WO2023116866A1 - 一种五元并六元化合物、制备方法、药物组合物和应用 - Google Patents

一种五元并六元化合物、制备方法、药物组合物和应用 Download PDF

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WO2023116866A1
WO2023116866A1 PCT/CN2022/141282 CN2022141282W WO2023116866A1 WO 2023116866 A1 WO2023116866 A1 WO 2023116866A1 CN 2022141282 W CN2022141282 W CN 2022141282W WO 2023116866 A1 WO2023116866 A1 WO 2023116866A1
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substituted
membered
unsubstituted
heteroatoms
alkyl
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English (en)
French (fr)
Chinese (zh)
Inventor
向少云
吴蕾
徐瑞
张强
杨刚
向麦可
童米雪
向蜜尔
刘渝鑫
王苏月
杨瑞
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Hangzhou Polymed Biopharmaceuticals Inc
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Hangzhou Polymed Biopharmaceuticals Inc
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Priority to CN202280030429.8A priority Critical patent/CN117177965B/zh
Priority to EP22910177.9A priority patent/EP4434981A4/en
Priority to JP2024538334A priority patent/JP7746587B2/ja
Priority to CN202410575992.4A priority patent/CN118530221A/zh
Publication of WO2023116866A1 publication Critical patent/WO2023116866A1/zh
Priority to US18/544,546 priority patent/US12195479B2/en
Anticipated expiration legal-status Critical
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
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    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
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    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
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Definitions

  • the invention relates to a five- and six-membered compound, a preparation method, a pharmaceutical composition and application.
  • FMS-like tyrosine kinase 3 is a type III receptor tyrosine kinase whose mutation is one of the most common genetic alterations and poor prognosis factors in patients with acute myeloid leukemia (AML).
  • FLT3 mutations are mainly internal tandem duplication mutations in the paramembrane domain (FLT3-ITD) and point mutations or deletions in the tyrosine kinase domain (FLT3-TKD), accounting for about 30% of AML patients (Kiyoi H, Kawashima N , Ishikawa Y. FLT3 mutations in acute myeloid leukemia: Therapeutic paradigm beyond inhibitor development. Cancer Sci. 2020 Feb; 111(2):312-322).
  • FLT3 Activated FLT3 induces abnormalities in multiple intracellular signaling pathways (such as RAS, PI3K, and STAT5), resulting in hematopoietic cell survival, proliferation, differentiation, and resistance to apoptosis.
  • mutant-wild-type allele ratio, insertion site, ITD length, karyotype, and the presence of NPM1 mutations can influence the prognostic role of FLT3-ITD in newly diagnosed patients with FLT3-ITD-mutated AML (Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019 Feb; 33(2):299-312.
  • the first-generation FTL3 inhibitors are broad-spectrum inhibitors, such as Lestaurtinib, Sunitinib, Sorafenib, Ponatinib, and Midostaurin, which can inhibit multiple kinases, but their efficacy is not good. There is no clear efficacy when combined with chemical drugs, and the toxicity increases significantly.
  • Midostaurin alone is not effective, but it can be used in combination with Cytarabine, Daunorubicin and Cytarabine (approved by FDA) for the treatment of AML with FLT3 mutation in adults.
  • Second-generation FLT3 kinase inhibitors such as Gilteritinib, Crenolanib, and Quizartinib are more selective, more active, and less toxic, but still have certain off-target effects.
  • Target-dependent mutations are common activation loops (such as aspartate 835, D835) and gating switch residues (such as phenylalanine 691, F691), among which D835 mutation is the most common target drug resistance mutation site.
  • the activation of related signaling pathways can also compensate for the inhibition of FLT3 signaling pathways.
  • some researchers have directly inhibited related signaling pathways (such as PI3K/AKT and/or RAS/MEK/MAPK) or jointly inhibited cell survival-related signaling pathways To reduce the proportion of non-target drug resistance, but the effect is still limited (Rabik CA, Wang J, Pratilas CA. FLT3-IRAK dual targeting: an exciting new therapeutic option guided by adaptive activation of immune response pathways. Ann Transl Med. 2020 Apr;8(7):511.). After Quizartinib and Gilteritinib were administered for a period of time, although the expression of pFLT3 and pSTAT5 was reduced, the tumor cells were not significantly inhibited.
  • IRAK4 can be used as a non-target drug resistance target.
  • Interleukin-1 receptor-associated kinases are serine/threonine protein kinases belonging to the tyrosine-like kinase (TLK) family, of which IRAK1 and IRAK4 have kinase activity. IRAKs are located downstream of toll like receptor and IL-1R pathways, and play an important role in innate immune signal transduction. Stimulation of TLRs recruits MYD88 and activates the receptor complex, which then forms a complex with IRAK4 to activate IRAK1. Subsequently, TRAF6 is activated by IRAK1, leading to NF-kB activation.
  • TLRs tyrosine-like kinase
  • Abnormal activation of the IRAK pathway in tumor cells can further promote disease progression through inflammatory responses in the tumor microenvironment (Gummadi VR, Boruah A, Ainan BR, Vare BR, Manda S, Gondle HP, Kumar SN, Mukherjee S, Gore ST, Krishnamurthy NR , Marappan S, Nayak SS, Nellore K, Balasubramanian Wr, Bhumireddy A, Giri S, Gopinath S, Samiulla Ds, Daginakatte G, Basavaraju a, Chelur S, ESWarappa R, BelliAppPPPPPPPPPPPPPPPPPPPP a C, Subramanya HS, Booher RN, Ramachandra M, Samajdar S.
  • the invention provides a five- and six-membered compound, a preparation method, a pharmaceutical composition and an application.
  • the compound of the present invention has an inhibitory effect on FLT3 and/or IRAK4, has potential clinical application value, and is expected to improve the prognosis of patients and reduce the possibility of drug resistance.
  • the present invention provides a five- and six-membered compound as shown in formula I or a pharmaceutically acceptable salt thereof,
  • Y is N or CH
  • E is N or CH
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • R 3 is hydrogen or does not exist; when R 3 does not exist, N and the atoms on the ring Cy 1 form a ring Cy 3 , or N and the atoms on the R 2 form a ring Cy 2 ;
  • Ring Cy 1 is a 5-membered heteroaryl ring, the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Ring Cy 2 is a 5 to 9-membered heterocyclic ring; the heteroatoms of the 5 to 9-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 and at least one heteroatom is an N atom;
  • Ring Cy3 is an oxo 5-9 membered heterocyclic ring; the heteroatoms of the oxo 5-9 membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 One or three and at least one heteroatom is N atom;
  • Each R is independently hydrogen, halogen, nitro, cyano, hydroxyl, -SO 2 -R a , -SO-R a , 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-4 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 1-5 , unsubstituted or substituted by one or more A 5- to 10-membered heteroaryl group substituted by R 1-6 , a C 1 -C 6 alkoxy group that is unsubstituted or substituted by one or more R 1-7 , a hydroxyl group substituted by R 1-8 , or -O- COR a ; the heteroatoms of the 3 to 11-
  • R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 is independently deuterium, halogen, oxo, Hydroxy, 3- to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , Cyano, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , 3 to 10-membered cycloalkyl unsubstituted or substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • R 1-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 is independently deuterium, unsubstituted or C 1 -C 6 alkyl substituted by one or more halogens, halogen, oxo, or hydroxyl;
  • R 2 is hydrogen, halogen, cyano, hydroxyl, nitro, -SO 2 -R a , -SO-R a , 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 2-2 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 2-5 , unsubstituted or substituted by one or more A 5- to 10-membered heteroaryl group substituted by R 2-6 , a hydroxyl group substituted by R 2-8 , a C 1 -C 6 alkoxy group unsubstituted or substituted by one or more R 2-7 , or -O- COR a ; the heteroatoms of the 3 to 11-membered
  • Each of R 2-1 , R 2-2 , R 2-4 , R 2-5 , R 2-6 and R 2-7 is independently deuterium, halogen, oxo, hydroxyl, unsubstituted or replaced by one or more R 2-1-1 substituted 3- to 11-membered heterocycloalkyl, Cyano, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-1-3 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-1-4 , 3 to 10-membered cycloalkyl unsubstituted or substituted by one or more R 2-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl, or 5 to 10 membered heteroaryl; the heteroatoms of the 3 to 11 membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1 1, 2 or 3
  • R 2-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • Each of R 2-1-1 , R 2-1-3 , R 2-1-4 and R 2-1-5 is independently deuterium, C 1 -C 6 alkane unsubstituted or substituted by one or more halogens radical, halogen, oxo or hydroxyl;
  • Each R4 is independently hydrogen, halogen, 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R4-1 , alkyl unsubstituted or substituted by one or more R4-2 , unsubstituted 3- to 11-membered heterocycloalkyl substituted or substituted by one or more R 4-3 , cycloalkyl unsubstituted or substituted by one or more R 4-4 , or unsubstituted or substituted by one or more R 4-5 substituted 6- to 10-membered aryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S or O, and the number of heteroatoms is 1 or 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;
  • each R 4-1 and R 4-5 is independently halogen, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 4-1-1 , cyano, oxo, hydroxyl or unsubstituted or substituted by one or more R 4-1-3 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 4-1-4 3 to A 10-membered cycloalkyl group, or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-1-5 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from N, S One or more of O and O, the number of heteroatoms is 1, 2 or 3;
  • R 4-2 , R 4-3 and R 4-4 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, Oxo or
  • Each of R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 is independently halogen, hydroxyl, 3 to 10-membered cycloalkyl, 3 to 11-membered heterocycloalkane C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens or C 1 -C 6 alkoxy unsubstituted or substituted by one or more halogens;
  • R 4-3-1 is H, C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • Each R a and each R b are independently H, unsubstituted or substituted by one or more R a-1 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R a-2 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R a-3 , 6 to 10 membered aryl unsubstituted or substituted by one or more R a-4 , Or a 5 to 10 membered heteroaryl group that is unsubstituted or substituted by one or more R a-5 ; or R a and R b form a 3 to 11 membered heterocyclic ring together with the atoms connected to it; the 3 to 11 membered heteroaryl
  • the heteroatoms of the cycloalkyl group are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to
  • Each of R a-1 , R a-2 , R a-3 , R a-4 and R a-5 is independently halogen, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; the heteroatom of said 3 to 11 membered heterocycloalkyl One or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3.
