WO2021027503A1 - Composé tricyclique, procédé de préparation, intermédiaire et utilisation associés - Google Patents

Composé tricyclique, procédé de préparation, intermédiaire et utilisation associés Download PDF

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WO2021027503A1
WO2021027503A1 PCT/CN2020/103225 CN2020103225W WO2021027503A1 WO 2021027503 A1 WO2021027503 A1 WO 2021027503A1 CN 2020103225 W CN2020103225 W CN 2020103225W WO 2021027503 A1 WO2021027503 A1 WO 2021027503A1
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alkyl
nhc
cycloalkyl
membered heterocycloalkyl
group
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PCT/CN2020/103225
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English (en)
Chinese (zh)
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冯加权
董加强
王铁林
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罗欣药业(上海)有限公司
山东罗欣药业集团股份有限公司
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Publication of WO2021027503A1 publication Critical patent/WO2021027503A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/18—Bridged systems

Definitions

  • the invention relates to a tricyclic compound, its preparation method, intermediates and applications.
  • Trk Tropomyosin receptor kinase
  • NTRK neurotrophic tyrosine kinase receptor
  • the Trk family mainly includes 3 members, NTRK1/TrkA, NTRK2/TrkB and NTRK3/TrkC.
  • the complete Trk kinase includes three parts: extracellular domain, transmembrane domain and intracellular domain. After the extracellular domain of Trk kinase is combined with the corresponding ligand, it can cause the kinase configuration to change and form a dimer.
  • Trk kinase Autophosphorylation of the intracellular region of Trk kinase activates its own kinase activity, which further activates downstream signal transduction pathways such as MAPK, AKT, PKC, etc., to produce corresponding biological functions; among them, NGF (nerve growth factor) binds TrkA , BDNF (derived neurotrophic factor) binds TrkB, and NT3 (neurotrophic factor 3) binds TrkC.
  • NGF nerve growth factor
  • TrkA binds TrkA
  • BDNF derived neurotrophic factor
  • TrkB binds TrkB
  • NT3 neurotrophic factor 3
  • Trk kinase plays important physiological functions in the development of nerves, including the growth and function maintenance of neuronal axons, the occurrence and development of memory, and the protection of neurons from damage.
  • Trk signal transduction pathway is also strongly related to the occurrence and development of tumors.
  • Activated Trk signaling proteins have been found in neurocytoma, prostate cancer, and breast cancer.
  • the discovery of a variety of Trk fusion proteins in recent years has shown its biological function of promoting tumorigenesis. The earliest TPM3-TrkA fusion protein was found in colon cancer cells, with an incidence of about 1.5% in clinical patients tested.
  • Trk fusion proteins such as CD74-NTRK1, MPRIP-NTRK1, QKI-NTRK2, ETV6, were found in different types of clinical tumor patient samples such as lung cancer, head and neck cancer, breast cancer, thyroid cancer, glioma, etc. -NTRK3, BTB1-NTRK3, etc.
  • These different NTRK fusion proteins are in a highly activated kinase activity state without ligand binding, so they can continuously phosphorylate downstream signal pathways, induce cell proliferation, and promote tumor occurrence and development. Therefore, in recent years, Trk fusion protein has become an effective anti-cancer target and research hotspot.
  • NTRK mutations have recently appeared clinically, such as NTRK1G595R and G667C mutations (Russo M. et al., Cancer Discovery, 2016, 6(1), 36-44), NTRK3G623R mutations (Drilon A. etc., Annals) of Oncology 2016,27(5),920-926).
  • the technical problem to be solved by the present invention is to provide a tricyclic compound with a new core structure, its preparation method, intermediates and applications.
  • Such compounds have the activity of inhibiting tropomyosin receptor kinase and can be used to treat cancer and other diseases.
  • the present invention provides a compound represented by formula I, its stereoisomer, its tautomer, its isotope derivative, its pharmaceutically acceptable salt or its solvate:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b , R 5 and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 Alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 Alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 4 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-OH , -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R 25a )(R 25b );
  • R 25a and R 25b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-12 membered hetero Aryl group, wherein the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 10 aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkane yl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1-4 alkyl) 2, - (C 1- 4 alkyl) -NH 2, C 3-6 cycloalkyl Substituents of
  • the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered hetero
  • X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );
  • R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl
  • R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O) C(
  • R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group
  • the group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents;
  • the heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;
  • p is 0 or 1;
  • X 8 is O or S
  • X 6 is N(R 13 );
  • R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;
  • X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;
  • R 3 , R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl)
  • R 3 , R 11 and X 5 together form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1- 4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1- 4 alkyl) 2 , -NHC(O)(C 1-4 alkyl),
  • R 3 and R 4 are connected together to form The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;
  • R 3 and R 4 are connected to each other so that And R 4 replaced with The g end of the wave line is connected to X 3 , and the end of the wave line f is connected to the carbon atom connected to M;
  • X 7 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • k 0, 1 or 2;
  • n 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;
  • X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • Each R 12 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally by one or more independent Selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4-alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O ) (C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 al
  • Each of R 10a , R 10b , R 14 and R 15 is independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , where Said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N ( C 1-4 alkyl
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alky
  • R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • n 0 or 1
  • condition (i) or (ii) is satisfied:
  • X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );
  • t is 0 or 1;
  • Y is The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not
  • Y 1 is C(R 6a ) or N;
  • Y 2 is C(R 6b ) or N;
  • R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7
  • the membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2.
  • Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • X 8 is O.
  • X 8 is S.
  • the structure of the compound represented by Formula I is as follows:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b , R 5 and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 Alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 Alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 4 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-OH , -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R 25a )(R 25b );
  • R 25a and R 25b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-12 membered hetero Aryl group, wherein the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 10 aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkane yl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1-4 alkyl) 2, - (C 1- 4 alkyl) -NH 2, C 3-6 cycloalkyl Substituents of
  • the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl (e.g. methyl), C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C (O) OR a or -C (O)NR a R b , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O(C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 Alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl (e.g. cyclopropyl), 3-6 membered heterocycloalkane Substituents of
  • X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );
  • R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl
  • R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O) C(
  • R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group
  • the group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents;
  • the heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;
  • X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;
  • R 3 , R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl)
  • R 3 , R 11 and X 5 together form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1- 4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1- 4 alkyl) 2 , -NHC(O)(C 1-4 alkyl),
  • R 3 and R 4 are connected together to form The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;
  • R 3 and R 4 are connected to each other so that And R 4 replaced with The g end of the wave line is connected to X 3 , and the end of the wave line f is connected to the carbon atom connected to M;
  • X 7 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • k 0, 1 or 2;
  • n 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;
  • X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • Each R 12 is hydrogen, C 1-6 alkyl, or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally by one or more independent Selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4-alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) 2, -NHC (O ) (C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 al
  • Each R 10a, R 10b, R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl (e.g. methyl), C 3- 6 cycloalkyl, 4-7 membered heterocyclic ring Alkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a, or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl)
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alky
  • R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl (e.g. methyl), C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a ,- SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1 -6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1- 4 alkyl)
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • n 0 or 1
  • condition (i) or (ii) is satisfied:
  • X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );
  • t is 0 or 1;
  • Y is The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not
  • Y 1 is C(R 6a ) or N;
  • Y 2 is C(R 6b ) or N;
  • R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7
  • the membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2.
  • Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the structure of the compound represented by Formula I is as follows:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered hetero
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;
  • X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;
  • R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally substituted by one Or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH , -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O )O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC (O) (C 1- 4 alkyl), - N (C 1-4 alkyl) C (O
  • n 0, 1, or 2, provided that the result of adding n and p is 1 or 2;
  • X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), -
  • R 10a , R 10b , R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1- 4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1 -4 alkyl
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alky
  • R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );
  • t is 0 or 1;
  • Y is The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not
  • Y 1 is C(R 6a ) or N;
  • Y 2 is C(R 6b ) or N;
  • R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7
  • Each membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)- NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O) N (C 1- 4 alkyl) 2, -NHC (O) (
  • Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the structure of the compound represented by Formula I is as follows:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered hetero
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;
  • X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;
  • R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally substituted by one Or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH , -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O )O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC (O) (C 1- 4 alkyl), - N (C 1-4 alkyl) C (O
  • n 0, 1, or 2, provided that the result of adding n and p is 1 or 2;
  • X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), -
  • R 10a , R 10b , R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1- 4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1 -4 alkyl
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alky
  • R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );
  • t is 0 or 1;
  • Y is The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not
  • Y 1 is C(R 6a ) or N;
  • Y 2 is C(R 6b ) or N;
  • R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7
  • Each membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)- NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O) N (C 1- 4 alkyl) 2, -NHC (O) (
  • Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the structure of the compound represented by Formula I is as follows:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b and R 5 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered hetero
  • X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );
  • R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl
  • R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O) C(
  • R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group
  • the group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents;
  • the heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;
  • X 5 is N
  • R 11 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), -
  • n 0 or 1
  • X 4 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), -
  • R 10a , R 10b , R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1- 4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1 -4 alkyl
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alky
  • R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl, and 4-7 membered heterocycloalkyl are each independently optionally substituted with one or more substituents independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH , -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the structure of the compound represented by Formula I is as follows:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b and R 5 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl) , -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 4 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 alkyl), -(C 1-4 alkyl)-OH , -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl or -C(O)N(R 25a )(R 25b );
  • R 25a and R 25b are each independently hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl, or 5-12 membered hetero Aryl group, wherein the C 1 -C 6 alkyl group, C 3 -C 6 cycloalkyl group, 3-8 membered heterocycloalkyl group, C 6 -C 10 aryl group and 5-12 membered heteroaryl group are each independently Optionally by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkane yl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1-4 alkyl) 2, - (C 1- 4 alkyl) -NH 2, C 3-6 cycloalkyl Substituents of
  • the 3-8 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6- Substituents of 10 aryl and 5-12 membered heteroaryl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, C 6-10 aryl and 5- Substituent substitution of 12-membered hetero
  • X 1 is a single bond, S, S(O), S(O) 2 , O, N(R 7 ) or C(R 24a )(R 24b );
  • R 7 , R 24a and R 24b are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl
  • R 7 and R 1a and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1- 4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)(C 1-4 alkyl Group), -N(C 1-4 alkyl) C(O) C(
  • R 7 and R 5 and the atoms to which they are connected together form a 4-7 membered heterocycloalkyl group or a 5-6 membered heteroaryl group, wherein the 4-7 membered heterocycloalkyl group and the 5-6 membered heteroaryl group
  • the group is optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2, -NH ( C 1-4 alkyl), - N (C 1- 4 alkyl) 2, and - (C 1-4 alkyl) -NH 2 substituents;
  • the heteroatom in the 5-6 membered heteroaryl group is nitrogen, and the number of heteroatoms is 1, 2 or 3;
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl is each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl and 3-6 membered heterocycloalkane Substituent substitution of the group;
  • X 5 is C(R 16 ) or N; and, when p is 0, X 5 is N;
  • R 3 , R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently any Selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) ) 2, -NHC (O) ( C 1- 4 alkyl), - N (C 1-4 alkyl)
  • R 3 , R 11 and X 5 together form a C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each Independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1- 4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O)O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1- 4 alkyl) 2 , -NHC(O)(C 1-4 alkyl),
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the structure of the compound represented by Formula I is as follows:
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is C (R 4a ) or N;
  • M 1 is C(R 4b ) or N;
  • R 2 , R 4a , R 4b , R 5 and R 6 are each independently hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O-(C 1-4 Alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH-(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 Alkyl) -NH 2 , C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl;
  • R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, -C(O)OR a, or -C(O)NR a R b , wherein the C 1-6 alkyl group, C 3-6 cycloalkyl group and 3-6 membered heterocycloalkyl group are optionally selected by one or more independently selected from halogen, -CN, and C 1-4 alkyl group , C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl),- N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , C 3-6 cycloalkyl (e.g. cyclopropyl), 3-6 membered heterocycloalkyl, C 6- Substituents of
  • X 5 is C(R 16 ) or N;
  • R 11 and R 16 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally substituted by one Or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH , -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O )O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC (O) (C 1- 4 alkyl), - N (C 1-4 alkyl) C (O
  • X 7 is S, S(O), S(O) 2 , O, N(R 12 ) or C(R 14 )(R 15 );
  • k 0, 1 or 2;
  • R 12 is hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl or C 3-6 cycloalkyl are each independently optionally selected from one or more halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1- 4 alkyl) -OH, -NH 2, - NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2 , -CO 2 H, -C(O)O(C 1- 4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 , -NHC(O)( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), -
  • Each R 10a, R 10b, R 14 and R 15 are each independently hydrogen, halogen, -CN, C 1-6 alkyl (e.g. methyl), C 3- 6 cycloalkyl, 4-7 membered heterocyclic ring Alkyl, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a, or -C(O)NR b R c , wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1- 4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl)
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1-4 alkyl) 2, - (C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alky
  • R 9a and R 9b are each independently hydrogen, halogen, -CN, C 1-6 alkyl (e.g. methyl), C 3-6 cycloalkyl, 4-7 membered heterocycloalkyl, -OR a ,- SR a , -NR b R c , -OC(O)R a , -NR a C(O)R b , -C(O)OR a or -C(O)NR b R c , wherein the C 1 -6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 alkyl) -OH, -NH 2, -NH ( C 1- 4 alkyl), - N (C 1- 4 alkyl)
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • the cycloalkyl groups are each independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),- (C 1-4 alkyl) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C (O ) O (C 1-4 alkyl), - C (O) NH 2, -C (O) NH (C 1- 4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NH
  • X 1 is N(R 7 );
  • R 7 forms together with R 5 and the atoms they are connected to
  • X 2 is S, S(O), S(O) 2 , O, N(R 2a ) or C(R 3a )(R 3b );
  • t is 0 or 1;
  • Y is The d end of the wavy line is connected to the X 2 end, and the c end of the wavy line is connected to the N atom; and, when X 2 is O and t is 1, Y is not
  • Y 1 is C(R 6a ) or N;
  • Y 2 is C(R 6b ) or N;
  • R 2a is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl or 4-7 membered heterocycloalkyl, wherein said C 1-6 alkyl, C 3-6 cycloalkyl and 4-7
  • the membered heterocycloalkyl group is independently optionally selected by one or more independently selected from halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl)-OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl)-NH 2.
  • Each R 3a , R 3b , R 5a , R 5b , R 6a , R 6b , R 7a and R 7b are each independently hydrogen, halogen, -CN, -OR a , -SR a , -NR b R c , -OC(O)R a , -NR b C(O)R a , -C(O)OR a , -C(O)NR b R c , C 1-6 alkyl, C 3-6 cycloalkyl Or 4-7 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 3-6 cycloalkyl and 4-7 membered heterocycloalkyl are each independently optionally selected by one or more independently selected from halogen , -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl),-(C 1-4 alkyl) -OH, -
  • R a, R b and R c are each independently hydrogen, C 1-4 alkyl or C 3-6 cycloalkyl;
  • heteroatoms in the heterocycloalkyl and heteroaryl groups are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the halogen and the halogen in the C 1-4 haloalkyl group may each independently be fluorine, chlorine, or bromine. Or iodine.
  • the C 1-4 alkyl group, the C 1-4 alkyl group in the C 1-4 haloalkyl group , the -O (C 1-4 alkyl) is C 1-4 alkyl
  • said - (C 1- 4 alkyl) -OH is C 1-4 alkyl
  • the C 1-4 alkyl in the -(C 1-4 alkyl) is -NH 2 C 1-4 alkyl
  • the -C (O) O (C 1-4 alkyl) is C 1-4 alkyl
  • the C 1-6 alkyl group may each independently be methyl, ethyl, n-propyl, isopropyl , N-butyl, isobutyl, sec-butyl or tert-butyl.
  • the C 3-6 cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclo Hexyl.
