vacuum-dried to obtain 1-(2-bromo-6-methyl-4- Nitrophenyl)-2-diazonium fluoroborate, yield 78.6%.
步骤c)：1-溴-2-氟-3-甲基-5-硝基苯的制备Step c): Preparation of 1-bromo-2-fluoro-3-methyl-5-nitrobenzene
将1-(2-溴-6-甲基-4-硝基苯基)-2-重氮氟硼酸盐(7.0g，21.277mmol)加入反应瓶中，155℃搅拌反应30min。将反应液冷却至室温，粗品经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝100/1到30/1)，得1-溴-2-氟-3-甲基-5-硝基苯，产率44.3％。Add 1-(2-bromo-6-methyl-4-nitrophenyl)-2-diazonium fluoroborate (7.0 g, 21.277 mmol) into the reaction flask, and stir at 155°C for 30 min. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=100/1 to 30/1) to obtain 1-bromo-2-fluoro-3-methyl-5 -Nitrobenzene, yield 44.3%.
步骤d-j)：(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step d-j): (R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazoline Preparation of -6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
制备方法参考实施例75的步骤a-g，经Prep-HPLC(方法3)分离得到(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率16.9％； 1H NMR(400MHz，DMSO-d 6)δ8.07(brs，1H)，7.94(s，1H)，7.78(s，1H)，7.40(d，J＝8.0Hz，1H)，7.34(s，1H)，7.12(d，J＝8.0Hz，1H)，6.47-6.44(m，1H)，6.28-6.26(m，1H)，5.77-5.73(m，1H)，4.77(s，2H)，3.85(s，3H)，3.59(s，2H)，3.38(s，3H)，3.02(s，3H)，2.80(s，3H)，2.33(s，3H)，2.11(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：532.0[M+H] +。 The preparation method refers to step ag of Example 75, and (R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methyl) is separated by Prep-HPLC (method 3) Phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, Yield 16.9%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.07(brs, 1H), 7.94(s, 1H), 7.78(s, 1H), 7.40(d, J=8.0Hz, 1H) , 7.34(s, 1H), 7.12(d, J=8.0Hz, 1H), 6.47-6.44(m, 1H), 6.28-6.26(m, 1H), 5.77-5.73(m, 1H), 4.77(s , 2H), 3.85(s, 3H), 3.59(s, 2H), 3.38(s, 3H), 3.02(s, 3H), 2.80(s, 3H), 2.33(s, 3H), 2.11(s, 3H), 1.54 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 532.0 [M+H] + .
实施例100Example 100
(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000201
Figure PCTCN2022101219-appb-000201
将(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺(60mg，0.113mmol)和溴化氢水溶液(2mL，48％)加入到反应瓶中，80℃搅拌反应0.5h。将反应液冷却至室温，减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率35.9％； 1H NMR(400MHz，DMSO-d 6)δ11.50(s，1H)，7.99(d，J＝8.0Hz，1H)，7.58(s，1H)，7.39(d，J＝8.0Hz，1H)，7.25(s，1H)，7.17(d，J＝4.0Hz，1H)，7.08(d，J＝8.0Hz，1H)，6.46-6.44(m，1H)，6.28-6.26(m，1H)，5.76-5.73(m，1H)，4.76(s，2H)，3.42(s，2H)，3.28(s，3H)，3.01(s，3H)，2.78(s，3H)，2.32(s，3H)，2.11(s，3H)，1.54(d，J＝8.0Hz，3H)；ESI-MS(m/z)：518.3[M+H] +。 (R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazoline-6- (methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide (60 mg, 0.113 mmol) and aqueous hydrogen bromide (2 mL, 48%) were added to the reaction In the bottle, stir the reaction at 80°C for 0.5h. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the obtained crude product was purified by Prep-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(5-amino-2-fluoro- 3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylethyl Amide, yield 35.9%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.50(s, 1H), 7.99(d, J=8.0Hz, 1H), 7.58(s, 1H), 7.39(d, J=8.0Hz, 1H), 7.25(s, 1H), 7.17(d, J=4.0Hz, 1H), 7.08(d, J=8.0Hz, 1H), 6.46-6.44(m, 1H), 6.28- 6.26(m, 1H), 5.76-5.73(m, 1H), 4.76(s, 2H), 3.42(s, 2H), 3.28(s, 3H), 3.01(s, 3H), 2.78(s, 3H) , 2.32 (s, 3H), 2.11 (s, 3H), 1.54 (d, J = 8.0 Hz, 3H); ESI-MS (m/z): 518.3 [M+H] + .
实施例101Example 101
(R)-N，N-二甲基-2-(3-(甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-6-氧代哒嗪-1(6H)-基)乙酰胺的制备(R)-N, N-dimethyl-2-(3-(methyl(2-methyl-4-((1-(2-methyl-3-(trifluoromethyl)phenyl) phenyl) ethyl Preparation of base) amino) quinazoline-6-yl) amino)-6-oxopyridazin-1 (6H)-yl) acetamide
Figure PCTCN2022101219-appb-000202
Figure PCTCN2022101219-appb-000202
将(R)-N 6，2-二甲基-N 4-(1-(2-甲基-3-(三氟甲基)苯基)乙基)喹唑啉-4，6-二胺(120mg，0.321mmol)、2-(3-溴-6-氧哒嗪-1(6H)-基)-N，N-二甲基乙酰胺(125mg，0.481mmol)、Cs 2CO 3(312mg，0.961mmol)、Pd(dba) 2(37mg，0.064mmol)、X-phos(61mg，0.128mmol)和甲苯(5mL)依次加入反应瓶中，氮气置换三次，升温至105℃搅拌反应5h。将反应液冷却至室温，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，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，得到的粗品经Prep-HPLC(方法3)纯化，得(R)-N，N-二甲基-2-(3-(甲基(2-甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)氨基)-6-氧代哒嗪-1(6H)-基)乙酰胺，产率74.5％； 1H NMR(400MHz，DMSO-d 6)δ8.50(d，J＝8.0Hz，1H)，8.21(s，1H)，7.76(d，J＝8.0Hz，1H)，7.60-7.50(m，3H)，7.34(t，J＝8.0Hz，1H)，7.08(d，J＝8.0Hz，1H)，6.79(d，J＝8.0Hz，1H)，5.76-5.68(m，1H)，4.83(s，2H)，3.31(s，3H)，3.04(s，3H)，2.86(s，3H)，2.65(s，3H)，2.34(s，3H)，1.54(d，J＝6.8Hz，3H)；ESI-MS(m/z)：554.0[M+H] +。 (R)-N 6 , 2-dimethyl-N 4 -(1-(2-methyl-3-(trifluoromethyl)phenyl)ethyl)quinazoline-4,6-diamine (120mg, 0.321mmol), 2-(3-bromo-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide (125mg, 0.481mmol), Cs 2 CO 3 (312mg , 0.961mmol), Pd(dba) 2 (37mg, 0.064mmol), X-phos (61mg, 0.128mmol) and toluene (5mL) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 5h. Cool the reaction solution to room temperature, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentration, the resulting crude product was purified by Prep-HPLC (method 3) to give (R)-N,N-dimethyl-2-(3-(methyl(2-methyl-4-((1-(2 -Methyl-3-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)amino)-6-oxopyridazin-1(6H)-yl)acetamide, yield 74.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.50(d, J=8.0Hz, 1H), 8.21(s, 1H), 7.76(d, J=8.0Hz, 1H), 7.60-7.50 (m, 3H), 7.34(t, J=8.0Hz, 1H), 7.08(d, J=8.0Hz, 1H), 6.79(d, J=8.0Hz, 1H), 5.76-5.68(m, 1H) , 4.83(s, 2H), 3.31(s, 3H), 3.04(s, 3H), 2.86(s, 3H), 2.65(s, 3H), 2.34(s, 3H), 1.54(d, J=6.8 Hz, 3H); ESI-MS (m/z): 554.0 [M+H] + .
实施例102Example 102
(R)-2-(3-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备(R)-2-(3-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino)-6-oxopyridazin-1 (6H)-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000203
Figure PCTCN2022101219-appb-000203
步骤a)：(R)-N 4-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺的制备 Step a): (R)-N 4 -(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6 - Preparation of diamines
将(R)-6-溴-N-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-2-甲基喹唑啉-4-胺(300mg，0.739mmol)、甲胺盐酸盐(495mg，7.389mmol)、Cs 2CO 3(2.9g，8.867mmol)、X-Phos(70mg，0.148mmol)、Pd(dba) 2(42mg，0.074mmol)和甲苯(20mL)加入反应瓶中，向反应瓶中鼓入氮气1min，密闭升温至110℃搅拌反应16h。反应结束后，将反应液冷却至室温，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＝20/1)，得(R)-N 4-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺，产率50.1％；ESI-MS(m/z)：357.2[M+H] +。 (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-methylphenyl)ethyl)-2-methylquinazolin-4-amine (300mg, 0.739 mmol), methylamine hydrochloride (495mg, 7.389mmol ), Cs2CO3 (2.9g, 8.867mmol), X-Phos (70mg, 0.148mmol), Pd(dba) 2 (42mg, 0.074mmol) and toluene (20 mL) was added to the reaction flask, nitrogen gas was bubbled into the reaction flask for 1 min, and the temperature was sealed and raised to 110° C. and stirred for 16 h. After the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-N 4 - (1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine, yield 50.1%; ESI- MS (m/z): 357.2 [M+H] + .
步骤b)：(R)-2-(3-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(3-((4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazole Preparation of hydrin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide
将(R)-N 4-(1-(3-(二氟甲基)-2-甲基苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(65mg，0.183mmol)、2-(3-溴-6-氧代哒嗪-1(6H)-基-N，N-二甲基乙酰胺(48mg，0.183mmol)、Cs 2CO 3(119mg，0.366mmol)、X-Phos(17.1mg，0.037mmol)、Pd(dba) 2(10mg，0.018mmol)和甲苯(5mL)加入反应瓶中，氮气置换3次，升温至105℃搅拌反应16h。将反应液冷却至室温，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法3)纯化，得(R)-2-(3-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺，产率40.8％； 1H NMR(400MHz，DMSO-d 6)δ8.47(s，1H)，8.22(s，1H)，7.65(d，J＝7.6Hz，1H)，7.62-7.51(m，2H)，7.38(d，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.21(t，J＝54.8Hz，1H)，7.07(d，J＝9.6Hz，1H)，6.79(d，J＝10.0Hz，1H)，5.75(p，J＝7.2Hz，1H)，4.82(s，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.56(s，3H)，2.36(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：536.2[M+H] +。 (R)-N 4 -(1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine (65mg, 0.183mmol), 2-(3-bromo-6-oxopyridazin-1(6H)-yl-N,N-dimethylacetamide (48mg, 0.183mmol), Cs 2 CO 3 (119mg , 0.366mmol), X-Phos (17.1mg, 0.037mmol), Pd(dba) 2 (10mg, 0.018mmol) and toluene (5mL) were added into the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 16h. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to obtain (R)-2-(3-((4-((1-(3-(difluoro Methyl)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl) -N,N-Dimethylacetamide, yield 40.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.47(s, 1H), 8.22(s, 1H), 7.65(d, J=7.6 Hz, 1H), 7.62-7.51(m, 2H), 7.38(d, J=7.6Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.21(t, J=54.8Hz, 1H), 7.07(d, J=9.6Hz, 1H), 6.79(d, J=10.0Hz, 1H), 5.75(p, J=7.2Hz, 1H), 4.82(s, 2H), 3.33(s, 3H), 3.04(s, 3H), 2.86(s, 3H), 2.56(s, 3H), 2.36(s, 3H), 1.53(d, J=7.2Hz, 3H); ESI-MS(m/z): 536.2 [M+H] + .
实施例103Example 103
(R)-2-(3-((4-((1-(3-氰基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备(R)-2-(3-((4-((1-(3-cyano)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)( Preparation of methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000204
Figure PCTCN2022101219-appb-000204
步骤a-b)：(R)-2-(3-((4-((1-(3-氰基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备Step a-b): (R)-2-(3-((4-((1-(3-cyano)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6 Preparation of -yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide
制备方法参考实施例102，所得粗品依次经硅胶柱层析纯化(洗脱剂/甲醇/二氯甲烷＝1/10)和Prep-HPLC纯化(方法3)，得(R)-2-(3-((4-((1-(3-氰基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺，收率17.2％； 1H NMR(400MHz，DMSO-d 6)δ8.48(d，J＝6.8Hz，1H)，8.20(s，1H)，7.78(d，J＝7.6Hz，1H)，7.63-7.54(m，3H)，7.36(t，J＝7.6Hz，1H)，7.07(d，J＝10.0Hz，1H)，6.79(d，J＝9.6Hz，1H)，5.68-5.61(m，1H)，4.82(s，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.72(s，3H)，2.36(s，3H)，1.53(d，J＝6.8Hz，3H)；ESI-MS(m/z)：511.0[M+H] +。 The preparation method refers to Example 102, and the obtained crude product is purified by silica gel column chromatography (eluent/methanol/dichloromethane=1/10) and Prep-HPLC (method 3) to obtain (R)-2-(3 -((4-((1-(3-cyano)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-6- Oxypyridazin-1(6H)-yl)-N,N-dimethylacetamide, yield 17.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.48 (d, J=6.8Hz, 1H), 8.20(s, 1H), 7.78(d, J=7.6Hz, 1H), 7.63-7.54(m, 3H), 7.36(t, J=7.6Hz, 1H), 7.07(d, J=10.0 Hz, 1H), 6.79(d, J=9.6Hz, 1H), 5.68-5.61(m, 1H), 4.82(s, 2H), 3.33(s, 3H), 3.04(s, 3H), 2.86(s , 3H), 2.72 (s, 3H), 2.36 (s, 3H), 1.53 (d, J=6.8Hz, 3H); ESI-MS (m/z): 511.0 [M+H] + .
实施例104Example 104
(R)-2-(4-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶)-1(2H)-基)-N，N-二甲基乙酰胺的制备(R)-2-(4-((4-((1-(3-(Difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-oxopyridinium) -1 (2H) -yl) -N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000205
Figure PCTCN2022101219-appb-000205
制备方法参考实施例101，经Pre-HPLC(方法3)纯化，得(R)-2-(4-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代吡啶)-1(2H)-基)-N，N-二甲基乙酰胺，产率36.7％； 1H NMR(400MHz，DMSO-d 6)δ8.51(d，J＝7.2Hz，1H)，8.35(s，1H)，7.69-7.61(m，2H)，7.57(d，J＝8.8，1H)，7.38(d，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.21(d，J＝7.6Hz，1H)，7.21(t，J＝54.8Hz，1H)，5.76(p，J＝7.2Hz，1H)，5.61(d，J＝7.6，1H)，5.44(s，1H)，4.64(s，2H)，3.32(s，3H)，3.02(s，3H)，2.83(s，3H)，2.56(s，3H)，2.37(s，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：535.2[M+H] +。 The preparation method refers to Example 101 and is purified by Pre-HPLC (method 3) to obtain (R)-2-(4-((4-((1-(3-(difluoromethyl)-2-methylbenzene Base) ethyl) amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyridin)-1(2H)-yl)-N,N-dimethylethyl Amide, yield 36.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.51(d, J=7.2Hz, 1H), 8.35(s, 1H), 7.69-7.61(m, 2H), 7.57( d, J=8.8, 1H), 7.38(d, J=7.6Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.21(d, J=7.6Hz, 1H), 7.21(t, J =54.8Hz, 1H), 5.76(p, J=7.2Hz, 1H), 5.61(d, J=7.6, 1H), 5.44(s, 1H), 4.64(s, 2H), 3.32(s, 3H) , 3.02(s, 3H), 2.83(s, 3H), 2.56(s, 3H), 2.37(s, 3H), 1.52(d, J=7.2Hz, 3H); ESI-MS(m/z): 535.2[M+H] + .
实施例105Example 105
(R)-2-(3-((4-((1-(3-(1，1-二氟-2-羟基乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备(R)-2-(3-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Preparation of ylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000206
Figure PCTCN2022101219-appb-000206
步骤a)：(R)-2-(3-((4-((1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备Step a): (R)-2-(3-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethane Base)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N , Preparation of N-dimethylacetamide
制备方法参考实施例101，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/20)，得(R)-2-(3-((4-((1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺，收率68.0％；ESI-MS(m/z)：684.3[M+H] +。 The preparation method refers to Example 101, and the obtained crude product is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/20) to obtain (R)-2-(3-((4-((1-( 3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline -6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide, yield 68.0%; ESI-MS (m/z) : 684.3[M+H] + .
步骤b)：(R)-2-(3-((4-((1-(3-(1，1-二氟-2-羟基乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(3-((4-((1-(3-(1,1-difluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino) Preparation of -2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N-dimethylacetamide
将(R)-2-(3-((4-((1-(3-(2-((叔丁基二甲基甲硅烷基)氧基)-1，1-二氟乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺(70mg，0.102mmol)、四丁基氟化铵的THF溶液(153.0μL，0.153mmol，1M)和THF(1mL)加入反应瓶中，室温反应5min。依次加入乙酸乙酯(20mL)、饱和食盐水(10mL)和1M氯化氢水溶液(10mL)，分液，有机相依次用饱和碳酸氢钠水溶液(20mL)洗涤、饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法3)纯化，得(R)-2-(3-((4-((1-(3-(1，1-二氟-2-羟基乙基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-6-氧代哒嗪-1(6H)-基)-N，N-二甲基乙酰胺，收率17.2％； 1H NMR(400MHz，DMSO-d 6)δ8.39(d，J＝7.2Hz，1H)，8.22(s，1H)，7.66-7.54(m，3H)，7.44-7.37(m，1H)，7.24(t，J＝7.6Hz，1H)，7.09(d，J＝10.0Hz，1H)，6.79(d，J＝10.0Hz，1H)，5.84-5.76(m，1H)，5.70(t，J＝6.4Hz，1H)，4.82(s，2H)，3.99-3.87(m，2H)，3.33(s，3H)，3.04(s，3H)，2.86(s，3H)，2.35(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：570.0[M+H] +。 (R)-2-(3-((4-((1-(3-(2-((tert-butyldimethylsilyl)oxy)-1,1-difluoroethyl)- 2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazin-1(6H)-yl)-N,N- Add dimethylacetamide (70mg, 0.102mmol), THF solution of tetrabutylammonium fluoride (153.0μL, 0.153mmol, 1M) and THF (1mL) into the reaction flask, and react at room temperature for 5min. Add ethyl acetate (20mL), saturated brine (10mL) and 1M aqueous hydrogen chloride solution (10mL) successively, separate the layers, and wash the organic phase successively with saturated aqueous sodium bicarbonate (20mL) and saturated brine (15mL), and anhydrous Dry over sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by Prep-HPLC (method 3) to give (R)-2-(3-((4-((1-(3-(1,1-di Fluoro-2-hydroxyethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-6-oxopyridazine-1(6H )-yl)-N,N-dimethylacetamide, yield 17.2%; 1 H NMR (400MHz, DMSO-d 6 )δ8.39 (d, J=7.2Hz, 1H), 8.22(s, 1H ), 7.66-7.54(m, 3H), 7.44-7.37(m, 1H), 7.24(t, J=7.6Hz, 1H), 7.09(d, J=10.0Hz, 1H), 6.79(d, J= 10.0Hz, 1H), 5.84-5.76(m, 1H), 5.70(t, J=6.4Hz, 1H), 4.82(s, 2H), 3.99-3.87(m, 2H), 3.33(s, 3H), 3.04 (s, 3H), 2.86 (s, 3H), 2.35 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 570.0 [M+H] + .
实施例106Example 106
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代嘧啶-1(2H)-基)-N，N-二甲基乙酰胺盐酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-oxopyrimidin-1 (2H)-yl)-N, the preparation of N-dimethylacetamide hydrochloride
Figure PCTCN2022101219-appb-000207
Figure PCTCN2022101219-appb-000207
步骤a)：(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6-(2-甲氧基嘧啶-5-基)-N 6，2-二甲基喹唑啉-4，6-二胺的 制备 Step a): (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 -(2-methoxypyrimidin-5-yl)- Preparation of N 6 ,2-dimethylquinazoline-4,6-diamine
将(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6，2-二甲基喹唑啉-4，6-二胺(209mg，0.583mmol)、5-溴-2-甲氧基嘧啶(132mg，0.696mmol)、Cs 2CO 3(382mg，1.166mmol)、X-Phos(58mg，0.120mmol)、Pd(dba) 2(33mg，0.058mmol)和甲苯(4mL)加入反应瓶中，氮气置换三次，升温至105℃搅拌反应3h。反应结束后，冷却至室温，过滤，滤饼用乙酸乙酯(20mL)淋洗，合并滤液，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(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6-(2-甲氧基嘧啶-5-基)-N 6，2-二甲基喹唑啉-4，6-二胺，收率58.9％；ESI-MS(m/z)：469.2[M+H] +。 (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 ,2-dimethylquinazoline-4,6-diamine ( 209mg, 0.583mmol), 5-bromo-2-methoxypyrimidine (132mg, 0.696mmol), Cs 2 CO 3 (382mg, 1.166mmol), X-Phos (58mg, 0.120mmol), Pd(dba) 2 ( 33mg, 0.058mmol) and toluene (4mL) were added into the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 3h. After the reaction was completed, cool to room temperature, filter, rinse the filter cake with ethyl acetate (20 mL), combine the filtrates, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=10 /1 to 1/1), to get (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 -(2-methoxypyrimidine- 5-yl)-N 6 , 2-dimethylquinazoline-4,6-diamine, yield 58.9%; ESI-MS (m/z): 469.2[M+H] + .