  • the present invention provides a five- and six-membered compound as shown in formula I or a pharmaceutically acceptable salt thereof,
  • Y is N or CH
  • E is N or CH
  • n 1, 2 or 3;
  • n 1, 2 or 3;
  • R 3 is hydrogen or does not exist; when R 3 does not exist, N and the atoms on the ring Cy 1 form a ring Cy 3 , or N and the atoms on the R 2 form a ring Cy 2 ;
  • Ring Cy 1 is a 5-membered heteroaryl ring, the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Ring Cy 2 is a 5 to 9-membered heterocyclic ring; the heteroatoms of the 5 to 9-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 and at least one heteroatom is an N atom;
  • Ring Cy3 is an oxo 5-9 membered heterocyclic ring; the heteroatoms of the oxo 5-9 membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 One or three and at least one heteroatom is N atom;
  • Each R is independently hydrogen, halogen, nitro, cyano, hydroxyl, -SO 2 -R a , -SO-R a , 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-4 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 1-5 , unsubstituted or substituted by one or more A 5- to 10-membered heteroaryl group substituted by R 1-6 , a C 1 -C 6 alkoxy group that is unsubstituted or substituted by one or more R 1-7 , a hydroxyl group substituted by R 1-8 , or -O- COR a ; the heteroatoms of the 3 to 11-
  • R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 is independently halogen, oxo, Hydroxy, 3- to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , Cyano, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , 3 to 10-membered cycloalkyl unsubstituted or substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • R 1-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 is independently unsubstituted or replaced by one or multiple halogen substituted C 1 -
  • R 2 is hydrogen, halogen, cyano, hydroxyl, nitro, -SO 2 -R a , -SO-R a , 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 2-2 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 2-5 , unsubstituted or substituted by one or more A 5- to 10-membered heteroaryl group substituted by R 2-6 , a hydroxyl group substituted by R 2-8 , a C 1 -C 6 alkoxy group unsubstituted or substituted by one or more R 2-7 , or -O- COR a ; the heteroatoms of the 3 to 11-membered
  • Each of R 2-1 , R 2-2 , R 2-4 , R 2-5 , R 2-6 and R 2-7 is independently halogen, oxo, hydroxyl, unsubstituted or replaced by one or more R 2 - 1-1 substituted 3 to 11 membered heterocycloalkyl, Cyano, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-1-3 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-1-4 , 3 to 10-membered cycloalkyl unsubstituted or substituted by one or more R 2-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl, or 5 to 10 membered heteroaryl; the heteroatoms of the 3 to 11 membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1 1, 2 or 3; the hetero
  • R 2-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • Each of R 2-1-1 , R 2-1-3 , R 2-1-4 and R 2-1-5 is independently unsubstituted or C 1 -C 6 alkyl substituted by one or more halogens, Halogen, oxo or hydroxy;
  • Each R4 is independently hydrogen, halogen, 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R4-1 , alkyl unsubstituted or substituted by one or more R4-2 , unsubstituted 3- to 11-membered heterocycloalkyl substituted or substituted by one or more R 4-3 , cycloalkyl unsubstituted or substituted by one or more R 4-4 , or unsubstituted or substituted by one or more R 4-5 substituted 6- to 10-membered aryl; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S or O, and the number of heteroatoms is 1 or 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;
  • each R 4-1 and R 4-5 is independently halogen, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 4-1-1 , cyano, oxo, hydroxyl or unsubstituted or substituted by one or more R 4-1-3 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 4-1-4 3 to A 10-membered cycloalkyl group, or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-1-5 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from N, S One or more of O and O, the number of heteroatoms is 1, 2 or 3;
  • R 4-2 , R 4-3 and R 4-4 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, Oxo or
  • Each of R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 is independently halogen, hydroxyl, 3 to 10-membered cycloalkyl, 3 to 11-membered heterocycloalkane C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens or C 1 -C 6 alkoxy unsubstituted or substituted by one or more halogens;
  • R 4-3-1 is H, C 1 -C 6 alkyl or C 1 -C 6 alkoxy
  • Each R a and each R b are independently H, unsubstituted or substituted by one or more R a-1 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R a-2 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R a-3 , 6 to 10 membered aryl unsubstituted or substituted by one or more R a-4 , Or a 5 to 10 membered heteroaryl group that is unsubstituted or substituted by one or more R a-5 ; or R a and R b form a 3 to 11 membered heterocyclic ring together with the atoms connected to it; the 3 to 11 membered heteroaryl
  • the heteroatoms of the cycloalkyl group are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to
  • Each of R a-1 , R a-2 , R a-3 , R a-4 and R a-5 is independently halogen, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; the heteroatom of said 3 to 11 membered heterocycloalkyl One or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3.
  • the definition of some groups can be as follows, and the definition of other groups can be as described in any scheme (hereinafter referred to as "In a certain preferred embodiment"): the ring Cy 2 is a 5-6 membered heterocyclic ring; the heteroatom of the 5-6 membered heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3.
  • the ring Cy 3 is an oxo 5- to 9-membered heterocyclic ring; the heteroatom of the oxo-substituted 5- to 9-membered heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3.
  • each R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , unsubstituted or 3 to 10 membered cycloalkyl substituted by one or more R 1-2 , or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one of N, S and O, or Two kinds, the number of heteroatoms is 1, 2 or 3.
  • each of R 1-1 , R 1-2 and R 1-4 is independently halogen, oxo, hydroxyl, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, or unsubstituted or substituted by one or more R 1-1-1 3 to 10 membered heterocycloalkyl, the heteroatom of said 3 to 10 membered heterocycloalkyl One or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • each of R 1-1 , R 1-2 and R 1-4 is independently deuterium, halogen, oxo, hydroxyl, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, or unsubstituted or substituted by one or more R 1-1-1 3 to 10 membered heterocycloalkyl, the heteroatom of said 3 to 10 membered heterocycloalkyl One or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • each R 1-1-1 is independently hydroxyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo, or halogen.
  • each R 1-1-1 is independently deuterium, hydroxyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo, or halogen.
  • each R 1-1-3 is independently hydroxyl or halogen.
  • each R 1-1-4 is independently hydroxyl or halogen.
  • each R 1-1-5 is independently hydroxyl or halogen.
  • each R 1-1-3 is independently deuterium, hydroxyl or halogen.
  • each R 1-1-4 is independently deuterium, hydroxyl or halogen.
  • each R 1-1-5 is independently deuterium, hydroxyl or halogen.
  • R 2 is hydrogen, hydroxyl, halogen, cyano, unsubstituted or 3 to 10 membered heterocycloalkyl substituted by one or more R 2-1 , unsubstituted or substituted by one or more R 2-2 substituted 3- to 8-membered cycloalkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , C unsubstituted or substituted by one or more R 2-7 1 -C 6 alkoxy or hydroxyl substituted by R 2-8 ; the heteroatoms of the 3- to 10-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 , 2 or 3.
  • each of R 2-1 , R 2-2 , R 2-4 and R 2-7 is independently oxo, hydroxyl, halogen, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycle Alkyl, or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • each of R 2-1 , R 2-2 , R 2-4 and R 2-7 is independently deuterium, oxo, hydroxyl, halogen, 3 to 6-membered cycloalkyl, 3 to 6-membered Heterocycloalkyl, or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • R 2-8 is 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl; the heteroatom of the 3 to 6 membered heterocycloalkyl is selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3.
  • each R 4 is independently hydrogen, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, benzene unsubstituted or substituted by one or more R 4-5 radical, unsubstituted or substituted by one or more R 4-1 5 to 6 membered heteroaryl, unsubstituted or 3 to 6 membered heterocycloalkyl substituted by one or more R 4-3 ; said 3
  • the heteroatoms of the 6-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5-6 membered heteroaryl groups Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • each R 4-1 is independently oxo, hydroxyl or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • each R 4-3 is independently halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or oxo.
  • each R 4-5 is independently oxo, hydroxyl or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • each R 4-3-1 is C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • each R a and each R b are independently hydrogen, or C 1 -C 6 alkyl unsubstituted or substituted by one or more R a-1 ; or R a and R b are connected to Atoms together form a 3 to 6-membered heterocyclic ring; the heteroatoms of the 3 to 6-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 .
  • each R a-1 is independently C 1 -C 6 alkyl, halogen or hydroxyl.
  • n 1
  • n 1
  • Y is N.
  • E is CH.
  • R 3 is hydrogen
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or 3 to 10-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3 to 10-membered heterocycloalkyl is one or more of N, O or S species, and the number of heteroatoms is 1 or 2.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 6-membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or 3 to 6-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3 to 6-membered heterocycloalkyl is one or both of N, O or S species, the number of heteroatoms is 1.
  • R 1 is A 3- to 6-membered cycloalkyl group substituted with a hydroxyl group, a 6-membered cycloalkyl group substituted with a -SO 2 -C 1 -C 6 alkyl group, or
  • each R 1-1 , R 1-2 and R 1-4 are independently deuterium, oxo, hydroxyl, halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, or unsubstituted or substituted by one or more R 1-1-1 3 to 10 membered heterocycloalkyl, the heteroatom of said 3 to 10 membered heterocycloalkyl One or more of N, O or S, and the number of heteroatoms is 1, 2 or 3.
  • each R 1-1 , R 1-2 and R 1-4 are independently deuterium, hydroxyl, Oxo, halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 substituted 3 to 6 membered cycloalkyl, or unsubstituted or 3 to 6 membered heterocycloalkyl substituted by one or more R 1-1-1 , said 3 to 6 membered heterocyclic
  • the heteroatoms of the alkyl group are one or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-1 is independently oxo, or C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 .
  • each R 1-2 is independently halogen, hydroxyl or -SO 2 -C 1 -C 6 alkyl.
  • each R 1-4 is independently deuterium, hydroxyl, Halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 or unsubstituted or substituted by one or more R 1-1 -1- substituted 3- to 6-membered heterocycloalkyl, the heteroatoms of the 3- to 6-membered heterocycloalkyl are one or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-1-1 is independently oxo or hydroxyl.
  • each R 1-1-1 is independently oxo, halogen or hydroxyl.
  • each R 1-1-4 is independently halogen.
  • each R 1-1-5 is independently a hydroxyl group.
  • R 2 is a 3- to 6-membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , C 3 -C unsubstituted or substituted by one or more R 2-2 6 cycloalkyl, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , Or a hydroxyl group substituted by R 2-8 ; the heteroatoms of the 3- to 6-membered heterocycloalkyl group are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.
  • R 2 is a 3- to 6-membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , C 1 -C unsubstituted or substituted by one or more R 2-7 6 alkoxy or C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 ; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from N and/or O, heteroatoms The number is 1 or 2.
  • R 2 is C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 or C 1 -C unsubstituted or substituted by one or more R 2-4 6 alkyl.
  • R 2-8 is 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl; the heteroatom of the 3 to 6 membered heterocycloalkyl is selected from one of N and O or two, and the number of heteroatoms is 1.
  • each R 2-1 is independently hydroxyl or halogen.
  • each R 2-2 is independently a hydroxyl group.
  • each R 2-4 is independently a hydroxyl group.
  • each R 2-7 is independently halogen.
  • each R 2-4 is independently deuterium, halogen or hydroxyl.
  • each R 2-7 is independently deuterium or halogen.
  • each R 4 is independently hydrogen, halogen, unsubstituted or substituted by one or more halogen alkyl, unsubstituted or substituted by one or more R 4-1 5 to 6-membered heteroaryl phenyl, unsubstituted or substituted by one or more R 4-5 , or 3 to 6 membered heterocycloalkyl unsubstituted or substituted by one or more R 4-3 , said 5 to 6 membered heteroaryl
  • the heteroatom of the group is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 3 to 6-membered heterocycloalkyl are selected from one or more of N, S and O, and the heteroatoms are The number of atoms is 1 or 2 (preferably each R 4 is independently unsubstituted or substituted by one or more R 4-1 5 to 6 membered heteroaryl, the heteroaryl of the 5 to 6 membered heteroaryl atom is N, and the number of heteroatoms
  • each R 4 is independently unsubstituted or substituted by one or more R 4-1 pyridyl.
  • each of R 4-1 and R 4-5 is independently a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more halogens.
  • each R 4-1 is independently unsubstituted C 1 -C 6 alkyl substituted by one, two, or three halogens.
  • each R 4-3 is independently halogen, unsubstituted or C 1 -C 6 alkyl substituted by one or more halogens.
  • each R a and each R b are independently H or C 1 -C 6 alkyl; or R a and R b form a 3 to 6-membered heterocycle together with the atoms connected to them; the 3 to 6
  • the heteroatom of the 6-membered heterocyclic ring is S, and the number of heteroatoms is 1.
