WO2022268209A1 - Dérivé ayant une structure cyclique fusionnée à la pyrimidine, et son utilisation - Google Patents

Dérivé ayant une structure cyclique fusionnée à la pyrimidine, et son utilisation 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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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/zh
Publication of WO2022268209A1 publication Critical patent/WO2022268209A1/fr

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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

Sont divulgués un dérivé ayant une structure cyclique fusionnée à la pyrimidine et son utilisation. Le composé a un effet inhibiteur significatif sur l'activité de la protéine SOS1 ; peut être utilisé en tant qu'inhibiteur de protéine SOS1 ; a une excellente pharmacopotentialité ; peut être utilisé pour préparer des médicaments pour le traitement de maladies médiées par la protéine SOS1, telles que le cancer et les éruptions pathogènes ; et a de vastes perspectives d'application.
PCT/CN2022/101219 2021-06-24 2022-06-24 Dérivé ayant une structure cyclique fusionnée à la pyrimidine, et son utilisation WO2022268209A1 (fr)

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Cited By (1)

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WO2019201848A1 (fr) * 2018-04-18 2019-10-24 Bayer Pharma Aktiengesellschaft 2-méthyl-aza-quinazolines
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