  • the 3-8 membered heterocycloalkyl group may independently be 3, 4, 5, 6, 7 or 8 membered Heterocycloalkyl.
  • the 4-7 membered heterocycloalkyl group may independently be a 4, 5, 6 or 7 membered heterocycloalkyl group .
  • the C 6-10 aryl group may independently be a phenyl group.
  • the 5-12 membered heteroaryl group may independently be a 5-6 membered heteroaryl group.
  • the 3-6 membered heterocycloalkyl group may independently be a 3, 4, 5, or 6 membered heterocycloalkyl group .
  • Z 1 is C and Z 2 is N.
  • Z 1 is N and Z 2 is C.
  • R 2 is halogen
  • R 2 is fluorine
  • R 4 when R 4 is present and not connected to other variables, R 4 is halogen.
  • R 4 is fluorine
  • R 4a is hydrogen
  • M is CH or N.
  • M is CH.
  • M is N in the compound of formula I as described in any of the preceding embodiments.
  • R 4b is hydrogen
  • M 1 is CH or N.
  • M 1 is CH.
  • R 5 is hydrogen
  • R 6 when R 6 is present and not connected to other variables, R 6 is hydrogen, -NH 2 , -NH-(C 1-4 alkyl) or -N(C 1-4 alkyl) 2 .
  • R 6 when R 6 is present and not connected to other variables, R 6 is hydrogen or -NH 2 .
  • R 6 is hydrogen
  • X 2 when X 2 is present, X 2 is C(R 3a )(R 3b ).
  • R 3a when R 3a is present, R 3a is hydrogen or halogen.
  • R 3a is hydrogen or fluorine.
  • R 3b is hydrogen or halogen.
  • R 3b is hydrogen or fluorine.
  • R 3a and R 3b are each independently hydrogen or halogen.
  • R 3a and R 3b are hydrogen.
  • R 3a and R 3b are fluorine.
  • R 5a when R 5a is present, R 5a is hydrogen or C 1-6 alkyl (e.g. methyl), wherein said C 1-6 alkyl is optionally selected by one or more independently selected from halogen (e.g.
  • R 5a when R 5a is present, R 5a is hydrogen or C 1-6 alkyl (e.g. methyl), wherein said C The 1-6 alkyl group is optionally substituted with one or more halogens (e.g., fluorine).
  • halogens e.g., fluorine
  • R 5a when R 5a is present, R 5a is hydrogen or C 1-6 alkyl (eg, methyl).
  • R 5a is hydrogen
  • R 5b is hydrogen
  • R 6a is hydrogen
  • R 6b is hydrogen
  • R 7a is hydrogen
  • R 7b is hydrogen
  • R 1b is hydrogen or a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted by one or more Independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH and C 3-6 ring Alkyl substituents are substituted.
  • R 1b is hydrogen or a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted by a C 3- 6 Cycloalkyl substituted.
  • R 1b is hydrogen
  • R 1a when R 1a is not connected to other variables, R 1a is hydrogen or C 1-6 alkyl, and the C 1 -6 alkyl optionally substituted with one or more substituents independently selected from halogen, C 1- 4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), - (C 1-4 Alkyl) -OH and C 3-6 cycloalkyl substituent substituted;
  • R 1a when R 1a is not connected to other variables, R 1a is hydrogen or C 1-6 alkyl, and the C 1 The -6 alkyl group is optionally substituted with a C 3-6 cycloalkyl group.
  • R 1a when R 1a is not connected to other variables, R 1a is C 1-6 alkyl, and the C 1-6 The alkyl group is optionally substituted with a C 3-6 cycloalkyl group.
  • R 1a when R 1a is not connected to other variables, R 1a is methyl or
  • X 1 is N(R 7 ).
  • R 7 is hydrogen or C 1-6 alkyl.
  • R 7 is hydrogen
  • each R 21 is independently halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C (O) O (C 1- 4 alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl ) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 ,
  • Each u is independently 0, 1, or 2;
  • R 20 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O) O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 ,- NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NH
  • R 20 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O(C 1-4 alkyl), -(C 1-4 alkyl)- OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H, -C( O) O (C 1- 4 alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl) 2 , -NHC (O) (C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 alkyl ), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 ,
  • R 20 when R 20 is present, R 20 is hydrogen or halogen.
  • R 20 is hydrogen or fluorine.
  • R 13 is hydrogen
  • R 16 is hydrogen
  • X 5 is N.
  • R 3 when R 3 is not connected to other variables, R 3 is hydrogen, C 1-6 alkyl or C 3-6 Cycloalkyl.
  • R 3 when R 3 is not connected to other variables, R 3 is hydrogen or C 1-6 alkyl.
  • R 11 is hydrogen
  • each R 23 is independently halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) ) -OH, -NH 2 , -NH (C 1-4 alkyl), -N (C 1-4 alkyl) 2 ,-(C 1-4 alkyl) -NH 2 , -CO 2 H,- C (O) O (C 1- 4 alkyl), - C (O) NH 2, -C (O) NH (C 1-4 alkyl), - C (O) N (C 1-4 alkyl ) 2, -NHC (O) ( C 1-4 alkyl), - N (C 1- 4 alkyl) C (O) (C 1-4 alkyl), - OC (O) ( C 1-4 Alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 ,
  • v 0, 1, 2 or 3;
  • R 22 is hydrogen, halogen, -CN, C 1-4 alkyl, C 1-4 haloalkyl, -OH, -O (C 1-4 alkyl), -(C 1-4 alkyl) -OH, -NH 2 , -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , -(C 1-4 alkyl) -NH 2 , -CO 2 H, -C(O) O(C 1-4 alkyl), -C(O)NH 2 , -C(O)NH(C 1-4 alkyl), -C(O)N(C 1-4 alkyl) 2 ,- NHC(O)(C 1-4 alkyl), -N(C 1-4 alkyl)C(O)(C 1-4 alkyl), -OC(O)(C 1-4 alkyl), -NHC(O)NH 2 , -NHC(O)N(C 1-4 alkyl) 2 , -NH
  • R 23 is C 1-4 alkyl, -OH, -O(C 1-4 alkane Group) or -(C 1-4 alkyl)-OH.
  • R 23 is -OH.
  • R 22 is hydrogen, C 1-4 alkyl, -OH, -O(C 1- 4 alkyl) or -(C 1-4 alkyl)-OH.
  • R 22 in the compound of Formula I as described in any of the preceding embodiments, when R 22 is present, R 22 is -OH.
  • X 5 is N
  • R 3 and R 11 are each independently hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl, wherein the C 1-6 alkyl and C 3-6 cycloalkyl are each independently optionally substituted by one Or multiple substituents independently selected from C 1-4 alkyl, -OH, -O(C 1-4 alkyl) and -(C 1-4 alkyl)-OH;
  • R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group, wherein the C 3-8 cycloalkyl group and the 3-8 membered heterocycloalkyl group are each independently optionally substituted by one or more One substituent independently selected from C 1-4 alkyl, -OH, -O(C 1-4 alkyl) and -(C 1-4 alkyl)-OH.
  • X 4 when X 4 is present, X 4 is C(R 14 )(R 15 ) or O.
  • R 14 is hydrogen
  • R 15 is hydrogen
  • R 14 and R 15 are both hydrogen.
  • X 4 is CH 2 or O.
  • X 4 is CH 2 .
  • R 9b is hydrogen
  • R 9a is hydrogen or C 1-6 alkyl.
  • R 9a is hydrogen or methyl
  • R 10a when R 10a is present and not connected to other variables, R 10a is hydrogen or C 1-6 alkyl, and The C 1-6 alkyl group is optionally substituted with one or more hydroxy groups.
  • R 10a is hydrogen, methyl, or
  • R 10b when R 10b is present and is not connected to other variables, R 10b is hydrogen or C 1-6 alkyl, and The C 1-6 alkyl group is optionally substituted with one or more hydroxy groups.