  • the five-membered and six-membered compound shown in formula I is a compound shown in formula Ia
  • the five-membered and six-membered compound shown in formula I is a compound shown in formula Ib
  • the five-membered and six-membered compound shown in formula I is a compound shown in formula Ic
  • R 1 is
  • R 2 is methoxy, isopropoxy, trifluoromethoxy, hydroxyl, -OCD 3 ,
  • each R 4 is independently hydrogen, bromine, trifluoromethyl
  • ring Cy 1 is
  • ring Cy 2 is
  • ring Cy 3 is
  • the five- and six-membered compound represented by formula I or a pharmaceutically acceptable salt thereof is any of the following compounds,
  • the present invention provides a five- and six-membered compound as shown in formula II or a pharmaceutically acceptable salt thereof,
  • n 1, 2 or 3;
  • E is N or CH
  • Ring Cy 1 is a 5-membered heteroaryl ring; the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • R 3 is hydrogen or absent; when R 3 is absent, N forms a ring Cy 3 with the atom on ring Cy 1 and the atom attached to it, or N forms a ring with the atom on R 2 and the atom attached to it Cy 2 ;
  • Ring Cy 2 is a 5 to 9-membered heterocyclic ring; the heteroatoms of the 5 to 9-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 and at least one heteroatom is an N atom;
  • Ring Cy3 is an oxo 5-9 membered heterocyclic ring; the heteroatoms of the oxo 5-9 membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 One or three and at least one heteroatom is N atom;
  • Each R is independently hydrogen, halogen, nitro, cyano, hydroxyl, -SO 2 -R a , -SO-R a , 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1 , 3 to 10 membered cycloalkyl substituted by one or more R 1-2 , C 1 -C 6 alkyl substituted by one or more R 1-4 , 6- to 10-membered aryl unsubstituted or substituted by one or more R 1-5 , unsubstituted or substituted by one or more R 1 -6 substituted 5- to 10-membered heteroaryl, unsubstituted or C 1 -C 6 alkoxy substituted by one or more R 1-7 , hydroxy substituted by R 1-8 or -O-COR a ;
  • the heteroatoms of the 3 to 11 membered heterocycloalkyl are selected from one or more of N, S and O, and the number of hetero
  • R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 is independently deuterium, halogen, oxo, Hydroxy, 3- to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , Cyano, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , 3 to 10-membered cycloalkyl unsubstituted or substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • R 1-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 is independently deuterium, unsubstituted or C 1 -C 6 alkyl substituted by one or more halogens, halogen, oxo, or hydroxyl;
  • R 2 is 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 8 membered cycloalkyl unsubstituted or substituted by one or more R 2-2 , unsubstituted Or C 1 -C 6 alkoxy substituted by one or more R 2-7 , hydroxyl substituted by R 2-8 , or C 1 -C 6 alkyl substituted by one or more R 2-4 ;
  • the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each of R2-1 and R2-7 is independently deuterium, hydroxyl, halogen, oxo, C1 - C6 alkyl unsubstituted or substituted by one or more halogens, 3 to 10 membered cycloalkyl, or A 3- to 8-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 2-1-1 ; the heteroatom of the 3- to 8-membered heterocycloalkyl group is selected from one of N, S and O, or Various, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-2 is independently deuterium, halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of said 3 to 8-membered heterocycloalkyl is selected from one of N, S and O One or more kinds, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-4 is independently deuterium, halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of said 3 to 8-membered heterocycloalkyl is selected from one of N, S and O One or more kinds, the number of heteroatoms is 1, 2 or 3;
  • R 2-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-1-1 is independently hydroxyl, halogen, oxo, C 1 -C 6 alkyl, 3 to 10 membered cycloalkyl, or 3 to 8 membered heterocycloalkyl; the 3 to 8 membered heterocycloalkyl
  • the heteroatoms of the cycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • R 2 is unsubstituted or substituted by one or more R 2-1 3- to 7-membered monoheterocycloalkyl
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4
  • each R 1-4 is independently deuterium, halogen, hydroxyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , cyano, 3- to 10-membered cycloalkyl group unsubstituted or substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or
  • Each R a and each R b are independently H, unsubstituted or substituted by one or more R a-1 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R a-2 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R a-3 , 6 to 10 membered aryl unsubstituted or substituted by one or more R a-4 , or 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R a-5 ;
  • R a and R b form a 3 to 11-membered heterocyclic ring together with the atoms connected to it; the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the heteroatom The number is 1, 2 or 3; the heteroatoms of the 3- to 11-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 indivual;
  • Each of R a-1 , R a-2 , R a-3 , R a-4 and R a-5 is independently halogen, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; the heteroatom of said 3 to 11 membered heterocycloalkyl One or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3;
  • Each R is independently 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R 4-1 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 4-5 , unsubstituted A 3- to 11-membered heterocycloalkyl group substituted or substituted by one or more R 4-3 ; the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or more of N, S and O, The number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each R 4-1 and R 4-5 is independently halogen, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 4-1-1 , cyano, oxo, hydroxyl or unsubstituted or substituted by one or more R 4-1-3 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 4-1-4 3 to A 10-membered cycloalkyl group, or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-1-5 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from N, S One or more of O and O, the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or oxo;
  • Each of R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 is independently halogen, hydroxyl, 3 to 10-membered cycloalkyl, 3 to 11-membered heterocycloalkane C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens or C 1 -C 6 alkoxy unsubstituted or substituted by one or more halogens; said 3 to 11-membered heterocycloalkane
  • the heteroatoms of the group are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • the present invention provides a five- and six-membered compound as shown in formula II or a pharmaceutically acceptable salt thereof,
  • n 1, 2 or 3;
  • E is N or CH
  • Ring Cy 1 is a 5-membered heteroaryl ring; the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • R 3 is hydrogen or absent; when R 3 is absent, N forms a ring Cy 3 with the atom on ring Cy 1 and the atom attached to it, or N forms a ring with the atom on R 2 and the atom attached to it Cy 2 ;
  • Ring Cy 2 is a 5 to 9-membered heterocyclic ring; the heteroatoms of the 5 to 9-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 and at least one heteroatom is an N atom;
  • Ring Cy3 is an oxo 5-9 membered heterocyclic ring; the heteroatoms of the oxo 5-9 membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 One or three and at least one heteroatom is N atom;
  • Each R is independently hydrogen, halogen, nitro, cyano, hydroxyl, -SO 2 -R a , -SO-R a , 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-4 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 1-5 , unsubstituted or substituted by one or more A 5- to 10-membered heteroaryl group substituted by R 1-6 , a C 1 -C 6 alkoxy group that is unsubstituted or substituted by one or more R 1-7 , a hydroxyl group substituted by R 1-8 , or -O- COR a ; the heteroatoms of the 3 to 11-
  • R 1-1 , R 1-2 , R 1-4 , R 1-5 , R 1-6 and R 1-7 is independently halogen, oxo, Hydroxy, 3- to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , Cyano, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , 3 to 10-membered cycloalkyl unsubstituted or substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • R 1-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • R 1-1-1 , R 1-1-3 , R 1-1-4 , R 1-1-5 , R 1-1-7 and R 1-1-8 is independently unsubstituted or replaced by one or multiple halogen substituted C 1 -C 6 alkyl, halogen, oxo, or hydroxyl;
  • R 2 is 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 8 membered cycloalkyl unsubstituted or substituted by one or more R 2-2 , unsubstituted Or C 1 -C 6 alkoxy substituted by one or more R 2-7 , hydroxyl substituted by R 2-8 , or C 1 -C 6 alkyl substituted by one or more R 2-4 ;
  • the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Each R 2-1 and R 2-7 is independently hydroxyl, halogen, oxo, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 10 membered cycloalkyl, or unsubstituted Or a 3- to 8-membered heterocycloalkyl group substituted by one or more R 2-1-1 ; the heteroatoms of the 3- to 8-membered heterocycloalkyl group are selected from one or more of N, S and O , the number of heteroatoms is 1, 2 or 3;
  • Each R 2-2 is independently halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of the 3 to 8-membered heterocycloalkyl is selected from one of N, S and O, or Various, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-4 is independently halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of the 3 to 8-membered heterocycloalkyl is selected from one of N, S and O, or Various, the number of heteroatoms is 1, 2 or 3;
  • R 2-8 is 3 to 10 membered cycloalkyl, 6 to 10 membered aryl, 3 to 11 membered heterocycloalkyl, or 5 to 10 membered heteroaryl; Atoms are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl group are selected from N, S and O One or more of, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-1-1 is independently hydroxyl, halogen, oxo, C 1 -C 6 alkyl, 3 to 10 membered cycloalkyl, or 3 to 8 membered heterocycloalkyl; the 3 to 8 membered heterocycloalkyl
  • the heteroatoms of the cycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • R is unsubstituted or substituted by one or more R 2-1 3 to 7 membered monoheterocycloalkyl or is unsubstituted or substituted by one or more R 2-2 3 to 6 membered cycloalkyl
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4
  • each R 1-4 is independently halogen, 3- to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , cyano, 3- to 10-membered cycloalkyl substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • Each R a and each R b are independently H, unsubstituted or substituted by one or more R a-1 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R a-2 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R a-3 , 6 to 10 membered aryl unsubstituted or substituted by one or more R a-4 , or 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R a-5 ;
  • R a and R b form a 3 to 11-membered heterocyclic ring together with the atoms connected to it; the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the heteroatom The number is 1, 2 or 3; the heteroatoms of the 3- to 11-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 indivual;
  • Each of R a-1 , R a-2 , R a-3 , R a-4 and R a-5 is independently halogen, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; the heteroatom of said 3 to 11 membered heterocycloalkyl One or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3;
  • Each R is independently 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R 4-1 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 4-5 , unsubstituted A 3- to 11-membered heterocycloalkyl group substituted or substituted by one or more R 4-3 ; the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or more of N, S and O, The number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each R 4-1 and R 4-5 is independently halogen, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 4-1-1 , cyano, oxo, hydroxyl or unsubstituted or substituted by one or more R 4-1-3 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 4-1-4 3 to A 10-membered cycloalkyl group, or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-1-5 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from N, S One or more of O and O, the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or oxo;
  • Each of R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 is independently halogen, hydroxyl, 3 to 10-membered cycloalkyl, 3 to 11-membered heterocycloalkane C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens or C 1 -C 6 alkoxy unsubstituted or substituted by one or more halogens;
  • Each R 4-3-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • ring Cy1 is a 5-membered heteroaryl ring, the heteroatoms of the 5-membered heteroaryl ring are selected from one or both of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • R is unsubstituted or substituted by one or more R 2-1 3 to 7 membered monoheterocycloalkyl or is unsubstituted or substituted by one or more R 2-2 3 to 6 membered cycloalkyl
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4
  • each R 1-4 is independently halogen, unsubstituted or substituted by one or more R 1-1-1 3 to 11 membered heterocycloalkyl, cyano, 3- to 10-membered cycloalkyl substituted by one or more R 1-1-5 , -SO 2 -R a , -SO-R a , 6 to 10 membered aryl groups that are unsubstituted or substituted by one or more R 1-1-8 , or 5 to 10 membered heteroaryl groups that are unsubstituted or substituted by one or more R 1-1-7 ;
  • the ring Cy 2 is a 5- to 6-membered heterocyclic ring; the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3.
  • the ring Cy 3 is an oxo 5- to 9-membered heterocyclic ring; the heteroatom of the oxo-substituted 5- to 9-membered heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl substituted by one or more R 1-2 or unsubstituted or A 3- to 11-membered heterocycloalkyl group substituted by one or more R 1-1 ; the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or both of N, S and O, and the heteroatom The number is 1, 2 or 3.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or A 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 1-1 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from one or both of N, S and O , the number of heteroatoms is 1, 2 or 3.