步骤b)：(R)-5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)嘧啶-2(1H)-酮的制备Step b): (R)-5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline-6- base) (methyl) amino) pyrimidin-2 (1H)-one
在室温下将(R)-N 4-(1-(3-(二氟甲基)-2-氟苯基)乙基)-N 6-(2-甲氧基嘧啶-5-基)-N 6，2-二甲基喹唑啉-4，6-二胺(160mg，0.340mmol)和33wt％溴化氢乙酸溶液(4mL)依次加入反应瓶中，升温至80℃反应30min。反应结束后，冷却至室温，减压浓缩，得(R)-5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)嘧啶-2(1H)-酮，产率100.0％；ESI-MS(m/z)：455.1[M+H] +。 (R)-N 4 -(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-N 6 -(2-methoxypyrimidin-5-yl)- N 6 , 2-dimethylquinazoline-4,6-diamine (160mg, 0.340mmol) and 33wt% hydrogen bromide acetic acid solution (4mL) were sequentially added into the reaction flask, and the temperature was raised to 80°C for 30min. After the reaction, cool to room temperature and concentrate under reduced pressure to obtain (R)-5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2 -Methylquinazolin-6-yl)(methyl)amino)pyrimidin-2(1H)-one, yield 100.0%; ESI-MS (m/z): 455.1 [M+H] + .
步骤c)：(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代嘧啶-1(2H)-基)-N，N-二甲基乙酰胺盐酸盐的制备Step c): (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline -6-yl)(methyl)amino)-2-oxopyrimidin-1(2H)-yl)-N, the preparation of N-dimethylacetamide hydrochloride
将(R)-5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)嘧啶-2(1H)-酮(160mg，0.350mmol)溶于DMF(3mL)中，依次加入碳酸钾(145mg，1.050mmol)、2-溴-N，N-二甲基乙酰胺(69mg，0.420mmol)，升温至60℃反应1h。反应结束后，冷却至室温，过滤，滤液加饱和氯化铵(10mL)淬灭，乙酸乙酯(15mL)萃取，饱和食盐水(15mL×2)洗两次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物经Prep-HPLC(方法1)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-氧代嘧啶-1(2H)-基)-N，N-二甲基乙酰胺盐酸盐，产率9.5％； 1H NMR(400MHz，DMSO-d 6)δ14.38(s，1H)，10.22(s，1H)，8.61(s，1H)，8.20(s，1H)，7.92(s，1H)，7.82-7.79(m，1H)，7.60-7.51(m，2H)，7.34-7.29(m，2H)，7.13-7.00(m，1H)，5.99-5.93(m，1H)，4.76(s，2H)，3.34(s，3H)，3.00(s，3H)，2.83(s，3H)，2.50(s，3H)，1.70(d，J＝6.8Hz，3H)；ESI-MS(m/z)：540.4[M+H] +。 (R)-5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)( Methyl)amino)pyrimidin-2(1H)-one (160mg, 0.350mmol) was dissolved in DMF (3mL), and potassium carbonate (145mg, 1.050mmol), 2-bromo-N,N-dimethylethyl Amide (69mg, 0.420mmol), heated to 60°C for 1h. After the reaction, cool to room temperature, filter, quench the filtrate with saturated ammonium chloride (10 mL), extract with ethyl acetate (15 mL), wash twice with saturated brine (15 mL×2), dry over anhydrous sodium sulfate, filter, The filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (Method 1) to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-oxopyrimidin-1(2H)-yl)-N,N-dimethylacetamide salt acid salt, yield 9.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ14.38(s, 1H), 10.22(s, 1H), 8.61(s, 1H), 8.20(s, 1H), 7.92 (s, 1H), 7.82-7.79(m, 1H), 7.60-7.51(m, 2H), 7.34-7.29(m, 2H), 7.13-7.00(m, 1H), 5.99-5.93(m, 1H) , 4.76(s, 2H), 3.34(s, 3H), 3.00(s, 3H), 2.83(s, 3H), 2.50(s, 3H), 1.70(d, J=6.8Hz, 3H); ESI- MS (m/z): 540.4 [M+H] + .
实施例107Example 107
(R)-6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮二盐酸盐的制备(R)-6-((4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Preparation of base)amino)-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one dihydrochloride
Figure PCTCN2022101219-appb-000208
Figure PCTCN2022101219-appb-000208
制备方法参考实施例101，经Prep-HPLC(方法1)纯化，得(R)-6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮二盐酸盐，产率74.5％； 1H NMR(400MHz，DMSO-d 6)δ14.80(s，1H)，10.49(s，1H)，10.15(s，1H)，8.79(d，J＝10.8Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.90(s，1H)，7.81(t，J＝7.6Hz，1H)，7.55(t，J＝7.6Hz，1H)，7.37-7.32(m，1H)，7.24(s，1H)，7.21(t，J＝44.0Hz，1H)，6.91(d，J＝10.0Hz，1H)，6.04-5.97(m，1H)，4.42-4.28(m，2H)，3.55-3.47(m，2H)，3.43(s，3H)，2.87(d，J＝4.8Hz，6H)，2.59(s，3H)，1.72(d，J＝7.2Hz，3H)；ESI-MS(m/z)：526.3[M+H] +。 The preparation method refers to Example 101 and is purified by Prep-HPLC (Method 1) to obtain (R)-6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl) )amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one dihydrochloride, Yield 74.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ 14.80(s, 1H), 10.49(s, 1H), 10.15(s, 1H), 8.79(d, J=10.8Hz, 1H) , 7.99(d, J=7.6Hz, 1H), 7.90(s, 1H), 7.81(t, J=7.6Hz, 1H), 7.55(t, J=7.6Hz, 1H), 7.37-7.32(m, 1H), 7.24(s, 1H), 7.21(t, J=44.0Hz, 1H), 6.91(d, J=10.0Hz, 1H), 6.04-5.97(m, 1H), 4.42-4.28(m, 2H ), 3.55-3.47(m, 2H), 3.43(s, 3H), 2.87(d, J=4.8Hz, 6H), 2.59(s, 3H), 1.72(d, J=7.2Hz, 3H); ESI - MS (m/z): 526.3 [M+H] + .
实施例108Example 108
(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-1-甲基-2-氧代-1，2-二氢吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N, the preparation of N-dimethylacetamide hydrochloride
Figure PCTCN2022101219-appb-000209
Figure PCTCN2022101219-appb-000209
制备方法参考实施例101，经Prep-HPLC(方法1)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-1-甲基-2-氧代-1，2-二氢吡啶-3-基)-N，N-二甲基乙酰胺盐酸盐，产率 42.3％； 1H NMR(400MHz，DMSO-d 6)δ14.38(s，1H)，10.19-10.04(m，1H)，7.88-7.81(m，2H)，7.78(s，1H)，7.59-7.56(m，2H)，7.39-7.31(m，2H)，7.25-7.11(m，2H)，6.03-5.96(m，1H)，3.46(s，2H)，3.45(s，3H)，3.35(s，3H)，3.04(s，3H)，2.80(s，3H)，2.54(s，3H)，1.74(d，J＝6.8Hz，3H)；ESI-MS(m/z)：553.6[M+H] +。 The preparation method refers to Example 101 and is purified by Prep-HPLC (Method 1) to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl) ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -1-methyl-2-oxo-1,2-dihydropyridin-3-yl) -N , N-dimethylacetamide hydrochloride, yield 42.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ14.38 (s, 1H), 10.19-10.04 (m, 1H), 7.88-7.81 ( m, 2H), 7.78(s, 1H), 7.59-7.56(m, 2H), 7.39-7.31(m, 2H), 7.25-7.11(m, 2H), 6.03-5.96(m, 1H), 3.46( s, 2H), 3.45(s, 3H), 3.35(s, 3H), 3.04(s, 3H), 2.80(s, 3H), 2.54(s, 3H), 1.74(d, J=6.8Hz, 3H ); ESI-MS (m/z): 553.6 [M+H] + .
实施例109Example 109
(R)-6-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮盐酸盐的制备(R)-6-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Preparation of base)amino)-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one hydrochloride
Figure PCTCN2022101219-appb-000210
Figure PCTCN2022101219-appb-000210
步骤a)：(R)-2-(2-(二甲氨基)乙基)-6-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)哒嗪-3(2H)-酮的制备Step a): (R)-2-(2-(Dimethylamino)ethyl)-6-((4-((1-(2-fluoro-3-methyl-5-nitrophenyl) Base)amino)-2-methylquinazolin-6-yl)(methyl)amino)pyridazin-3(2H)-one
制备方法参考实施例101，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/6)，得(R)-2-(2-(二甲氨基)乙基)-6-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)哒嗪-3(2H)-酮，收率90.2％；ESI-MS(m/z)：535.2[M+H] +。 The preparation method refers to Example 101, and the obtained crude product is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/6) to obtain (R)-2-(2-(dimethylamino)ethyl)- 6-((4-((1-(2-fluoro-3-methyl-5-nitrophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino ) pyridazin-3(2H)-one, yield 90.2%; ESI-MS (m/z): 535.2[M+H] + .
步骤b)：(R)-6-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮盐酸盐的制备Step b): (R)-6-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazoline-6- base) (methyl) amino) -2-(2-(dimethylamino) ethyl) pyridazin-3 (2H)-one hydrochloride
将(R)-2-(2-(二甲氨基)乙基)-6-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)哒嗪-3(2H)-酮(68mg，0.127mmol)溶于甲醇(3mL)中，加入铁粉(35mg，0.635mmol)和饱和氯化铵水溶液(1.5mL)，90℃反应0.5h。将反应液降至室温，加入乙酸乙酯(20mL)和水(10mL)，过滤，滤液分液，有机相经用饱和食盐水洗涤(10ml)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法1)纯化，得(R)-6-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮盐酸盐，产率7.8％； 1H NMR(400MHz，DMSO-d 6)δ14.79(s，1H)，10.42(s，1H)，8.76(s，1H)，8.08-7.92(m，1H)，7.83(d，J＝9.2Hz，1H)，7.25(d，J＝10.0Hz，2H)，7.05-6.87(m，2H)，5.96-5.87(m，1H)，4.50-4.21(m，2H)，3.55-3.48(m，2H)，3.45(s，3H)，2.86(s，6H)，2.60(s，3H)，2.49(s，2H)，2.24(s，3H)，1.68(d，J＝6.8Hz，3H)；ESI-MS(m/z)：505.3[M+H] +。 (R)-2-(2-(dimethylamino)ethyl)-6-((4-((1-(2-fluoro-3-methyl-5-nitrophenyl)ethyl)amino )-2-methylquinazolin-6-yl)(methyl)amino)pyridazin-3(2H)-one (68 mg, 0.127 mmol) was dissolved in methanol (3 mL), iron powder (35 mg, 0.635 mmol) and saturated aqueous ammonium chloride (1.5 mL), react at 90°C for 0.5h. The reaction solution was lowered to room temperature, added ethyl acetate (20 mL) and water (10 mL), filtered, the filtrate was separated, the organic phase was washed with saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure , the resulting crude product was purified by Prep-HPLC (Method 1) to give (R)-6-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)- 2-Methylquinazolin-6-yl)(methyl)amino)-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one hydrochloride, yield 7.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ14.79(s, 1H), 10.42(s, 1H), 8.76(s, 1H), 8.08-7.92(m, 1H), 7.83(d, J=9.2 Hz, 1H), 7.25(d, J=10.0Hz, 2H), 7.05-6.87(m, 2H), 5.96-5.87(m, 1H), 4.50-4.21(m, 2H), 3.55-3.48(m, 2H), 3.45(s, 3H), 2.86(s, 6H), 2.60(s, 3H), 2.49(s, 2H), 2.24(s, 3H), 1.68(d, J=6.8Hz, 3H); ESI-MS (m/z): 505.3 [M+H] + .
实施例110Example 110
(R)-N 4-(1-(5-氨基-2-氟-3-甲基苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-N 6，2-二甲基喹唑啉-4，6-二胺的制备 (R)-N 4 -(1-(5-amino-2-fluoro-3-methylphenyl)ethyl)-N 6 -(5-(2-(dimethylamino)ethyl)-6- Preparation of methoxypyridin-3-yl)-N 6 ,2-dimethylquinazoline-4,6-diamine
Figure PCTCN2022101219-appb-000211
Figure PCTCN2022101219-appb-000211
步骤a)：2-(5-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step a): 2-(5-((4-((1-(2-fluoro-3-methyl-5-nitrophenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl) amino) -2-methoxypyridin-3-yl) -N, the preparation of N-dimethylacetamide
制备方法参考实施例101，得2-(5-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，收率85.8％；ESI-MS(m/z)：562.2[M+H] +。 The preparation method refers to Example 101 to obtain 2-(5-((4-((1-(2-fluoro-3-methyl-5-nitrophenyl)ethyl)amino)-2-methylquinazole Phenyl-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 85.8%; ESI-MS (m/z): 562.2 [M+H] + .
步骤b)：(R)-N 4-(1-(5-氨基-2-氟-3-甲基苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-N 6，2-二甲基喹唑啉-4，6-二胺的制备 Step b): (R)-N 4 -(1-(5-amino-2-fluoro-3-methylphenyl)ethyl)-N 6 -(5-(2-(dimethylamino)ethyl )-6-Methoxypyridin-3-yl)-N 6 , Preparation of 2-dimethylquinazoline-4,6-diamine
将2-(5-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺(123mg，0.219mmol)、四氢铝锂(42mg，1.115mmol)和THF(3mL)加入到反应瓶中，50℃搅拌反应1h。将反应液冷却至0℃，加入乙酸乙酯(20mL)，加入结晶硫酸钠固体(3g)淬灭反应，过滤，滤饼用乙酸乙酯(10mL)淋洗，合并滤液，减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-N 4-(1-(5-氨基-2-氟-3-甲基苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-N 6，2-二甲基喹唑啉-4，6-二胺。收率81.8％； 1H NMR(400MHz，DMSO-d 6)δ8.05(d，J＝7.2Hz，1H)，7.88(s，1H)，7.75(s，1H)，7.44(s，1H)，7.38(d，J＝9.2Hz，1H)，7.09(d，J＝9.2，1H)，6.46(d，J＝6.0，1H)，6.27(d，J＝6.4，1H)，5.74(t，J＝7.2Hz，1H)，5.1-4.52(s，2H)，3.88(s，3H)，3.38(s，3H)，2.70-2.63(m，2H)，2.49(s，3H)，2.33(s，3H)，2.21-2.15 (m，5H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：518.0[M+H] +。 2-(5-((4-((1-(2-fluoro-3-methyl-5-nitrophenyl) ethyl) amino)-2-methylquinazolin-6-yl)( Methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide (123 mg, 0.219 mmol), lithium aluminum hydride (42 mg, 1.115 mmol) and THF (3 mL) were added To the reaction flask, stirred at 50 ° C for 1h. Cool the reaction solution to 0°C, add ethyl acetate (20 mL), add crystalline sodium sulfate solid (3 g) to quench the reaction, filter, rinse the filter cake with ethyl acetate (10 mL), combine the filtrates, and concentrate under reduced pressure to obtain The crude product was purified by Prep-HPLC (Method 3) to give (R)-N 4 -(1-(5-amino-2-fluoro-3-methylphenyl)ethyl)-N 6 -(5-(2 -(dimethylamino)ethyl)-6-methoxypyridin-3-yl) -N6,2 -dimethylquinazoline-4,6-diamine. Yield 81.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.05(d, J=7.2Hz, 1H), 7.88(s, 1H), 7.75(s, 1H), 7.44(s, 1H) , 7.38(d, J=9.2Hz, 1H), 7.09(d, J=9.2, 1H), 6.46(d, J=6.0, 1H), 6.27(d, J=6.4, 1H), 5.74(t, J=7.2Hz, 1H), 5.1-4.52(s, 2H), 3.88(s, 3H), 3.38(s, 3H), 2.70-2.63(m, 2H), 2.49(s, 3H), 2.33(s , 3H), 2.21-2.15 (m, 5H), 2.11 (s, 3H), 1.53 (d, J=7.2Hz, 3H); ESI-MS (m/z): 518.0 [M+H] + .
实施例111Example 111
(R)-5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-(2-(二甲氨基)乙基)吡啶-2-醇的制备(R)-5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Preparation of base) amino)-3-(2-(dimethylamino) ethyl) pyridin-2-ol
Figure PCTCN2022101219-appb-000212
Figure PCTCN2022101219-appb-000212
将(R)-N 4-(1-(5-氨基-2-氟-3-甲基苯基)乙基)-N 6-(5-(2-(二甲氨基)乙基)-6-甲氧基吡啶-3-基)-N 6，2-二甲基喹唑啉-4，6-二胺(60mg，0.116mmol)和溴化氢醋酸溶液(33％，2mL)加入反应瓶中，升温至80℃反应20min。反应结束后，将反应液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-3-(2-(二甲氨基)乙基)吡啶-2-醇，收率9.9％； 1H NMR(400MHz，DMSO-d 6)δ11.50(s，1H)，8.00(d，J＝8.0Hz，1H)，7.58(s，1H)，7.37(d，J＝9.2Hz，1H)，7.24(s，1H)，7.18(s，1H)，7.05(d，J＝9.2Hz，1H)，6.45(d，J＝6.0Hz，1H)，6.27(d，J＝6.0Hz，1H)，5.80-5.68(m，1H)，4.76(s，2H)，3.27(s，3H)，2.46-2.38(m，4H)，2.32(s，3H)，2.14(s，6H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：504.0[M+H] +。 (R)-N 4 -(1-(5-amino-2-fluoro-3-methylphenyl)ethyl)-N 6 -(5-(2-(dimethylamino)ethyl)-6 -Methoxypyridin-3-yl)-N 6 , 2-dimethylquinazoline-4,6-diamine (60mg, 0.116mmol) and hydrobromic acetic acid solution (33%, 2mL) were added to the reaction flask , the temperature was raised to 80°C for 20 minutes. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to obtain (R)-5-((4-((1-(5-amino-2-fluoro-3-methyl phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-3-(2-(dimethylamino)ethyl)pyridin-2-ol, yield 9.9%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.50(s, 1H), 8.00(d, J=8.0Hz, 1H), 7.58(s, 1H), 7.37(d, J=9.2Hz , 1H), 7.24(s, 1H), 7.18(s, 1H), 7.05(d, J=9.2Hz, 1H), 6.45(d, J=6.0Hz, 1H), 6.27(d, J=6.0Hz , 1H), 5.80-5.68(m, 1H), 4.76(s, 2H), 3.27(s, 3H), 2.46-2.38(m, 4H), 2.32(s, 3H), 2.14(s, 6H), 2.11 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 504.0 [M+H] + .
实施例112Example 112
(R)-1-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-3-甲基咪唑啉-2-酮的制备(R)-1-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino) -2-methoxypyridinium) -3-yl) -3-methylimidazolin-2-one preparation
Figure PCTCN2022101219-appb-000213
Figure PCTCN2022101219-appb-000213
制备方法参考实施例101，经Prep-HPLC(方法3)纯化，得(R)-1-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶)-3-基)-3-甲基咪唑啉-2-酮，产率21.7％； 1H NMR(400MHz，DMSO-d 6)δ8.19(d，J＝7.2Hz，1H)，7.90(s，1H)，7.78(s，1H)，7.70(t，J＝7.2Hz，1H)，7.57(s，1H)，7.49(t，J＝7.2Hz，1H)，7.42(d，J＝9.2Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.22(d，J＝9.2，1H)，5.81(q，J＝7.2Hz，1H)，3.90(s，3H)，3.79-3.69(m，2H)，3.42-3.38(m，5H)，2.71(s，3H)，2.30(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：566.2[M+H] +。 The preparation method refers to Example 101 and is purified by Prep-HPLC (Method 3) to obtain (R)-1-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-3-methylimidazolin-2-one, Yield 21.7%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.19(d, J=7.2Hz, 1H), 7.90(s, 1H), 7.78(s, 1H), 7.70(t, J= 7.2Hz, 1H), 7.57(s, 1H), 7.49(t, J=7.2Hz, 1H), 7.42(d, J=9.2Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.24 (t, J=54.4Hz, 1H), 7.22(d, J=9.2, 1H), 5.81(q, J=7.2Hz, 1H), 3.90(s, 3H), 3.79-3.69(m, 2H), 3.42-3.38(m, 5H), 2.71(s, 3H), 2.30(s, 3H), 1.61(d, J=7.2Hz, 3H); ESI-MS(m/z): 566.2[M+H] + .
实施例113Example 113
(R)-5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-1-(2-(二甲氨基)乙基)吡啶-2(1H)-酮盐酸盐的制备(R)-5-((4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl Preparation of base) amino)-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one hydrochloride
Figure PCTCN2022101219-appb-000214
Figure PCTCN2022101219-appb-000214
制备方法参考实施例106，，经Prep-HPLC(方法1)纯化，得(R)-5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-1-(2-(二甲氨基)乙基)吡啶-2(1H)-酮盐酸盐，产率27.2％； 1H NMR(400 MHz，Methanol-d4)δ7.89(d，J＝9.2Hz，2H)，7.77(t，J＝6.4Hz，1H)，7.62-7.51(m，4H)，7.33(t，J＝7.6Hz，1H)，7.04(t，J＝54.4Hz，1H)，6.74(d，J＝9.6Hz，1H)，6.12-6.06(m，1H)，4.49-4.45(m，2H)，3.66(t，J＝5.6Hz，2H)，3.46(s，3H)，3.07(s，6H)，2.63(s，3H)，1.83(d，J＝7.2Hz，3H)；ESI-MS(m/z)：525.2[M+H]+。 Preparation method Reference Example 106, purified by Prep-HPLC (method 1) to obtain (R)-5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethane Base)amino)-2-methylquinazolin-6-yl)(methyl)amino)-1-(2-(dimethylamino)ethyl)pyridin-2(1H)-one hydrochloride, product Yield 27.2%; 1 H NMR (400 MHz, Methanol-d4) δ7.89 (d, J=9.2Hz, 2H), 7.77 (t, J=6.4Hz, 1H), 7.62-7.51 (m, 4H), 7.33(t, J=7.6Hz, 1H), 7.04(t, J=54.4Hz, 1H), 6.74(d, J=9.6Hz, 1H), 6.12-6.06(m, 1H), 4.49-4.45(m ,2H), 3.66(t, J=5.6Hz, 2H), 3.46(s, 3H), 3.07(s, 6H), 2.63(s, 3H), 1.83(d, J=7.2Hz, 3H); ESI - MS (m/z): 525.2 [M+H]+.
