WO2023198114A1 - Inhibiteur de kinase alk2 - Google Patents

Inhibiteur de kinase alk2 Download PDF

Info

Publication number
WO2023198114A1
WO2023198114A1 PCT/CN2023/087857 CN2023087857W WO2023198114A1 WO 2023198114 A1 WO2023198114 A1 WO 2023198114A1 CN 2023087857 W CN2023087857 W CN 2023087857W WO 2023198114 A1 WO2023198114 A1 WO 2023198114A1
Authority
WO
WIPO (PCT)
Prior art keywords
ring
alkyl
amino
halogen
membered
Prior art date
Application number
PCT/CN2023/087857
Other languages
English (en)
Chinese (zh)
Inventor
杨欣
崔荣
温俏冬
殷建明
郑鹛
吕裕斌
Original Assignee
杭州邦顺制药有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杭州邦顺制药有限公司 filed Critical 杭州邦顺制药有限公司
Publication of WO2023198114A1 publication Critical patent/WO2023198114A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • C07D491/20—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicinal chemistry and relates to an ALK2 kinase inhibitor, its pharmaceutical composition, preparation method and its use in preparing, preventing and/or treating drugs for indications related to the ALK2 signaling pathway.
  • ALK2 (also known as ACVR1 protein) is an activin receptor-like kinase, bone morphogenetic protein (BMP) type I receptor, and a member of the transforming growth factor TGF- ⁇ family.
  • BMP bone morphogenetic protein
  • TGF- ⁇ family The binding of ligands to type II receptors induces the phosphorylation of type I receptors.
  • Type I receptors affect cell function by recruiting and phosphorylating downstream receptor-related Smads and further regulating the expression of related genes (PLoS One 2013 Apr 30;8(4):e62721).
  • ALK2 abnormal activation of ALK2 can lead to the occurrence and development of various diseases. For example, most patients with fibrodysplasia ossificans progressiva (FOP) are found to have ALK2 R206H mutations, which enhance downstream SMAD signaling and overactivate the BMP pathway. 20-32% of diffuse endophytic pontine gliomas (DIPG) have ACVR1 mutations. ALK2 has also been found to play a carcinogenic role in ovarian cancer, prostate cancer, and erythroleukemia (Cells 2019, 8, 1366).
  • FOP fibrodysplasia ossificans progressiva
  • DIPG diffuse endophytic pontine gliomas
  • ALK2 is a key receptor that regulates the iron-dependent upregulation of hepcidin expression, and high levels of hepcidin can lead to iron limitation erythropoiesis, manifested as iron-refractory iron deficiency anemia (IRIDA) and inflammatory anemia (AI).
  • IRIDA iron-refractory iron deficiency anemia
  • AI inflammatory anemia
  • Inflammatory anemia also known as anemia of chronic disease (ACD) is the second most common anemia disease in the world after iron deficiency anemia. It is common in patients with chronic diseases or hospitalization.
  • Inflammatory anemia refers to anemia caused by chronic infections (including tuberculosis, acquired immunodeficiency syndrome), autoimmune diseases (such as rheumatoid arthritis, lupus erythematosus, inflammatory bowel disease, etc.) and certain tumors (including those related to cytokines Anemia caused by long-term inflammation caused by increased related hematological tumors such as Hodgkin lymphoma, myelofibrosis, MDS, MM, etc., and common solid tumors such as ovarian cancer, lung cancer, etc.). This type of inflammatory anemia can seriously affect patients' quality of life, physiological functions, and reduce survival (N Engl J Med 2019;381:1148-57).
  • Patent WO2021102258 discloses the use of ALK2 inhibitors in combination with JAK2 inhibitors for the treatment of myeloproliferative neoplasms (MPN) and related anemia. This suggests the application potential of ALK2 inhibitors in this indication.
  • the object of the present invention is to provide an ALK2 kinase inhibitor, its pharmaceutical composition, preparation method and its use in the preparation, prevention and/or treatment of drugs for indications related to the ALK2 signaling pathway.