  • R 10b is hydrogen, methyl, or
  • R 10b is hydrogen
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is CH or N
  • M 1 is N
  • R 2 and R 4 are each independently hydrogen or halogen
  • R 5 and R 6 are hydrogen
  • R 1b is hydrogen
  • R 1a is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a C 3-6 cycloalkyl group;
  • X 1 is N(R 7 );
  • R 7 is hydrogen or C 1-6 alkyl
  • R 7 and R 1a and the atoms to which they are attached together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted by one or more halogens;
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen
  • X 5 is N; and, when p is 0, X 5 is N;
  • R 11 is hydrogen
  • R 3 is hydrogen, C 1-6 alkyl or C 3-6 alkyl
  • R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group, wherein each of the 3-8 membered heterocycloalkyl group is independently optionally selected by one or more independently selected from C 1-4 Alkyl, -OH, -O (C 1-4 alkyl) and -(C 1-4 alkyl) -OH substituents;
  • R 3 and R 4 are connected together to form The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;
  • n 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;
  • X 4 is O or CH 2 ;
  • R 10a and R 10b are each independently hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH;
  • R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group
  • R 9a and R 9b are each independently hydrogen or C 1-6 alkyl
  • R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group
  • n 0 or 1
  • condition (i) or (ii) is satisfied:
  • R 3a and R 3b are each independently hydrogen or halogen
  • R 5a is hydrogen or C 1-6 alkyl
  • heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is CH or N
  • M 1 is N
  • R 2 and R 4 are each independently hydrogen or halogen
  • R 5 and R 6 are hydrogen
  • R 1b is hydrogen
  • R 1a is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a C 3-6 cycloalkyl group;
  • X 1 is N(R 7 );
  • R 7 is hydrogen or C 1-6 alkyl
  • R 7 and R 1a and the atoms to which they are attached together form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted by one or more halogens;
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen
  • X 5 is N; and, when p is 0, X 5 is N;
  • R 11 is hydrogen
  • R 3 is hydrogen, C 1-6 alkyl or C 3-6 alkyl
  • R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group, wherein each of the 3-8 membered heterocycloalkyl group is independently optionally selected by one or more independently selected from C 1-4 Alkyl, -OH, -O (C 1-4 alkyl) and -(C 1-4 alkyl) -OH substituents;
  • R 3 and R 4 are connected together to form The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;
  • n 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;
  • X 4 is O or CH 2 ;
  • R 10a and R 10b are each independently hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH;
  • R 10a and R 10b and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group
  • R 9a and R 9b are each independently hydrogen or C 1-6 alkyl
  • R 9a and R 10a and the carbon atoms to which they are attached together form a C 3-6 cycloalkyl group
  • n 0 or 1
  • condition (i) or (ii) is satisfied:
  • R 3a and R 3b are each independently hydrogen or halogen
  • heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • Z 1 is C or N; when Z 1 is C, Z 2 is N; when Z 1 is N, Z 2 is C;
  • M is CH or N
  • M 1 is N
  • R 2 and R 4 are each independently hydrogen or halogen
  • R 5 and R 6 are hydrogen
  • R 1b is hydrogen
  • R 1a is a C 1-6 alkyl group, wherein the C 1-6 alkyl group is optionally substituted by a C 3-6 cycloalkyl group;
  • X 1 is N(R 7 );
  • R 7 is hydrogen or C 1-6 alkyl
  • p is 0 or 1;
  • X 6 is N(R 13 );
  • R 13 is hydrogen
  • X 5 is N; and, when p is 0, X 5 is N;
  • R 11 is hydrogen
  • R 3 is hydrogen, C 1-6 alkyl or C 3-6 alkyl
  • R 3 , R 11 and X 5 together form a 3-8 membered heterocycloalkyl group, wherein each of the 3-8 membered heterocycloalkyl group is independently optionally selected by one or more independently selected from C 1-4 Alkyl, -OH, -O (C 1-4 alkyl) and -(C 1-4 alkyl) -OH substituents;
  • R 3 and R 4 are connected together to form The wavy line a is connected to X 5 , and the wavy line b is connected to the position where R 4 is connected;
  • n 0, 1, or 2, provided that the sum of m, n, and p is 1 or 2;
  • X 4 is O or CH 2 ;
  • R 10a and R 10b are each independently hydrogen or C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more -OH;
  • n 0 or 1
  • condition (i) or (ii) is satisfied:
  • heteroatoms in the heterocycloalkyl group are independently selected from N, O and S, and the number of heteroatoms is 1, 2, or 3.
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • the compound represented by Formula I has any of the following structures:
  • the present invention also provides a method for preparing the compound represented by formula I as described above, which is selected from any of the following schemes:
  • Scheme 1 includes the following steps: in a solvent, the compound represented by formula II and the compound Carry out the condensation reaction as shown below in the presence of carbonyl diimidazole to obtain the compound shown in formula I; wherein p is 1, X 5 is N, R 3 is not connected to R 4 , and other variables are defined as above
  • p is 1, X 5 is N, R 3 is not connected to R 4 , and other variables are defined as above
  • the compound described in any one of the schemes is described in the compound represented by formula I;
  • Scheme 2 includes the following steps: in a solvent, the compound represented by formula III and the compound Carry out the condensation reaction shown below to obtain the compound shown in formula I; wherein p is 1, X 5 is N, R 3 is not connected to R 4 , and the definitions of other variables are as described in any of the foregoing schemes. As described in the compound represented by formula I;
  • Scheme 3 includes the following steps: in a solvent, the compound represented by formula IV and the compound
  • a condensing agent such as EDCI or pentafluorophenyl diphenyl phosphonate
  • the condensation reaction shown below can be carried out to obtain the compound shown in formula I; wherein p is 0 and X 5 is N, R 3 is not connected to R 4 , and the definitions of other variables are as described in any of the foregoing schemes as described in the compound represented by formula I;
  • Scheme 4 includes the following steps: in a solvent, the compound represented by formula V is subjected to the condensation reaction shown below in the presence of a base to obtain the compound represented by formula I; where p is 1, X 5 Is N, R 3 and R 4 are connected together to form The definitions of other variables are as described in the compound represented by formula I as described in any of the foregoing schemes;
  • Scheme 5 includes the following steps: in a solvent, the compound represented by formula VI is subjected to the condensation reaction shown below in the presence of a condensing agent (such as EDCI, pentafluorophenyl diphenyl phosphonate) and a base to obtain The compound shown in formula I is sufficient; wherein p is 0, X 5 is N, and R 3 and R 4 are connected together to form The definitions of other variables are as described in the compound represented by formula I as described in any of the foregoing schemes;
  • a condensing agent such as EDCI, pentafluorophenyl diphenyl phosphonate
  • the method for preparing the compound represented by formula VI may include the following steps; in a solvent, the compound represented by formula VI-1 is subjected to the oxidation reaction shown below in the presence of an oxidizing agent (such as NaClO 2 ) , It is sufficient to obtain the compound represented by formula VI; the definition of each variable is as described in the compound represented by formula VI described in any of the foregoing schemes;
  • an oxidizing agent such as NaClO 2
  • the method for preparing the compound represented by formula III may include the following steps; in a solvent, the compound represented by formula II as described above is combined with Carry out the substitution reaction as shown below in the presence of a base to obtain the compound represented by formula III; the definition of each variable is as described in the compound represented by formula III as described in any of the foregoing schemes ;
  • the method for preparing the compound represented by formula V may include the following steps: in a solvent, the compound represented by formula V-1 is subjected to the de-Boc reaction shown below in the presence of an acid, It suffices to obtain the compound represented by formula VI; the definition of each variable is as described in the compound represented by formula V as described in any of the foregoing schemes;
  • the compound represented by formula V-1 may include the following steps: in a solvent, the compound represented by formula V-2 and Carry out the substitution reaction as shown below in the presence of a base to obtain the compound shown in formula V-1; the definition of each variable is as shown in any one of the preceding schemes as shown in formula V-1 Described in the compound;
  • the compound represented by formula V-2 may include the following steps: in a solvent, the compound represented by formula V-3 is subjected to the following reduction reaction in the presence of Fe and NH 4 Cl to obtain The compound represented by formula V-2 is sufficient; wherein X 6 is NH; the definition of other variables is as described in the compound represented by formula V-2 as described in any of the foregoing schemes;
  • the present invention also provides a compound of any of the following structures:
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned compound represented by formula I, its stereoisomers, its tautomers, its isotopic derivatives, and its pharmaceutically acceptable salts Or its solvates, and pharmaceutical excipients.