实施例114Example 114
(R)-1-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑啉-2-酮的制备(R)-1-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-3-methylimidazolin-2-one preparation
Figure PCTCN2022101219-appb-000215
Figure PCTCN2022101219-appb-000215
制备方法参考实施例111，经Prep-HPLC(方法3)纯化，得(R)-1-(5-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑啉-2-酮，收率48.6％； 1H NMR(400MHz，DMSO-d 6)δ11.83(s，1H)，8.13(d，J＝7.6Hz，1H)，7.69(t，J＝7.6Hz，1H)，7.56(s 1H)，7.51-7.46(m，2H)，7.40(d，J＝9.2Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.24(t，J＝54.4Hz，1H)，7.23(s，1H)，7.15(d，J＝9.2，1H)，5.82(p，J＝7.2Hz，1H)，3.94-3.83(m，2H)，3.36(t，J＝8.0Hz，2H)，3.29(s，3H)，2.69(s，3H)，2.29(s，3H)，1.61(d，J＝7.2Hz，3H)；ESI-MS(m/z)：552.2[M+H] +。 The preparation method refers to Example 111, and is purified by Prep-HPLC (method 3) to obtain (R)-1-(5-((4-((1-(3-(difluoromethyl)-2-fluorophenyl) ) ethyl) amino)-2-methylquinazolin-6-yl) (methyl) amino)-2-hydroxypyridin-3-yl)-3-methylimidazolin-2-one, yield 48.6 %; 1 H NMR (400MHz, DMSO-d 6 ) δ11.83(s, 1H), 8.13(d, J=7.6Hz, 1H), 7.69(t, J=7.6Hz, 1H), 7.56(s 1H ), 7.51-7.46(m, 2H), 7.40(d, J=9.2Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.24(t, J=54.4Hz, 1H), 7.23(s , 1H), 7.15(d, J=9.2, 1H), 5.82(p, J=7.2Hz, 1H), 3.94-3.83(m, 2H), 3.36(t, J=8.0Hz, 2H), 3.29( s, 3H), 2.69 (s, 3H), 2.29 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 552.2 [M+H] + .
实施例115Example 115
(R)-1-(5-((4-((1-(3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-二甲基咪唑啉-2-酮的制备(R)-1-(5-((4-((1-(3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl )amino)-2-methoxypyridin-3-yl)-3-dimethylimidazolin-2-one preparation
Figure PCTCN2022101219-appb-000216
Figure PCTCN2022101219-appb-000216
制备方法参考实施例101，经Pre-HPLC(方法3)纯化，得(R)-1-(5-((4-((1-(3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-二甲基咪唑啉-2-酮，产率64.5％； 1H NMR(400MHz，DMSO-d 6)δ8.17(d，J＝7.6Hz，1H)，7.89(s，1H)，7.74(s，1H)，7.67(s，1H)，7.64(d，J＝7.8Hz，1H)，7.56(s，1H)，7.48(t，J＝7.6Hz，1H)，7.43(s，1H)，7.41(s，1H)，7.21(d，J＝9.2，1H)，7.03(t，J＝56.0Hz，1H)，5.68(p，J＝7.2Hz，1H)，3.90(s，3H)，3.78-3.69(m，2H)，3.42-3.38(m，5H)，2.71(s，3H)，2.35(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：548.2[M+H] +。 The preparation method refers to Example 101 and is purified by Pre-HPLC (method 3) to obtain (R)-1-(5-((4-((1-(3-(difluoromethyl)phenyl)ethyl) Amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-3-dimethylimidazolin-2-one, yield 64.5% ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.17(d, J=7.6Hz, 1H), 7.89(s, 1H), 7.74(s, 1H), 7.67(s, 1H), 7.64(d , J=7.8Hz, 1H), 7.56(s, 1H), 7.48(t, J=7.6Hz, 1H), 7.43(s, 1H), 7.41(s, 1H), 7.21(d, J=9.2, 1H), 7.03(t, J=56.0Hz, 1H), 5.68(p, J=7.2Hz, 1H), 3.90(s, 3H), 3.78-3.69(m, 2H), 3.42-3.38(m, 5H ), 2.71 (s, 3H), 2.35 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 548.2 [M+H] + .
实施例116Example 116
(R)-1-(5-((4-((1-(3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑啉-2-酮的制备(R)-1-(5-((4-((1-(3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl )amino)-2-hydroxypyridin-3-yl)-3-methylimidazolin-2-one preparation
Figure PCTCN2022101219-appb-000217
Figure PCTCN2022101219-appb-000217
制备方法参考实施例111，，经Prep-HPLC(方法3)纯化，得(R)-1-(5-((4-((1-(3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑啉-2-酮，收率44.1％； 1H NMR(400MHz，DMSO-d 6)δ11.83(s，1H)，8.11(d，J＝8.0Hz，1H)，7.66(s，1H)，7.63(d，J＝7.6Hz，1H)，7.53(s，1H)，7.50-7.44(m，2H)，7.43-7.38(m，2H)，7.22(s，1H)，7.14(d，J＝9.2，1H)，7.02(t，J＝56.0Hz，1H)，5.67(p，J＝7.2Hz，1H)，3.93-3.83(m，2H)，3.35(t，J＝8.0Hz，2H)，3.27(s，3H)，2.68(s，3H)，2.33(s，3H)，1.62(d，J＝7.2Hz，3H)；ESI-MS(m/z)：534.2[M+H] +。 Preparation method referring to Example 111, purified by Prep-HPLC (method 3) to obtain (R)-1-(5-((4-((1-(3-(difluoromethyl)phenyl)ethyl )amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-3-methylimidazolin-2-one, yield 44.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.83(s, 1H), 8.11(d, J=8.0Hz, 1H), 7.66(s, 1H), 7.63(d, J=7.6Hz, 1H), 7.53(s, 1H), 7.50-7.44(m, 2H), 7.43-7.38(m, 2H), 7.22(s, 1H), 7.14(d, J=9.2, 1H), 7.02(t, J=56.0 Hz, 1H), 5.67(p, J=7.2Hz, 1H), 3.93-3.83(m, 2H), 3.35(t, J=8.0Hz, 2H), 3.27(s, 3H), 2.68(s, 3H ), 2.33 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 534.2 [M+H] + .
实施例117Example 117
(R)-2-(5-((4-((1-(3-氨基-5-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯 基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000218
Figure PCTCN2022101219-appb-000218
制备方法参考实施例109，，经Prep-HPLC制备纯化(方法3)，得2-(5-((4-(((1R)-1-(3-氨基-5-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率19.3％； 1H NMR(400MHz，DMSO-d 6)δ8.07(d，J＝8.0Hz，1H)，7.63(s，1H)，7.34(d，J＝9.2Hz，1H)，7.08-7.02(m，2H)，6.99(s，1H)，6.90(s，1H)，6.83(t，J＝56.4Hz，1H)，6.78(s，2H)，6.58(s，1H)，5.64-5.57(m，1H)，5.34(s，2H)，3.76(s，3H)，3.57(s，2H)，3.33(s，3H)，2.98(s，3H)，2.78(s，3H)，2.35(s，3H)，1.56(d，J＝6.8Hz，3H)；ESI-MS(m/z)：549.0[M+H] +。 The preparation method refers to Example 109, and is prepared and purified by Prep-HPLC (Method 3) to obtain 2-(5-((4-(((1R)-1-(3-amino-5-(difluoromethyl) Phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 19.3 %; 1 H NMR (400MHz, DMSO-d 6 ) δ8.07(d, J=8.0Hz, 1H), 7.63(s, 1H), 7.34(d, J=9.2Hz, 1H), 7.08-7.02( m, 2H), 6.99(s, 1H), 6.90(s, 1H), 6.83(t, J=56.4Hz, 1H), 6.78(s, 2H), 6.58(s, 1H), 5.64-5.57(m , 1H), 5.34(s, 2H), 3.76(s, 3H), 3.57(s, 2H), 3.33(s, 3H), 2.98(s, 3H), 2.78(s, 3H), 2.35(s, 3H), 1.56 (d, J = 6.8 Hz, 3H); ESI-MS (m/z): 549.0 [M+H] + .
实施例118Example 118
(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-(2-((甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(5-(2-((methylamino)methyl)phenyl)thiophene-2 -yl) ethyl) amino) quinazoline-6-yl) amino) pyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000219
Figure PCTCN2022101219-appb-000219
步骤a)：(R)-(2-(5-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-2-基)苄基)(甲基)氨基甲酸苄酯的制备Step a): (R)-(2-(5-(1-((6-((5-(2-(dimethylamino)-2-oxyethyl))-6-methoxypyridine-3- Preparation of base) (methyl) amino)-2-methylquinazolin-4-yl) amino) ethyl) thiophen-2-yl) benzyl) (methyl) benzyl carbamate
制备方法参考实施例101，经硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)，得(R)-(2-(5-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-2-基)苄基)(甲基)氨基甲酸苄酯，产率75.3％；ESI-MS(m/z)：744.3[M+H] +。 The preparation method refers to Example 101, and is purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-(2-(5-(1-((6-((5 -(2-(Dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)(methyl)amino)-2-methylquinazolin-4-yl)amino)ethyl yl)thiophen-2-yl)benzyl)benzyl (methyl)carbamate, yield 75.3%; ESI-MS (m/z): 744.3 [M+H] + .
步骤b)：(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-(2-((甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(5-(2-((methylamino)methyl)phenyl )thiophen-2-yl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-N, the preparation of N-dimethylacetamide
将(R)-(2-(5-(1-((6-((5-(2-(二甲氨基)-2-氧乙基)-6-甲氧基吡啶-3-基)(甲基)氨基)-2-甲基喹唑啉-4-基)氨基)乙基)噻吩-2-基)苄基)(甲基)氨基甲酸苄酯(140mg，0.181mmol)溶于甲醇(3mL)中，加入10％Pd/C(39mg)，氢气置换三次，室温搅拌过夜。过滤，滤液减压浓缩，残余物经Prep-HPLC(方法3)纯化，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-(2-((甲氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)吡啶-3-基)-N，N-二甲基乙酰胺的制备；收率55.4％； 1H NMR(400MHz，DMSO-d 6)δ8.30(d，J＝8.4Hz，1H)，7.93(s，1H)，7.63(s，1H)，7.49(d，J＝7.6Hz，1H)，7.41(d，J＝9.2Hz，1H)，7.35-7.24(m，4H)，7.15(s，1H)，7.12-7.07(m，2H)，5.99(p，J＝7.2Hz，1H)，3.84(s，3H)，3.66(s，2H)，3.58(s，2H)，3.33(s，3H)，3.00(s，3H)，2.79(s，3H)，2.44(s，3H)，2.25(s，3H)，1.73(d，J＝6.8Hz，3H)；ESI-MS(m/z)：610.3[M+H] +。 (R)-(2-(5-(1-((6-((5-(2-(dimethylamino)-2-oxoethyl)-6-methoxypyridin-3-yl)( Methyl)amino)-2-methylquinazolin-4-yl)amino)ethyl)thiophen-2-yl)benzyl)(methyl)benzyl carbamate (140mg, 0.181mmol) was dissolved in methanol ( 3 mL), 10% Pd/C (39 mg) was added, replaced by hydrogen three times, and stirred overnight at room temperature. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by Prep-HPLC (method 3) to obtain (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1- (5-(2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)amino)pyridin-3-yl)-N,N-di Preparation of methylacetamide; yield 55.4%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.30(d, J=8.4Hz, 1H), 7.93(s, 1H), 7.63(s, 1H) , 7.49(d, J=7.6Hz, 1H), 7.41(d, J=9.2Hz, 1H), 7.35-7.24(m, 4H), 7.15(s, 1H), 7.12-7.07(m, 2H), 5.99(p, J=7.2Hz, 1H), 3.84(s, 3H), 3.66(s, 2H), 3.58(s, 2H), 3.33(s, 3H), 3.00(s, 3H), 2.79(s , 3H), 2.44 (s, 3H), 2.25 (s, 3H), 1.73 (d, J=6.8Hz, 3H); ESI-MS (m/z): 610.3 [M+H] + .
实施例119Example 119
(R)-1-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-甲基咪唑啉-2-酮的制备(R)-1-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxypyridin-3-yl)-3-methylimidazolin-2-one preparation
Figure PCTCN2022101219-appb-000220
Figure PCTCN2022101219-appb-000220
制备方法参考实施例109，经Pre-HPLC(方法3)纯化，得(R)-1-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-3-甲基咪唑啉-2-酮；收率32.5％； 1H NMR(400MHz，DMSO-d 6)δ8.15(s，1H)，7.90(s，1H)，7.82(s，1H)，7.56(s，1H)，7.42(d，J＝9.2Hz，1H)，7.21(d，J＝9.2， 1H)，6.46-6.43(m，1H)，6.28-6.25(m，1H)，5.74(p，J＝7.2Hz，1H)，4.79(s，2H)，3.90(s，3H)，3.78-3.69(m，2H)，3.43-3.38(m，5H)，2.70(s，3H)，2.34(s，3H)，2.10(d，J＝2.0Hz，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：545.3[M+H] +。 Preparation method referring to Example 109, purified by Pre-HPLC (method 3) to obtain (R)-1-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-methoxypyridin-3-yl) -3-methylimidazolin-2-one; Yield 32.5%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.15(s, 1H), 7.90(s, 1H), 7.82(s, 1H), 7.56(s, 1H), 7.42(d, J =9.2Hz, 1H), 7.21(d, J=9.2, 1H), 6.46-6.43(m, 1H), 6.28-6.25(m, 1H), 5.74(p, J=7.2Hz, 1H), 4.79( s, 2H), 3.90(s, 3H), 3.78-3.69(m, 2H), 3.43-3.38(m, 5H), 2.70(s, 3H), 2.34(s, 3H), 2.10(d, J= 2.0 Hz, 3H), 1.52 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 545.3 [M+H] + .
实施例120Example 120
(R)-1-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑啉-2-酮的制备(R)-1-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxypyridin-3-yl)-3-methylimidazolin-2-one preparation
Figure PCTCN2022101219-appb-000221
Figure PCTCN2022101219-appb-000221
制备方法参考实施例111，经Prep-HPLC(方法3)纯化，得((R)-1-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-3-甲基咪唑啉-2-酮，收率38.8％； 1H NMR(400MHz，DMSO-d 6)δ11.85(s，1H)，8.00(d，J＝7.6Hz，1H)，7.60(s，1H)，7.47(s，1H)，7.39(d，J＝9.2Hz，1H)，7.22(d，J＝2.8Hz，1H)，7.13(d，J＝9.2，1H)，6.45-6.43(m，1H)，6.27-6.25(m，1H)，5.73(p，J＝7.2Hz，1H)，4.77(s，2H)，3.94-3.82(m，2H)，3.36(d，J＝8.0Hz，2H)，3.29(s，3H)，2.68(s，3H)，2.31(s，3H)，2.10(s，3H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：531.3[M+H] +。 Preparation method referring to Example 111, purified by Prep-HPLC (method 3) to obtain ((R)-1-(5-((4-((1-(5-amino-2-fluoro-3-methylbenzene Base) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -2-hydroxypyridin-3-yl) -3-methylimidazolin-2-one, yield 38.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.85(s, 1H), 8.00(d, J=7.6Hz, 1H), 7.60(s, 1H), 7.47(s, 1H), 7.39 (d, J=9.2Hz, 1H), 7.22(d, J=2.8Hz, 1H), 7.13(d, J=9.2, 1H), 6.45-6.43(m, 1H), 6.27-6.25(m, 1H ), 5.73(p, J=7.2Hz, 1H), 4.77(s, 2H), 3.94-3.82(m, 2H), 3.36(d, J=8.0Hz, 2H), 3.29(s, 3H), 2.68 (s, 3H), 2.31 (s, 3H), 2.10 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 531.3 [M+H] + .
实施例121Example 121
(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备(R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(5-(2-((methylamino)methyl)phenyl)thiophene- Preparation of 2-yl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000222
Figure PCTCN2022101219-appb-000222
制备方法参考实施例118，经Prep-HPLC(方法3)纯化，得(R)-2-(2-甲氧基-5-(甲基(2-甲基-4-((1-(5-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺；收率80.3％； 1H NMR(400MHz，DMSO-d 6)δ8.27(d，J＝8.4Hz，1H)，7.56(s，1H)，7.50(d，J＝7.2Hz，1H)，7.37(d，J＝9.2Hz，1H)，7.35-7.26(m，3H)，7.15(s，1H)，7.10-7.02(m，3H)，6.98(d，J＝8.8Hz，1H)，6.90(s，1H)，5.99(p，J＝7.2Hz，1H)，3.76(s，3H)，3.68(s，2H)，3.56(s，2H)，3.29(s，3H)，2.98(s，3H)，2.78(s，3H)，2.43(s，3H)，2.26(s，3H)，1.74(d，J＝6.8Hz，3H)；ESI-MS(m/z)：609.3[M+H] +。 The preparation method refers to Example 118, and is purified by Prep-HPLC (method 3) to obtain (R)-2-(2-methoxy-5-(methyl(2-methyl-4-((1-(5 -(2-((Methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide ; Yield 80.3%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.27(d, J=8.4Hz, 1H), 7.56(s, 1H), 7.50(d, J=7.2Hz, 1H), 7.37(d, J=9.2Hz, 1H), 7.35-7.26(m, 3H), 7.15(s, 1H), 7.10-7.02(m, 3H), 6.98(d, J=8.8Hz, 1H), 6.90 (s, 1H), 5.99(p, J=7.2Hz, 1H), 3.76(s, 3H), 3.68(s, 2H), 3.56(s, 2H), 3.29(s, 3H), 2.98(s, 3H), 2.78(s, 3H), 2.43(s, 3H), 2.26(s, 3H), 1.74(d, J=6.8Hz, 3H); ESI-MS (m/z): 609.3 [M+H ] + .
实施例122Example 122
(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000223
Figure PCTCN2022101219-appb-000223
制备方法参考实施例109，经Prep-HPLC(方法3)纯化，收率73.1％； 1H NMR(400MHz，DMSO-d 6)δ8.02(d，J＝6.4Hz，1H)，7.69(s，1H)，7.34(d，J＝9.2Hz，1H)，7.10-7.02(m，2H)，7.01-6.95(m，1H)，6.90(s，1H)，6.46(d，J＝6.0Hz，1H)，6.27(d，J＝6.0Hz，1H)，5.79-5.70(m，1H)，4.78(s，2H)，3.77(s，3H)，3.57(s，2H)，3.35(s，3H)，2.99(s，3H)，2.78(s，3H)，2.32(s，3H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H))；ESI-MS(m/z)：531.0[M+H] +。 The preparation method refers to Example 109, purified by Prep-HPLC (Method 3), the yield is 73.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.02 (d, J=6.4Hz, 1H), 7.69(s , 1H), 7.34(d, J=9.2Hz, 1H), 7.10-7.02(m, 2H), 7.01-6.95(m, 1H), 6.90(s, 1H), 6.46(d, J=6.0Hz, 1H), 6.27(d, J=6.0Hz, 1H), 5.79-5.70(m, 1H), 4.78(s, 2H), 3.77(s, 3H), 3.57(s, 2H), 3.35(s, 3H ), 2.99(s, 3H), 2.78(s, 3H), 2.32(s, 3H), 2.11(s, 3H), 1.53(d, J=7.2Hz, 3H)); ESI-MS (m/z ): 531.0[M+H] + .
实施例123Example 123
(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000224
Figure PCTCN2022101219-appb-000224
将(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(200mg，0.377mmol)和二氯甲烷(15mL)加入反应瓶中，0℃条件下加入三溴化硼(480mg，1.916mmol)，室温反应0.5h。加入饱和碳酸氢钠水溶液(30mL)淬灭反应，用乙酸乙酯(40mL)萃取，有机相用饱和食盐水洗涤(20mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺，收率50.1％； 1H NMR(400MHz，DMSO-d 6)δ9.54(s，1H)，7.99(d，J＝8.0Hz，1H)，7.61(s，1H)，7.31(d，J＝9.2Hz，1H)，7.01(d，J＝9.2Hz，1H)，6.93-6.90(m，1H)，6.88(s，1H)，6.83(d，J＝8.4Hz，1H)，6.46(d，J＝6.0Hz，1H)，6.27(d，J＝6.0Hz，1H)，5.77-5.72(m，1H)，4.78(s，2H)，3.56(s，2H)，3.32(s，3H)，3.01(s，3H)，2.80(s，3H)，2.31(s，3H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：517.0[M+H] +。 (R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazoline-6- Base) (methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide (200mg, 0.377mmol) and dichloromethane (15mL) were added to the reaction flask, and added at 0°C Boron tribromide (480mg, 1.916mmol) was reacted at room temperature for 0.5h. Add saturated aqueous sodium bicarbonate (30 mL) to quench the reaction, extract with ethyl acetate (40 mL), wash the organic phase with saturated brine (20 mL×2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product Purification by Prep-HPLC (Method 3) gave (R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)- 2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide, yield 50.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.54(s, 1H), 7.99(d, J=8.0Hz, 1H), 7.61(s, 1H), 7.31(d, J=9.2Hz, 1H), 7.01(d, J=9.2Hz , 1H), 6.93-6.90(m, 1H), 6.88(s, 1H), 6.83(d, J=8.4Hz, 1H), 6.46(d, J=6.0Hz, 1H), 6.27(d, J= 6.0Hz, 1H), 5.77-5.72(m, 1H), 4.78(s, 2H), 3.56(s, 2H), 3.32(s, 3H), 3.01(s, 3H), 2.80(s, 3H), 2.31 (s, 3H), 2.11 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 517.0 [M+H] + .