  • the present invention discloses a compound having the structure shown in general formula (I), its deuterated product, stereoisomer or pharmaceutically acceptable salt:
  • Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
  • Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
  • L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
  • R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
  • R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
  • R 2 is selected from 4-10 membered heterocycloalkyl or cycloalkyl, and is optionally substituted by 1-3 R 6 ;
  • R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
  • R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, -CO-NR c R d , C 1-6 alkyl, C 1-6 alkoxy, -(CR a R b ) n -OH;
  • R 6 is selected from halogen, hydroxyl, cyano, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
  • R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
  • n is selected from an integer from 1 to 3.
  • Ring A is a 5-10 membered heteroaryl group, optionally substituted by 1-3 R 3 ;
  • Ring B is a 6-15 membered ring group, and optionally 1-3 link carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • L 1 is selected from chemical bond, C 1-6 alkyl, imino, carbonyl, -CO-NH-, phenyl, 5-6 membered heteroaryl, -phenyl-CO-NH-;
  • L 2 is selected from chemical bond, -(CR a R b ) n -, imino group, ether bond, -C 1-6 alkyl-O-;
  • R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
  • R 2 is selected from 4-10 membered heterocycloalkyl, and R 2 is optionally substituted by 1-3 R 6 ;
  • R 3 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl;
  • R 4 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, halogenated C 1-6 alkyl;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
  • R a , R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
  • n is selected from an integer from 1 to 3.
  • Ring A is a 6-10 membered heteroaryl group, containing 1-3 heteroatoms selected from N, O, and S, optionally substituted by 1-3 R 3 ;
  • Ring B is selected from 6-9-membered carbocyclyl or 6-13-membered heterocyclyl, and optionally 1 link carbon atom is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • L 1 is selected from imino, carbonyl, -CO-NH-, 5-6 membered heteroaryl, -phenyl-CO-NH-;
  • L 2 is selected from chemical bond, -(CR a R b ) n -, -C 1-3 alkyl-O-;
  • R 1 is selected from C 1-3 alkyl, 6-8 membered cycloalkyl, 6-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 ;
  • R 2 is selected from 4-9 membered heterocycloalkyl, containing 1-2 heteroatoms selected from N, O, S, R 2 is optionally substituted by 1-3 R 6 ;
  • R 3 is selected from cyano, amino, C 1-3 alkyl
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 5 is selected from halogen, hydroxyl, cyano, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, and is optionally substituted by 1-3 R e ;
  • R a , R b are independently selected from H or C 1-3 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H or C 1-3 alkyl
  • R e is selected from halogen, cyano, C 1-3 alkoxy
  • n is selected from an integer from 1 to 3.
  • Ring A is selected from
  • L 1 is selected from imino, -CO-NH-, carbonyl, -phenyl-CO-NH-;
  • R 1 is selected from C 1-3 alkyl, the R 1 is optionally substituted by 1-3 R 5 ;
  • R 3 is selected from cyano, amino, C 1-3 alkyl
  • R 5 is selected from halogen, cyano, hydroxyl, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R a and R b are independently selected from H or C 1-3 alkyl
  • n is selected from an integer from 1 to 3.
  • Ring B is selected from
  • Ring B is selected from
  • L 2 is selected from chemical bond, -(CR a R b ) n -, -C 1-3 alkyl-O-;
  • R 2 is selected from, H, halogen, hydroxyl, cyano, or
  • R 2 is selected from and optionally substituted by 1-3 R 6 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 6 is selected from halogen, hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, C 1-6 alkoxy, optionally substituted by 1-3 Re ;
  • R a , R b are independently selected from H or C 1-3 alkyl, or
  • R a , R b and the attached carbon atoms form a 3-6 membered cycloalkyl group
  • R c and R d are independently selected from H or C 1-3 alkyl
  • R e is selected from halogen, hydroxyl, cyano, C 1-3 alkoxy;
  • n is selected from an integer from 1 to 3.
  • the compound provided by the present invention further has the structure shown in formula (II):
  • X 1 and X 2 are independently selected from CH or N;
  • R 1 is selected from 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, optionally substituted by 1-3 R 5 ;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH;
  • Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N.
  • Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 2 is a 4-8 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
  • R 6 is selected from -CO-R c , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
  • R a and R b are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy;
  • n is selected from an integer from 1 to 3.