  • each of R 1-1 , R 1-2 and R 1-4 is independently deuterium, halogen, oxo, hydroxyl, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, or 3 to 10 membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1-1 , the heteroatom of the 3 to 10 membered heterocycloalkyl One or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • each of R 1-1 , R 1-2 and R 1-4 is independently halogen, oxo, hydroxyl, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 1-1-3 , -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 10 membered cycloalkyl, or 3 to 10 membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1-1 , the heteroatom of the 3 to 10 membered heterocycloalkyl One or two of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • each R 1-1-1 is independently hydroxyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo, or halogen.
  • each R 1-1-1 is independently deuterium, hydroxyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo, or halogen.
  • each R 1-1-1 is independently hydroxyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo, or halogen.
  • each R 1-1-3 is independently deuterium, hydroxyl or halogen.
  • each R 1-1-4 is independently deuterium, hydroxyl or halogen.
  • each R 1-1-5 is independently deuterium, hydroxyl or halogen.
  • R 2 is a 3- to 10-membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , a 3- to 6-membered unsubstituted or substituted by one or more R 2-2 Cycloalkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 , or Hydroxyl substituted by R 2-8 ; the heteroatoms of the 3- to 10-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1, 2 or 3.
  • each R 2-1 and R 2-7 is independently deuterium, oxo, hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 6 A membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group; the heteroatoms of the 3- to 8-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1 or 2.
  • each R 2-1 and R 2-7 is independently deuterium, oxo, hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 6 A membered cycloalkyl group, or a 3- to 8-membered heterocycloalkyl group; the heteroatoms of the 3- to 8-membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1 or 2.
  • each R 2-2 is independently deuterium, halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatoms of the 3- to 8-membered heterocycloalkyl are selected from N, One or more of S and O, the number of heteroatoms is 1 or 2.
  • each R 2-2 is independently a hydroxyl group or a hydroxyl group substituted by a 3- to 8-membered heterocycloalkyl group; the heteroatom of the 3- to 8-membered heterocycloalkyl group is selected from N, S and O One or more of , and the number of heteroatoms is 1 or 2.
  • each R 2-4 is independently deuterium, halogen, hydroxyl or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatoms of the 3- to 8-membered heterocycloalkyl are selected from N, One or more of S and O, the number of heteroatoms is 1 or 2.
  • each R 2-4 is independently a hydroxyl group or a hydroxyl group substituted by a 3- to 8-membered heterocycloalkyl group; the heteroatom of the 3- to 8-membered heterocycloalkyl group is selected from N, S and O One or more of , and the number of heteroatoms is 1 or 2.
  • R 2-8 is 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl; the heteroatom of the 3 to 6 membered heterocycloalkyl is selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3.
  • each R 4 is independently unsubstituted or substituted by one or more R 4-5 phenyl, unsubstituted or substituted by one or more R 4-1 5 to 6-membered heteroaryl , 3 to 6-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 4-3 ;
  • the heteroatoms of the 3 to 6-membered heterocycloalkyl are selected from one or more of N, S and O species, the number of heteroatoms is 1, 2 or 3;
  • the heteroatoms of the 5- to 6-membered heteroaryl are selected from one or more of N, S or O, and the number of heteroatoms is 1 , 2 or 3.
  • each of R 4-1 and R 4-5 is independently oxo, hydroxyl or C 1 -C 6 alkyl that is unsubstituted or substituted by one or more halogens.
  • each R 4-3 is independently halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or oxo.
  • each R 4-3-1 is independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • E is CH.
  • each R a and each R b are independently H or C 1 -C 6 alkyl; or R a and R b form a 3 to 6-membered heterocycle together with the atoms connected to them; the 3 to 6
  • the heteroatom of the 6-membered heterocyclic ring is S, and the number of heteroatoms is 1.
  • R 2 is 3 to 7 membered monoheterocycloalkyl unsubstituted or substituted by one or more R 2-1
  • R 1 is C substituted by one or more R 1-4
  • each R 1-4 is independently deuterium, hydroxyl, halogen, unsubstituted or 3 to 8 membered heterocycloalkyl substituted by one or more R 1-1-1 , substituted by one or A 3- to 10-membered cycloalkyl group substituted by multiple R 1-1-5 , -SO 2 -R a or
  • the heteroatoms of the 3- to 8-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.
  • R 2 when R 2 is unsubstituted or substituted by one or more R 2-1 3 to 7 membered monoheterocycloalkyl or unsubstituted or substituted by one or more R 2-2 3 to 7 6-membered cycloalkyl, and when R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 ; each R 1-4 is independently halogen, 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , 3 to 10 membered cycloalkyl substituted by one or more R 1-1-5 , -SO 2 - R a , -SO-R a or
  • the heteroatoms of the 3- to 8-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.
  • n 1
  • R 3 is hydrogen
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl substituted by one or more R 1-2 or unsubstituted or A 3- to 10-membered heterocycloalkyl group substituted by one or more R 1-1 ; the heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O or S, and the heteroatom The number is 1 or 2.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or A 3- to 10-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3- to 10-membered heterocycloalkyl group is one or more of N, O or S , the number of heteroatoms is 1 or 2.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 6-membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3 to 8-membered heterocycloalkyl is one or both of N, O or S species, the number of heteroatoms is 1.
  • R 1 is A 3- to 6-membered cycloalkyl group substituted with a hydroxyl group, a 6-membered cycloalkyl group substituted with a -SO 2 -C 1 -C 6 alkyl group, or
  • each R 1-1 , R 1-2 and R 1-4 are independently deuterium, oxo, hydroxyl, Halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-1-5 , or unsubstituted
  • each R 1-1 , R 1-2 and R 1-4 are independently deuterium, hydroxyl, Oxo, Halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 6 membered cycloalkyl, or unsubstituted or 3 to 6 membered heterocycloalkyl substituted by one or more R 1-1-1 , the heteroatom of said 3 to 6 membered heterocycloalkyl One or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-1 is independently oxo, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 or 3 to 6 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 ,
  • the heteroatoms of the 3- to 6-membered heterocycloalkyl are one or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-2 is independently halogen, hydroxyl or -SO 2 -C 1 -C 6 alkyl.
  • each R 1-4 is independently deuterium, hydroxyl, Halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 or unsubstituted or substituted by one or more R 1-1 -1- substituted 3- to 6-membered heterocycloalkyl, the heteroatoms of the 3- to 6-membered heterocycloalkyl are one or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-1-1 is independently oxo, halogen, or hydroxyl.
  • each R 1-1-4 is independently halogen.
  • each R 1-1-5 is independently a hydroxyl group.
  • R 2 is a 3- to 8-membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , C 3 -C unsubstituted or substituted by one or more R 2-2 6 cycloalkyl, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 , C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , Hydroxyl substituted by R 2-8 ; the heteroatoms of the 3- to 8-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.
  • R 2 is a 3- to 6-membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , C 1 -C unsubstituted or substituted by one or more R 2-7 6 alkoxy or C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 ; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from N and/or O, heteroatoms The number is 1 or 2.
  • R 2 is C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 or C 1 -C unsubstituted or substituted by one or more R 2-4 6 alkyl.
  • R 2-8 is 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl; the heteroatom of the 3 to 6 membered heterocycloalkyl is selected from one of N and O or two, and the number of heteroatoms is 1.
  • each R 2-1 is independently hydroxyl or halogen.
  • each R 2-2 is independently a hydroxyl group.
  • each R 2-4 is independently deuterium, hydroxyl or halogen.
  • each R 2-7 is independently deuterium or halogen.
  • R 4 is unsubstituted or substituted by one or more R 4-5 phenyl, unsubstituted or substituted by one or more R 4-1 5-6 membered heteroaryl or unsubstituted Or a 3- to 6-membered heterocycloalkyl group substituted by one or more R 4-3 , the heteroatom of the 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1, 2 or 3;
  • the heteroatoms of the 3 to 6-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1 or 2 (preferably, each R 4 is independently unsubstituted Or a 5- to 6-membered heteroaryl group substituted by one or more R 4-1 , the heteroatom of the 5- to 6-membered heteroaryl group is N, and the number of heteroatoms is 1 or 2).
  • each R 4 is independently unsubstituted or substituted by one or more R 4-1 pyridyl.
  • each of R 4-1 and R 4-5 is independently a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more halogens.
  • each R 4-1 is independently unsubstituted C 1 -C 6 alkyl substituted by one, two, or three halogens.
  • each R 4-3 is independently halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo or
  • each R 4-3-1 is independently C 1 -C 6 alkyl or C 1 -C 6 alkoxy.