  • the present invention also provides a compound as shown in formula I, its stereoisomers, its tautomers, its isotopic derivatives, its pharmaceutically acceptable salts or solvates thereof, or The application of the above-mentioned pharmaceutical composition in the preparation of a medicine for treating cancer, pain, neurological disease, autoimmune disease or inflammation.
  • the present invention also provides a method for the treatment of cancer, pain, neurological disease, autoimmune disease or inflammation, which comprises administering to a patient in need of such treatment a therapeutically effective amount of the compound represented by formula I as described above, and its three-dimensional Isomers, tautomers, isotopic derivatives thereof, pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions as described above.
  • the cancer can be non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer, colon cancer, acute myeloid cell Leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, pilocytic astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast cancer, fibrosarcoma, nephroma, or breast.
  • the cancer may be the following cancers related to Trk: non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer , Colon cancer, acute myeloid leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, pilocytic astrocytoma, low-grade glioma, lung adenocarcinoma, salivary gland cancer, secretory breast cancer, fiber Sarcoma, kidney tumor, breast.
  • Trk non-small cell lung cancer, papillary thyroid cancer, glioblastoma multiforme, acute myeloid leukemia, colorectal cancer, large cell neuroendocrine cancer, prostate cancer , Colon cancer, acute myeloid leukemia, sarcoma, pediatric glioma, intrahepatic cholangiocarcinoma, pilocytic astrocytoma
  • the present invention also provides a method for inhibiting the activity of Trk kinase, which comprises combining cells containing Trk kinase with an effective amount of the compound represented by formula I, its stereoisomers, and its tautomers as described above. , Its isotope derivative, its pharmaceutically acceptable salt or its solvate contact, said contact is carried out in vivo or in vitro.
  • the present invention also provides a compound represented by formula I, its stereoisomers, its tautomers, its isotope derivatives, its pharmaceutically acceptable salts or solvates as described above.
  • Trk kinase inhibitors are also provided.
  • the Trk kinase may be TrkA kinase, such as one or more of wild-type TrkA kinase, G595R mutant TrkA kinase, and G667C mutant TrkA kinase.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.
  • patient refers to any animal that is about to or has received administration of a compound or composition, mammals are preferred, and humans are preferred.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound with a relatively non-toxic, pharmaceutically acceptable acid or base.
  • pharmaceutically acceptable base addition salts include, but are not limited to: lithium salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, diethanolamine salt.
  • the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • a pharmaceutically acceptable acid include inorganic acids, and the inorganic acids include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (ie 4,4'-methylene-bis( 3-hydroxy-2-naphthoic acid)), amino acids (for example, glutamic acid, arginine), and the like.
  • the compound of the present invention When the compound of the present invention contains relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt.
  • a base addition salt or an acid addition salt For details, please refer to Berge et al., “Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a saturated linear or branched hydrocarbon group.
  • C 1-6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as C 1 alkyl (ie methyl), C 2 alkyl (ie ethyl), C 3 Alkyl, C 4 alkyl, C 5 alkyl or C 6 alkyl.
  • C 1-4 alkyl refers to an alkyl group having 1, 2, 3 or 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl.
  • haloalkyl means that one or more hydrogen atoms in the alkyl group are replaced by halogen, and the number of halogens can be one or more; when the number of halogens is more than one, the halogens are the same or different.
  • haloalkyl include, but are not limited to, 2-chloro-1,1,2-trifluoroethyl, trifluoromethyl, and difluoromethyl.
  • cycloalkyl refers to a non-aromatic saturated or partially unsaturated cyclic hydrocarbon group. Cycloalkyl groups can be monocyclic or polycyclic (for example, bicyclic and tricyclic), and can be fused, spiro, and bridged ring structures. The cycloalkyl group optionally contains one or more double bonds or triple bonds.
  • the C 3-6 cycloalkyl group refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms in the ring.
  • a C 5 cycloalkyl group refers to a cycloalkyl group having 5 carbon atoms in the ring.
  • C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocycloalkyl refers to a group formed by replacing at least one carbon atom on the cycloalkyl ring with a heteroatom (for example, N, O, or S).
  • a 3-6 membered heterocycloalkyl group refers to a heterocycloalkyl group in which the number of atoms in the ring is 3, 4, 5, or 6, and at least one of the atoms is a heteroatom.
  • Examples of 3-6 membered heterocycloalkyl include, but are not limited to, aziridinyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl and the like.
  • aryl refers to any stable monocyclic or polycyclic (eg, bicyclic or tricyclic) carbocyclic ring with up to 7 atoms in each ring, in which at least one ring is aromatic.
  • aryl groups include but are not limited to phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthracenyl, or acenaphthyl. It is understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the connection is made through the aromatic ring.
  • heteroaryl refers to a stable monocyclic or polycyclic (for example, bicyclic or tricyclic) carbocyclic ring with up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains at least one selected from O, N and S heteroatom. Heteroaryl groups can be connected to other parts of the molecule through heteroatoms or carbon atoms.
  • heteroaryl groups include, but are not limited to, acridinyl, carbazolyl, cinolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl , Benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl (e.g., pyrrol-1 -Based Pyrrol-2-yl ), Tetrahydroquinolinyl.
  • acridinyl carbazolyl, cinolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl, benzothienyl , Benzofuranyl, quin
  • a 5-6 membered heteroaryl group refers to a heteroaryl group in which the number of atoms in the ring is 5 or 6, in which at least one ring atom is a heteroatom, and the remaining ring atoms are carbon atoms.
  • Examples of 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, pyridyl, pyrazolyl and the like.
  • linking group When the number of a linking group is 0, such as -(X) 0 -, it means that the linking group is a single bond. When one of the variables is selected from a single bond, it means that the two groups connected are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ. For example, in -M 1 -(M 2 ) y -M 3 -, when y is 0, -M 1 -(M 2 ) m -M 3 -is actually -M 1 -M 3 -.
  • substituted or “substituent” means that one or more hydrogen atoms are replaced by a specified group.
  • substitution position is not specified, the substitution can be at any position, but only the formation of a stable or chemically feasible chemical is allowed.
  • any variable such as R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • solvates refers to a substance formed by combining a compound with a stoichiometric or non-stoichiometric solvent.
  • the solvent molecules in the solvate can exist in an ordered or non-ordered arrangement.
  • the solvent includes, but is not limited to: water, methanol, ethanol and the like.
  • crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at intervals; due to the above-mentioned periodic arrangement, there may be many Crystal form, that is, polymorphism.
  • amorphous means that the ions or molecules present in a disorderly distribution state, that is, there is no periodic arrangement between the ions and molecules.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of a compound relative to all stereoisomers of the compound is not less than 95%.
  • the atoms in the "compounds”, “pharmaceutically acceptable salts” and “solvates” described herein may exist in the form of their natural abundance or non-natural abundance (ie isotopic derivatives).
  • ie isotopic derivatives For example, with the structure of the present invention, in addition to using “deuterium” or “tritium” instead of hydrogen, or using 18 F-fluorine label ( 18 F isotope) instead of fluorine, or using 11 C-, 13 C-, or 14 C-rich Compounds in which collective carbons ( 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes) replace carbon atoms are within the scope of the present invention.
  • the isotopic derivative is deuterated.
  • the isotopic derivative is a derivative obtained by replacing the hydrogen at the R 9a and/or R 9b position with deuterium.
  • pharmaceutical excipients refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for the active ingredients. See also Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) alleviating one or more biological manifestations of the disease or disease, (2) interfering with (a) one or more points in the biological cascade causing or causing the disease, or (b) ) One or more biological manifestations of the disease, (3) Improve one or more symptoms, effects or side effects related to the disease, or one or more symptoms, effects or side effects related to the disease or its treatment, Or (4) to slow down the development of the disease or one or more biological manifestations of the disease.