  • R 1 is selected from
  • R 5 is selected from hydroxyl, halogen, C 1-6 alkyl, -(CR a R b ) n -OH;
  • R a and R b are independently selected from H and C 1-3 alkyl
  • n is selected from an integer from 1 to 3.
  • R 1 is selected from
  • R 5 is selected from hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  • the compound provided by the present invention further has the structure shown in formula (II-1):
  • Ring B is Y 1 , Y 2 , Y 3 are independently selected from CH or N.
  • Ring C is a parallel 5-6 membered ring group. Any one carbon atom in ring C is substituted by oxygen; ring B is optionally substituted by 1- 3 R 4 substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 2 is a 5-7 membered heterocycloalkyl group, containing 1-3 heteroatoms selected from N, O, S, and optionally substituted by 1-3 R 6 ;
  • R 6 is selected from -CO-R c , -SO 2 -R c , or
  • R 6 is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
  • R c is independently selected from H, hydroxyl, amino or C 1-6 alkyl
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkoxy.
  • Ring B is selected from
  • Ring B is Ring C is a parallel 5-membered carbocyclyl or heterocyclyl, and any one carbon atom in Ring C is substituted by oxygen; Ring B is optionally substituted by 1-3 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • Ring B is selected from
  • Ring B is optionally substituted with 1-3 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl.
  • R 2 is selected from preferred and optionally substituted by 1 R 6 ;
  • R 6 is selected from -CO-R c , -SO 2 -R c , or
  • R 6 is selected from C 1-3 alkyl, 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl, optionally substituted by 1-3 R e ;
  • R c is independently selected from H or C 1-3 alkyl
  • R e is selected from halogen, cyano, C 1-3 alkoxy.
  • R 2 is selected from preferred and replaced by 1 R 6 ;
  • R 6 is a 4-6 membered heterocycloalkyl group, containing 1 O atom, preferably More preferred
  • the compound provided by the present invention further has the structure shown in formula (III):
  • Ring B is Ring C is a parallel 5-6 membered ring group, optionally containing 1-2 heteroatoms selected from N; Ring B is optionally substituted by 1-2 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, and halogenated C 1-3 alkyl;
  • R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 2 heteroatoms selected from N, O, and S, preferably More preferred R 1 is optionally replaced by 1-3 R 5 ;
  • R 5 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, -(CR a R b ) n -OH, preferably hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH , -C(CH 3 ) 2 OH;
  • L 2 is selected from chemical bonds, -(CR a R b ) n -;
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, hydroxyl, amino, cyano, or
  • R 6 is selected from 4-7 membered cycloalkyl, 4-7 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 Re substitution ;
  • R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
  • R e is halogen
  • n is an integer from 1 to 3.
  • Ring B is selected from
  • Ring B is selected from
  • L 2 is selected from chemical bond, C 1-3 alkylene
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, or
  • R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1-2 selected from N, O heteroatoms, C 1-3 alkyl, and is optionally replaced by 1-3 R e replaced.
  • Ring B is selected from
  • R 1 is selected from optionally substituted by 1 R 5 ;
  • R 5 is selected from hydroxyl, -CH 2 OH
  • L 2 is selected from chemical bonds
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1 R 6 ;
  • R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O, C 1-3 alkyl, and is optionally substituted by 1-3 R e ;
  • R e is halogen
  • R 2 is selected from preferred
  • R 6 is selected from Cyclohexyl, C 1-3 alkyl, preferably C 1-3 alkyl.
  • R 1 and R 5 form the following structure:
  • Ring B is selected from
  • R 1 is selected from optionally substituted by 1 R 5 ;
  • R 5 is selected from hydroxyl, -CH 2 OH
  • L 2 is selected from chemical bonds
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 N, substituted by 1 R 6 ;
  • R 6 is selected from 4-6 membered heterocycloalkyl groups containing 1-2 heteroatoms selected from N and O.