  • the five-membered and six-membered compound shown in formula II is a compound shown in formula II-a, II-b, II-c or II-d
  • R 1 is
  • R 2 is methoxy, -OCD 3 , isopropoxy, trifluoromethoxy,
  • each R 4 is independently
  • ring Cy 1 is
  • the five- and six-membered compound represented by formula II or a pharmaceutically acceptable salt thereof is any of the following compounds,
  • the present invention provides a five- and six-membered compound as shown in formula III or a pharmaceutically acceptable salt thereof,
  • ring Cy 4 is an imidazole ring, an oxazole ring, a thiazole ring, a 5-membered heterocycle or an oxo 5-membered heterocycle; the heteroatom of the 5-membered heterocycle is selected from one or more of N, S and O species, the number of heteroatoms is 1, 2 or 3;
  • X is N or C;
  • Q is N or C;
  • E is N or CH;
  • R 3 is hydrogen or absent; when R 3 is absent, N forms a ring Cy 3 with the atom on ring Cy 1 and the atom attached to it, or N forms a ring with the atom on R 2 and the atom attached to it Cy 2 ;
  • Ring Cy 1 is a 5-membered heteroaryl ring; the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Ring Cy 2 is a 5 to 9-membered heterocyclic ring; the heteroatoms of the 5 to 9-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 and at least one heteroatom is an N atom;
  • Ring Cy3 is an oxo 5-9 membered heterocyclic ring; the heteroatoms of the oxo 5-9 membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 One or three and at least one heteroatom is N atom;
  • Each R 1 is independently C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or unsubstituted Or a 3 to 11 membered heterocycloalkyl group substituted by one or more R 1-1 , the heteroatom of the 3 to 11 membered heterocycloalkyl group is selected from one or more of N, O and S, the heteroatom The number is 1, 2 or 3;
  • Each R 1-4 is independently 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , deuterium, hydroxyl, halogen, unsubstituted or substituted by one or more R 1- 1-5 substituted 3- to 10-membered cycloalkyl, Or -SO 2 -C 1 -C 6 alkyl; the heteroatoms of the 3- to 8-membered heterocycloalkyl are N and/or O, and the number of heteroatoms is 1, 2 or 3;
  • Each R 1-1 is independently deuterium, halogen, oxo, hydroxyl, 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 10 membered cycloalkane A group or a 6- to 10-membered aryl group; the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3;
  • Each R 1-2 is independently deuterium, hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or -SO 2 -C 1 -C 6 alkyl;
  • Each R 1-1-1 is independently C 1 -C 6 alkyl, oxo, halogen, or hydroxyl;
  • Each R 1-1-5 is independently unsubstituted or substituted by one or more halogen C 1 -C 6 alkyl, halogen, oxo or hydroxyl;
  • At least one R 1 is a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 1-1 ,
  • the 3- to 11-membered heterocycloalkyl group is bicyclic;
  • R 2 is -OCD 3
  • ring Cy 1 is a 5-membered heteroaryl ring; the heteroatom of the 5-membered heteroaryl ring is N, and the number of heteroatoms is 2;
  • R 2 is 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 8 membered cycloalkyl unsubstituted or substituted by one or more R 2-2 , unsubstituted Or C 1 -C 6 alkoxy substituted by one or more R 2-7 , hydroxyl substituted by R 2-8 , or C 1 -C 6 alkyl substituted by one or more R 2-4 ;
  • the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Each of R 2-1 , R 2-2 and R 2-7 is independently deuterium, hydroxyl, halogen, oxo, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 10 members Cycloalkyl, or a 3 to 8 membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 2-1-1 ; the heteroatoms of the 3 to 8 membered heterocycloalkyl group are selected from N, S and O One or more of them, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-4 is independently deuterium, halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of said 3 to 8-membered heterocycloalkyl is selected from one of N, S and O One or more kinds, the number of heteroatoms is 1, 2 or 3;
  • R 2-8 is 3 to 10 membered cycloalkyl or 3 to 11 membered heterocycloalkyl; the heteroatom of the 3 to 11 membered heterocycloalkyl is selected from one or more of N, S and O, The number of heteroatoms is 1, 2 or 3;
  • Each R 2-1-1 is independently deuterium, hydroxyl, halogen, oxo, C 1 -C 6 alkyl, 3 to 10 membered cycloalkyl, or 3 to 8 membered heterocycloalkyl;
  • the heteroatoms of the membered heterocycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each R 1 is independently C 1 -C 6 substituted by one or more R 1-4 Alkyl, 3 to 10 membered cycloalkyl substituted by one or more hydroxyl groups or halogen, 3 to 10 membered cycloalkyl substituted by one or more -SO 2 -R a , 3 to 8-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , and each R 1-4 is independently hydroxyl, deuterium, halogen, unsubstituted or substituted by one or more R 1 -1-1 substituted 3 to 8 membered N or S heterocycloalkyl, unsubstituted or 3 to 6 membered cycloalkyl substituted by one or more R 1-1-5 , SO 2 -R a , -SO -R a or The heteroatoms of the 3- to
  • R 2 is unsubstituted or substituted by one or more R 2-1 6-membered monoheterocycloalkyl or unsubstituted 3 to 6-membered cycloalkyl
  • each R 1 is independently substituted by one or more R
  • each R 1-4 substituted C 1 -C 6 alkyl each R 1-4 is independently unsubstituted or substituted by one or more R 1-1-1 3 to 8 membered heterocycloalkyl, deuterium, halogen , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-1-5 or
  • the heteroatoms of the 3- to 8-membered heterocycloalkyl are N and/or O, and the number of heteroatoms is 1, 2 or 3;
  • Each R is independently 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R 4-1 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 4-5 , unsubstituted A 3- to 11-membered heterocycloalkyl group substituted or substituted by one or more R 4-3 ; the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or more of N, S and O, The number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each R 4-1 and R 4-5 is independently halogen, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 4-1-1 , cyano, oxo, hydroxyl or unsubstituted or substituted by one or more R 4-1-3 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 4-1-4 3 to A 10-membered cycloalkyl group, or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-1-5 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from N, S One or more of O and O, the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or oxo;
  • Each of R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 is independently halogen, hydroxyl, 3 to 10-membered cycloalkyl, 3 to 11-membered heterocycloalkane C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens or C 1 -C 6 alkoxy unsubstituted or substituted by one or more halogens; said 3 to 11-membered heterocycloalkane
  • the heteroatoms of the group are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each R a and each R b are independently H, unsubstituted or substituted by one or more R a-1 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R a-2 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R a-3 , 6 to 10 membered aryl unsubstituted or substituted by one or more R a-4 , or 5 to 10-membered heteroaryl unsubstituted or substituted by one or more R a-5 ;
  • the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from one or more of N, S and O , the number of heteroatoms is 1, 2 or 3;
  • the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • R a and R b form a 3 to 11-membered heterocyclic ring together with the atoms connected to it; the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the heteroatom The number is 1, 2 or 3;
  • Each of R a-1 , R a-2 , R a-3 , R a-4 and R a-5 is independently halogen, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; the heteroatom of said 3 to 11 membered heterocycloalkyl One or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3.
  • the present invention provides a five- and six-membered compound as shown in formula III or a pharmaceutically acceptable salt thereof,
  • ring Cy 4 is an imidazole ring, a 5-membered heterocycle or an oxo 5-membered heterocycle; the heteroatoms of the 5-membered heterocycle are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • X is N or C;
  • Q is N or C;
  • E is N or CH;
  • R 3 is hydrogen or absent; when R 3 is absent, N forms a ring Cy 3 with the atom on ring Cy 1 and the atom attached to it, or N forms a ring with the atom on R 2 and the atom attached to it Cy 2 ;
  • Ring Cy 1 is a 5-membered heteroaryl ring; the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Ring Cy 2 is a 5 to 9-membered heterocyclic ring; the heteroatoms of the 5 to 9-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 and at least one heteroatom is an N atom;
  • Ring Cy3 is an oxo 5-9 membered heterocyclic ring; the heteroatoms of the oxo 5-9 membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 One or three and at least one heteroatom is N atom;
  • Each R 1 is independently C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or unsubstituted Or a 3 to 11 membered heterocycloalkyl group substituted by one or more R 1-1 , the heteroatom of the 3 to 11 membered heterocycloalkyl group is selected from one or more of N, O and S, the heteroatom The number is 1, 2 or 3;
  • Each R 1-4 is independently unsubstituted or substituted by one or more R 1-1-1 3 to 8 membered heterocycloalkyl, hydroxyl, halogen, unsubstituted or substituted by one or more R 1-1-1 5- substituted 3- to 10-membered cycloalkyl, Or -SO 2 -C 1 -C 6 alkyl; the heteroatom of the 3- to 8-membered heterocycloalkyl is N, and the number of heteroatoms is 1, 2 or 3;
  • Each R 1-1 is independently halogen, oxo, hydroxyl, 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 10 membered cycloalkane A group or a 6- to 10-membered aryl group; the heteroatom of the 3- to 8-membered heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3;
  • Each R 1-2 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or -SO 2 -C 1 -C 6 alkyl;
  • Each R 1-1-1 is independently C 1 -C 6 alkyl, oxo or hydroxyl;
  • Each R 1-1-5 is independently unsubstituted or substituted by one or more halogen C 1 -C 6 alkyl, halogen, oxo or hydroxyl;
  • R 2 is 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 8 membered cycloalkyl unsubstituted or substituted by one or more R 2-2 , unsubstituted Or C 1 -C 6 alkoxy substituted by one or more R 2-7 , hydroxyl substituted by R 2-8 , or C 1 -C 6 alkyl substituted by one or more R 2-4 ;
  • the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • Each of R 2-1 , R 2-2 and R 2-7 is independently hydroxyl, halogen, oxo, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, 3 to 10 membered cycloalkane A group, or a 3 to 8 membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 2-1-1 ; the heteroatoms of the 3 to 8 membered heterocycloalkyl group are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3;
  • Each R 2-4 is independently halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of the 3 to 8-membered heterocycloalkyl is selected from one of N, S and O, or Various, the number of heteroatoms is 1, 2 or 3;
  • R 2-8 is 3 to 10 membered cycloalkyl or 3 to 11 membered heterocycloalkyl; the heteroatom of the 3 to 11 membered heterocycloalkyl is selected from one or more of N, S and O, The number of heteroatoms is 1, 2 or 3;
  • Each R 2-1-1 is independently hydroxyl, halogen, oxo, C 1 -C 6 alkyl, 3 to 10 membered cycloalkyl, or 3 to 8 membered heterocycloalkyl; the 3 to 8 membered heterocycloalkyl
  • the heteroatoms of the cycloalkyl group are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each R 1 is independently C 1 -C 6 substituted by one or more R 1-4 Alkyl, and each R 1-4 is independently hydroxyl, SO 2 -R a , -SO-R a or
  • R 2 is unsubstituted or substituted by one or more R 2-1 6-membered monoheterocycloalkyl or unsubstituted 3 to 6-membered cycloalkyl, and each R 1 is independently substituted by one or more R
  • each R 1-4 substituted C 1 -C 6 alkyl each R 1-4 is independently 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , unsubstituted or 3 to 10 membered cycloalkyl substituted by one or more R 1-1-5 or
  • the heteroatom of the 3- to 8-membered heterocycloalkyl is N, and the number of heteroatoms is 1, 2 or 3;
  • Each R is independently 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R 4-1 , 6 to 10 membered aryl unsubstituted or substituted by one or more R 4-5 , unsubstituted A 3- to 11-membered heterocycloalkyl group substituted or substituted by one or more R 4-3 ; the heteroatom of the 3- to 11-membered heterocycloalkyl group is selected from one or more of N, S and O, The number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3;
  • each R 4-1 and R 4-5 is independently halogen, C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 4-1-1 , cyano, oxo, hydroxyl or unsubstituted or substituted by one or more R 4-1-3 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R 4-1-4 3 to A 10-membered cycloalkyl group, or a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-1-5 ; the heteroatoms of the 3- to 11-membered heterocycloalkyl group are selected from N, S One or more of O and O, the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3 is independently hydroxyl, halogen, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, or oxo;
  • Each of R 4-1-1 , R 4-1-3 , R 4-1-4 and R 4-1-5 is independently halogen, hydroxyl, 3 to 10-membered cycloalkyl, 3 to 11-membered heterocycloalkane C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens or C 1 -C 6 alkoxy unsubstituted or substituted by one or more halogens; said 3 to 11-membered heterocycloalkane
  • the heteroatoms of the group are selected from one or more of N, S or O, and the number of heteroatoms is 1, 2 or 3;
  • Each R 4-3-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each R a and each R b are independently H, unsubstituted or substituted by one or more R a-1 C 1 -C 6 alkyl, unsubstituted or substituted by one or more R a-2 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl unsubstituted or substituted by one or more R a-3 , 6 to 10 membered aryl unsubstituted or substituted by one or more R a-4 , or 5 to 10 membered heteroaryl unsubstituted or substituted by one or more R a-5 ;
  • R a and R b form a 3 to 11-membered heterocyclic ring together with the atoms connected to it; the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from one or more of N, S and O, and the heteroatom The number is 1, 2 or 3; the heteroatoms of the 3- to 11-membered heterocyclic ring are selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3 indivual;
  • Each of R a-1 , R a-2 , R a-3 , R a-4 and R a-5 is independently halogen, cyano, hydroxyl, nitro, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, 3 to 10 membered cycloalkyl, 3 to 11 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl; the heteroatom of said 3 to 11 membered heterocycloalkyl One or more selected from N, S and O, the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 5- to 10-membered heteroaryl are selected from N, S and O One or more, the number of heteroatoms is 1, 2 or 3.
  • ring Cy 4 is an imidazole ring, an oxazole ring, a thiazole ring, a 5-membered heterocycle or an oxo 5-membered heterocycle; the heteroatom of the 5-membered heterocycle is O, the number of heteroatoms is 1, and the heteroatom of the oxo 5-membered heterocyclic ring is N, and the number of heteroatoms is 1.
  • the ring Cy 4 is an imidazole ring, a 5-membered heterocyclic ring or an oxo 5-membered heterocyclic ring; the heteroatom of the 5-membered heterocyclic ring is O, and the number of heteroatoms is 1, and the oxo 5-membered heterocyclic ring is The heteroatom of the membered heterocyclic ring is N, and the number of the heteroatom is 1.
  • the ring Cy 1 is a 5-membered heteroaryl ring
  • the heteroatoms of the 5-membered heteroaryl ring are selected from one or both of N, S and O, and the number of heteroatoms is 1, 2 or 3.
  • the ring Cy 2 is a 5- to 6-membered heterocyclic ring; the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3.
  • the ring Cy 3 is an oxo 5- to 9-membered heterocyclic ring; the heteroatom of the oxo-substituted 5- to 9-membered heterocyclic ring is N, and the number of heteroatoms is 1, 2 or 3.