  • terapéuticaally effective amount refers to an amount of a compound that is sufficient to effectively treat the diseases or conditions described herein when administered to a patient.
  • the “therapeutically effective amount” will vary according to the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention is to provide a tricyclic compound with a new core structure, its preparation method, intermediates and applications.
  • Such compounds have the activity of inhibiting tropomyosin receptor kinase and can be used to treat cancer and other diseases.
  • Step A Synthesis of diethyl 2-(2-((tert-butyldimethylsilyl)oxo)ethyl)malonate
  • Step B Synthesis of 7-hydroxy-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one
  • Step D Synthesis of 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine
  • Step A Synthesis of diethyl 2-(3-((tert-butyldimethylsilyl)oxo)propyl)malonate
  • Step B Synthesis of 7-hydroxy-6-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one
  • Step D Synthesis of 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine
  • Step A Synthesis of (R,E)-N-(5-fluoro-2-hydroxybenzylidene)-2-methylpropane-2-sulfinamide
  • Step B Synthesis of (R)-N-((R)-1-(5-fluoro-2-hydroxyphenyl)ethyl)-2-methylpropane-2-sulfinamide
  • Step C Synthesis of tert-butyl((S)-2-(2-((R)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy (Base) propyl) carbamate
  • Step D Synthesis of tert-butyl((S)-2-(2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)carbamate
  • Post-treatment add saturated brine (100 mL) to quench the reaction. It was extracted with ethyl acetate (50 ml ⁇ 3 times), and the obtained organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain 4.0 g of oily tert-butyl((S)-2-(2-((R)-1-aminoethyl)-4-fluorophenoxy)propyl)aminomethyl Acid ester.
  • 5-Fluoro-2-methoxy-3-pyridinecarbaldehyde (20.00 g, 129.0 mmol) was dissolved in dry tetrahydrofuran (200 mL) and replaced with nitrogen three times. After stirring for 10 minutes at -78°C, methylmagnesium bromide (3 mol/L, 129 ml, 387.0 mmol) was added thereto. The reaction was then carried out at -78 degrees Celsius for 2 hours, then the reaction was gradually warmed to room temperature and stirred overnight. The reaction was stopped, and the reactant was added to ice water (200 ml) under vigorous stirring to quench the reaction.
  • Step B Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one
  • Step D Synthesis of 3-acetyl-5-fluoropyridin-2-yl trifluoromethanesulfonate
  • Step E Synthesis of (E)-3-(1-((tert-butylsulfinyl ⁇ sulfinyl>)imino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate
  • Step F Synthesis of 3-(1-((tert-butylsulfinyl ⁇ sulfinyl>)amino)ethyl)-5-fluoropyridin-2-yl trifluoromethanesulfonate
  • Step G Synthesis of tert-butyl((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyridin-2-yl)butyl- 3-yn-2-yl) carbamate
  • Step H Synthesis of tert-butyl((2R)-4-(3-(1-((tert-butylsulfinyl)amino)ethyl)-5-fluoropyrimidin-2-yl)butyl- 2-yl) carbamate
  • Step I Synthesis of tert-butyl((2R)-4-(3-(1-aminoethyl)-5-fluoropyrimidin-2-yl)butyl-2-yl)carbamate
  • 5-Fluoro-2-methoxy-3-pyridinecarbaldehyde (20.00 g, 129.0 mmol) was dissolved in dry tetrahydrofuran (200 mL) and replaced with nitrogen three times. After stirring for 10 minutes at -78 degrees Celsius, methylmagnesium bromide (3 mol/L, 129 mL, 387.0 mmol) was added thereto. The reaction was then carried out at -78 degrees Celsius for 2 hours, then the reaction was gradually warmed to room temperature and stirred overnight. The reaction was quenched by adding ice water (200 mL) with vigorous stirring.
  • Step B Synthesis of 1-(5-fluoro-2-methoxypyridin-3-yl)ethane-1-one
  • Example 1 (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-7 -Aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one
  • Step A Synthesis of 5-chloro-6-(2-chloroethyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde
  • Step B Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate
  • Step C Synthesis of 5-((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl )Ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid
  • Step D Synthesis of 5-((R)-1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-6,7-di Hydrogen-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid
  • Step E Synthesis of (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-7 -Aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one
  • Example 2 (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one
  • Step A Synthesis of 5-chloro-6-(3-chloropropyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde
  • Step B Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-formyl-7,8-dihydropyrazolo[1,5-a ]Pyrido[2,3-d]pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate
  • Step C Synthesis of 5-((R)-1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl )Ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid
  • Step D Synthesis of 5-((R)-1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)ethyl)-5,6,7 ,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid
  • Step E Synthesis of (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxa -7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclosinfan-8-one
  • Example 3 (1 3 E,1 4 E,2R,5S)-35-fluoro-2,5-dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-7, 9-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclononan-8-one
  • Step A Synthesis of 5-chloro-6-(2-chloroethyl)-3-nitropyrazolo[1,5-a]pyrimidine
  • Step B Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1, 5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate
  • Step C Synthesis of tert-butyl((S)-2-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate
  • Step D Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H- Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)propyl)carbamate
  • Step E Synthesis of phenyl(5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-6, 7-Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate
  • Step F Synthesis of (1 3 E, 1 4 E, 2R, 5S)-35-fluoro-2,5-dimethyl-1 6 ,1 7 -dihydro-1 5 H-4-oxa-7, 9-Diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclononan-8-one
  • Example 4 (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxa -7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclononfan- 8-ketone
  • Step A Synthesis of 5-chloro-6-(3-chloropropyl)-3-nitropyrazolo[1,5-a]pyrimidine
  • Step B Synthesis of tert-butyl((S)-2-(4-fluoro-2-((R)-1-(3-nitro-7,8-dihydropyrazolo[1,5-a ]Pyrido[2,3-d]pyrimidine-5(6H)-yl)ethyl)phenoxy)propyl)carbamate
  • Step C Synthesis of tert-butyl((S)-2-(2-((R)-1-(3-amino-7,8-dihydropyrazolo[1,5-a]pyrido[2 ,3-d)pyrimidine-5(6H)-yl)ethyl)-4-fluorophenoxy)propyl)carbamate
  • Step D Synthesis of tert-butyl ((S)-2-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-7,8-dihydropyrazolo) [1,5-a]pyrido[2,3-d]pyrimidino-5(6H)-yl)ethyl)phenoxy)propyl)carbamate
  • Step E Synthesis of phenyl(5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-5, 6,7,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3-yl)carbamate
  • Step F Synthesis of (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxa -7,9-Diaza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(1,2)-benzocyclononfan- 8-ketone
  • Phenyl (5-((R)-1-(2-(((S)-1-aminopropyl-2-yl)oxy)-5-fluorophenyl)ethyl)-5,6,7 ,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3-yl)carbamate (260 mg, 0.52 mmol) was dissolved in acetonitrile (20 mL), Add ethyl diisopropylamine (0.3 mL), heat to 45 degrees Celsius and stir overnight.
  • LCMS detects the complete reaction of the raw materials, concentrates under reduced pressure, adds ethyl acetate (60 mL) and dilutes with saturated sodium chloride solution (60 mL x 1
  • Example 5 (1 3 E,1 4 E,2R,6R)-3 5 -fluoro-6-(hydroxymethyl)-2-methyl-1 6 ,1 7 -dihydro-1 5 H-4 -Oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzo ring Renfan-8-one
  • Step A Synthesis of tert-butyl(1-(2-((R)-1-(((R)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)-3- Hydroxypropyl-2-yl) carbamate
  • Step B Synthesis of tert-butyl (1-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate
  • Step C Synthesis of tert-butyl (1-(4-fluoro-2-((R)-1-(3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a] Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate
  • the tert-butyl (1-(2-((R)-1-aminoethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl) carbamate (2.0 g, 7.0 milli Mol) was dissolved in N,N-dimethylformamide (40 ml), potassium carbonate (4.80 g, 35.0 mmol) and 5-chloro-6-(2-chloroethyl)-3-nitropyrazole And [1,5-a]pyrimidine (1.83 g, 7.0 mmol) was added to the reaction system, and the reaction was stirred at 110 degrees Celsius for 1 hour. The reaction solution was diluted by adding ethyl acetate (100 mL).