  • R 2 is selected from preferred
  • R 6 is selected from preferred
  • R 1 and R 5 form the following structure:
  • Ring B is selected from
  • R 1 is selected from optionally substituted by 1 R 5 ;
  • R 5 is selected from hydroxyl, -CH 2 OH
  • L 2 is selected from chemical bond, C 1-3 alkylene
  • R 2 is a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, or
  • R 6 is selected from 4-6 membered cycloalkyl, 4-6 membered heterocycloalkyl containing 1 O, and is optionally substituted by 1-3 R e ;
  • R e is halogen
  • R 2 is selected from preferred
  • R 6 is selected from halogen, or
  • R 6 is selected from Cyclohexyl, preferably and optionally substituted by 1-3 Re ;
  • R e is halogen
  • R 1 and R 5 form the following structure:
  • the compound provided by the present invention further has a structure represented by formula (IV):
  • X 1 and X 2 are independently selected from CH or N;
  • R 1 is selected from 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O, and S, preferably More preferred optionally substituted by 1-2 R5 ;
  • R 5 is selected from C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, halogen, OH, amino, amide group, and cyano group;
  • Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen; ring B is optionally replaced by 1-2 R 4 replace;
  • R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl;
  • L 2 is a chemical bond, -(CR a R b ) n -;
  • R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
  • R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano;
  • R a and R b are independently selected from H or C 1-3 alkyl, or R a , R b and the attached carbon atom form a 3-6 membered cycloalkyl group;
  • n is an integer from 1 to 3.
  • Ring B is selected from
  • Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
  • R 4 is selected from halogen, C 1-3 alkyl, C 1-3 alkoxy, and hydroxyl.
  • X 1 and X 2 are CH;
  • Ring B is r is an integer from 1 to 2, be a single bond or a double bond.
  • Ring B is preferred The * end is connected to pyridine, and the ** end is connected to L 2 Connection, r is an integer from 1 to 2, be a single bond or a double bond.
  • L 2 is a chemical bond or C 1-3 alkylene group
  • R 2 is selected from H, halogen, hydroxyl, cyano, amino, or
  • R 2 is selected from 4-6 membered heterocycloalkyl or 4-6 membered cycloalkyl, preferably 4-6 membered heterocycloalkyl or 4-6 membered containing 1-2 heteroatoms selected from N, O, S Cycloalkyl, more preferably Further preferred and optionally substituted by 1-2 R 6 ;
  • R 6 is selected from halogen, hydroxyl, C 1-3 alkyl, C 1-3 alkoxy, and cyano.
  • R 1 is selected from preferred optionally substituted by 1-2 R5 ;
  • R 5 is selected from halogen, OH, C 1-3 alkyl, C 1-3 alkoxy, -C 1-3 alkyl-OH, preferably F, Cl, -OH, methyl, -CH 2 -OH;
  • R 1 and R 5 form the following structure:
  • Ring B is selected from preferred Further preferred
  • the * end is connected to pyridine, and the ** end is connected to L 2 ;
  • L 2 is a chemical bond, C 1-3 alkylene group, preferably a chemical bond or isopropyl group;
  • R2 is H or Preferably H or
  • the compound provided by the present invention further has a structure represented by formula (V):
  • M is selected from CH or N;
  • R 6a is selected from C 1-3 alkoxy, preferably methoxy, ethoxy, propoxy;
  • R 6b is selected from C 1-6 alkyl, 4-8 membered cycloalkyl, 4-8 membered heterocycloalkyl, preferably methyl, ethyl, isopropyl, Isopropyl is more preferred.
  • Compounds represented by general formula (1) include the following specific compounds:
  • Another aspect of the present invention also provides a pharmaceutical composition, which contains the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt and its pharmaceutically acceptable carrier.
  • Another aspect of the present invention also provides the use of the above-mentioned compound, its deuterated product, stereoisomer or pharmaceutically acceptable salt or the above-mentioned pharmaceutical composition in preparing a medicament for treating and/or preventing ALK2-related diseases.
  • the ALK2-related diseases include anemia, inflammation, tumors and some ALK2-related genetic diseases.
  • the ALK2-related diseases include fibrodysplasia ossificans progressiva, diffuse endogenous pontine glioma, iron-refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, multiple Anemia associated with myeloma and myeloproliferative neoplasms.
  • the drug is used alone or in combination with other therapeutic agents.
  • the other therapeutic agent is a JAK2 inhibitor for the treatment of myeloproliferative neoplasm-related anemia.
  • the compound provided by the invention has strong medicinal efficacy, good pharmacokinetic properties and low toxic and side effects, and is an ideal ALK2 inhibitor.