  • each R 1 is independently C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 10-membered unsubstituted or substituted by one or more R 1-2 Cycloalkyl, 3 to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1 ; the heteroatoms of the 3 to 11-membered heterocycloalkyl are selected from N, O and S One or two kinds, and the number of heteroatoms is 1 or 2.
  • each R 1-4 is independently unsubstituted or substituted by one or more R 1-1-1 3- to 8-membered heterocycloalkyl, hydroxyl, halogen, unsubstituted or substituted by one or more 3 to 10-membered cycloalkyl or -SO 2 -C 1 -C 6 alkyl substituted by R 1-1-5 ; the heteroatom of the 3 to 8-membered heterocycloalkyl is N, and the number of heteroatoms is 1, 2 or 3.
  • each R 1-4 is independently deuterium, 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 , hydroxyl, halogen, unsubstituted or substituted by one or multiple R 1-1-5 substituted 3 to 10 membered cycloalkyl groups, Or -SO 2 -C 1 -C 6 alkyl; the heteroatoms of the 3- to 8-membered heterocycloalkyl are one or two of N, S or O, and the number of heteroatoms is 1 or 2 or 3.
  • each R 1-1 is independently oxo, hydroxyl, or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • each R 1-1 is independently halogen, oxo, hydroxyl, 3 to 8 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, said 3 to 8 membered
  • the heteroatom of the heterocycloalkyl group is N, and the number of heteroatoms is 1, 2 or 3.
  • each R 1-2 is independently hydroxyl or halogen.
  • each R 1-2 is independently hydroxyl, -SO 2 -C 1 -C 6 alkyl or halogen.
  • each R 1-1-1 is independently C 1 -C 6 alkyl, oxo or hydroxyl.
  • each R 1-1-1 is independently deuterium, C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens, oxo, halogen or hydroxyl.
  • R 2 is a 3- to 11-membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , a 3- to 6-membered unsubstituted or substituted by one or more R 2-2 Cycloalkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , hydroxyl substituted by R 2-8 , or unsubstituted or substituted by one or more R 2-7 C 1 -C 6 alkoxy; the heteroatoms of the 3- to 11-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.
  • each of R 2-1 and R 2-2 is independently oxo, hydroxyl or C 1 -C 6 alkyl that is unsubstituted or substituted by one or more halogens.
  • each of R 2-1 and R 2-2 is independently deuterium, oxo, halogen, hydroxyl or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • each R 2-4 is independently halogen, hydroxyl, or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatom of the 3- to 8-membered heterocycloalkyl is N, S or O One or two of them, and the number of heteroatoms is 1 or 2.
  • each R 2-4 is independently deuterium, halogen, hydroxyl or hydroxyl substituted by 3 to 8-membered heterocycloalkyl; the heteroatoms of the 3- to 8-membered heterocycloalkyl are N, S Or one or two of O, and the number of heteroatoms is 1 or 2.
  • R 2-8 is 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl; the heteroatom of the 3 to 6 membered heterocycloalkyl is selected from one of N and O or two, and the number of heteroatoms is 1 or 2.
  • each R 2-7 is independently halogen.
  • each R 2-7 is independently deuterium or halogen.
  • each R 4 is independently unsubstituted or substituted by one or more R 4-5 phenyl, unsubstituted or substituted by one or more R 4-1 5 to 6-membered heteroaryl or unsubstituted or substituted by one or more R 4-3 3 to 6 membered heterocycloalkyl, the heteroatom of the 5 to 6 membered heteroaryl is N, and the number of heteroatoms is 1, 2 or 3; the heteroatoms of the 3- to 6-membered heterocycloalkyl are selected from one or more of N, S and O, and the number of heteroatoms is 1 or 2.
  • each of R 4-1 and R 4-5 is independently a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more halogens.
  • each R 4-3 is independently halogen or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • the ring Cy 1 is a 5-membered heteroaryl ring
  • the heteroatoms of the 5-membered heteroaryl ring are selected from one or both of N and O, and the number of heteroatoms is 2.
  • the ring Cy 2 is a 5- to 6-membered heterocyclic ring; the heteroatom of the 5- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2.
  • the ring Cy 3 is an oxo 5- to 6-membered heterocyclic ring; the heteroatom of the oxo-substituted 5- to 6-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2.
  • each R 1 is independently C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 6-membered unsubstituted or substituted by one or more R 1-2 Cycloalkyl, 3 to 6-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3 to 6-membered heterocycloalkyl is N, O or S One or two, and the number of heteroatoms is 1 or 2.
  • each R 1 is independently C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 6-membered unsubstituted or substituted by one or more R 1-2 Cycloalkyl, 3 to 8-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 1-1 ; the heteroatom of the 3 to 8-membered heterocycloalkyl is N, O or S One or two, and the number of heteroatoms is 1 or 2.
  • R 1 is C 1 -C 6 alkyl substituted by one or more R 1-4 , 3 to 6-membered cycloalkyl unsubstituted or substituted by one or more R 1-2 , or unsubstituted or substituted by one or more R 1-1 3 to 6-membered heterocycloalkyl; the heteroatoms of the 3 to 6-membered heterocycloalkyl are selected from one or both of N, O or S , and the number of heteroatoms is 1 or 2.
  • R 1 is A 3- to 6-membered cycloalkyl group substituted with a hydroxyl group, a 6-membered cycloalkyl group substituted with a -SO 2 -C 1 -C 6 alkyl group,
  • each R 1-1 , R 1-2 and R 1-4 are independently deuterium, hydroxyl, Oxo, Halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 , unsubstituted or substituted by one or more R 1-1-5 Substituted 3 to 6 membered cycloalkyl, or unsubstituted or 3 to 6 membered heterocycloalkyl substituted by one or more R 1-1-1 , the heteroatom of said 3 to 6 membered heterocycloalkyl One or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-1 is independently oxo, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 or 3 to 6 membered heterocycloalkyl unsubstituted or substituted by one or more R 1-1-1 ,
  • the heteroatoms of the 3- to 6-membered heterocycloalkyl are one or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-2 is independently halogen, hydroxyl or -SO 2 -C 1 -C 6 alkyl.
  • each R 1-4 is independently deuterium, hydroxyl, Halogen, -SO 2 -C 1 -C 6 alkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 1-1-4 or unsubstituted or substituted by one or more R 1-1 -1- substituted 3- to 8-membered heterocycloalkyl group, the heteroatom of the 3- to 8-membered heterocycloalkyl group is one or two of N, O or S, and the number of heteroatoms is 1.
  • each R 1-4 is independently unsubstituted or substituted by one or more R 1-1-1 3- to 8-membered heterocycloalkyl, deuterium, hydroxyl, halogen, unsubstituted or substituted by one or multiple R 1-1-5 substituted 3 to 6-membered cycloalkyl or -SO 2 -C 1 -C 6 alkyl; the heteroatom of the 3 to 8-membered heterocycloalkyl is N, and the number of heteroatoms The number is 1.
  • each R 1-1 is independently halogen, oxo, hydroxyl, or C 1 -C 6 alkyl unsubstituted or substituted by one or more halogens.
  • each R 1-2 is independently hydroxyl or halogen.
  • each R 1-1-1 is independently C 1 -C 6 alkyl or hydroxyl.
  • each R 1-1-1 is independently C 1 -C 6 alkyl, halogen or hydroxyl that is unsubstituted or substituted by one or more halogens.
  • R 2 is 3 to 7 membered heterocycloalkyl unsubstituted or substituted by one or more R 2-1 , 3 to 6 membered unsubstituted or substituted by one or more R 2-2 Cycloalkyl, C 1 -C 6 alkyl unsubstituted or substituted by one or more R 2-4 , or C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 ;
  • the heteroatoms of the 3- to 7-membered heterocycloalkyl are selected from one or both of N and O, and the number of heteroatoms is 1 or 2.
  • R 2 is a 5- to 6-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 2-1 , C 1 -C 6 alkyl substituted by one or more R 2-4 , or C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 ; the heteroatoms of the 5 to 6 heterocycloalkyl are selected from one or both of N and O, The number of heteroatoms is 1 or 2.
  • R 2 is a 5- to 6-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 2-1 , C 1 -C 6 alkyl substituted by one or more R 2-4 , or C 1 -C 6 alkoxy unsubstituted or substituted by one or more R 2-7 ; the heteroatom of the 5 to 6 heterocycloalkyl is N, and the number of heteroatoms is 1.
  • each of R 2-1 and R 2-2 is independently a hydroxyl group.
  • each R 2-1 is independently hydroxyl or halogen.
  • the 3- to 11-membered heterocycloalkyl is a spiro ring or a five-membered monocyclic ring.
  • each R 2-4 is independently a hydroxyl group.
  • each R 2-4 is independently hydroxyl, deuterium or halogen.
  • each R 2-7 is independently halogen.
  • each R 2-7 is independently halogen or deuterium.
  • each R 4 is independently 5 to 6 membered heteroaryl unsubstituted or substituted by one or more R 4-1 or phenyl unsubstituted or substituted by one or more R 4-5 , the heteroatom of the 5- to 6-membered heteroaryl is N, and the number of heteroatoms is 1 or 2.
  • each R 4 is independently unsubstituted or substituted by one or more R 4-1 pyridyl.
  • each of R 4-1 and R 4-5 is independently a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more fluorines.
  • each R 4-1 is independently unsubstituted C 1 -C 6 alkyl substituted by one, two, or three halogens.
  • the five-membered and six-membered compound shown in formula III is a compound shown in formula III-a, III-d, III-e or III-b
  • the five-membered and six-membered compound shown in formula III is as shown in formula III-c, III-f or III-g
  • each R 1 is independently
  • R 2 is methoxy, -OCD 3 , isopropoxy, trifluoromethoxy, hydroxyl,
  • each R 4 is independently hydrogen, bromine, trifluoromethyl
  • ring Cy 1 is
  • ring Cy 2 is
  • ring Cy 2 is
  • ring Cy 3 is
  • the five- and six-membered compound represented by formula III or a pharmaceutically acceptable salt thereof is any of the following compounds,
  • the heteroatoms of the 5-membered heteroaryl ring are selected from one or more of N, S and O, and the number of heteroatoms is 2;
  • the 5-membered heteroaryl ring is preferably is an oxazole ring, a pyrazole ring, a thiazole ring or an imidazole ring, for example
  • the 5 to 9-membered heterocyclic ring can be a 6-membered heterocyclic ring, the heteroatom of the 6-membered heterocyclic ring is N, and the number of heteroatoms is 1 or 2; preferably piperazine ring or piperidine ring.
  • the oxo 5-9 membered heterocyclic ring is a 6-membered heterocyclic ring whose heteroatom is N and the number of heteroatoms is 1 or 2; it is preferably an oxopiperazine ring or an oxygen Piperidine ring, such as
  • R 1 is halogen
  • said halogen is fluorine, chlorine, bromine or iodine.
  • the 3- to 11-membered heterocycloalkyl group can be a 3- to 9-membered heterocycle Alkyl
  • the 3 to 9-membered heterocycloalkyl is preferably piperidinyl, tetrahydropyrrolyl, 2-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, morpholinyl, Tetrahydropyranyl, azabicyclo[2.2.1]heptyl, tetrahydrothiopyranyl, 2-azaspiro[3.5]nonane, or diazabicyclo[2.2.1]heptyl, azabicyclo [3.2.1] octane, azaspiro [3.4] octane or oxabicyclo [3.2.1] octane;
  • R 1 is a 3 to 10 membered cycloalkyl group that is unsubstituted or substituted by one or more R 1-2
  • the 3 to 10 membered cycloalkyl group can be C 3 -C 6 cycloalkyl group , can also be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example, cyclopropyl, cyclobutyl or cyclohexyl
  • each R 1-2 is independently preferably -SO 2 -R a , halogen or Hydroxy
  • R a is C 1 -C 6 alkyl
  • 3 to 10 membered cycloalkyl unsubstituted or substituted by one or more R 1-2 is preferably
  • R 1 is a C 1 -C 6 alkyl group that is unsubstituted or substituted by one or more R 1-4
  • the C 1 -C 6 alkyl group can be methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, primary pentyl, sec-pentyl, tert-pentyl or neopentyl, It can also be methyl, ethyl, n-propyl, isopropyl or isopentyl; each R 1-4 is independently preferably deuterium, halogen, hydroxyl, -SO 2 -R a , 3 to 6 membered cycloalkyl substituted by hydroxy, 3 to 8 membered heterocycloalkyl substituted by hydroxy or 3 to 8
  • the halogen can be fluorine, chlorine, Bromine or iodine, eg fluorine.