实施例124Example 124
(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(5-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺的制备(R)-2-(2-Hydroxy-5-(methyl(2-methyl-4-((1-(5-(2-((methylamino)methyl)phenyl)thiophene-2- Base) ethyl) amino) quinazoline-6-yl) amino) phenyl) -N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000225
Figure PCTCN2022101219-appb-000225
制备方法参考实施例111，经Prep-HPLC(方法3)纯化，得(R)-2-(2-羟基-5-(甲基(2-甲基-4-((1-(5-(2-((甲基氨基)甲基)苯基)噻吩-2-基)乙基)氨基)喹唑啉-6-基)氨基)苯基)-N，N-二甲基乙酰胺，收率38.8％； 1H NMR(400MHz，DMSO-d 6)δ9.55(s，1H)，8.24(d，J＝8.4Hz，1H)，7.51-7.46(m，2H)，7.38-7.19(m，5H)，7.15(s，1H)，7.09(s，1H)，7.01(d，J＝9.2，1H)，6.92-6.86(m，2H)，6.82(d，J＝8.4Hz，1H)，5.98(p，J＝7.2Hz，1H)，3.65(s，2H)，3.56(s，2H)，3.26(s，3H)，3.00(s，3H)，2.79(s，3H)，2.42(s，3H)，2.25(s，3H)，1.73(d，J＝7.2Hz，3H)；ESI-MS(m/z)：595.3[M+H] +。 The preparation method refers to Example 111, and is purified by Prep-HPLC (method 3) to obtain (R)-2-(2-hydroxyl-5-(methyl(2-methyl-4-((1-(5-( 2-((methylamino)methyl)phenyl)thiophen-2-yl)ethyl)amino)quinazolin-6-yl)amino)phenyl)-N,N-dimethylacetamide, yield Yield 38.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ9.55(s, 1H), 8.24(d, J=8.4Hz, 1H), 7.51-7.46(m, 2H), 7.38-7.19(m , 5H), 7.15(s, 1H), 7.09(s, 1H), 7.01(d, J=9.2, 1H), 6.92-6.86(m, 2H), 6.82(d, J=8.4Hz, 1H), 5.98(p, J=7.2Hz, 1H), 3.65(s, 2H), 3.56(s, 2H), 3.26(s, 3H), 3.00(s, 3H), 2.79(s, 3H), 2.42(s , 3H), 2.25 (s, 3H), 1.73 (d, J=7.2Hz, 3H); ESI-MS (m/z): 595.3 [M+H] + .
实施例125Example 125
2-(5-((4-((1-(2-氨基-3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备2-(5-((4-((1-(2-amino-3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl )amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000226
Figure PCTCN2022101219-appb-000226
步骤a)：2-(5-((4-((1-(3-(二氟甲基)-2-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step a): 2-(5-((4-((1-(3-(difluoromethyl)-2-nitrophenyl)ethyl)amino)-2-methylquinazoline-6- base) (methyl) amino) -2-methoxyphenyl) -N, the preparation of N-dimethylacetamide
制备方法参考实施例101，经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/19)，得(R)-2-(5-((4-((1-(2-氟-3-甲基-5-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，收率86.4％；ESI-MS(m/z)：578.2[M+H] +。 The preparation method refers to Example 101, and is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/19) to obtain (R)-2-(5-((4-((1-(2- Fluoro-3-methyl-5-nitrophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N, N-Dimethylacetamide, yield 86.4%; ESI-MS (m/z): 578.2[M+H] + .
步骤b)：2-(5-((4-((1-(2-氨基-3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备Step b): 2-(5-((4-((1-(2-amino-3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-methoxyphenyl)-N, the preparation of N-dimethylacetamide
将2-(5-((4-((1-(3-(二氟甲基)-2-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺(120mg，0.207mmol)溶于乙酸乙酯(2mL)中，加入10％Pd/C(120mg)，氢气置换三次，在氢气氛下室温反应2h。反应液过滤，乙酸乙酯(10mL)淋洗滤饼，合并滤液，减压浓缩，所得粗品经Prep-HPLC(方法3)纯化，得2-(5-((4-((1-(2-氨基-3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，收率26.0％； 1H NMR(400MHz，DMSO-d 6)δ8.04(d，J＝8.0Hz，1H)，7.55(s，1H)，7.49(d，J＝7.6Hz，1H)，7.35(d，J＝9.2Hz，1H)，7.24-7.18(m，1H)，7.12-6.90(m，4H)，6.88(s，1H)，6.70(t，J＝7.6Hz，1H)，5.82-5.73(m，1H)，5.67(s，2H)，3.76(s，3H)，3.56(s，2H)，3.29(s，3H)，2.97(s，3H)，2.77(s，3H)，2.42(s，3H)，1.62(d，J＝6.8Hz，3H)；ESI-MS(m/z)：549.0[M+H] +。 2-(5-((4-((1-(3-(difluoromethyl)-2-nitrophenyl) ethyl) amino)-2-methylquinazolin-6-yl)( Methyl)amino)-2-methoxyphenyl)-N,N-dimethylacetamide (120mg, 0.207mmol) was dissolved in ethyl acetate (2mL), 10%Pd/C (120mg) was added, The hydrogen was replaced three times, and the reaction was carried out at room temperature under a hydrogen atmosphere for 2 h. The reaction solution was filtered, ethyl acetate (10mL) rinsed the filter cake, the combined filtrates were concentrated under reduced pressure, and the resulting crude product was purified by Prep-HPLC (method 3) to obtain 2-(5-((4-((1-(2 -amino-3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxyphenyl)-N, N-Dimethylacetamide, yield 26.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.04(d, J=8.0Hz, 1H), 7.55(s, 1H), 7.49(d, J =7.6Hz, 1H), 7.35(d, J=9.2Hz, 1H), 7.24-7.18(m, 1H), 7.12-6.90(m, 4H), 6.88(s, 1H), 6.70(t, J= 7.6Hz, 1H), 5.82-5.73(m, 1H), 5.67(s, 2H), 3.76(s, 3H), 3.56(s, 2H), 3.29(s, 3H), 2.97(s, 3H), 2.77 (s, 3H), 2.42 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); ESI-MS (m/z): 549.0 [M+H] + .
实施例126Example 126
2-(5-((4-((1-(2-氨基-3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备2-(5-((4-((1-(2-amino-3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl )amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide formate
Figure PCTCN2022101219-appb-000227
Figure PCTCN2022101219-appb-000227
步骤a)：2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-((4-((1-(3-(二氟甲基)-2-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)苯基)-N，N-二甲基乙酰胺的制备Step a): 2-(2-((tert-butyldimethylsilyl)oxy)-5-((4-((1-(3-(difluoromethyl)-2-nitrobenzene Base) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, the preparation of N-dimethylacetamide
制备方法参考实施例101，所得粗品经硅胶柱层析纯化(洗脱剂：甲醇/二氯甲烷＝1/19)，得2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-((4-((1-(3-(二氟甲基)-2-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)苯基)-N，N-二甲基乙酰胺，收率87.5％；ESI-MS(m/z)：679.3[M+H] +。 The preparation method refers to Example 101, and the obtained crude product is purified by silica gel column chromatography (eluent: methanol/dichloromethane=1/19) to obtain 2-(2-((tert-butyldimethylsilyl)oxy Base)-5-((4-((1-(3-(difluoromethyl)-2-nitrophenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl (yl)amino)phenyl)-N,N-dimethylacetamide, yield 87.5%; ESI-MS (m/z): 679.3 [M+H] + .
步骤b)：2-(5-((4-((1-(3-(二氟甲基)-2-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺的制备Step b): 2-(5-((4-((1-(3-(difluoromethyl)-2-nitrophenyl)ethyl)amino)-2-methylquinazoline-6- base) (methyl) amino) -2-hydroxyphenyl) -N, the preparation of N-dimethylacetamide
将2-(2-((叔丁基二甲基甲硅烷基)氧基)-5-((4-((1-(3-(二氟甲基)-2-硝基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)苯基)-N，N-二甲基乙酰胺(190mg，0.280mmol)、四丁基氟化铵的THF溶液(310.0μL，0.310mmol，1M)和THF(3mL)加入反应瓶中，室温反应5min。向反应液中加入饱和食盐水(20mL)和氯化氢水溶液(10mL，1M)淬灭反应，用乙酸乙酯(30mL)萃取，有机相依次用饱和碳酸氢钠水溶液(20mL)、饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，所得粗品直接进行下一步反应，产率88.6％；ESI-MS m/z＝565.2[M+H] +。 2-(2-((tert-butyldimethylsilyl)oxy)-5-((4-((1-(3-(difluoromethyl)-2-nitrophenyl) Base) amino) -2-methylquinazolin-6-yl) (methyl) amino) phenyl) -N, N-dimethylacetamide (190mg, 0.280mmol), tetrabutylammonium fluoride THF solution (310.0 μL, 0.310 mmol, 1M) and THF (3 mL) were added into the reaction flask, and reacted at room temperature for 5 min. Saturated brine (20mL) and aqueous hydrogen chloride (10mL, 1M) were added to the reaction solution to quench the reaction, extracted with ethyl acetate (30mL), and the organic phase was sequentially washed with saturated aqueous sodium bicarbonate (20mL) and saturated brine (20mL ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was directly subjected to the next reaction with a yield of 88.6%; ESI-MS m/z=565.2[M+H] + .
步骤c)：2-(5-((4-((1-(2-氨基-3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐的制备Step c): 2-(5-((4-((1-(2-amino-3-(difluoromethyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-2-hydroxyl phenyl)-N, the preparation of N-dimethylacetamide formate
制备方法参考实施例125的步骤b，经Prep-HPLC(方法2)纯化，得2-(5-((4-((1-(2-氨基-3-(二氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基苯基)-N，N-二甲基乙酰胺甲酸盐，产率22.4％； 1H NMR(400MHz，DMSO-d 6)δ12.68(s，1H)，9.54(s，1H)，8.13(s，1H)，8.05(s，1H)，7.52-7.45(m，2H)，7.33(d，J＝9.2Hz，1H)，7.22(d，J＝7.6Hz，1H)，7.12-6.96(m，2H)，6.93-6.84(m，2H)，6.84-6.78(m，1H)，6.71(t，J＝7.6Hz，1H)，5.85-5.70(s，1H)，5.66(s，2H)，3.55(s，2H)，3.27(s，3H)，2.99(s，3H)，2.79(s，3H)，2.42(s，3H)，1.62(d，J＝6.8Hz，3H)；ESI-MS(m/z)：535.4[M+H] +。 The preparation method refers to step b of Example 125, and is purified by Prep-HPLC (method 2) to obtain 2-(5-((4-((1-(2-amino-3-(difluoromethyl)phenyl) Ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxyphenyl)-N,N-dimethylacetamide formate, yield 22.4%; 1 H NMR (400MHz, DMSO-d 6 ) δ12.68(s, 1H), 9.54(s, 1H), 8.13(s, 1H), 8.05(s, 1H), 7.52-7.45(m, 2H), 7.33(d, J=9.2Hz, 1H), 7.22(d, J=7.6Hz, 1H), 7.12-6.96(m, 2H), 6.93-6.84(m, 2H), 6.84-6.78(m, 1H) , 6.71(t, J=7.6Hz, 1H), 5.85-5.70(s, 1H), 5.66(s, 2H), 3.55(s, 2H), 3.27(s, 3H), 2.99(s, 3H), 2.79 (s, 3H), 2.42 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H); ESI-MS (m/z): 535.4 [M+H] + .
实施例127Example 127
(R)-6-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮的制备(R)-6-((4-((1-(3-(difluoromethyl)-2-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl)( Preparation of Methyl)amino)-2-(2-(Dimethylamino)ethyl)pyridazin-3(2H)-one
Figure PCTCN2022101219-appb-000228
Figure PCTCN2022101219-appb-000228
制备方法参考实施例101，经Prep-HPLC(方法3)纯化，得(R)-6-((4-((1-(3-(二氟甲基)-2-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-(2-(二甲氨基)乙基)哒嗪-3(2H)-酮，产率19.9％； 1H NMR(400MHz，DMSO-d 6)δ8.41(d，J＝7.2Hz，1H)，8.21(s，1H)，7.64(d，J＝7.6Hz，1H)，7.57(s，2H)，7.38(d，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.21(t，J＝54.8Hz，1H)，7.04(d，J＝10.0Hz，1H)，6.76(d，J＝10.0Hz，1H)，5.75(p，J＝7.2Hz，1H)，4.06(s，2H)，3.36(s，3H)，2.63(t，J＝6.8Hz，2H)，2.55(s，3H)，2.35(s，3H)，2.21(s，6H)，1.52(d，J＝7.2Hz，3H)；ESI-MS(m/z)：522.3[M+H] +。 The preparation method refers to Example 101, and is purified by Prep-HPLC (method 3) to obtain (R)-6-((4-((1-(3-(difluoromethyl)-2-methylphenyl)ethane Base)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-(2-(dimethylamino)ethyl)pyridazin-3(2H)-one, yield 19.9 %; 1 H NMR (400MHz, DMSO-d 6 ) δ8.41(d, J=7.2Hz, 1H), 8.21(s, 1H), 7.64(d, J=7.6Hz, 1H), 7.57(s, 2H), 7.38(d, J=7.6Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.21(t, J=54.8Hz, 1H), 7.04(d, J=10.0Hz, 1H) , 6.76(d, J=10.0Hz, 1H), 5.75(p, J=7.2Hz, 1H), 4.06(s, 2H), 3.36(s, 3H), 2.63(t, J=6.8Hz, 2H) , 2.55(s, 3H), 2.35(s, 3H), 2.21(s, 6H), 1.52(d, J=7.2Hz, 3H); ESI-MS(m/z): 522.3[M+H] + .
实施例128Example 128
(R)-2-(5-((4-((1-(3-氨基-5-(二氟甲氧基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(difluoromethoxy)phenyl)ethyl)amino)-2-methylquinazoline-6- base) (methyl) amino) -2-methoxyphenyl) -N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000229
Figure PCTCN2022101219-appb-000229
制备方法参考实施例109，经Prep-HPLC纯化(方法3)，得(R)-2-(5-((4-((1-(3-氨基-5-(二氟甲氧基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基苯基)-N，N-二甲基乙酰胺，产率36.8％； 1H NMR(400MHz，DMSO-d 6)δ8.03(d，J＝8.4Hz，1H)，7.63(s，1H)，7.36-7.25(m，2H)，7.08-7.02(m，2H)，6.98(d，J＝8.8Hz，1H)，6.90-6.88(m，1H)，6.50(s，1H)，6.39(s，1H)，6.19(s，1H)，5.59-5.52(m，1H)，5.36(s，2H)，3.76(s，3H)，3.57(s，2H)，3.32(s，3H)，2.98(s，3H)，2.78(s，3H)，2.36(s，3H)，1.54(d，J＝7.2Hz，3H)；ESI-MS(m/z)：565.3[M+H] +。 The preparation method refers to Example 109, which is purified by Prep-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(3-amino-5-(difluoromethoxy))benzene Base) ethyl) amino)-2-methylquinazolin-6-yl) (methyl) amino)-2-methoxyphenyl)-N,N-dimethylacetamide, yield 36.8% ; 1 H NMR (400MHz, DMSO-d 6 ) δ8.03(d, J=8.4Hz, 1H), 7.63(s, 1H), 7.36-7.25(m, 2H), 7.08-7.02(m, 2H) , 6.98(d, J=8.8Hz, 1H), 6.90-6.88(m, 1H), 6.50(s, 1H), 6.39(s, 1H), 6.19(s, 1H), 5.59-5.52(m, 1H ), 5.36(s, 2H), 3.76(s, 3H), 3.57(s, 2H), 3.32(s, 3H), 2.98(s, 3H), 2.78(s, 3H), 2.36(s, 3H) , 1.54 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 565.3 [M+H] + .
实施例129Example 129
(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-1-甲基-2-氧杂-1，2-二氢吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-1-methyl-2-oxa-1,2-dihydropyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000230
Figure PCTCN2022101219-appb-000230
制备方法参考实施例109，经Prep-HPLC纯化(方法3)，得(R)-2-(5-((4-((1-(5-氨基-2-氟-3-甲基苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-1-甲基-2-氧代-1，2-二氢吡啶-3-基)-N，N-二甲基乙酰胺，产率38.4％； 1H NMR(400MHz，DMSO-d 6)δ8.00(d，J＝8.0Hz，1H)，7.67(s，1H)，7.61(s，1H)，7.39(d，J＝9.2Hz，1H)，7.19(s，1H)，7.11-7.08(m，1H)，6.46-6.44(m，1H)，6.28-6.26(m，1H)，5.78-5.71(m，1H)，4.77(s，2H)，3.45(s，5H)，3.30(s，3H)，3.02(s，3H)，2.78(s，3H)，2.32(s，3H)，2.11(s，3H)，1.53(d，J＝7.2Hz，3H)；ESI-MS(m/z)：532.3[M+H] +。 The preparation method refers to Example 109, and is purified by Prep-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(5-amino-2-fluoro-3-methylphenyl ) ethyl) amino) -2-methylquinazolin-6-yl) (methyl) amino) -1-methyl-2-oxo-1,2-dihydropyridin-3-yl) -N , N-dimethylacetamide, yield 38.4%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.00 (d, J=8.0Hz, 1H), 7.67(s, 1H), 7.61(s, 1H), 7.39(d, J=9.2Hz, 1H), 7.19(s, 1H), 7.11-7.08(m, 1H), 6.46-6.44(m, 1H), 6.28-6.26(m, 1H), 5.78 -5.71(m, 1H), 4.77(s, 2H), 3.45(s, 5H), 3.30(s, 3H), 3.02(s, 3H), 2.78(s, 3H), 2.32(s, 3H), 2.11 (s, 3H), 1.53 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 532.3 [M+H] + .
实施例130Example 130
(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-4-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-yl ) (methyl) amino)-4-methoxypyridin-3-yl)-N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000231
Figure PCTCN2022101219-appb-000231
制备方法参考实施例101，经Prep-HPLC(方法3)纯化，得(R)-2-(6-((4-((1-(3-(二氟甲基)-2-氟苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-4-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率18.1％； 1H NMR(400MHz，DMSO-d 6)δ8.42(d，J＝7.2Hz，1H)，8.35(s，1H)，7.76(s，1H)，7.69-7.64(m，2H)，7.60(d，J＝8.8Hz，1H)，7.49(t，J＝6.8Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.23(t，J＝54.4Hz，1H)，6.20(s，1H)，5.81(p，J＝7.2Hz，1H)，3.59(s，3H)，3.51(s，3H)，3.45(s，2H)，3.04(s，3H)，2.82(s，3H)，2.35(s，3H)，1.58(d，J＝7.2Hz，3H)；ESI-MS(m/z)：553.0[M+H] +。 The preparation method refers to Example 101 and is purified by Prep-HPLC (Method 3) to obtain (R)-2-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl )ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-4-methoxypyridin-3-yl)-N,N-dimethylacetamide, yield 18.1%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.42(d, J=7.2Hz, 1H), 8.35(s, 1H), 7.76(s, 1H), 7.69-7.64(m, 2H) , 7.60(d, J=8.8Hz, 1H), 7.49(t, J=6.8Hz, 1H), 7.28(t, J=7.6Hz, 1H), 7.23(t, J=54.4Hz, 1H), 6.20 (s, 1H), 5.81(p, J=7.2Hz, 1H), 3.59(s, 3H), 3.51(s, 3H), 3.45(s, 2H), 3.04(s, 3H), 2.82(s, 3H), 2.35 (s, 3H), 1.58 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 553.0 [M+H] + .
实施例131Example 131
(R)-2-(5-((4-((1-(3-(二氟甲基)-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazole Preparation of phen-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000232
Figure PCTCN2022101219-appb-000232
制备方法参考实施例102，经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率87.8％； 1H NMR(400MHz，DMSO-d 6)δ8.24(d，J＝7.6Hz，1H)，8.02(d，J＝12.4Hz，2H)，7.94(s，1H)，7.79(s，1H)，7.65(s，1H)，7.40(d，J＝9.2Hz，1H)，7.35(s，1H)，7.15(t，J＝55.6Hz，1H)，7.11(d，J＝9.2，1H)，5.68(p，J＝7.2Hz，1H)，3.84(s，3H)，3.59(s，2H)，3.37(s，3H)，3.02(s，3H)，2.80(s，3H)，2.33(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：603.2[M+H] +。 The preparation method refers to Example 102 and is purified by Prep-HPLC (Method 3) to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-5-(trifluoromethyl) Methyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethyl Acetamide, yield 87.8%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.24(d, J=7.6Hz, 1H), 8.02(d, J=12.4Hz, 2H), 7.94(s, 1H ), 7.79(s, 1H), 7.65(s, 1H), 7.40(d, J=9.2Hz, 1H), 7.35(s, 1H), 7.15(t, J=55.6Hz, 1H), 7.11(d , J=9.2, 1H), 5.68(p, J=7.2Hz, 1H), 3.84(s, 3H), 3.59(s, 2H), 3.37(s, 3H), 3.02(s, 3H), 2.80( s, 3H), 2.33 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 603.2 [M+H] + .