  • the organic phase was washed with saturated brine (20 ml ⁇ 3 times), and the organic phase was dried over anhydrous sodium sulfate.
  • Step D Synthesis of tert-butyl(1-(2-((R)-1-(3-amino-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2, 3-d)pyrimidin-5-yl)ethyl)-4-fluorophenoxy)-3-hydroxypropyl-2-yl)carbamate
  • Step E Synthesis of tert-butyl (1-(4-fluoro-2-((R)-1-(3-((phenoxycarbonyl)amino)-6,7-dihydro-5H-pyrazolo[ 1,5-a]pyrrolo[2,3-d]pyrimidine-5-yl)ethyl)phenoxy)-3-hydroxypropyl-2-yl)carbamate
  • Step F Synthesis of phenyl(5-((1R)-1-(2-(2-amino-3-hydroxypropoxy)-5-fluorophenyl)ethyl)-6,7-dihydro-5H -Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidin-3-yl)carbamate
  • Step G Synthesis of (1 3 E,1 4 E,2R,6R)-3 5 -fluoro-6-(hydroxymethyl)-2-methyl-1 6 ,1 7 -dihydro-1 5 H-4 -Oxa-7,9-diaza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzo ring Renfan-8-one
  • Step A Synthesis of (1 4 R,2 3 E,2 4 E,3R)-4 5 -fluoro-3-methyl-2 6 ,2 7 -dihydro-2 5 H-5-oxa-2( 3,5)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-1(1,4)-imidazopentidine-4(1,2)-benzocyclohexane -12-ketone
  • Example 7 (1 3 E,1 4 E,2R,5S)-2-(cyclopropylmethyl)-3 5 -fluoro-5-methyl-1 6 ,1 7 -dihydro-1 5 H -4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclooctane Fan-8-one
  • Step B Synthesis of 2-cyclopropyl-1-(5-fluoro-2-methoxyphenyl)ethane-1-one
  • Step C Synthesis of 2-cyclopropyl-1-(5-fluoro-2-hydroxyphenyl)ethane-1-one
  • Step D Synthesis of tert-butyl(S)-(2-(2-(2-cyclopropylacetyl)-4-fluorophenoxy)propyl)carbamate
  • Step E Synthesis of tert-butyl((2S)-2-(2-(1-amino-2-cyclopropylethyll)-4-fluorophenoxy)propyl)carbamate
  • Step F Synthesis of tert-butyl ((2S)-2-(2-(2-cyclopropyl-1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5- a]pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)-4-fluorophenoxy)propyl)carbamate
  • Step G Synthesis of 5-(1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl)-2- Cyclopropylethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid
  • reaction solution was diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (20 mL ⁇ 3 times), and the organic phase was dried over anhydrous sodium sulfate. The solvent was removed by concentration under reduced pressure. After concentration, 150 mg of yellow solid 5-(1-(2-(((S)-1-((tert-butoxycarbonyl)amino)propan-2-yl)oxo)-5-fluorophenyl was obtained )-2-Cyclopropylethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid. It is directly used in the next reaction without purification.
  • Step H Synthesis of 5-(1-(2-(((S)-1-aminopropan-2-yl)oxo)-5-fluorophenyl)-2-cyclopropylethyl)-6,7 -Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid
  • Step I Synthesis of (1 3 E,1 4 E,2R,5S)-2-(cyclopropylmethyl)-3 5 -fluoro-5-methyl-1 6 ,1 7 -dihydro-1 5 H -4-oxa-7-aza-1(5,3)-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(1,2)-benzocyclooctane Fan-8-one
  • Example 8 (1 3 E,1 4 E,6R)-3 5 -fluoro-2,6-dimethyl-1 6 ,1 7 -dihydro-1 5 H-7-aza-1 (5 ,3)-Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridocyclosinfan-8-one
  • Step A Synthesis of tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-6,7-dihydro-5H-pyrazolo[1,5-a] Pyrrolo[2,3-d]pyrimidin-5-yl)ethyl)pyrimidin-2-yl)butyl-2-yl)carbamate
  • Step B Synthesis of 5-(1-(2-((R)-3-((tert-butoxycarbonyl)amino)butyl)-5-fluoropyridin-3-yl)ethyl)-6,7 -Dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid
  • Step C Synthesis of 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl)-6,7-dihydro-5H-pyrazolo[ 1,5-a]pyrrolo[2,3-d]pyrimidine-3-carboxylic acid
  • Step D Synthesis of (1 3 E,1 4 E,6R)-3 5 -fluoro-2,6-dimethyl-1 6 ,1 7 -dihydro-1 5 H-7-aza-1(5 ,3)-Pyrazolo[1,5-a]pyrrolo[2,3-d]pyrimidine-3(3,2)-pyridocyclosinfan-8-one
  • Example 9 (1 3 E,1 4 E,2R,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-7-aza -1(5,3)-Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one
  • Example 10 (1 3 E,1 4 E,2S,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-7-aza -1(5,3)-Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one
  • Step A Synthesis of tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrazolo[1,5-a]pyrido[ 2,3-d)pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate
  • Step B Synthesis of tert-butyl((2R)-4-(5-fluoro-3-(1-(3-formyl-7,8-dihydropyrrolo[1,5-a]pyrido[2 ,3-d)pyrimidine-5(6H)-yl)ethyl)pyridin-2-yl)butyl-2-yl)carbamate
  • Step C Synthesis of 5-(1-(2-((R)-3-aminobutyl)-5-fluoropyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo [1,5-a]pyrido[2,3-d]pyrimidine-3-carboxylic acid
  • Step D Synthesis of (1 3 E,1 4 E,2R,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-7-aza -1(5,3)-Pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one
  • Example 9 (1 3 E,1 4 E,2R,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-7-aza- 1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one data:
  • Example 10 (1 3 E,1 4 E,2S,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-7-aza- 1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidin-3(3,2)-pyridocyclosimphan-8-one data:
  • Step B Synthesis of 5-(1-(2,5-difluorophenyl)ethyl)-3-nitro-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[ 2,3-d]pyrimidine
  • Extract with ethyl acetate 50 ml ⁇ 3 times
  • combine the obtained organic phases and wash with saturated brine 50 ml ⁇ 2 times
  • dry the organic phase with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain
  • Step C Synthesis of 5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2,3-d ]Pyrimidine-3-amine
  • Step D Synthesis of phenyl(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrolo[2, 3-d)pyrimidin-3-yl)carbamate
  • Step E Synthesis of (3S)-N-(5-(1-(2,5-difluorophenyl)ethyl)-6,7-dihydro-5H-pyrazolo[1,5-a]pyrrole And [2,3-d]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
  • Step B Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-10-nitropyrimido[1,2-b] Indazole
  • Step C Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole-10- amine
  • Step D Synthesis of (S)-N-(2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2- b]Indazol-10-yl)-3-hydroxypyrrolidine-1-carboxamide
  • Step A Synthesis of methyl 3-amino-2-cyanobenzoate
  • Step B Synthesis of methyl 3-amino-1H-indazole-4-carboxylate
  • Methyl 3-amino-2-cyanobenzoate (4 g, 23 mmol) was dissolved in concentrated hydrochloric acid (30 ml), cooled to 0 degrees Celsius, and sodium nitrite (1.88 g)/water (30 ml) was added dropwise. Ml), stir for 1 hour and 30 minutes under ice bath, then add stannous chloride dihydrate (42.5 g)/concentrated hydrochloric acid (30 ml) dropwise, and continue stirring under ice bath for 1 hour. The reaction was stopped, the reaction solution was filtered, the filter residue was washed with water (10 ml), and after drying, 3.5 g of methyl 3-amino-1H-indazole-4-carboxylate was obtained.