  • the compound provided by the present invention has better ALK2 inhibitory activity, and its inhibitory activity on ALK2 is much greater than ALK5, and has better selectivity.
  • the compounds of the present invention are ideal highly active ALK2 inhibitors and can be used to treat and/or prevent diseases, including anemia, inflammation, tumors and some rare diseases, such as fibrodysplasia ossificans progressiva and diffuse endogenous pontine type.
  • Glioma iron-refractory iron deficiency anemia, inflammatory anemia, myelodysplastic syndrome, multiple myeloma, combined use of JAK2 inhibitors to treat anemia associated with myeloproliferative neoplasms.
  • group A is optionally substituted by 1 to 3 groups B
  • group A is unsubstituted by group B, group A being substituted by 1 group B, and group A being substituted by 2 groups B. Substitution, group A is replaced by three groups B. There are four cases.
  • Substituted or “substituted” as used herein means that any one or more hydrogen atoms on any atom in a certain group or fragment are replaced by substituents, which may include deuterium and hydrogen variants, as long as The valence state of a particular atom is normal and the substituted compound is stable.
  • substituents which may include deuterium and hydrogen variants, as long as The valence state of a particular atom is normal and the substituted compound is stable.
  • substituent oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary based on what is chemically feasible.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • combinations of substituents and/or variants thereof may only be used if such combinations result in stable compounds. It is only allowed in the case of compounds.
  • a connecting group When the number of a connecting group is 0, such as -(CR a R b ) 0 -, it means that the connecting group is a single bond/chemical bond.
  • one of the variables is selected from chemical bond/single bond, it means that the two groups connected to it are directly connected.
  • L 1 in AL 1 -R 1 represents a single bond, it means that the structure is actually AR 1 .
  • substituent When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
  • the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the connection direction is arbitrary.
  • the linking group L 1 in ring AL 1 -R 1 is -MW-.
  • -MW- can be pressed from left to right.
  • the ring A and R 1 can be connected in the same direction in the right reading order to form the ring AMWR 1 , or the ring A and R 1 can be connected in the opposite direction to the reading order from left to right to form the ring AWMR 1 .
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned, and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced accordingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be in the form of a straight solid line bond. dashed key express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the carbon atoms in the group;
  • the dotted lines in indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 4;
  • connection site of the group or fragment is located on the ring connected by the dotted line.
  • Any connection point on the nitrogen-containing spirocyclic ring of the group can be connected to other groups through a chemical bond, including at least These 3 connection methods;
  • Any connection point on the benzene ring of this group can be connected to other groups through a chemical bond, including at least These 4 connection methods.
  • connection site of the group or fragment can be any connection site.
  • Any connection point on the nitrogen-containing spirocyclic ring of the group can be connected to other groups through a chemical bond, including at least These two connection methods.
  • double bonds and single bonds have no limiting meaning.
  • Both refer to benzene ring or phenyl group, in which the double bond or Specifically refers to large ⁇ bonds delocalized on the plane of the benzene ring; , when ring C is limited to a 5-membered aryl or heteroaryl, ring B and ring C form a conjugated ring-aryl or ring-heteroaryl group, and non-limiting examples thereof include even though The left-center ring contains only two double bonds, but still includes For this group, the double bond at this time represents the large ⁇ bond delocalized on the aromatic ring.
  • numerical ranges include endpoint values and any number between the endpoint values.
  • “0-3” may include 0, 1, 2, or 3
  • “1-3” may include 1, 2, or 3.
  • C 1-n as used herein includes C 1-2 , C 1-3 ,...C 1-n .
  • a “C 1-6 " group means that there are 1 to 6 carbon atoms in the moiety, that is, the group contains 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • C 1-4 alkyl refers to an alkyl group containing 1 to 4 carbon atoms, that is, the alkyl group is selected from methyl, ethyl, propyl, isopropyl, n-butyl , isobutyl, sec-butyl and tert-butyl. Numeric ranges, such as “1-6", in this document refer to each integer within the given range.
  • the link atoms refer to the non-hydrogen atoms used in the ring group to form the ring.