实施例132Example 132
(R)-2-(5-((4-((1-(3-(二氟甲基)-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-(difluoromethyl)-5-(trifluoromethyl)phenyl)ethyl)amino)-2-methylquinazole Preparation of olin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide
Figure PCTCN2022101219-appb-000233
Figure PCTCN2022101219-appb-000233
制备方法参考实施例111，经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-(二氟甲基)-5-(三氟甲基)苯基)乙基)氨基)-2-甲基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，收率26.2％； 1H NMR(400MHz，DMSO-d 6)δ11.61(s，1H)，8.19(d，J＝7.6Hz，1H)，8.02(s，1H)，7.99(s，1H)，7.79(s，1H)，7.48(s，1H)，7.40(d，J＝9.2Hz，1H)，7.27(s，1H)，7.18(s，1H)，7.15(t，J＝55.2Hz，1H)，7.08(d，J＝9.2，1H)，5.68(p，J＝7.2Hz，1H)，3.41(s，2H)，3.27(s，3H)，3.01(s，3H)，2.78(s，3H)，2.32(s，3H)，1.66(d，J＝7.2Hz，3H)；ESI-MS(m/z)：589.2[M+H] +。 The preparation method refers to Example 111 and is purified by Prep-HPLC (Method 3) to obtain (R)-2-(5-((4-((1-(3-(difluoromethyl)-5-(trifluoromethyl) Methyl)phenyl)ethyl)amino)-2-methylquinazolin-6-yl)(methyl)amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide , yield 26.2%; 1 H NMR (400MHz, DMSO-d 6 ) δ11.61(s, 1H), 8.19(d, J=7.6Hz, 1H), 8.02(s, 1H), 7.99(s, 1H ), 7.79(s, 1H), 7.48(s, 1H), 7.40(d, J=9.2Hz, 1H), 7.27(s, 1H), 7.18(s, 1H), 7.15(t, J=55.2Hz , 1H), 7.08(d, J=9.2, 1H), 5.68(p, J=7.2Hz, 1H), 3.41(s, 2H), 3.27(s, 3H), 3.01(s, 3H), 2.78( s, 3H), 2.32 (s, 3H), 1.66 (d, J = 7.2 Hz, 3H); ESI-MS (m/z): 589.2 [M+H] + .
实施例133Example 133
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-环丙基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-cyclopropylquinazoline-6- Base) (methyl) amino) -2-methoxypyridin-3-yl) -N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000234
Figure PCTCN2022101219-appb-000234
步骤a)：(R)-6-溴-2-环丙基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺的制备Step a): (R)-6-Bromo-2-cyclopropyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine preparation of
将6-溴-4-氯-2-环丙基喹唑啉(200mg，0.709mmol)、(R)-1-(3-硝基-5-(三氟甲基)苯基)乙-1-胺盐酸盐(191mg，0.709mmol)、DIPEA(274mg，2.127mmol)和DMF(10mL)依次加入反应瓶中，氮气保护下升温至80℃搅拌反应3h。将反应液冷却至室温，加饱和氯化铵水溶液(30mL)淬灭反应，以乙酸乙酯萃取(50mL×3)，合并有机相，用饱和食盐水洗涤(50mL)，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＝1/1)，得(R)-6-溴-2-环丙基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺，产率81.3％；ESI-MS(m/z)：481.0[M+H] +。 6-Bromo-4-chloro-2-cyclopropylquinazoline (200mg, 0.709mmol), (R)-1-(3-nitro-5-(trifluoromethyl)phenyl) B-1 - Amine hydrochloride (191mg, 0.709mmol), DIPEA (274mg, 2.127mmol) and DMF (10mL) were sequentially added to the reaction flask, heated to 80°C under nitrogen protection and stirred for 3h. The reaction solution was cooled to room temperature, quenched by adding saturated aqueous ammonium chloride (30 mL), extracted with ethyl acetate (50 mL×3), combined the organic phases, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate=1/1) to obtain (R)-6-bromo-2-cyclopropyl-N-( 1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine, yield 81.3%; ESI-MS(m/z): 481.0[M+H] + .
步骤b)：(R)-2-(5-((2-环丙基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step b): (R)-2-(5-((2-cyclopropyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinone Preparation of oxazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
将(R)-6-溴-2-环丙基-N-(1-(3-硝基-5-(三氟甲基)苯基)乙基)喹唑啉-4-胺(200mg，0.417mmol)、2-(2-甲氧基-5-(甲氨基)吡啶-3-基)-N，N-二甲基乙酰胺(93mg，0.417mmol)、Cs 2CO 3(407mg，1.251mmol)、Pd(dba) 2(48mg，0.083mmol)、X-phos(79mg，0.166mmol)和甲苯(6mL)依次加入反应瓶中，氮气置换三次，升温至105℃搅拌反应2h。将反应液冷却至室温，加水(20mL)淬灭反应，用乙酸乙酯萃取(20mL×3)，合并有机相，用饱和食盐水洗涤(20mL)，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＝20/1)，得(R)-2-(5-((2-环丙基-4-((1-(3-硝基-5-(三氟甲基)苯基)乙基)氨基)喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率80.1％；ESI-MS(m/z)：624.2[M+H] +。 (R)-6-Bromo-2-cyclopropyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)quinazolin-4-amine (200mg, 0.417mmol), 2-(2-methoxy-5-(methylamino)pyridin-3-yl)-N,N-dimethylacetamide (93mg, 0.417mmol), Cs 2 CO 3 (407mg, 1.251 mmol), Pd(dba) 2 (48mg, 0.083mmol), X-phos (79mg, 0.166mmol) and toluene (6mL) were sequentially added into the reaction flask, replaced with nitrogen three times, heated to 105°C and stirred for 2h. Cool the reaction solution to room temperature, add water (20 mL) to quench the reaction, extract with ethyl acetate (20 mL×3), combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate, and the residue is purified by silica gel column chromatography (eluent: dichloromethane/methanol=20/1) to obtain (R)-2-(5-((2-cyclopropyl-4-((1- (3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)quinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N , N-dimethylacetamide, yield 80.1%; ESI-MS (m/z): 624.2[M+H] + .
步骤c)：(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-环丙基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺的制备Step c): (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-cyclopropylquinazole Preparation of phen-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylacetamide
制备方法参考实施例109的步骤b，经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-环丙基喹唑啉-6-基)(甲基)氨基)-2-甲氧基吡啶-3-基)-N，N-二甲基乙酰胺，产率73.0％； 1H NMR(400MHz，DMSO-d 6)δ8.12(d，J＝7.2Hz，1H)，7.92(s，1H)，7.70(s，1H)，7.37(d，J＝9.2Hz，1H)，7.32(s，1H)，7.09(d，J＝9.2Hz，1H)，6.84(s，1H)，6.81(s，1H)，6.68(s，1H)，5.50(s，2H)，5.35-5.30(m，1H)，3.84(s，3H)，3.58(s，2H)，3.36(s，3H)，3.01(s，3H)，2.80(s，3H)，1.89-1.84(m，1H)，1.55(d，J＝7.2Hz，3H)，1.02-0.96(m，1H)，0.83-0.77(m，1H)，0.73-0.63(m，2H)；ESI-MS(m/z)：594.0[M+H] +。 The preparation method refers to step b of Example 109, and is purified by Prep-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl )phenyl)ethyl)amino)-2-cyclopropylquinazolin-6-yl)(methyl)amino)-2-methoxypyridin-3-yl)-N,N-dimethylethyl Amide, yield 73.0%; 1 H NMR (400MHz, DMSO-d 6 ) δ8.12(d, J=7.2Hz, 1H), 7.92(s, 1H), 7.70(s, 1H), 7.37(d, J=9.2Hz, 1H), 7.32(s, 1H), 7.09(d, J=9.2Hz, 1H), 6.84(s, 1H), 6.81(s, 1H), 6.68(s, 1H), 5.50( s, 2H), 5.35-5.30(m, 1H), 3.84(s, 3H), 3.58(s, 2H), 3.36(s, 3H), 3.01(s, 3H), 2.80(s, 3H), 1.89 -1.84(m, 1H), 1.55(d, J=7.2Hz, 3H), 1.02-0.96(m, 1H), 0.83-0.77(m, 1H), 0.73-0.63(m, 2H); ESI-MS (m/z): 594.0 [M+H] + .
实施例134Example 134
(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-环丙基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺的制备(R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)amino)-2-cyclopropylquinazoline-6- Base) (methyl) amino) -2-hydroxypyridin-3-yl) -N, the preparation of N-dimethylacetamide
Figure PCTCN2022101219-appb-000235
Figure PCTCN2022101219-appb-000235
制备方法参考实施例111，经Prep-HPLC(方法3)纯化，得(R)-2-(5-((4-((1-(3-氨基-5-(三氟甲基)苯基)乙基)氨基)-2-环丙基喹唑啉-6-基)(甲基)氨基)-2-羟基吡啶-3-基)-N，N-二甲基乙酰胺，产率54.0％； 1H NMR(400MHz，DMSO-d 6)δ11.55(s，1H)，8.07(d，J＝7.2Hz，1H)，7.51(s，1H)，7.36(d，J＝9.2Hz，1H)，7.24(s，1H)，7.17(s，1H)，7.05(d，J＝9.2Hz，1H)，6.84(s，1H)，6.80(s，1H)，6.68(s，1H)，5.50(s，2H)，5.35-5.28(m，1H)，3.41(s，2H)，3.26(s，3H)，3.01(s，3H)，2.78(s，3H)，1.89-1.82(m，1H)，1.55(d，J＝7.2Hz，3H)，1.00-0.94(m， 1H)，0.83-0.76(m，1H)，0.74-0.61(m，2H)；ESI-MS(m/z)：580.0[M+H] +。 Preparation method referring to Example 111, purified by Prep-HPLC (method 3) to obtain (R)-2-(5-((4-((1-(3-amino-5-(trifluoromethyl)phenyl) ) ethyl) amino)-2-cyclopropylquinazolin-6-yl) (methyl) amino)-2-hydroxypyridin-3-yl)-N,N-dimethylacetamide, productive rate 54.0 %; 1 H NMR (400MHz, DMSO-d 6 ) δ11.55(s, 1H), 8.07(d, J=7.2Hz, 1H), 7.51(s, 1H), 7.36(d, J=9.2Hz, 1H), 7.24(s, 1H), 7.17(s, 1H), 7.05(d, J=9.2Hz, 1H), 6.84(s, 1H), 6.80(s, 1H), 6.68(s, 1H), 5.50(s, 2H), 5.35-5.28(m, 1H), 3.41(s, 2H), 3.26(s, 3H), 3.01(s, 3H), 2.78(s, 3H), 1.89-1.82(m, 1H), 1.55(d, J=7.2Hz, 3H), 1.00-0.94(m, 1H), 0.83-0.76(m, 1H), 0.74-0.61(m, 2H); ESI-MS(m/z) : 580.0[M+H] + .
生物活性测试Biological activity test
试验例1：SOS1抑制活性测定Test Example 1: Determination of SOS1 inhibitory activity
通过均相时间分辨荧光技术(HTRF)检测SOS1抑制剂对SOS1与KRAS蛋白之间相互作用的影响，从而评估其对SOS1蛋白的抑制水平。所用蛋白和检测试剂采用KRAS-G12D/SOS1 BINDING ASSAY KITS(Cisbio)，首先将2mM受试化合物母液用Diluent试剂(5％DMSO)稀释20倍(100μM)，再用Diluent试剂逐次进行5倍浓度梯度稀释，得到受试化合物工作液共8个浓度。在384孔板中，每孔依次加入4μL tag2-KRAS G12D蛋白(含50μM GTP)、2μL受试化合物(10×)、4μL tag1-SOS1蛋白，双复孔，室温孵育15min。每孔依次加入Anti-tag1-Tb 3+工作液和Anti-tag2-XL665工作液各5μL，在4℃孵育3h。将384孔板置于多功能酶标仪上读值，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 SOS1 inhibitor on the interaction between SOS1 and KRAS protein was detected by homogeneous time-resolved fluorescence technique (HTRF), so as to evaluate the inhibition level of SOS1 protein. The protein and detection reagent used were KRAS-G12D/SOS1 BINDING ASSAY KITS (Cisbio). First, the 2mM mother solution of the test compound was diluted 20 times (100 μM) with Diluent reagent (5% DMSO), and then the Diluent reagent was used to carry out a 5-fold concentration gradient successively. Diluted to obtain a total of 8 concentrations of the working solution of the test compound. In a 384-well plate, 4 μL tag2-KRAS G12D protein (containing 50 μM GTP), 2 μL test compound (10×), 4 μL tag1-SOS1 protein were sequentially added to each well, and incubated for 15 minutes at room temperature. Add 5 μL each of Anti-tag1-Tb 3+ working solution and Anti-tag2-XL665 working solution to each well in turn, and incubate at 4°C for 3 hours. Place the 384-well plate on a multi-functional microplate reader to read the value, 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=104×665nm signal value/620nm signal value. The inhibition rate was calculated by the following formula:
Figure PCTCN2022101219-appb-000236
Figure PCTCN2022101219-appb-000236
IC 50通过抑制率由GraphPad Prism软件进行计算。每个化合物每次测定2个复孔，每组实验独立重复三次。 IC50 was calculated by GraphPad Prism software by inhibition rate. Each compound was measured in 2 replicate wells, and each group of experiments was repeated three times independently.
第一批次测定实施例1～30的化合物，测试数据如表1所示；第二批次测定实施例31～100的化合物，测试数据如表2所示；第三批次测定实施例101～134的化合物，测试数据如表3所示。The first batch assays the compounds of Examples 1-30, and the test data are shown in Table 1; the second batch assays the compounds of Examples 31-100, and the test data are shown in Table 2; the third batch assays Example 101 ~134 compounds, the test data are shown in Table 3.
表1实施例1～30化合物SOS1抑制活性Table 1 Example 1～30 compound SOS1 inhibitory activity
Figure PCTCN2022101219-appb-000237
Figure PCTCN2022101219-appb-000237
表2实施例31～100化合物SOS1抑制活性Table 2 Example 31～100 compounds SOS1 inhibitory activity
Figure PCTCN2022101219-appb-000238
Figure PCTCN2022101219-appb-000238
Figure PCTCN2022101219-appb-000239
Figure PCTCN2022101219-appb-000239
表3实施例101～134化合物SOS1抑制活性Table 3 Example 101～134 compound SOS1 inhibitory activity
Figure PCTCN2022101219-appb-000240
Figure PCTCN2022101219-appb-000240
阳性对照采用的是如下结构化合物(BI-3406)：The positive control uses the following structural compound (BI-3406):
Figure PCTCN2022101219-appb-000241
Figure PCTCN2022101219-appb-000241
试验例2：CYP3A4抑制活性测定Test Example 2: Determination of CYP3A4 Inhibitory Activity
药物代谢的主要场所是肝脏，而肝脏中存在的混合功能氧化酶系的主要成分是CYP450酶，该酶系引起了临床上大多数药物的相互作用，进而导致药物不良反应发生率提高。CYP450是一组由许多同工酶组成的超基因大家族，其中CYP3A4作为主要代谢酶，参与了临床上将近一半药物的代谢。因此，早期通过测试化合物对CYP3A4的抑制活性，可评判发生药物-药物相互作用的风险，提高用药安全性。The main site of drug metabolism is the liver, and the main component of the mixed-function oxidase system in the liver is CYP450 enzyme, which causes most drug interactions in clinical practice, which in turn leads to an increase in the incidence of adverse drug reactions. CYP450 is a large supergene family composed of many isoenzymes, among which CYP3A4, as the main metabolic enzyme, participates in the metabolism of nearly half of drugs in clinical practice. Therefore, by testing the inhibitory activity of compounds on CYP3A4 in the early stage, the risk of drug-drug interaction can be evaluated and the safety of medication can be improved.
在本发明中，采用人肝微粒体作为CYP3A4酶源，以睾酮为CYP3A4的特异性探针底物(CYP 3A4-T表示)，分别与一系列浓度的受试化合物在辅因子NADPH存在的条件下孵育。使用LC-MS/MS测定孵育体系中探针底物的代谢产物的生成量，计算受试化合物对CYP3A4的IC 50值，评价其对CYP3A4的抑制作用。实验时，在孵育体系中依次加入49μL PBS，50μL探针底物，50μL人肝微粒体工作液，然后加入1μL各个浓度的受试化合物工作液，混合均匀；在37℃预孵5min后，加入50μL NADPH启动反应。孵育相应时间后，加入适量含内标的冰乙腈终止反应，涡旋混匀，离心取上清，进样LC-MS/MS检测探针底物的代谢产物的生成量。以0浓度点酶活性(以代谢产物生成量表征)为100％，计算不同受试化合物浓度下代谢产物的剩余酶活百分比。IC 50通过剩余酶活由Graphpad Prism软件进行计算。实施例中化合物测试数据如表4所示： In the present invention, human liver microsomes are used as the source of CYP3A4 enzyme, and testosterone is used as the specific probe substrate of CYP3A4 (represented by CYP 3A4-T). incubate. Use LC-MS/MS to measure the amount of metabolites of the probe substrate in the incubation system, calculate the IC 50 value of the test compound against CYP3A4, and evaluate its inhibitory effect on CYP3A4. During the experiment, add 49 μL of PBS, 50 μL of probe substrate, 50 μL of human liver microsome working solution to the incubation system in sequence, and then add 1 μL of the test compound working solution of various concentrations and mix well; after pre-incubating at 37°C for 5 minutes, add Reactions were initiated with 50 μL NADPH. After incubating for the corresponding time, add an appropriate amount of glacial acetonitrile containing an internal standard to terminate the reaction, vortex to mix, centrifuge to get the supernatant, and inject LC-MS/MS to detect the amount of metabolites of the probe substrate. Taking the enzyme activity at 0 concentration point (characterized by the amount of metabolite production) as 100%, the percentage of remaining enzyme activity of metabolites under different test compound concentrations was calculated. IC50 was calculated by Graphpad Prism software from remaining enzyme activity. Compound test data are shown in table 4 in the embodiment:
表4Table 4
实施例编号Example number CYP 3A4-T抑制活性(IC 50，μM) CYP 3A4-T inhibitory activity (IC 50 , μM)
实施例37Example 37 ＞10>10
实施例38Example 38 ＞10>10
实施例59Example 59 ＞10>10
实施例60Example 60 ＞10>10
实施例62Example 62 ＞10>10
实施例91Example 91 ＞10>10
实施例104Example 104 ＞10>10
实施例106Example 106 ＞10>10
实施例108Example 108 7.67.6
实施例109Example 109 ＞10>10
实施例111Example 111 ＞10>10
实施例118Example 118 ＞10>10
实施例120Example 120 8.08.0
BI-3406BI-3406 4.14.1
BI-3406已被报道具有SOS1抑制活性，与曲美替尼(MEKi)联用可抑制不同亚型KRAS突变的结直肠癌、胰腺癌的生长，且疗效优于SOSi或MEKi单用(2020年AACR大会：DOI：10.1158/1538-7445.AM2020-1091 Published August 2020；DOI：10.1158/2159-8290.CD-20-0142)。BI-3406 has been reported to have SOS1 inhibitory activity, combined with trametinib (MEKi) can inhibit the growth of colorectal cancer and pancreatic cancer with different subtypes of KRAS mutations, and the efficacy is better than SOSi or MEKi alone (2020 AACR Conference: DOI: 10.1158/1538-7445.AM2020-1091 Published August 2020; DOI: 10.1158/2159-8290.CD-20-0142).
从以上数据可以看出，本发明化合物对SOS1具有明显的抑制作用，部分化合物的活性与阳性化合物相当或更具优势，可用作SOS1抑制剂，在由SOS1蛋白介导的癌症、病原性皮疹病等疾病等领域具有广阔的应用前景。此外，本发明代表性化合物对CYP3A4-T无明显抑制活性，显著优于参照化合物BI-3406，有利于降低药物-药物相互作用的风险。As can be seen from the above data, the compound of the present invention has obvious inhibitory effect on SOS1, and the activity of some compounds is equivalent to or more advantageous than that of the positive compound. Diseases and other diseases have broad application prospects. In addition, the representative compound of the present invention has no obvious inhibitory activity on CYP3A4-T, which is significantly better than the reference compound BI-3406, which is beneficial to reduce the risk of drug-drug interaction.