  • Step C Synthesis of methyl 2-hydroxypyrimido[1,2-b]indazole-10-carboxylate
  • Methyl 3-amino-1H-indazole-4-carboxylate (3.5 g, 18 mmol) was dissolved in nitrogen, nitrogen-dimethylformamide (100 ml), and cesium carbonate (12 g, 36 Millimoles) and ethyl ethoxyacrylate (3.2 g, 9.6 millimoles), heated to 110 degrees Celsius and stirred overnight.
  • Step D Synthesis of methyl 2-chloropyrimido[1,2-b]indazole-10-carboxylate
  • Methyl 2-hydroxypyrimido[1,2-b]indazole-10-carboxylate (1.5 g) was dissolved in 30 ml of acetonitrile, and phosphorus oxychloride (5.7 ml) was added dropwise under ice. After the addition is complete, the temperature is raised to 100 degrees Celsius and stirred overnight. The reaction solution was cooled, poured slowly into ice water, extracted with ethyl acetate (100 mL), the organic phase was dried, and concentrated under reduced pressure. The obtained solid was slurried by adding acetonitrile (5 ml), cooled, and filtered to obtain 300 mg of methyl 2-chloropyrimido[1,2-b]indazole-10-carboxylate.
  • Step E Synthesis of methyl 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole- 10-carboxylate
  • Step F Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole-10- carboxylic acid
  • the pH of the aqueous phase was adjusted to between 5-6 with 1 molar dilute hydrochloric acid solution, and then extracted with ethyl acetate (20 ml ⁇ 3 times).
  • the organic phases were combined, dried, and concentrated under reduced pressure to obtain 80 mg of 2-((2R, 4S)-2-(2,5-Difluorophenyl)-4-fluoropyrrolidin-1-yl)pyrimido[1,2-b]indazole-10-carboxylic acid.
  • Step G Synthesis of 2-((2R,4S)-2-(2,5-difluorophenyl)-4-fluoropyrrolidin-1-yl)-N-ethylpyrimido[1,2-b] Indazole-10-carboxamide
  • Step D Synthesis of (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-10-nitropyrimido[1,2-b]indazole
  • Step E Synthesis of (R)-2-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrimido[1,2-b]indazole-10-amine
  • Step F Synthesis of (S)-N-(2-((R)-2-(2,5-difluorophenyl)pyrrol-1-yl)pyrimido[1,2-b]indazole-10- Yl)-3-hydroxypyrrolidine-1-carboxamide
  • Example 15 ((1 3 E,1 4 E,2R,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxy 7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridinecyclosimphan-8-one
  • Step A Synthesis of 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridine And [2,3-d]pyrimidine-3-carbaldehyde
  • Step B Synthesis of 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-5,6,7,8-tetrahydropyrazolo[1,5-a]pyridine And [2,3-d]pyrimidine-3-carboxylic acid
  • reaction was quenched by adding saturated brine (200 mL). It was extracted with ethyl acetate (200 ml ⁇ 3 times), the obtained organic phases were combined, washed with water, dried, and concentrated to obtain 3.00 g of yellow solid. No purification is required and it is used directly in the next step.
  • Step C Synthesis of 5-(1-(5-fluoro-2-methoxypyridin-3-yl)ethyl)-N-((R)-1-hydroxypropyl-2-yl)-5,6 ,7,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-carboxamide
  • Step D Synthesis of 5-(1-(5-fluoro-2-hydroxypyridin-3-yl)ethyl)-N-((R)-1-hydroxypropyl-2-yl)-5,6,7 ,8-Tetrahydropyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3-amide
  • Step E Synthesis of ((1 3 E,1 4 E,2R,6R)-3 5 -fluoro-2,6-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxy 7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridinecyclosimphan-8-one
  • di-tert-butyl azodicarboxylate 124 mg, 0.54 mmol
  • tetrahydrofuran 2 mL
  • the reaction was quenched by adding saturated brine (20 mL). It was extracted with ethyl acetate (20 ml ⁇ 3 times), the obtained organic phases were combined, washed with water, dried, and concentrated.
  • white solid ((1 3 E,1 4 E,2R,6R)-3 5 -fluoro-2,6-dimethyl Group-1 5 ,1 6 ,1 7 ,1 8 -Tetrahydro-4-oxo7-aza-1(5,3)-pyrazolo[1,5-a]pyrid
  • Example 16 (1 3 E,1 4 E,2R,5S)-3 5 -fluoro-2,5-dimethyl-1 5 ,1 6 ,1 7 ,1 8 -tetrahydro-4-oxy- 7-Aza-1(5,3)-pyrazolo[1,5-a]pyrido[2,3-d]pyrimidine-3(3,2)-pyridinecyclosimphan-8-one
  • step C The synthesis method is the same as in Example 15.
  • step C (S)-1-aminopropyl-2-ol is substituted for (R)-2-aminopropyl-1-ol.

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  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé tricyclique, un procédé de préparation, un intermédiaire et une utilisation associés. De tels composés ont une activité d'inhibition de la kinase du récepteur lié à la tropomyosine et peuvent être utilisés pour traiter des cancers, la douleur, des maladies neurologiques, des maladies auto-immunes, l'inflammation et d'autres maladies.
PCT/CN2020/103225 2019-08-12 2020-07-21 Composé tricyclique, procédé de préparation, intermédiaire et utilisation associés WO2021027503A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023179600A1 (fr) * 2022-03-21 2023-09-28 杭州德睿智药科技有限公司 Nouveaux composés macrohétérocycliques substitués et leur utilisation
WO2024046512A3 (fr) * 2022-12-01 2024-04-18 中国医药研究开发中心有限公司 Composé macrocyclique contenant de l'azote, et son procédé de préparation et son utilisation médicale

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102596957A (zh) * 2009-07-09 2012-07-18 阵列生物制药公司 作为TRK激酶抑制剂的被取代的吡唑并[1,5-a]嘧啶化合物
CN106170289A (zh) * 2014-01-24 2016-11-30 Tp生物医药公司 作为蛋白质激酶的调节剂的二芳基巨环
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
CN109516999A (zh) * 2017-11-01 2019-03-26 郑州泰基鸿诺医药股份有限公司 用作蛋白质激酶调节剂的化合物及其应用
CN109575025A (zh) * 2018-01-23 2019-04-05 深圳市塔吉瑞生物医药有限公司 取代的吡唑并[1,5-a]嘧啶类的大环化合物
CN109715165A (zh) * 2016-07-28 2019-05-03 Tp生物医药公司 巨环激酶抑制剂
WO2019126122A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Inhibiteurs macrocycliques de kinase et leur utilisation
WO2019126121A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Composés macrocycliques pour le traitement de maladie

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102596957A (zh) * 2009-07-09 2012-07-18 阵列生物制药公司 作为TRK激酶抑制剂的被取代的吡唑并[1,5-a]嘧啶化合物
CN106170289A (zh) * 2014-01-24 2016-11-30 Tp生物医药公司 作为蛋白质激酶的调节剂的二芳基巨环
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
CN109715165A (zh) * 2016-07-28 2019-05-03 Tp生物医药公司 巨环激酶抑制剂
CN109516999A (zh) * 2017-11-01 2019-03-26 郑州泰基鸿诺医药股份有限公司 用作蛋白质激酶调节剂的化合物及其应用
WO2019126122A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Inhibiteurs macrocycliques de kinase et leur utilisation
WO2019126121A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Composés macrocycliques pour le traitement de maladie
CN109575025A (zh) * 2018-01-23 2019-04-05 深圳市塔吉瑞生物医药有限公司 取代的吡唑并[1,5-a]嘧啶类的大环化合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023179600A1 (fr) * 2022-03-21 2023-09-28 杭州德睿智药科技有限公司 Nouveaux composés macrohétérocycliques substitués et leur utilisation
WO2024046512A3 (fr) * 2022-12-01 2024-04-18 中国医药研究开发中心有限公司 Composé macrocyclique contenant de l'azote, et son procédé de préparation et son utilisation médicale

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