  • the link atoms in are 3 carbon atoms;
  • the middle link atoms are three carbon atoms and one oxygen atom;
  • the middle link atoms are 1 N atom and 5 carbon atoms;
  • the middle link atoms are 8 carbon atoms and 1 nitrogen atom.
  • n-m element refers to the number of link atoms in the ring group.
  • a "3-8 yuan” group means that the part has 3-8 link atoms, that is, the group contains 3 link atoms, 4 link atoms, 5 link atoms, 6 link atoms, 7 link atoms or 8 link atoms.
  • 3-8 membered cycloalkyl refers to a saturated cyclic hydrocarbon group containing 3-8 carbon atoms, that is, the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, cycloheptyl, cyclooctyl.
  • hydrocarbyl used herein alone or in combination refers to an atomic group consisting only of carbon and hydrogen, including saturated, unsaturated or aromatic hydrocarbon groups, such as alkyl, alkenyl, alkynyl, cyclic Alkyl, cycloalkenyl, cycloalkynyl, aryl. Unless otherwise specified, the “hydrocarbyl group” may be linear, branched or cyclic.
  • alkyl refers to an optionally substituted straight chain or optionally substituted branched chain saturated aliphatic hydrocarbon. This article The “alkyl group” may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms.
  • Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl base, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl- 1-pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-di Methyl-l-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, tert-amyl, hexyl, etc.
  • alkyl when “alkyl” appears in a numerical range, for example, "C 1 - 6 alkyl” means that it can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, An alkyl group composed of 5 carbon atoms or 6 carbon atoms.
  • the alkyl group herein also includes cases where the numerical range is not specified.
  • Alkyl groups may be optionally substituted or unsubstituted.
  • Alkyl as used in combination herein refers to an alkyl group attached to another group, for example, an alkyl group in an alkoxy group, and is defined the same as when used alone.
  • alkylene refers to a saturated aliphatic divalent hydrocarbon radical obtained by removing two hydrogen atoms from a linear or branched saturated aliphatic hydrocarbon radical.
  • the "alkylene group” herein may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms.
  • Non-limiting examples of alkylene include -CH 2 - (i.e., methylene), -CH 2 -CH 2 - (i.e., ethylene), -CH 2 -CH 2 -CH 2 -, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 -, -CH 2 -C(CH 3 )-CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -C(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -C(CH 3 )-CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -, etc.
  • Alkylene groups may be optionally substituted or unsubstituted.
  • alkenyl refers to an optionally substituted straight chain or optionally substituted unsaturated aliphatic hydrocarbon having one or more carbon-carbon double bonds.
  • Alkenyl herein may preferably have 1 to 6 carbon atoms, such as 1 to 5 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms.
  • Non-limiting examples of alkyl groups include vinyl, propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl, 1,3 -Pentadienyl, 1,4-pentadienyl and 1,4-hexadienyl groups/moieties. Unless otherwise stated, the term “alkenyl” does not include “cycloalkenyl”.
  • alkoxy or "-O-alkyl” as used herein, alone or in combination, means “alkyl-O-”.
  • alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • Alkoxy groups may be optionally substituted or unsubstituted.
  • cyclyl or "ring” as used herein alone or in combination refers to any organic compound having a cyclic structure, wherein the cyclic group may be saturated or unsaturated (including aryl) and may have at its carbon
  • the skeleton contains one or more heteroatoms such as N, O or S.
  • cyclic groups include carbocyclyl and heterocyclyl groups as discussed below, and may specifically be cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl.
  • any one of the rings is optionally selected from cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl; when one or more of the rings is When it is an aryl group, the remaining ring may be an aryl group or a non-aromatic cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl group.
  • the number of rings in the ring group can be monocyclic, bicyclic or polycyclic.
  • bicyclic or polycyclic ring groups can be divided into spiro rings and bridged rings (including pendant rings or fused rings) according to different connection methods.
  • the ring group is a 3-15-membered ring group, which means that it contains 3 to 12 link atoms, preferably a 3-12-membered ring group, and more preferably a 3-10-membered ring group.
  • spiro ring refers to a cyclic group with two or more cyclic structures and the single rings share one atom (called a spiro atom) with each other.
  • the preferred value here is 7-15 yuan, and the more preferred value is 8-9 yuan.
  • spiro rings are divided into single spiro, double spiro or polyspiro ring groups.