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 (36)

  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、同位素标记物、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, isotope labels, pharmaceutically acceptable salts, co-crystals:
    Figure PCTCN2022101219-appb-100001
    Figure PCTCN2022101219-appb-100001
    其中：in:
    A 1选自CH、CH 2或N、NR 28、O、S，A 2选自C或N，A 3选自CH、CH 2、N、NR 28、O、S，A 4选自CH、CH 2或键，优选地，A 4选自CH、CH 2或单键； A 1 is selected from CH, CH 2 or N, NR 28 , O, S, A 2 is selected from C or N, A 3 is selected from CH, CH 2 , N, NR 28 , O, S, A 4 is selected from CH, CH 2 or a bond, preferably, A 4 is selected from CH, CH 2 or a single bond;
    Y选自键、CR 6R 7、O、NR 5、S、S(O)；当A 1、A 3、A 4为CH且A 2为C时，Y不为键； Y is selected from bond, CR 6 R 7 , O, NR 5 , S, S(O); when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond;
    R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、烷基；优选地，R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、C1～C6烷基，进一步优选H、C1～C3烷基，更优选H、甲基； R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are independently selected from H and alkyl; preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 28 are independently selected from H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl;
    Ar选自芳基、杂芳基、脂杂环基，且当环A不具备芳香性时，所述杂芳基不为吡啶基，其中，所述芳基、杂芳基、脂杂环基任选地被一个或多个R 8取代； Ar is selected from aryl, heteroaryl, and heterocyclic aliphatic, and when ring A does not have aromaticity, the heteroaryl is not pyridyl, wherein the aryl, heteroaryl, heterocyclic aliphatic optionally substituted by one or more R 8 ;
    R 8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、-OR a、-NR bR c、-SR d、-C(O)R 10、-C(O)NR bR c、-C(O)OR a，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R 11取代； Each occurrence of R is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 10 , -C(O)NR b R c , -C(O)OR a , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more R 11 are substituted;
    R 11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、-OR a、-NR bR c、-SR d、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，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R 13取代； Each occurrence of R 11 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by one or multiple R 13 substitutions;
    R 13每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR a、-NR bR c、-SR d、-C(O)R 14、-C(O)NR bR c、-C(O)OR a； Each occurrence of R 13 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR a , -NR b R c , -SR d , -C(O)R 14 , -C (O)NR b R c , -C(O)OR a ;
    R 1选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、-OR e、-NR fR g、-SR h、-C(O)R 15、-C(O)NR fR g、-C(O)OR e，其中，烷基、环烷基、脂杂环基任选地被一个或多个R 16取代； R 1 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, -OR e , -NR f R g , -SR h , -C(O)R 15 , -C (O)NR f R g , -C(O)OR e , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 16 ;
    R 16每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR e、-NR fR g、-SR h、-C(O)R 17、-C(O)NR fR g、-C(O)OR e； Each occurrence of R 16 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR e , -NR f R g , -SR h , -C(O)R 17 , -C (O)NR f R g , -C(O)OR e ;
    环E选自环烷基、脂杂环基、芳基、杂芳基，其中，环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R 18取代； Ring E is selected from cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, wherein cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl is optionally substituted by one or more R 18 ;
    R 18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、-OR i、-NR jR k、-SR m、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的环E上的环原子共同组成环烷基、脂杂环基、芳基、杂芳基，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R 25取代； Each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR i , -NR j R k , -SR m , -C( O)R 19 , -C(O)NR j R k , -C(O)OR i , or two adjacent R 18 and the ring atoms on the ring E to which they are connected together form a cycloalkyl group or an aliphatic heterocyclic group , aryl, heteroaryl, wherein the alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted by one or more R 25 ;
    优选地，R 18每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的环E上的环原子共同组成环烷基、脂杂环基、芳基、杂芳基，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R 25取代； Preferably, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , or two adjacent R 18 and the ring atoms on the ring E to which they are connected together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, Heteroaryl, wherein the alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally substituted by one or more R 25 ;
    R 25每次出现时独立选自卤素、氰基、烷基、-NR jR k取代的烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 26、-C(O)NR jR k、-C(O)OR i； Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, -NR j R k substituted alkyl, cycloalkyl, aliphatic heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C(O)NR j R k , -C(O)OR i ;
    优选地，R 25每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 26、-C(O)NR jR k、-C(O)OR i； Preferably, each occurrence of R 25 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C(O)NR j R k , -C(O)OR i ;
    R a、R b、R c、R d、R e、R f、R g、R h、R i、R j、R k、R m每次出现时独立选自H、烷基、环烷基、脂杂环基、-C(O)R 20，或R b、R c与其相连的N原子共同组成脂杂环基，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； Each occurrence of R a , R b , R c , R d , Re , R f , R g , Rh , R i , R j , R k , R m is independently selected from H, alkyl, cycloalkyl , aliphatic heterocyclic group, -C(O)R 20 , or R b , R c and the N atoms connected to them together form an aliphatic heterocyclic group, wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally Substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, aliphatic;
    R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自H、烷基、环烷基、脂杂环基，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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each independently selected from H, alkyl, cycloalkyl, and aliphatic heterocyclic group, and the alkyl, Cycloalkyl, heteroalicyclic are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxy, amino, alkyl, cycloalkyl, heteroalicyclic.
  2. 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、同位素标记物、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, isotope labels, pharmaceutically acceptable salts, co-crystals:
    Figure PCTCN2022101219-appb-100002
    Figure PCTCN2022101219-appb-100002
    其中：in:
    A 1选自CH、CH 2或N、NR 28、O、S，A 2选自C或N，A 3选自CH、CH 2、N、NR 28、O、S，A 4选自CH、CH 2或键，优选地，A 4选自CH、CH 2或单键； A 1 is selected from CH, CH 2 or N, NR 28 , O, S, A 2 is selected from C or N, A 3 is selected from CH, CH 2 , N, NR 28 , O, S, A 4 is selected from CH, CH 2 or a bond, preferably, A 4 is selected from CH, CH 2 or a single bond;
    Y选自键、CR 6R 7、O、NR 5、S、S(O)；当A 1、A 3、A 4为CH且A 2为C时，Y不为键； Y is selected from bond, CR 6 R 7 , O, NR 5 , S, S(O); when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond;
    R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、烷基；优选地，R 2、R 3、R 4、R 5、R 6、R 7、R 28分别独立选自H、C1～C6烷基，进一步优选H、C1～C3烷基，更优选H、甲基； R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 28 are independently selected from H and alkyl; preferably, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 28 are independently selected from H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl;
    Ar选自芳基或杂芳基，且当环A不具备芳香性时，所述杂芳基不为吡啶基，其中，所述芳基或杂芳基任选地被一个或多个R 8取代； Ar is selected from aryl or heteroaryl, and when ring A does not possess aromaticity, said heteroaryl is not pyridyl, wherein said aryl or heteroaryl is optionally replaced by one or more R 8 replace;
    R 8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、-OR a、-NR bR c、-SR d、-C(O)R 10、-C(O)NR bR c、-C(O)OR a，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R 11取代； Each occurrence of R is independently selected from halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 10 , -C(O)NR b R c , -C(O)OR a , wherein, alkyl, cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl are optionally replaced by one or more R 11 are substituted;
    R 11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、-OR a、-NR bR c、-SR d、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，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R 13取代； Each occurrence of R 11 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, -OR a , -NR b R c , -SR d , -C( O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by one or multiple R 13 substitutions;
    R 13每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR a、-NR bR c、-SR d、-C(O)R 14、-C(O)NR bR c、-C(O)OR a； Each occurrence of R 13 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR a , -NR b R c , -SR d , -C(O)R 14 , -C (O)NR b R c , -C(O)OR a ;
    R 1选自氢、卤素、氰基、烷基、环烷基、脂杂环基、芳基、-OR e、-NR fR g、-SR h、-C(O)R 15、-C(O)NR fR g、-C(O)OR e，其中，烷基、环烷基、脂杂环基任选地被一个或多个R 16取代； R 1 is selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, -OR e , -NR f R g , -SR h , -C(O)R 15 , -C (O)NR f R g , -C(O)OR e , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 16 ;
    R 16每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR e、-NR fR g、-SR h、-C(O)R 17、-C(O)NR fR g、-C(O)OR e； Each occurrence of R 16 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR e , -NR f R g , -SR h , -C(O)R 17 , -C (O)NR f R g , -C(O)OR e ;
    环E选自环烷基、脂杂环基、芳基、杂芳基，其中，环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R 18取代； Ring E is selected from cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl, wherein cycloalkyl, aliphatic heterocyclic, aryl, heteroaryl is optionally substituted by one or more R 18 ;
    R 18每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基、环烷基、脂杂环基任选地被一个或多个R 25取代； Each occurrence of R 18 is independently selected from halogen, cyano, alkyl, cycloalkyl, heteroalicyclic, -OR i , -NR j R k , -SR m , -C(O)R 19 , -C (O)NR j R k , -C(O)OR i , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic groups are optionally substituted by one or more R 25 ;
    R 25每次出现时独立选自卤素、氰基、烷基、环烷基、脂杂环基、-OR i、-NR jR k、-SR m、-C(O)R 26、-C(O)NR jR k、-C(O)OR i； Each occurrence of R 25 is independently selected from halogen, cyano, alkyl, cycloalkyl, heterocyclyl, -OR i , -NR j R k , -SR m , -C(O)R 26 , -C (O)NR j R k , -C(O)OR i ;
    R a、R b、R c、R d、R e、R f、R g、R h、R i、R j、R k、R m每次出现时独立选自H、烷基、环烷基、脂杂环基、-C(O)R 20，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； Each occurrence of R a , R b , R c , R d , Re , R f , R g , Rh , R i , R j , R k , R m is independently selected from H, alkyl, cycloalkyl , aliphatic heterocyclic group, -C(O)R 20 , wherein the alkyl, cycloalkyl, and aliphatic heterocyclic group are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino , alkyl, cycloalkyl, aliphatic heterocyclic;
    R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自H、烷基、环烷基、脂杂环基，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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each independently selected from H, alkyl, cycloalkyl, and aliphatic heterocyclic group, and the alkyl, Cycloalkyl, heteroalicyclic are optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl, cycloalkyl, heteroalicyclic.
  3. 根据权利要求1或2所述化合物，其特征在于，R a、R b、R c、R d每次出现时独立选自H、烷基、-C(O)R 20，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、烷基； The compound according to claim 1 or 2, wherein each occurrence of R a , R b , R c , and R d is independently selected from H, alkyl, -C(O)R 20 , wherein the alkyl The group is optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl;
    进一步地，R a、R b、R c、R d每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 , R c , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
    进一步地，R a、R b、R c、R d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 , R c , and R d 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，R a、R b、R c、R d每次出现时独立选自H、甲基，优选地，R b、R c为甲基。 Furthermore, each occurrence of R a , R b , R c , and R d is independently selected from H and methyl, preferably, R b , R c are methyl.
  4. 根据权利要求1或2所述化合物，其特征在于，R i、R j、R k、R d每次出现时独立选自H、烷基、-C(O)R 20，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、烷基； The compound according to claim 1 or 2, wherein R i , R j , R k , and R d are each independently selected from H, alkyl, -C(O)R 20 , wherein the alkyl The group is optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, alkyl;
    进一步地，R i、R j、R k、R d每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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 i , R j , R k , and R d is independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl is optionally replaced by one or more The following substituents are substituted: halogen, cyano, hydroxyl, amino, C1~C6 alkyl;
    进一步地，R i、R j、R k、R d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 i , R j , R k , and R d 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，R i、R j、R k、R d每次出现时独立选自H、甲基、二氟甲基，优选H、甲基，优选H。 Further, R i , R j , R k , R d are each independently selected from H, methyl, difluoromethyl, preferably H, methyl, preferably H at each occurrence.
  5. 根据权利要求1或2所述化合物，其特征在于，A 1选自CH、CH 2或N，优选为CH； According to the described compound of claim 1 or 2, it is characterized in that, A1 is selected from CH, CH2 or N, preferably CH;
    优选地，A 2选自C或N，更优选为C； Preferably, A is selected from C or N, more preferably C;
    优选地，A 3选自CH、CH 2、N、NR 28、O、S，其中，R 28选自H、烷基，更优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基；进一步地，A 3选自CH或N； Preferably, A 3 is selected from CH, CH 2 , N, NR 28 , O, S, wherein R 28 is selected from H, alkyl, more preferably H, C1-C6 alkyl, more preferably H, C1-C3 alkane Base, more preferably H, methyl; Further, A3 is selected from CH or N;
    优选地，A 4选自CH、CH 2或键，更优选为CH、CH 2或单键，更优选为CH。 Preferably, A4 is selected from CH, CH2 or a bond, more preferably CH, CH2 or a single bond, more preferably CH.
  6. 根据权利要求1～5任一项所述化合物，其特征在于，其结构中
    Figure PCTCN2022101219-appb-100003
    选自如下基团：     The compound according to any one of claims 1 to 5, characterized in that, in its structure
    Figure PCTCN2022101219-appb-100003
    selected from the following groups:
    Figure PCTCN2022101219-appb-100004
    Figure PCTCN2022101219-appb-100004
    优选自如下基团：It is preferably selected from the following groups:
    Figure PCTCN2022101219-appb-100005
    Figure PCTCN2022101219-appb-100005
    更优选
    Figure PCTCN2022101219-appb-100006
    more preferred
    Figure PCTCN2022101219-appb-100006
    更优选
    Figure PCTCN2022101219-appb-100007
    more preferred
    Figure PCTCN2022101219-appb-100007
    其中，R 28如权利要求1、2、5任意一项所定义。 Wherein, R 28 is as defined in any one of claims 1, 2, and 5.
  7. 根据权利要求1～6任一项所述化合物，其特征在于，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、同位素标记物、药学上可接受的盐、共晶：The compound according to any one of claims 1 to 6, characterized in that it has the structure shown in formula II or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable Salt, eutectic:
    Figure PCTCN2022101219-appb-100008
    Figure PCTCN2022101219-appb-100008
    环E选自C3～C6环烷基、4～7元脂杂环基、苯基、5～6元杂芳基，优选5～7元脂杂环基、苯基，进一步优选含N的6元脂杂环基、苯基，更优选苯基；其中，环烷基、脂杂环基、苯基、杂芳基任选地被一个或多个R 18取代，R 18如权利要求1或2所定义； Ring E is selected from C3-C6 cycloalkyl, 4-7 membered aliphatic heterocyclic group, phenyl, 5-6 membered heteroaryl group, preferably 5-7 membered aliphatic heterocyclic group, phenyl group, more preferably N-containing 6 Aliphatic heterocyclic group, phenyl, more preferably phenyl; Wherein, cycloalkyl, aliphatic heterocyclic group, phenyl, heteroaryl are optionally substituted by one or more R 18 , R 18 is as claimed in claim 1 or as defined in 2;
    优选地，环E选自苯基、5～6元N杂芳基、5～6元硫杂芳基，更优选苯基、6元N杂芳基、5元硫杂芳基，更优选苯基、吡啶基或噻吩基；其中，所述苯基、5～6元N杂芳基、5～6元硫杂芳基、6元N杂芳基、5元硫杂芳基、吡啶基、噻吩基任选地被一个或多个R 18取代，R 18如权利要求1或2所定义； Preferably, ring E is selected from phenyl, 5-6 membered N-heteroaryl, 5-6 membered thioaryl, more preferably phenyl, 6-membered N-heteroaryl, 5-membered thiaryl, more preferably benzene Base, pyridyl or thienyl; wherein, the phenyl, 5-6 membered N heteroaryl, 5-6 membered thiaaryl, 6-membered N heteroaryl, 5-membered thiaryl, pyridyl, Thienyl is optionally substituted by one or more R 18 , R 18 is as defined in claim 1 or 2;
    优选地，环E选自苯基、5～6元N杂芳基，优选苯基、6元N杂芳基，更优选苯基或吡啶基；其中，苯基、吡啶基、N杂芳基任选地被一个或多个R 18取代，R 18如权利要求1或2所定义； Preferably, ring E is selected from phenyl, 5-6 membered N heteroaryl, preferably phenyl, 6 membered N heteroaryl, more preferably phenyl or pyridyl; wherein, phenyl, pyridyl, N heteroaryl optionally substituted by one or more R 18 , R 18 as defined in claim 1 or 2;
    优选地，环E为苯基、哌啶基，其中，苯基、哌啶基任选地被一个或多个R 18取代，R 18如权利要求1或2所定义； Preferably, ring E is phenyl, piperidinyl, wherein, phenyl, piperidinyl are optionally substituted by one or more R 18 , R 18 is as defined in claim 1 or 2;
    进一步地，当环E为哌啶基时，R 18为C1～C6烷基，其中，所述烷基任选地被1～3个烷基、卤素、羟基、氨基、氰基取代； Further, when ring E is piperidinyl, R 18 is C1-C6 alkyl, wherein the alkyl is optionally substituted by 1-3 alkyl, halogen, hydroxyl, amino, cyano;
    进一步地，当环E为哌啶基时，R 18为非取代或被羟基取代的C1～C3烷基； Further, when ring E is piperidinyl, R 18 is C1-C3 alkyl unsubstituted or substituted by hydroxyl;
    进一步地，环E为哌啶基时，为如下结构：
    Figure PCTCN2022101219-appb-100009
    优选如下结构：     Further, when Ring E is piperidinyl, it has the following structure:
    Figure PCTCN2022101219-appb-100009
    The following structure is preferred:
    Figure PCTCN2022101219-appb-100010
    n 2选自1～3的整数，优选2；
    Figure PCTCN2022101219-appb-100010
    n 2 is an integer selected from 1 to 3, preferably 2;
    进一步地，当环E为噻吩基时，R 18为芳基，其中，所述芳基任选地被1～3个烷基取代，所述烷基任选地被一个或多个-NR jR k取代； Further, when ring E is a thienyl group, R 18 is an aryl group, wherein the aryl group is optionally substituted by 1 to 3 alkyl groups, and the alkyl group is optionally substituted by one or more -NR j R k substitution;
    n 1选自0～5的整数，优选1～3的整数，优选1、2，更优选2。 n 1 is an integer selected from 0-5, preferably an integer of 1-3, preferably 1, 2, more preferably 2.
  8. 根据权利要求1-7任意一项所述化合物，其特征在于，具有式III或式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、同位素标记物、药学上可接受的盐、共晶：According to any one of claims 1-7, the compound is characterized in that it has the structure shown in formula III or formula III' or its tautomers, stereoisomers, solvates, metabolites, isotope labels, Pharmaceutically acceptable salts, co-crystals:
    Figure PCTCN2022101219-appb-100011
    Figure PCTCN2022101219-appb-100011
    其中，各取代基如权利要求1-7任意一项所定义；Wherein, each substituent is as defined in any one of claims 1-7;
    优选地，
    Figure PCTCN2022101219-appb-100012
    为
    Figure PCTCN2022101219-appb-100013
    其中R 22、R 23、R 24分别独立选自H、卤素、氰基、C1～C6烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基任选地被一个或多个R 25取代；     Preferably,
    Figure PCTCN2022101219-appb-100012
    for
    Figure PCTCN2022101219-appb-100013
    Wherein R 22 , R 23 , and R 24 are independently selected from H, halogen, cyano, C1~C6 alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , wherein the alkyl group is optionally substituted by one or more R 25 ;
    进一步地，R 22、R 23、R 24分别独立选自H、卤素、C1～C3烷基、-NR jR k，其中所述烷基任选地被一个或多个R 25取代； Further, R 22 , R 23 , and R 24 are each independently selected from H, halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 ;
    其中，所述R i、R j、R k、R 19、R 25如权利要求1-7任意一项所定义； Wherein, the R i , R j , R k , R 19 , R 25 are as defined in any one of claims 1-7;
    优选地，R 22选自H或卤素，优选为H或F，更优选为H； Preferably, R is selected from H or halogen, preferably H or F, more preferably H;
    R 23选自C1～C3烷基、被卤素和/或羟基取代的C1～C3烷基，优选为甲基、二氟甲基、三氟甲基、CF 2CH 2OH、C(OH)CH 3CH 3，更优选为三氟甲基； R 23 is selected from C1-C3 alkyl, C1-C3 alkyl substituted by halogen and/or hydroxyl, preferably methyl, difluoromethyl, trifluoromethyl, CF 2 CH 2 OH, C(OH)CH 3 CH 3 , more preferably trifluoromethyl;
    R 24选自H、NH 2，优选为NH 2。 R 24 is selected from H, NH 2 , preferably NH 2 .