  • the 3- to 11-membered heterocycloalkyl group is preferably a 3- to 7-membered heterocycloalkyl group, and the heteroatoms of the 3- to 11-membered heterocycloalkyl group are preferably is N and/or O, and the number of heteroatoms is 1 or 2;
  • the 3- to 11-membered heterocycloalkyl group is preferably tetrahydropyrrolyl, oxetanyl or oxygen and/or azaspiroheptyl ,For example
  • the C 1 -C 6 alkyl can be C 1 -C 4 alkyl, and can also be methyl, ethyl, n-propyl, isopropyl, n-butyl Base, isobutyl, primary butyl, sec-butyl or tert-butyl, can also be isopropyl, methyl or ethyl.
  • each R 1-1-1 is independently C 1 -C 6 alkyl
  • the C 1 -C 6 alkyl can be C 1 -C 4 alkyl, methyl, ethyl Base, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl or tert-butyl, and also methyl or ethyl.
  • the halogen when R 2 is halogen, the halogen may be fluorine, chlorine, bromine or iodine.
  • the 3- to 11-membered heterocycloalkyl group can be a 3- to 8-membered heterocycle Alkyl, the heteroatoms of the 3- to 11-membered heterocycloalkyl are preferably N and/or O, and the number of heteroatoms is 1 or 2;
  • the 3- to 11-membered heterocycloalkyl is preferably piperidinyl , Tetrahydropyrrolyl, 2-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, morpholinyl, tetrahydropyranyl, oxetanyl, azabicyclo[2.2.
  • each R 2-1 is independently preferably halogen, oxo or hydroxyl, the 3 to substituted or substituted by one or more R 2-1 8-membered heterocycloalkyl is preferably
  • R 2 is a 3- to 10-membered cycloalkyl group that is unsubstituted or substituted by one or more R 2-2
  • the 3- to 10-membered cycloalkyl group can be C 3 -C 6 cycloalkyl group , can also be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl, cyclobutyl or cyclohexyl
  • each R 2-2 is independently preferably halogen or hydroxyl
  • unsubstituted or replaced by one or multiple R 2-2 substituted 3 to 10 membered cycloalkyl groups are preferably
  • the C 1 -C 6 alkyl group can be methyl, ethyl, n-propyl base, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, primary pentyl, sec-pentyl, tert-pentyl or neopentyl, It can also be methyl, ethyl, n-propyl, isopropyl or isopentyl; each R 2-4 is independently preferably deuterium, halogen, hydroxyl, -SO 2 -R a or R a is C 1 -C 6 alkyl, R b is hydrogen; the C 1 -C 6 alkyl that is unsubstituted or substitute
  • the C 1 -C 6 alkoxy can be C 1 -C 4 alkane Oxygen can also be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, primary butoxy, sec-butoxy or tert-butoxy, and may be methoxy, ethoxy, or isopropoxy; each R 2-7 is independently preferably deuterium or halogen; the C 1 -C 6 alkane unsubstituted or substituted by one or more R 2-7 Oxy is preferably methoxy, isopropoxy, deuteromethoxy or trifluoromethoxy.
  • R 2 when R 2 is a hydroxyl group substituted by R 2-8 , R 2-8 can be 3 to 6 membered cycloalkyl or 3 to 6 membered heterocycloalkyl, and the 3 to 6 membered heterocycloalkane
  • the heteroatom of the base is oxygen, and the number of heteroatoms is 1; the hydroxyl group substituted by R 2-8 is preferably
  • the halogen may be fluorine, chlorine, Bromine or iodine, eg fluorine.
  • the 3- to 11-membered heterocycloalkyl group may be a 5- to 8-membered heterocycloalkyl group, and the heteroatoms of the 3- to 11-membered heterocycloalkyl group It is preferably N and/or O, and the number of heteroatoms is 1 or 2;
  • the 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 2-1-1 is preferably tetrahydropyrrolyl , oxetanyl or contain an oxygen and/or an azaspiroheptyl, for example
  • each R 2-1-1 is independently C 1 -C 6 alkyl
  • the C 1 -C 6 alkyl can be C 1 -C 4 alkyl, methyl, ethyl Base, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl or tert-butyl, and also methyl or ethyl.
  • R 4 when R 4 is a 5- to 10-membered heteroaryl group that is unsubstituted or substituted by one or more R 4-1 , the 5- to 10-membered heteroaryl group can be a 6-membered heteroaryl group, and the The 6-membered heteroaryl is preferably pyridazinyl or pyridyl; each R 4-1 is independently preferably C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens; 5 to 10 membered heteroaryl substituted or substituted by one or more R 4-1 is preferably
  • R 4 is a 6- to 10-membered aryl group that is unsubstituted or substituted by one or more R 4-5
  • the 6- to 10-membered aryl group can be a phenyl group; each R 4-5 is independently Preferred is C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens.
  • R 4 when R 4 is a 3- to 11-membered heterocycloalkyl group that is unsubstituted or substituted by one or more R 4-3 , the 3- to 11-membered heterocycloalkyl group is a 6-membered heterocycloalkyl group, Preferably piperazinyl, piperidinyl, thiomorpholinyl or morpholinyl; each R 4-3 is independently preferably halogen, C 1 -C 6 alkyl or C 1 -C substituted by one or more halogens 6 alkyl, oxo or R 4-3-1 is hydrogen, C 1 -C 6 alkyl or C 1 -C 6 alkoxy; the 3- to 8-membered heterocycloalkyl that is unsubstituted or substituted by one or more R 4-3 more preferably
  • each R 4 when each R 4 is independently halogen, the halogen may be fluorine, chlorine, bromine or iodine, such as bromine.
  • the C 1 -C 6 alkyl can be C 1 -C 4 alkyl, and Can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl or tert-butyl, can also be isopropyl, methyl or ethyl;
  • the halogen may be fluorine, chlorine, bromine or iodine, such as fluorine;
  • the C 1 -C 6 alkyl that is unsubstituted or substituted by one or more halogens is preferably a C 1 -C 6 alkyl substituted by fluorine, such as Difluoromethyl or trifluoromethyl.
  • the C 1 -C 6 alkyl when R 4-3 is C 1 -C 6 alkyl, can be C 1 -C 4 alkyl, and can also be methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl or tert-butyl, and can also be methyl or ethyl.
  • the C 1 -C 6 alkyl can be C 1 -C 4 alkyl, and can also be methyl, ethyl, n- Propyl, isopropyl, n-butyl, isobutyl, primary butyl, sec-butyl or tert-butyl, and also methyl or ethyl.
  • the heteroatoms of the 5-membered heterocyclic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2,
  • the heteroatoms of the 5-membered heterocyclic ring are selected from one or two of N, S and O, and the number of heteroatoms is 1 or 2,
  • the heteroatoms of the oxo 5-membered heterocyclic ring are selected from one or both of N and S, and the number of heteroatoms is 1 or 2
  • the oxo 5-membered heterocyclic ring is preferably
  • the 3 to 11 membered heterocyclic group can be a 3 to 6 membered heterocycloalkyl group, and the 3 to 6
  • the heteroatom of the membered heterocycloalkyl group is preferably N, O or S, and the number of heteroatoms is 1; the 3- to 11-membered heterocycle can be
  • -SO 2 -R a is preferably
  • the present invention also provides a method for preparing the five-membered and six-membered compound shown in formula I, II or III,
  • the preparation method of the five-membered and six-membered compound shown in formula I comprises the following steps: in a solvent, in the presence of a base and a condensing agent, the compound shown in formula I-A and the compound shown in formula I-B carry out the following steps: condensation reaction,
  • R 3 is hydrogen, n, m, Y, E, R 3 , ring Cy 1 , ring Cy 2 , ring Cy 3 , R 1 , R 2 and R 4 are as defined above;
  • the preparation method of the five-membered and six-membered compound shown in the formula II comprises the following steps: in a solvent, in the presence of a base and a condensing agent, the compound shown in the formula II-A is carried out with the compound shown in the formula II-B
  • R 3 is hydrogen, n, m, E, R 3 , ring Cy 1 , ring Cy 2 , ring Cy 3 , R 1 , R 2 and R 4 are as defined above;
  • the preparation method of the five-membered and six-membered compound shown in the formula III comprises the following steps: in a solvent, in the presence of a base and a condensing agent, the compound shown in the formula III-A is carried out with the compound shown in the formula III-B
  • R 3 is hydrogen, and n, m, E, X, Q, R 3 , ring Cy 1 , ring Cy 2 , ring Cy 3 , ring Cy 4 , R 1 , R 2 and R 4 are as defined above.
  • the solvent is a conventional solvent for this type of reaction in the art, preferably an amide solvent, more preferably DMF, such as anhydrous DMF.
  • the amount of the solvent is the amount of conventional solvents in the art, preferably the volume mole of the solvent and the compound shown in formula I-A, the compound shown in formula II-A or the compound shown in formula III-A
  • the ratio is (20-5):1 mL/mmol, eg 12:1 mL/mmol or 12.5:1.
  • the base is a conventional base for this type of reaction in the art, preferably a nitrogen-containing organic base, such as N,N-diisopropylethylamine.
  • the amount of the base is the amount of conventional bases in the art, preferably the molar ratio of the base to the compound shown in formula I-A, the compound shown in formula II-A or the compound shown in formula III-A It is (1-5):1, such as 1.5:1, 2:1 or 3:1.
  • the condensing agent is a condensing agent for this type of reaction in the art, preferably a phosphate condensing agent, such as tripyrrolidinylphosphonium bromide hexafluorophosphate or 2-(7-azabenzotriazine azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • a phosphate condensing agent such as tripyrrolidinylphosphonium bromide hexafluorophosphate or 2-(7-azabenzotriazine azole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • the amount of the condensing agent is the amount of common condensing agents in the art, preferably the condensing agent and the compound shown in formula I-A, the compound shown in formula II-A or the compound shown in formula III-A
  • the molar ratio of is (1-2):1, for example 1:1, 1.2:1, 1.3:1 or 1.5:1.
  • the reaction temperature of the condensation reaction is a conventional reaction temperature in the art, preferably -10°C-30°C, such as 0°C.
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned five- and six-membered compounds represented by formula I, formula II or formula III or pharmaceutically acceptable salts thereof, and pharmaceutical excipients.
  • the present invention also provides a pharmaceutical composition, which comprises the aforementioned five- and six-membered compounds represented by formula I, formula II or formula III or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides a substance Z used in the preparation of FLT3 and/or IRAK4 inhibitors or medicines for treating and/or preventing FLT3 and/or IRAK4-related diseases, the substance Z is the aforementioned five-membered formula I, II or III And hexa-membered compound or its pharmaceutically acceptable salt.
  • the FLT3-related diseases include hematological tumors and/or solid tumors.