  • single spiro and double spiro ring groups are preferred, and 4-membered/5-membered and 4-membered/6-membered are preferred.
  • 5-membered/5-membered or 5-membered/6-membered spirocyclic group include, but are not limited to, spiro[3.5]nonane, bicyclo[3.2.1]octane.
  • bridged ring refers to a polycyclic cyclic group containing two or more cyclic structures and sharing two or more atoms.
  • parallel ring or “fused ring” is a special bridged ring, which refers to a polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other.
  • the preferred value here is 7-15 yuan, and the more preferred value is 8-9 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups preferably bicyclic or tricyclic, here preferably bicyclic or tricyclic, more preferably 5-membered/5-membered, 5-membered/6-membered One-membered or 6-membered/6-membered bicyclic bridged ring base.
  • Non-limiting examples thereof include, but are not limited to, bicyclo[2.2.2]octane, spirocyclo[3.4]octane.
  • spiro rings and bridged rings can also be applied to cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl discussed below, including spirocycloalkyl, spirocycloalkenyl, and spiroheterocycles. Cycloalkyl, spiroheterocycloalkenyl, bridged cycloalkyl, bridged cycloalkenyl, bridged heterocycloalkyl, bridged heterocycloalkenyl.
  • Condensed rings include fused ring alkyl, fused ring alkenyl, fused heterocycloalkyl, fused heterocycloalkenyl, fused ring aryl, and fused ring heteroaryl.
  • the definitions of the above terms are similar to those of spiro ring, bridged ring, parallel ring or fused ring.
  • Carbocyclyl as used herein, alone or in combination, includes alicyclic and aryl groups, including monocyclic, fused, bridged and spirocyclic rings.
  • heterocyclyl groups include cycloalkyl, cycloalkenyl, and aryl groups as discussed below. Preferred here are 3-10 membered monocyclic, bicyclic or tricyclic carbocyclic groups.
  • cycloalkyl refers to a saturated monocyclic, bicyclic or polycyclic carbocyclic ring, which may be spiro or bridged.
  • a 3-12-membered cycloalkyl group is preferred, a 3-10-membered cycloalkyl group is more preferred, and a 3-8-membered cycloalkyl group is most preferred.
  • Non-limiting examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and other cycloalkyl groups, which may be optionally substituted or un replaced.
  • spiro ring refers to an all-carbon polycyclic group with two or more cyclic structures and each single ring shares one carbon atom (called a spiro atom).
  • a spiro atom it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan.
  • the spiro ring is divided into single spiro, double spiro or polyspiral cycloalkyl groups.
  • the preferred ones here are single spiro and double spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/ 6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl group.
  • fused ring refers to an all-carbon polycyclic group containing two or more cyclic structures and sharing a pair of carbon atoms with each other.
  • it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan.
  • it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups.
  • bicyclic or tricyclic is preferred, and more preferably 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered.
  • bridged ring refers to a ring structure containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. all-carbon polycyclic groups. Here, it is preferably 6 to 12 yuan, and more preferably 8 to 9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic or tricyclic.
  • cycloalkenyl refers to a nonaromatic monocyclic, bicyclic or polycyclic carbocyclic ring having one or more carbon-carbon double bonds, which may be spirocyclic or bridged.
  • a 3-12-membered cyclic alkenyl group is preferred, a 3-10-membered cyclic alkenyl group is more preferred, and a 3-8-membered cyclic alkenyl group is most preferred.
  • Non-limiting examples of cycloalkenyl include, but are not limited to, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, and cyclohex-1,3-dien-1-yl, which may are optionally substituted or unsubstituted.
  • aryl refers to an aromatic hydrocarbyl ring.
  • aryl includes monocyclic aromatic hydrocarbons and polycyclic fused ring aromatic hydrocarbons, in which all fused ring systems (excluding any ring systems that are part of or formed from optional substituents) ) is aromatic. Examples of aryl groups/moieties include phenyl, naphthyl, anthracenyl and phenanthrenyl. Unless otherwise stated, the term “aryl” does not include “heteroaryl”.