  9. 根据权利要求1～8任意一项所述化合物，其特征在于，R 18每次出现时独立选自卤素、氰基、烷基、芳基、杂芳基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的环E上的环原子共同组成环烷基、脂杂环基、芳基、杂芳基，其中所述环烷基、脂杂环基、芳基、杂芳基任选地被一个或多个R 25取代； The compound according to any one of claims 1 to 8, wherein R 18 is independently selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR i , -NR j R k each time it occurs , -C(O)R 19 , -C(O)NR j R k , -C(O)OR i , or the ring atoms on the ring E to which two adjacent R 18 are connected together form a cycloalkyl group, Aliphatic heterocyclic group, aryl group, heteroaryl group, wherein said cycloalkyl group, aliphatic heterocyclic group, aryl group, heteroaryl group are optionally substituted by one or more R 25 ;
    进一步地，R 18每次出现时独立选自卤素、氰基、烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，或两个相邻的R 18与其相连的原子共同组成环烷基、脂杂环基、芳基、杂芳基，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R 25取代； Further, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , or two adjacent R 18 and the atoms connected to it together form a cycloalkyl group, an aliphatic heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, cycloalkyl group, and aliphatic heterocyclic group , aryl, heteroaryl are optionally substituted by one or more R 25 ;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、C1～C6烷氧基、-OH、苯基、-NR jR k，或两个相邻的R 18与其相连的环E上的环原子共同组成C5～C10环烷基、5～10元脂杂环基、C5～C10芳基、5～10元杂芳基，其中所述烷基、烷氧基、苯基、环烷基、脂杂环基、芳基、杂芳基任选地被1～4个R 25取代，R j、R k每次出现时独立选自H、C1～C6烷基； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, -OH, phenyl, -NR j R k , or two adjacent R 18 The ring atoms on the ring E connected to it together form a C5-C10 cycloalkyl group, a 5-10-membered aliphatic heterocyclic group, a C5-C10 aryl group, and a 5-10-membered heteroaryl group, wherein the alkyl group, alkoxy group , phenyl, cycloalkyl, aliphatic heterocyclic group, aryl, heteroaryl are optionally substituted by 1 to 4 R 25 , each occurrence of R j and R k are independently selected from H, C1 ~ C6 alkyl ;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、-NR jR k，或两个相邻的R 18与其相连的原子共同组成C5～C10环烷基、5～10元脂杂环基、C5～C10芳基、5～10元杂芳基，其中所述烷基、环烷基、脂杂环基、芳基、杂芳基任选地被1～4个R 25取代，R j、R k每次出现时独立选自H、C1～C6烷基； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1~C6 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to them together form a C5~C10 cycloalkyl, 5-10 membered aliphatic heterocyclic group, C5-C10 aryl group, 5-10 membered heteroaryl group, wherein the alkyl group, cycloalkyl group, aliphatic heterocyclic group, aryl group, and heteroaryl group are optionally replaced by 1- 4 R 25 substitutions, each occurrence of R j and R k are independently selected from H, C1-C6 alkyl;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、C1～C3烷氧基、-OH、苯基、-NR jR k，或两个相邻的R 18与其相连的环E上的环原子共同组成C5～C6环烷基、5～6元脂杂环基、5～6元杂芳基，其中所述烷基、烷氧基、苯基、环烷基、脂杂环基、杂芳基任选地被1～3个R 25取代，R j、R k每次出现时独立选自H、C1～C3烷基； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR j R k , or two adjacent R 18 The ring atoms on the ring E connected to it together form a C5-C6 cycloalkyl group, a 5-6-membered aliphatic heterocyclic group, and a 5-6-membered heteroaryl group, wherein the alkyl, alkoxy, phenyl, cycloalkane The radical, aliphatic heterocyclic group, and heteroaryl group are optionally substituted by 1 to 3 R 25 , R j and R k are independently selected from H, C1 to C3 alkyl at each occurrence;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、-NR jR k，或两个相邻的R 18与其相连的原子共同组成C5～C6环烷基、5～6元脂杂环基、5～6元杂芳基，其中所述烷基、环烷基、脂杂环基、杂芳基任选地被1～3个R 25取代，R j、R k每次出现时独立选自H、C1～C3烷基； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1~C3 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to them together form a C5~C6 cycloalkyl, 5-6 membered aliphatic heterocyclic group, 5-6 membered heteroaryl group, wherein the alkyl, cycloalkyl, aliphatic heterocyclic group, and heteroaryl group are optionally substituted by 1 to 3 R 25 , R j , Each occurrence of R k is independently selected from H, C1-C3 alkyl;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、C1～C3烷氧基、-OH、苯基、-NR jR k，或两个相邻的R 18与其相连的环E上的环原子共同组成环戊烷基、四氢呋喃基、吡咯基，其中所述C1～C3烷基、C1～C3烷氧基、苯基、环戊烷基、四氢呋喃基、吡咯基任选地被1～3个R 25取代，R j、R k均为H； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, C1-C3 alkoxy, -OH, phenyl, -NR j R k , or two adjacent R 18 The ring atoms on the ring E connected to it together form cyclopentyl, tetrahydrofuranyl, pyrrolyl, wherein the C1～C3 alkyl, C1～C3 alkoxyl, phenyl, cyclopentyl, tetrahydrofuranyl, pyrrole The group is optionally substituted by 1 to 3 R 25 , and both R j and R k are H;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C3烷基、-NR jR k，或两个相邻的R 18与其相连的原子共同组成环戊烷基、四氢呋喃基、吡咯基，其中所述C1～C3烷基、环戊烷基、四氢呋喃基、吡咯基任选地被1～3个R 25取代，R j、R k均为H； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C3 alkyl, -NR j R k , or two adjacent R 18 and the atoms connected to form cyclopentyl, tetrahydrofuryl , pyrrolyl, wherein the C1-C3 alkyl, cyclopentyl, tetrahydrofuranyl, pyrrolyl are optionally substituted by 1-3 R 25 , R j , R k are both H;
    优选地，R 18每次出现时独立选自卤素、氰基、烷基、-OR i、-NR jR k、-C(O)R 19、-C(O)NR jR k、-C(O)OR i，其中所述烷基任选地被一个或多个R 25取代； Preferably, each occurrence of R 18 is independently selected from halogen, cyano, alkyl, -OR i , -NR j R k , -C(O)R 19 , -C(O)NR j R k , -C (O) OR i , wherein the alkyl group is optionally substituted by one or more R 25 ;
    进一步地，R 18每次出现时独立选自卤素、氰基、C1～C6烷基、-OR i、-NR jR k，其中所述烷基任选地被一个或多个R 25取代； Further, each occurrence of R 18 is independently selected from halogen, cyano, C1-C6 alkyl, -OR i , -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 ;
    进一步地，R 18每次出现时独立选自卤素、C1～C3烷基、-NR jR k，其中所述烷基任选地被一个或多个R 25取代； Further, each occurrence of R 18 is independently selected from halogen, C1-C3 alkyl, -NR j R k , wherein the alkyl is optionally substituted by one or more R 25 ;
    优选地，R 18每次出现时独立选自卤素、氰基、羟基、氨基、甲基、CF 3、-CF 2CH 3、-CF 2H、-CF 2CH 2OH、-C(CH 3) 2OH、-OCF 2H、-CH 2NHCH 3取代的苯基或吡啶基，或者，两个相邻的R 18与其相连的环E上的环原子共同组成环戊烷基、四氢呋喃基、吡咯基，其中所述环戊烷基、四氢呋喃基、吡咯基任选地被一个或多个F原子取代。 Preferably, each occurrence of R 18 is independently selected from halogen, cyano, hydroxy, amino, methyl, CF 3 , -CF 2 CH 3 , -CF 2 H, -CF 2 CH 2 OH, -C(CH 3 ) 2 OH, -OCF 2 H, -CH 2 NHCH 3 substituted phenyl or pyridyl, or, the ring atoms on the ring E to which two adjacent R 18 are connected together form cyclopentyl, tetrahydrofuranyl, Pyrrolyl, wherein the cyclopentyl, tetrahydrofuranyl, pyrrolyl is optionally substituted by one or more F atoms.
  10. 根据权利要求9所述化合物，其特征在于，R 25每次出现时独立选自卤素、C1～C6烷基、-OR i、-CH 2NR jR k、-NR jR k，优选卤素、C1～C6烷基、-OR i、-NR jR k，优选卤素、C1～C3烷基、-OR i，更优选卤素或-OR i，更优选卤素，其中，R i、R j、R k如权利要求1所定义，优选地，R i、R j、R k独立选自H、烷基，更优选地，R i、R j、R k为H；进一步地，R 25每次出现时独立选自F、Cl、甲基、乙基、丙基、羟基，优选F、羟基、-CH 2NHCH 3，优选F、甲基、羟基，更优选F、羟基。 The compound according to claim 9, wherein each occurrence of R 25 is independently selected from halogen, C1-C6 alkyl, -OR i , -CH 2 NR j R k , -NR j R k , preferably halogen, C1～C6 alkyl, -OR i , -NR j R k , preferably halogen, C1～C3 alkyl, -OR i , more preferably halogen or -OR i , more preferably halogen, wherein, R i , R j , R k is as defined in claim 1, preferably, R i , R j , R k are independently selected from H, alkyl, more preferably, R i , R j , R k are H; further, each occurrence of R 25 is independently selected from F, Cl, methyl, ethyl, propyl, hydroxyl, preferably F, hydroxyl, -CH 2 NHCH 3 , preferably F, methyl, hydroxyl, more preferably F, hydroxyl.
  11. 根据权利要求1～10任意一项所述化合物，其特征在于，R 18每次出现时独立选自-F、-CN、-NH 2、-OH、-CH 3、-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH、-OCF 2H、
    Figure PCTCN2022101219-appb-100014
    或两个相邻的R 18与其相连的原 子共同组成
    Figure PCTCN2022101219-appb-100015
    The compound according to any one of claims 1-10, characterized in that each occurrence of R 18 is independently selected from -F, -CN, -NH 2 , -OH, -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, -OCF 2 H,
    Figure PCTCN2022101219-appb-100014
    Or two adjacent R 18 together with the atoms they are connected to form
    Figure PCTCN2022101219-appb-100015
    进一步地，R 18每次出现时独立选自-F、-CN、-NH 2、-CH 3、-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH、-C(OH)CH 3CH 3，或两个相邻的R 18与其相连的原子共同组成
    Figure PCTCN2022101219-appb-100016
    Further, each occurrence of R 18 is independently selected from -F, -CN, -NH 2 , -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, -C( OH)CH 3 CH 3 , or two adjacent R 18 and the atoms they are connected to form together
    Figure PCTCN2022101219-appb-100016
    进一步地，R 18每次出现时独立选自-F、-CN、-NH 2、-CH 3、-CHF 2、-CF 3、-CF 2CH 3、-CF 2CH 2OH，或两个相邻的R 18与其相连的原子共同组成
    Figure PCTCN2022101219-appb-100017
    Further, each occurrence of R 18 is independently selected from -F, -CN, -NH 2 , -CH 3 , -CHF 2 , -CF 3 , -CF 2 CH 3 , -CF 2 CH 2 OH, or two Adjacent R 18 together with the atom to which it is attached
    Figure PCTCN2022101219-appb-100017
  12. 根据权利要求1～11任意一项所述的化合物，其特征在于，环E选自如下结构：The compound according to any one of claims 1-11, wherein ring E is selected from the following structures:
    Figure PCTCN2022101219-appb-100018
    Figure PCTCN2022101219-appb-100018
    进一步地，环E选自如下结构：Further, ring E is selected from the following structures:
    Figure PCTCN2022101219-appb-100019
    Figure PCTCN2022101219-appb-100019
    进一步地，环E选自如下结构：Further, ring E is selected from the following structures:
    Figure PCTCN2022101219-appb-100020
    Figure PCTCN2022101219-appb-100020
    Figure PCTCN2022101219-appb-100021
    Figure PCTCN2022101219-appb-100021
  13. 根据权利要求1～12任意一项所述化合物，其特征在于，Y选自键、-CR 6R 7-、-O-、-NR 5-，当A 1、A 3、A 4为CH且A 2为C时，Y不为键；其中，R 5、R 6、R 7分别独立选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基； The compound according to any one of claims 1-12, wherein Y is selected from a bond, -CR 6 R 7 -, -O-, -NR 5 -, when A 1 , A 3 , A 4 are CH and When A 2 is C, Y is not a bond; wherein, R 5 , R 6 , and R 7 are independently selected from H and alkyl groups, preferably H, C1-C6 alkyl groups, more preferably H, C1-C3 alkyl groups, and more preferably Preferably H, methyl;
    进一步地，Y选自键、O、NR 5，当A 1、A 3、A 4为CH且A 2为C时，Y不为键；其中，R 5选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基；或者，R 5为C1～C6烷基，优选C1～C3烷基，更优选甲基； Further, Y is selected from bond, O, NR 5 , when A 1 , A 3 , A 4 are CH and A 2 is C, Y is not a bond; wherein, R 5 is selected from H, alkyl, preferably H, C1～C6 alkyl, more preferably H, C1～C3 alkyl, more preferably H, methyl; or, R 5 is C1～C6 alkyl, preferably C1～C3 alkyl, more preferably methyl;
    进一步地，Y选自O、NR 5；其中，R 5选自H、烷基，优选H、C1～C6烷基，更优选H、C1～C3烷基，更优选H、甲基；或者，R 5为C1～C6烷基，优选C1～C3烷基，更优选甲基； Further, Y is selected from O, NR 5 ; wherein, R 5 is selected from H, alkyl, preferably H, C1-C6 alkyl, more preferably H, C1-C3 alkyl, more preferably H, methyl; or, R 5 is C1～C6 alkyl, preferably C1～C3 alkyl, more preferably methyl;
    优选地，Y选自-NH-、-O-或-NCH 3-。 Preferably, Y is selected from -NH-, -O- or -NCH 3 -.
  14. 根据权利要求1～13任意一项所述化合物，其特征在于，Ar选自C6～C10芳基、5～10元杂芳基、3～10元脂杂环基，其中，所述芳基、杂芳基、脂杂环基任选地被一个或多个R 8取代； According to the compound described in any one of claims 1-13, it is characterized in that, Ar is selected from C6-C10 aryl, 5-10 membered heteroaryl, 3-10 membered aliphatic heterocyclic group, wherein, said aryl, Heteroaryl, aliphatic heterocyclic groups are optionally substituted by one or more R 8 ;
    进一步地，Ar选自苯基、6～9元杂芳基、5～6元脂杂环基，其中，所述苯基、杂芳基、脂杂环基任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, 6-9 membered heteroaryl, and 5-6 membered aliphatic heterocyclic groups, wherein the phenyl, heteroaryl, and aliphatic heterocyclic groups are optionally replaced by one or more R 8 replaced;
    进一步地，Ar选自苯基、6元N杂芳基、9元N杂芳基、N杂环己二烯酮基，其中，所述苯基、6元N杂芳基、9元N杂芳基、N杂环己二烯酮基任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, 6-membered N-heteroaryl, 9-membered N-heteroaryl, and N-heterocyclohexadienone, wherein the phenyl, 6-membered N-heteroaryl, 9-membered N-hetero Aryl, N heterocyclohexadienone are optionally substituted by one or more R 8 ;
    进一步地，Ar选自苯基、6元N杂芳基、N杂环己二烯酮基，其中，所述苯基、6元N杂芳基、N杂环己二烯酮基任选地被一个或多个R 8取代； Further, Ar is selected from phenyl, 6-membered N heteroaryl, N heterocyclohexadienone, wherein, the phenyl, 6-member N heteroaryl, N heterocyclohexadienone optionally Replaced by one or more R 8 ;
    进一步地，Ar选自苯基、吡啶基、
    Figure PCTCN2022101219-appb-100022
    其中，所述苯基、吡啶基、
    Figure PCTCN2022101219-appb-100023
    任选地被一个或多个R 8取代；     Further, Ar is selected from phenyl, pyridyl,
    Figure PCTCN2022101219-appb-100022
    Among them, the phenyl, pyridyl,
    Figure PCTCN2022101219-appb-100023
    optionally substituted by one or more R 8 ;
    进一步地，Ar选自苯基、吡啶基、
    Figure PCTCN2022101219-appb-100024
    其中，所述苯基、吡啶基、
    Figure PCTCN2022101219-appb-100025
    Figure PCTCN2022101219-appb-100026
    任选地被一个或多个R 8取代；     Further, Ar is selected from phenyl, pyridyl,
    Figure PCTCN2022101219-appb-100024
    Among them, the phenyl, pyridyl,
    Figure PCTCN2022101219-appb-100025
    Figure PCTCN2022101219-appb-100026
    optionally substituted by one or more R 8 ;
    优选地，Ar选自苯基或5～10元杂芳基，更优选苯基或6～9元杂芳基，更优选苯基或N杂6～9元杂芳基，更优选苯基、吡啶基、9元N杂芳基，其中，所述苯基、吡啶基、杂芳基任选地被一个或多个R 8取代，所述R 8如权利要求1所定义。 Preferably, Ar is selected from phenyl or 5-10-membered heteroaryl, more preferably phenyl or 6-9-membered heteroaryl, more preferably phenyl or N hetero6-9-membered heteroaryl, more preferably phenyl, Pyridyl, 9-membered N heteroaryl, wherein the phenyl, pyridyl, and heteroaryl are optionally substituted by one or more R 8 , and the R 8 is as defined in claim 1.
  15. 根据权利要求1～14任一项所述化合物，其特征在于，Ar任选地被1～3个R 8取代；进一步地，Ar任选地被1～2个R 8取代。 The compound according to any one of claims 1-14, wherein Ar is optionally substituted by 1-3 R 8 ; further, Ar is optionally substituted by 1-2 R 8 .
  16. 根据权利要求1～15任意一项所述化合物，其特征在于，R 8每次出现时独立选自卤素、氰基、C1～C6烷基、C3～C6元环烷基、3～6元脂杂环基、-OR a、-NR bR c，其中，烷基、环烷基、脂杂环基任选地被一个或多个R 11取代，所述R a、R b、R c、R 11如权利要求1所定义； The compound according to any one of claims 1 to 15, wherein R is independently selected from halogen, cyano, C1 to C6 alkyl, C3 to C6 cycloalkyl, and 3 to 6 lipids each time it appears. Heterocyclic group, -OR a , -NR b R c , wherein the alkyl group, cycloalkyl group and aliphatic heterocyclic group are optionally substituted by one or more R 11 , said R a , R b , R c , R 11 is as defined in claim 1;
    进一步地，R 8每次出现时独立选自C1～C3烷基、-OR a、-NR bR c，其中，烷基任选地被一个或多个R 11取代，所述R a、R b、R c、R 11如权利要求1所定义； Further, each occurrence of R 8 is independently selected from C1～C3 alkyl, -OR a , -NR b R c , wherein the alkyl group is optionally substituted by one or more R 11 , said R a , R b , R c , R 11 are as defined in claim 1;
    进一步地，R 8每次出现时独立选自C1～C3烷基、-OR a、-NR bR c，其中，R a选自H、烷基，R b、R c分别独立选自H、烷基，或R b、R c与其相连的N原子共同组成脂杂环基，所述烷基、脂杂环基任选地被一个或多个R 11取代； Further, each occurrence of R 8 is independently selected from C1～C3 alkyl, -OR a , -NR b R c , wherein R a is selected from H and alkyl, and R b and R c are independently selected from H, Alkyl, or R b , R c and the N atoms connected to them together form an aliphatic heterocyclic group, and the alkyl and aliphatic heterocyclic groups are optionally substituted by one or more R 11 ;
    进一步地，R 8每次出现时独立选自甲基、乙基、丙基、-OR a、-NR bR c，其中，R a选自H、C1～C6烷基，R b、R c分别独立选自C1～C6烷基，或R b、R c与其相连的N原子共同组成5元脂杂环基，所述甲基、乙基、丙基、烷基、脂杂环基任选地被一个或多个R 11取代； Further, each occurrence of R 8 is independently selected from methyl, ethyl, propyl, -OR a , -NR b R c , wherein R a is selected from H, C1-C6 alkyl, R b , R c are independently selected from C1-C6 alkyl groups, or R b , R c and the N atoms connected to them together form a 5-membered aliphatic heterocyclic group, and the methyl, ethyl, propyl, alkyl, and aliphatic heterocyclic groups are optionally is substituted by one or more R 11 ;
    进一步地，R 8每次出现时独立选自甲基、乙基、-OR a、-NR bR c，其中，R a选自H、C1～C3烷基，R b、R c分别独立选自C1～C3烷基，或R b、R c与N原子共同组成
    Figure PCTCN2022101219-appb-100027
    所述甲基、乙基、烷基、
    Figure PCTCN2022101219-appb-100028
    任选地被一个或多个R 11取代；     Further, each occurrence of R 8 is independently selected from methyl, ethyl, -OR a , -NR b R c , wherein R a is selected from H, C1～C3 alkyl, R b and R c are independently selected from From C1～C3 alkyl, or R b , R c and N atom together
    Figure PCTCN2022101219-appb-100027
    The methyl, ethyl, alkyl,
    Figure PCTCN2022101219-appb-100028
    optionally substituted by one or more R 11 ;
    进一步地，R 8每次出现时独立选自-OH、-OCH 3、-N(CH 3) 2、-NHCH 3、-CH 2C(O)N(CH 3) 2、-CH 2CH 2C(O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、-CH 2CN、
    Figure PCTCN2022101219-appb-100029
    Further, each occurrence of R 8 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , -NHCH 3 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CN,
    Figure PCTCN2022101219-appb-100029
    进一步地，R 8每次出现时独立选自-OH、-OCH 3、-N(CH 3) 2、-CH 2C(O)N(CH 3) 2、-CH 2CH 2C(O)N(CH 3) 2、-CH 2CH 2N(CH 3) 2、-CH 2CN、
    Figure PCTCN2022101219-appb-100030
    Further, each occurrence of R 8 is independently selected from -OH, -OCH 3 , -N(CH 3 ) 2 , -CH 2 C(O)N(CH 3 ) 2 , -CH 2 CH 2 C(O) N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CN,
    Figure PCTCN2022101219-appb-100030
    进一步地，R 8每次出现时独立选自-OCH 3、-OH、
    Figure PCTCN2022101219-appb-100031
    -CH 2C(O)N(CH 3) 2、
    Figure PCTCN2022101219-appb-100032
    -CH 2CH 2N(CH 3) 2、-CH 2CN、-CH 3；     Further, each occurrence of R 8 is independently selected from -OCH 3 , -OH,
    Figure PCTCN2022101219-appb-100031
    -CH 2 C(O)N(CH 3 ) 2 ,
    Figure PCTCN2022101219-appb-100032
    -CH2CH2N ( CH3 ) 2 , -CH2CN , -CH3 ;
    进一步地，R 8每次出现时独立选自-OCH 3、-OH、
    Figure PCTCN2022101219-appb-100033
    -CH 2C(O)N(CH 3) 2、
    Figure PCTCN2022101219-appb-100034
    -CH 2CH 2N(CH 3) 2、-CH 2CN。     Further, each occurrence of R 8 is independently selected from -OCH 3 , -OH,
    Figure PCTCN2022101219-appb-100033
    -CH 2 C(O)N(CH 3 ) 2 ,
    Figure PCTCN2022101219-appb-100034
    -CH2CH2N ( CH3 )2 , -CH2CN .