  • the hematological tumor may be selected from acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic neutrophil leukemia, acute undifferentiated leukemia, anaplastic large cell Lymphoma, prolymphocytic leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, non-Hodgkin's lymphoma, multiple myeloma, myeloproliferative disorders, mantle cell lymphoma, and de novo acute myeloid leukemia in adults one or more of
  • the solid tumor may be selected from one or more of colorectal cancer, renal cell carcinoma, non-small cell lung cancer, bladder cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric adenocarcinoma, prostate cancer and lung cancer.
  • the IRAK4-related diseases include autoimmune diseases, inflammatory diseases, cardiovascular diseases, cancer or central nervous system diseases.
  • the autoimmune disease may be selected from rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetic (eg type I diabetes) psoriasis, psoriatic arthritis, atopic dermatitis
  • diabetic eg type I diabetes
  • psoriasis e.g. type I diabetes
  • psoriatic arthritis e.g., atopic dermatitis
  • atopic dermatitis e.g type I diabetes
  • the inflammatory disease may be selected from, without limitation, rheumatoid arthritis, osteoarthritis, juvenile arthritis, multiple sclerosis, lupus, diabetic (such as type I diabetes) psoriasis, psoriatic arthritis, specific One or more of dermatitis, chronic obstructive pulmonary disease, Crohn's disease, ulcerative colitis, and irritable bowel syndrome.
  • the cardiovascular disease may be stroke or atherosclerosis.
  • the present invention also provides a method for treating and/or preventing FLT3 and/or IRAK4-related diseases, which includes administering an effective amount of substance Z to the patient, and the substance Z is the aforementioned compound represented by formula I, II or III or its Pharmaceutically acceptable salts.
  • compound and “pharmaceutically acceptable salt”, if tautomers exist, may exist as a single tautomer or as a mixture thereof, preferably as a more stable tautomer Body-based form exists.
  • linking group is expressed as "absent"
  • the structures on both sides of the linking group are directly linked by a single bond, for example -A-B-C-, when B does not exist, -A-B-C- is -A-C-.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • oxo refers to the replacement of a hydrogen or a lone pair of electrons on a non-oxygen atom with an oxygen, for example, Oxygenated to Oxygenated to
  • cycloalkyl refers to a saturated monocyclic cyclic group consisting only of carbon atoms with a specified number of carbon atoms (eg, C 3 -C 10 ). Wherein the monocyclic alkyl group includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • alkyl refers to a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (eg, C 1 -C 6 ).
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, and the like.
  • heterocycloalkyl refers to a specified number of heteroatoms (such as 1, 2 or 3), a specified number of heteroatoms (such as 3 to 11 members, or 3 to 8 members) cyclic groups of species (one or more of N, O, and S) in which the heteroatom may or may not be attached to other groups as a linking group (e.g., piperidinyl may be etc.) which are monocyclic, bicyclic, bridged or spiro, and each ring is saturated.
  • Heterocycloalkyl includes, but is not limited to, azetidinyl, tetrahydropyrrolyl, tetrahydrofuranyl, morpholinyl, piperidinyl, and the like.
  • heterocycle refers to a specified number of ring atoms (such as 3 to 11 members, also such as 3 to 8 members), a specified number of heteroatoms (such as 1, 2 or 3), a specified heteroatom type ( One or more of N, O and S) cyclic group, wherein the heteroatom can be used as a linking group to be connected to other groups, or not to be connected to other groups, (for example, the piperidine ring can be etc.) It is a monocyclic ring, a double ring, a bridged ring or a spiro ring.
  • Heterocyclic rings include, but are not limited to, azetidinyl rings, tetrahydropyrrole rings, tetrahydrofuran rings, morpholine rings, piperidinyl rings.
  • aryl refers to a cyclic group consisting only of carbon atoms with a specified number of carbon atoms (such as C 6 to C 10 ), which is monocyclic or polycyclic, and at least one ring is aromatic ( in accordance with Huckel's rule).
  • the aryl group is connected to other segments in the molecule through an aromatic ring or a non-aromatic ring.
  • Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.
  • heteroaryl refers to a specified number of ring atoms (such as 5 to 10 members, also such as 5 to 8 members), a specified number of heteroatoms (such as 1, 2 or 3), and a specified heteroatom type (one or more of N, O, and S) cyclic groups, which are monocyclic or polycyclic, and at least one ring is aromatic (in accordance with Huckel's rule). Heteroaryl groups are linked to other moieties in the molecule through aromatic rings or non-aromatic rings.
  • Heteroaryl groups include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, and the like.
  • a "-" at the end of a group means that the group is attached to other fragments in the molecule through this site.
  • the structural fragment in the structure fragment means that the structural fragment is connected to other fragments in the molecule through this site.
  • any variable (such as the group R 1-1 ) appears multiple times in the definition of a compound, their definitions are independent of each other and do not affect each other.
  • a C 6 ⁇ C 10 aryl group substituted by 3 R 1-1 means that the C 6 ⁇ C 10 aryl group will be substituted by 3 R 1-1 , and the definitions of the 3 R 1-1 are independent of each other. Influence.
  • pharmaceutically acceptable salt refers to a salt obtained by reacting a compound with a pharmaceutically acceptable (relatively non-toxic, safe, and suitable for use by patients) acid or base.
  • base addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, bismuth salts, ammonium salts, and the like.
  • acid addition salts can be obtained by contacting the free form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochlorides, acetates, trifluoroacetates, sulfates, methanesulfonates, and the like. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, 2002) for details.
  • pharmaceutical excipients refers to the excipients and additives used in the production of drugs and the preparation of prescriptions, and refers to all substances contained in pharmaceutical preparations except for active ingredients. For details, see Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical EMcipients (Raymond C Rowe, 2009).
  • treating refers to any of the following: (1) amelioration of one or more biological manifestations of disease; (2) interference with one or more points in the biological cascade leading to disease; (3) slowing of disease The development of one or more biological manifestations.
  • prevention refers to reducing the risk of developing a disease.
  • patient refers to any animal, preferably a mammal, most preferably a human, who has been or is about to be treated. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is that: when the FLT3 inhibitor is used as a monotherapy, the disease relapses quickly, and target-dependent and non-target-dependent drug resistance has appeared; although the combination of drugs inhibiting cell survival-related signaling pathways can reduce non- The proportion of target drug resistance occurs, but the effect is still relatively limited.
  • the compounds of the present invention have inhibitory effect on FLT3 and/or IRAK4.
  • the compound developed in the present invention can be used as a dual-target inhibitor of FLT3 and IRAK4, has potential clinical application value, and is expected to improve the prognosis of patients and reduce the possibility of drug resistance.
  • Embodiment II-1 Synthesis II-1
  • Embodiment II-2 Synthesis II-2
  • Dissolve II-2-2 (50mg, 0.18mmol) in DMF (2mL), then add PyBOP (190mg, 0.36mmol), DIPEA (71mg, 0.55mmol), and stir the reaction at room temperature for 2 hours until the reaction is complete.
  • Embodiment II-8 Synthesis II-8
  • reaction solution was diluted with H 2 O (10 mL), stirred and extracted with EA (10 mL X 3), the combined organic phases were washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to obtain a crude product.
  • Lithium hydroxide (40.48 mg, 1.69 mmol) was added to a solution of II-8-1 (0.23 g, 845.03 ⁇ mol), H 2 O (1 mL) and THF (3 mL), and the mixture was stirred at 25° C. under nitrogen for 3 hours until the reaction is complete.
  • Add H 2 O (10 mL) to the reaction mixture for dilution, acidify the solution to pH 3-4 with stirring, extract the mixture with EA (10 mL X 3), wash the combined organic phases with brine (20 mL), anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to give white solid product II-8-2, 0.2 g, crude, MS (ESI) m/z: 259.0 [M+H] + .
  • Embodiment II-4 Synthesis II-4
  • Embodiment II-6 Synthesis II-6
  • 6-methoxy-5-nitro-2H-indazole (2.7g, 13.98mmol)
  • tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate (5.47g, 19.57mmol)
  • cesium carbonate 13.66g, 41.93mmol
  • anhydrous N,N-dimethylformamide (12mL) mixed solution was warmed up to 110°C and stirred for 0.5 hours until the reaction was complete.
  • reaction solution was diluted with H 2 O (20 mL), stirred and extracted with EA (15 mL X 3), the combined organic phases were washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo to obtain a crude product.
  • Lithium hydroxide (51.61 mg, 2.15 mmol) was added to a solution of II-10-1 (220.00 mg, 1.08 mmol), H 2 O (1 mL) and THF (3 mL), and stirred at 25° C. for 2 hours under nitrogen protection until the reaction is complete.
  • Step 1 Synthesis of INT-01-1
  • II-95-6 (20 mg, 0.03 mmol) was added into HCl-dioxane (1M, 2 mL) and stirred for 3 hours until the reaction was complete. The reaction mixture was filtered and the filter cake was washed with a small amount of dioxane, and the filter cake was dried in vacuo to obtain yellow solid product II-95, 7.26 mg, yield 50%, MS (ESI) m/z: 481.1 [M+H] + .
  • the IC 50 value of the compounds for the competitive binding of ATP to the kinases IRAK4 and FLT3 was determined.
  • the initial detection concentration of the compound was 10 ⁇ M, diluted down to 0.38 nM in a 4-fold gradient, and detected in duplicate wells.
  • commercial staurosporine was used as the standard control in this experiment.
  • Reagent and consumable information are as follows:
  • Substrate peptide FAM-P2 (GL Biochem, Cat.No.112394, Lot.No.P131014-XP112394)
  • Substrate peptide FAM-P8 (GL Biochem, Cat.No.112396, Lot.No.P170731-SY112396)
  • ATP adenosine triphosphate, Sigma, Cat.No.A7699-1G, CAS No.987-65-5)
  • DMSO dimethylsulfoxide
  • EDTA ethylenediaminetetraacetic acid, Sigma, Cat.No.E5134, CAS No.60-00-4)
  • Kinase reaction and termination add 10 ⁇ L of kinase buffer solution to a 384-well plate containing 5 ⁇ L of the compound to be tested, and incubate at room temperature for 10 minutes; add another 10 ⁇ L of buffer solution containing substrate peptide and adenosine triphosphate to a 384-well plate, and incubate at 28°C. After incubation for one hour, 25 ⁇ L of stop solution (100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent#3 and 0.015% Brij-35) was added to each well to stop the reaction.
  • stop solution 100 mM HEPES pH 7.5, 50 mM EDTA, 0.2% Coating Reagent#3 and 0.015% Brij-35
  • Reagent and consumable information are as follows:
  • MV4-11 cells ATCC, Cat.No.CRL-9591
  • DPBS Duchener's phosphate buffered saline, Biosera, Cat.No.LM-S2041/500
  • Penicillin streptomycin solution (Invitrogen, Cat.No.15140122)
  • CellTiter-Glo Luminescent Cell Viability Assay CellTiter-Glo chemiluminescent detection of cell viability, Promega, Cat.No.G7573
  • IMDM complete medium IMDM+10% fetal bovine serum+1% Penicillin-Streptomycin, penicillin-streptomycin mixture.

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CN120344521A (zh) * 2023-06-21 2025-07-18 杭州多域生物技术有限公司 一种五元并六元化合物的晶型、盐型、制备方法、药物组合物和应用

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WO2024133560A1 (en) * 2022-12-21 2024-06-27 Dark Blue Therapeutics Ltd Imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrazine derivatives as mllt1 and mllt3 inhibitors
CN120344521A (zh) * 2023-06-21 2025-07-18 杭州多域生物技术有限公司 一种五元并六元化合物的晶型、盐型、制备方法、药物组合物和应用
CN120344521B (zh) * 2023-06-21 2026-04-17 杭州多域生物技术有限公司 一种五元并六元化合物的晶型、盐型、制备方法、药物组合物和应用
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