  17. 根据权利要求1～16任意一项所述化合物，其特征在于，R 11每次出现时独立选自卤素、氰基、烷基、芳基、杂芳基、-OR a、-NR bR c、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被一个或多个R 13取代； The compound according to any one of claims 1 to 16, wherein R 11 is independently selected from halogen, cyano, alkyl, aryl, heteroaryl, -OR a , -NR b R c each time it appears , -C(O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally replaced by one or more R 13 replace;
    进一步地，R 11每次出现时独立选自卤素、氰基、C1～C6烷基、6～10元芳基、5～9元杂芳基、-OR a、-NR bR c、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被一个或多个R 13取代； Further, each occurrence of R 11 is independently selected from halogen, cyano, C1-C6 alkyl, 6-10 membered aryl, 5-9 membered heteroaryl, -OR a , -NR b R c , -C (O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally substituted by one or more R 13 ;
    进一步地，R 11每次出现时独立选自卤素、氰基、C1～C6烷基、5～6元杂芳基、-OR a、-NR bR c、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被1～3个R 13取代； Further, each occurrence of R 11 is independently selected from halogen, cyano, C1-C6 alkyl, 5-6 membered heteroaryl, -OR a , -NR b R c , -C(O)R 12 , - C(O)NR b R c , -C(O)OR a , wherein the alkyl, aryl, and heteroaryl are optionally substituted by 1 to 3 R 13 ;
    进一步地，R 11每次出现时独立选自氰基、C1～C3烷基、5元杂芳基、-NR bR c、-C(O)NR bR c，其中，所述烷基、芳基、杂芳基任选地被1～3个R 13取代； Further, each occurrence of R 11 is independently selected from cyano, C1-C3 alkyl, 5-membered heteroaryl, -NR b R c , -C(O)NR b R c , wherein the alkyl, Aryl and heteroaryl are optionally substituted by 1 to 3 R 13 ;
    进一步地，R 11中的5元杂芳基选自噻唑基、咪唑基，其中，所述噻唑基、咪唑基任选地被1～2个R 13取代；可选地，R 11中的噻唑基、咪唑基为为如下结构：
    Figure PCTCN2022101219-appb-100035
    Further, the 5-membered heteroaryl group in R 11 is selected from thiazolyl and imidazolyl, wherein the thiazolyl and imidazolyl are optionally substituted by 1 to 2 R 13 ; optionally, thiazole in R 11 Base and imidazolyl are of the following structure:
    Figure PCTCN2022101219-appb-100035
    进一步地，R 11每次出现时独立选自氰基、甲基、乙基、丙基、
    Figure PCTCN2022101219-appb-100036
    -N(CH 3) 2、-C(O)N(CH 3) 2、
    Figure PCTCN2022101219-appb-100037
     Further , each occurrence of R is independently selected from cyano, methyl, ethyl, propyl,
    Figure PCTCN2022101219-appb-100036
    -N(CH 3 ) 2 , -C(O)N(CH 3 ) 2 ,
    Figure PCTCN2022101219-appb-100037
    优选地，R 11每次出现时独立选自烷基、6～10元芳基、5～9元杂芳基、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述烷基、芳基、杂芳基任选地被一个或多个R 13取代，所述R a、R b、R c、R 12、R 13如权利要求1所定义； Preferably, each occurrence of R 11 is independently selected from alkyl, 6-10-membered aryl, 5-9-membered heteroaryl, -C(O)R 12 , -C(O)NR b R c , -C (O) OR a , wherein the alkyl group, aryl group, and heteroaryl group are optionally substituted by one or more R 13 , and the R a , R b , R c , R 12 , and R 13 are as claimed in the claims as defined in 1;
    进一步地，R 11每次出现时独立选自5～6元杂芳基、-C(O)R 12、-C(O)NR bR c、-C(O)OR a，其中，所述杂芳基任选地被一个或多个R 13取代，所述R a、R b、R c、R 12、R 13如权利要求1所定义； Further, each occurrence of R 11 is independently selected from 5-6 membered heteroaryl, -C(O)R 12 , -C(O)NR b R c , -C(O)OR a , wherein, the Heteroaryl is optionally substituted by one or more R 13 , said R a , R b , R c , R 12 , R 13 are as defined in claim 1;
    进一步地，R 11每次出现时独立选自5元杂芳基、-C(O)NR bR c，优选-C(O)NR bR c，其中，所述杂芳基任选地被一个或多个R 13取代，所述R b、R c、R 13如权利要求1所定义； Further, each occurrence of R 11 is independently selected from 5-membered heteroaryl, -C(O)NR b R c , preferably -C(O)NR b R c , wherein the heteroaryl is optionally One or more R 13 are substituted, and the R b , R c , R 13 are as defined in claim 1;
    进一步地，R 11每次出现时独立选自噻唑基、咪唑基、-C(O)NR bR c，其中，所述噻唑基、咪唑基任选地 被一个或多个R 13取代，所述R b、R c、R 13如权利要求1所定义； Further, each occurrence of R 11 is independently selected from thiazolyl, imidazolyl, -C(O)NR b R c , wherein the thiazolyl and imidazolyl are optionally substituted by one or more R 13 , the The R b , R c , R 13 are as defined in claim 1;
    进一步地，R 11中可选的噻唑基、咪唑基为如下结构：
    Figure PCTCN2022101219-appb-100038
    Further, the optional thiazolyl and imidazolyl groups in R11 have the following structures:
    Figure PCTCN2022101219-appb-100038
  18. 根据权利要求1～17任意一项所述的化合物，其特征在于，R 13每次出现时独立选自卤素、C1～C6烷基、-OR a、-NR bR c、-C(O)R 14、-C(O)NR bR c、-C(O)OR a，所述R a、R b、R c、R 14如权利要求1所定义； The compound according to any one of claims 1-17, wherein R 13 is independently selected from halogen, C1-C6 alkyl, -OR a , -NR b R c , -C(O) each time it appears R 14 , -C(O)NR b R c , -C(O)OR a , said R a , R b , R c , and R 14 are as defined in claim 1;
    进一步地，R 13每次出现时独立选自卤素、C1～C6烷基，优选C1～C3烷基，优选甲基。 Further, each occurrence of R 13 is independently selected from halogen, C1-C6 alkyl, preferably C1-C3 alkyl, preferably methyl.
  19. 根据权利要求1～18任意一项所述化合物，其特征在于，R 11每次出现时独立选自烷基、-C(O)NR bR c、-NR bR c、氰基，其中，R b、R c分别独立选自H、烷基，或R b、R c与其相连的N原子共同组成脂杂环基； The compound according to any one of claims 1 to 18, wherein R 11 is independently selected from alkyl, -C(O)NR b R c , -NR b R c , and cyano each time it appears, wherein, R b and R c are independently selected from H and an alkyl group, or R b and R c are connected to the N atom together to form an aliphatic heterocyclic group;
    进一步地，R 11每次出现时独立选自C1～C6烷基、-C(O)NR bR c、-NR bR c、氰基，其中，R b、R c分别独立选自H、C1～C6烷基，或R b、R c与N原子共同组成5～6元脂杂环基； Further, each occurrence of R 11 is independently selected from C1～C6 alkyl, -C(O)NR b R c , -NR b R c , and cyano, wherein R b and R c are independently selected from H, C1-C6 alkyl, or R b , R c and N atoms together form a 5-6 membered aliphatic heterocyclic group;
    进一步地，R 11每次出现时独立选自C1～C3烷基、-C(O)NR bR c、-NR bR c、氰基，其中，R b、R c分别独立选自C1～C3烷基，或R b、R c与N原子共同组成5元脂杂环基； Further, each occurrence of R 11 is independently selected from C1～C3 alkyl, -C(O)NR b R c , -NR b R c , and cyano, wherein R b and R c are independently selected from C1～C3 C3 alkyl group, or R b , R c and N atom together form a 5-membered aliphatic heterocyclic group;
    进一步地，R 11每次出现时独立选自甲基、-C(O)NR bR c、-NR bR c、氰基，其中，R b、R c均为甲基，或R b、R c与N原子共同组成四氢吡咯基； Further, each occurrence of R 11 is independently selected from methyl, -C(O)NR b R c , -NR b R c , cyano, wherein R b and R c are both methyl, or R b , R c and N atoms together form tetrahydropyrrolyl;
    进一步地，R 11每次出现时独立选自甲基、-C(O)N(CH 3) 2、
    Figure PCTCN2022101219-appb-100039
    -N(CH 3) 2、氰基。     Further, each occurrence of R 11 is independently selected from methyl, -C(O)N(CH 3 ) 2 ,
    Figure PCTCN2022101219-appb-100039
    -N(CH 3 ) 2 , cyano.
  20. 根据权利要求1～19任意一项所述化合物，其特征在于，Ar选自如下基团：The compound according to any one of claims 1-19, wherein Ar is selected from the following groups:
    Figure PCTCN2022101219-appb-100040
    Figure PCTCN2022101219-appb-100040
    进一步地，Ar选自如下基团：Further, Ar is selected from the following groups:
    Figure PCTCN2022101219-appb-100041
    Figure PCTCN2022101219-appb-100041
    Figure PCTCN2022101219-appb-100042
    Figure PCTCN2022101219-appb-100042
    进一步地，Ar选自如下基团：Further, Ar is selected from the following groups:
    Figure PCTCN2022101219-appb-100043
    Figure PCTCN2022101219-appb-100043
  21. 根据权利要求1～20任意一项所述化合物，其特征在于，具有式IV或式V或式VI所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、同位素标记物、药学上可接受的盐、共晶：The compound according to any one of claims 1 to 20, characterized in that it has the structure shown in formula IV or formula V or formula VI or its tautomers, stereoisomers, solvates, metabolites, isotope labels Substances, pharmaceutically acceptable salts, co-crystals:
    Figure PCTCN2022101219-appb-100044
    Figure PCTCN2022101219-appb-100044
    Figure PCTCN2022101219-appb-100045
    Figure PCTCN2022101219-appb-100045
    其中，A 1、A 2、A 3、A 4、R 1、R 11、R 18、R a、R b、R c、Y如权利要求1所定义； Wherein, A 1 , A 2 , A 3 , A 4 , R 1 , R 11 , R 18 , R a , R b , R c , Y are as defined in claim 1;
    A 5、A 6分别独立选自CR 27或N，其中R 27选自H、C1～C3烷基，优选H； A 5 and A 6 are independently selected from CR 27 or N, wherein R 27 is selected from H, C1-C3 alkyl, preferably H;
    R 21选自H、C1～C6烷基、-OR a、-NR bR c，优选C1～C3烷基、-OR a、-NR bR c，优选甲基、乙基、-OR a、-NR bR c，更优选-OR a； R 21 is selected from H, C1～C6 alkyl, -OR a , -NR b R c , preferably C1～C3 alkyl, -OR a , -NR b R c , preferably methyl, ethyl, -OR a , -NR b R c , more preferably -OR a ;
    优选地，R a、R b、R c各自独立选自H或甲基；优选为甲基； Preferably, R a , R b , and R c are each independently selected from H or methyl; preferably methyl;
    优选地，式IV的结构进一步为式IV’：Preferably, the structure of formula IV is further of formula IV':
    Figure PCTCN2022101219-appb-100046
    Figure PCTCN2022101219-appb-100046
    式V的结构进一步为式V’：The structure of formula V is further formula V':
    Figure PCTCN2022101219-appb-100047
    Figure PCTCN2022101219-appb-100047
    其中，各基团如权利要求1-20任意一项所定义；Wherein, each group is as defined in any one of claims 1-20;
    优选地；式IV或式IV’中、式V或式V’中，Y为NR 5；式VI中，Y选自键、O、NR 5。 Preferably; in formula IV or IV', in formula V or formula V', Y is NR 5 ; in formula VI, Y is selected from a bond, O, and NR 5 .
  22. 根据权利要求21所述化合物，其特征在于，According to the described compound of claim 21, it is characterized in that,
    式IV或式IV’中，
    Figure PCTCN2022101219-appb-100048
    选自如下结构：     In formula IV or formula IV',
    Figure PCTCN2022101219-appb-100048
    Choose from the following structures:
    Figure PCTCN2022101219-appb-100049
    Figure PCTCN2022101219-appb-100049
    式V或V’中，
    Figure PCTCN2022101219-appb-100050
    选自如下结构：     Formula V or V',
    Figure PCTCN2022101219-appb-100050
    Choose from the following structures:
    Figure PCTCN2022101219-appb-100051
    Figure PCTCN2022101219-appb-100051
    式VI中，
    Figure PCTCN2022101219-appb-100052
    选自如下结构：     In Formula VI,
    Figure PCTCN2022101219-appb-100052
    Choose from the following structures:
    Figure PCTCN2022101219-appb-100053
    Figure PCTCN2022101219-appb-100053
  23. 根据权利要求22所述化合物，其特征在于，According to the described compound of claim 22, it is characterized in that,
    式IV或式IV’中，
    Figure PCTCN2022101219-appb-100054
    选自如下结构：
    Figure PCTCN2022101219-appb-100055
    In formula IV or formula IV',
    Figure PCTCN2022101219-appb-100054
    Choose from the following structures:
    Figure PCTCN2022101219-appb-100055
    式V或V’中，
    Figure PCTCN2022101219-appb-100056
    为
    Figure PCTCN2022101219-appb-100057
    Formula V or V',
    Figure PCTCN2022101219-appb-100056
    for
    Figure PCTCN2022101219-appb-100057
    式VI中，
    Figure PCTCN2022101219-appb-100058
    为
    Figure PCTCN2022101219-appb-100059
    In Formula VI,
    Figure PCTCN2022101219-appb-100058
    for
    Figure PCTCN2022101219-appb-100059
  24. 根据权利要求21或23所述化合物，其特征在于，
    Figure PCTCN2022101219-appb-100060
    选自如下结构：     According to the described compound of claim 21 or 23, it is characterized in that,
    Figure PCTCN2022101219-appb-100060
    Choose from the following structures:
    Figure PCTCN2022101219-appb-100061
    优选为
    Figure PCTCN2022101219-appb-100062
    Figure PCTCN2022101219-appb-100061
    preferably
    Figure PCTCN2022101219-appb-100062
  25. 根据权利要求1～24任意一项所述的化合物，其特征在于，具有式VII所示结构或其互变异构体、立体异构体、溶剂化物、代谢产物、同位素标记物、药学上可接受的盐、共晶：The compound according to any one of claims 1 to 24, characterized in that it has the structure shown in formula VII or its tautomers, stereoisomers, solvates, metabolites, isotope labels, pharmaceutically acceptable Accepted salts, co-crystals:
    Figure PCTCN2022101219-appb-100063
    Figure PCTCN2022101219-appb-100063
    其中，各基团定义如权利要求1-24中任一项。Wherein, each group is as defined in any one of claims 1-24.
  26. 根据权利要求1～25任意一项所述化合物，其特征在于，R 1选自氢、卤素、氰基、C1～C6烷基、C3～C6环烷基、6～10元芳基、-OR e、-NR fR g、-C(O)R 15、-C(O)NR fR g、-C(O)OR e，其中，烷基任选地被一个或多个R 16取代； The compound according to any one of claims 1-25, wherein R is selected from hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, 6-10 membered aryl, -OR e , -NR f R g , -C(O)R 15 , -C(O)NR f R g , -C(O)OR e , wherein the alkyl group is optionally substituted by one or more R 16 ;
    进一步地，R 1选自氢、卤素、氰基、C1～C3烷基、环丙烷基、-OR e、-NR fR g，其中，烷基任选地被一个或多个R 16取代； Further, R 1 is selected from hydrogen, halogen, cyano, C1~C3 alkyl, cyclopropyl, -OR e , -NR f R g , wherein the alkyl is optionally substituted by one or more R 16 ;
    更进一步地，R 1选自卤素、C1～C3烷基； Further, R 1 is selected from halogen, C1～C3 alkyl;
    进一步地，R 1选自氢、卤素、C1～C6烷基，其中，烷基任选地被一个或多个R 16取代； Further, R 1 is selected from hydrogen, halogen, C1-C6 alkyl, wherein the alkyl is optionally substituted by one or more R 16 ;
    优选地，R 1选自H、Cl、Br、I、羟基、氰基、甲基、二氟甲基、乙基、-CH 2OH、-CH 2NH 2、-NHCH 3、-OCH 2CH 3，更优选为H、Cl、甲基、乙基、-CH 2CH 2OH；更优选为甲基或Cl； Preferably, R 1 is selected from H, Cl, Br, I, hydroxyl, cyano, methyl, difluoromethyl, ethyl, -CH 2 OH, -CH 2 NH 2 , -NHCH 3 , -OCH 2 CH 3 , more preferably H, Cl, methyl, ethyl, -CH 2 CH 2 OH; more preferably methyl or Cl;
    优选地，R 1选自Cl、甲基、-CH 2CH 2OH、-CH 2CH 3、环丙烷基； Preferably, R 1 is selected from Cl, methyl, -CH 2 CH 2 OH, -CH 2 CH 3 , cyclopropanyl;
    优选地，R 16每次出现时独立选自卤素、氰基、C1～C6烷基、-OR e、-NR fR g、-C(O)R 17、-C(O)NR fR g、-C(O)OR e； Preferably, each occurrence of R 16 is independently selected from halogen, cyano, C1-C6 alkyl, -OR e , -NR f R g , -C(O)R 17 , -C(O)NR f R g , -C(O)OR e ;
    进一步地，R 16每次出现时独立选自卤素、C1～C3烷基、-OR e、-NR fR g； Further, each occurrence of R 16 is independently selected from halogen, C1～C3 alkyl, -OR e , -NR f R g ;
    进一步地，R 16为-OR e。 Further, R 16 is -OR e .
  27. 根据权利要求1～26任意一项所述化合物，其特征在于，R e、R f、R g、R h每次出现时独立选自H、C1～C6烷基、-C(O)R 20，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； The compound according to any one of claims 1 to 26, wherein R e , R f , R g , and Rh are each independently selected from H, C1-C6 alkyl, -C(O)R 20 , wherein the alkyl group is optionally substituted by one or more of the following substituents: halogen, cyano, hydroxyl, amino, C1-C6 alkyl;
    进一步地，R e、R f、R g、R h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 e , R f , R g , and Rh 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，R e、R f、R g、R h每次出现时独立选自H、甲基、乙基； Furthermore, R e , R f , R g , and Rh are independently selected from H, methyl, and ethyl each time they appear;
    更进一步地，R e为H。 Further, R e is H.
  28. 根据权利要求1～27任意一项所述化合物，其特征在于，The compound according to any one of claims 1-27, characterized in that,
    Figure PCTCN2022101219-appb-100064
    的构型为
    Figure PCTCN2022101219-appb-100065
    进一步地，
    Figure PCTCN2022101219-appb-100066
    的构型为
    Figure PCTCN2022101219-appb-100067
    Figure PCTCN2022101219-appb-100064
    is configured as
    Figure PCTCN2022101219-appb-100065
    further,
    Figure PCTCN2022101219-appb-100066
    is configured as
    Figure PCTCN2022101219-appb-100067
  29. 根据权利要求1～28任意一项所述化合物，其特征在于，R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自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 1-28, wherein R 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 are each 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，R 10、R 12、R 14、R 15、R 17、R 19、R 20、R 26每次出现时分别独立选自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 10 , R 12 , R 14 , R 15 , R 17 , R 19 , R 20 , and R 26 is independently selected from H, C1-C3 alkyl, and the alkyl is optionally replaced by Substituted by one or more of the following substituents: halogen, hydroxyl, amino, C1-C3 alkyl.
  30. 根据权利要求1或2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 claim 1 or 2, wherein the compound structure is selected from one of the following:
    Figure PCTCN2022101219-appb-100068
    Figure PCTCN2022101219-appb-100068
    Figure PCTCN2022101219-appb-100069
    Figure PCTCN2022101219-appb-100069
    Figure PCTCN2022101219-appb-100070
    Figure PCTCN2022101219-appb-100070
    Figure PCTCN2022101219-appb-100071
    Figure PCTCN2022101219-appb-100071
    Figure PCTCN2022101219-appb-100072
    Figure PCTCN2022101219-appb-100072
    Figure PCTCN2022101219-appb-100073
    Figure PCTCN2022101219-appb-100073
  31. 权利要求1-30任一项所述化合物的制备方法，其特征在于，所述方法包括以下步骤：式1-1化合物与式1-2化合物进行成环反应得式1-3化合物，式1-3化合物与POX3进行反应得到式1-4化合物；The preparation method of the compound described in any one of claims 1-30, characterized in that the method comprises the following steps: the compound of formula 1-1 and the compound of formula 1-2 are subjected to ring-forming reaction to obtain the compound of formula 1-3, formula 1 -3 compound reacts with POX3 to obtain formula 1-4 compound;
    Figure PCTCN2022101219-appb-100074
    Figure PCTCN2022101219-appb-100074
    其中，X表示卤素；A、A 1、A 2、A 3、A 4的定义同式(I)化合物，R 1’的定义同式(I)化合物中的R 1。 Wherein, X represents halogen; the definition of A, A 1 , A 2 , A 3 , A 4 is the same as that of the compound of formula (I), and the definition of R 1' is the same as that of R 1 in the compound of formula (I).
  32. 一种药用组合物，其特征在于，该药用组合物活性成份选自权利要求1～30任一权利要求所述的化合物或其互变异构体、立体异构体、溶剂化物、代谢产物、同位素标记物、药学上可接受的盐或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 tautomer, stereoisomer, solvate, metabolic One or a combination of two or more of products, isotope labels, pharmaceutically acceptable salts or co-crystals.
  33. 权利要求1～30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、同位素标记物、药学上可接受的盐或共晶、权利要求32所述药物组合物在制备SOS1抑制剂中的用途。The compound described in any one of claims 1-30 or its tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt or co-crystal, the drug described in claim 32 Use of the composition in the preparation of SOS1 inhibitors.
  34. 权利要求1～30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、同位素标记物、药学上可接受的盐或共晶、权利要求32所述药物组合物在制备用于治疗由SOS1介导的疾病的药物中的用途；The compound described in any one of claims 1-30 or its tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt or co-crystal, the drug described in claim 32 Use of the composition in the preparation of a medicament for treating diseases mediated by SOS1;
    优选地，所述疾病选自：癌症、病原性皮疹病；Preferably, the disease is selected from: cancer, pathogenic rash disease;
    更优选地，所述癌症选自：非小细胞肺癌、肺癌、胰腺癌、卵巢癌、膀胱癌、前列腺癌、慢性粒细胞白血病、结直肠癌、脑癌、肝癌、肾癌、胃癌、及乳腺癌；More preferably, the cancer is selected from the group consisting of 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, and breast cancer cancer;
    更优选地，所述病原性皮疹病选自：努南综合症、心面皮肤综合症、I型遗传性牙龈纤维瘤病。More preferably, the pathogenic rash disease is selected from the group consisting of Noonan syndrome, cardiofacial skin syndrome, and hereditary gingival fibromatosis type I.
  35. 权利要求1～30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、同位素标记物、药学上可接受的盐或共晶、权利要求32所述药物组合物在制备治疗致使SOS1蛋白过度表达的疾病的药物中的用途。The compound described in any one of claims 1-30 or its tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt or co-crystal, the drug described in claim 32 Use of the composition in the preparation of medicines for treating diseases that cause SOS1 protein overexpression.
  36. 权利要求1～30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、同位素标记物、药学上可接受的盐或共晶、权利要求32所述药物组合物在制备治疗SOS1蛋白过度表达所致疾病的药物中的用途。The compound described in any one of claims 1-30 or its tautomer, stereoisomer, solvate, metabolite, isotope label, pharmaceutically acceptable salt or co-crystal, the drug described in claim 32 Use of the composition in preparing medicine for treating diseases caused by overexpression of SOS1 protein.
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