  • heterocyclyl as used herein, alone or in combination, includes alicyclic and heteroaryl groups in which one or more (such as one, two, three or four) link atoms are heteroatoms, such as oxygen, nitrogen , sulfur atoms, etc., including single ring, fused ring, bridged ring and spiro ring.
  • heterocyclyl groups include heterocycloalkyl, heterocycloalkenyl, and heteroaryl as discussed below.
  • Preferred here are 3-10 membered monocyclic, bicyclic or tricyclic heterocyclyl groups, which may contain 1, 2 or 3 ring atoms selected from nitrogen, oxygen and/or sulfur.
  • heterocyclyl examples include azetidinyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-oxo-pyrrolidine base, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, dioxolyl, oxothiolanyl, piperidinyl, 2-oxo-piperidinyl, tetrahydrogen Pyranyl, thiyl, piperazinyl, piperazin-2-one, dioxanyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl wait.
  • Heterocyclyl groups may be optionally substituted or unsubstituted.
  • spirocycle refers to a polycyclic ring group with two or more cyclic structures and the single rings share one atom with each other.
  • the ring contains several unsaturated bonds, but Aromatic systems in which none of the rings have fully conjugated ⁇ electrons, in which one or more link atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) n (where n is selected from 0, 1, or 2), and the remaining link atoms for carbon.
  • the preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan.
  • the spiro ring is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group, and more preferably It is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclic group.
  • Non-limiting examples thereof include, but are not limited to, 7-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, and 2-azaspiro[3.4]octane.
  • bridged ring refers to a polycyclic ring group containing two or more cyclic structures and sharing two or more atoms with each other.
  • One or more rings may contain several An aromatic system with unsaturated bonds but none of the rings having fully conjugated ⁇ electrons, in which one or more link atoms are selected from nitrogen, oxygen, or S(O) n (where n is selected from 0, 1, or 2) Heteroatoms, the remaining link atoms are carbon.
  • the preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic or tricyclic.
  • fused ring refers to a polycyclic ring group containing two or more cyclic structures and sharing a pair of atoms with each other.
  • One or more rings may contain several unsaturated bonds.
  • the preferred value here is 6-12 yuan, and the more preferred value is 8-9 yuan.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups.
  • heterocycloalkyl refers to a saturated monocyclic, bicyclic or polycyclic ring in which one or more (such as one, two, three or four) ring atoms are heteroatoms. Heterocyclyl, which can be a spiro ring or a bridged ring.
  • a 3-12-membered cycloalkyl group is preferred, a 3-10-membered cycloalkyl group is more preferred, and a 3-8-membered cycloalkyl group is most preferred.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include, but are not limited to, propylene oxide, thiirane, aziridine, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrofuran, Hydrothiophene, tetrahydropyrrole, oxazolidine, thiazolidine, imidazolidine, tetrahydropyran, piperidine, dioxane, azepane.
  • heterocycloalkenyl refers to a nonaromatic monocyclic, bicyclic or polycyclic ring having one or more unsaturated double bonds, in which one or more (such as one, two (one, three or four) link atoms are heteroatoms in a saturated heterocyclyl group, which can be a spiro ring or a bridged ring.
  • it is preferably a 3-12-membered heterocyclic alkenyl group, more preferably a 3-10-membered heterocyclic alkenyl group, and most preferably a 3-8-membered heterocyclic alkenyl group.
  • Non-limiting examples of heterocycloalkenyl include, but are not limited to, aziridine, oxane, thiane, oxetene, pyran.
  • heteroaryl refers to a 5-12 membered (preferably 5-10 membered, more preferably 5-6 membered) monocyclic, bicyclic or tricyclic ring system in which at least one ring is aromatic, And at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and at the same time, the heteroaryl group also has one or more attachment points connected to the rest of the molecule.
  • heteroaryl group of the bicyclic or tricyclic system, if it contains a saturated or unsaturated heterocycloalkyl group or.
  • heteroaryl include furyl, imidazolyl, isoxazolyl, oxazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thienyl, Thiazolyl, etc.; also includes the following bicyclic rings, but is not limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl, oxoindolyl, indolyl, imidazopyridine base, pyrazopyridinyl, pyrazopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole, 1,8-naphthyridine, benzo[d]isoxazole, benzo[ d] Thiazole, pyrrole[3,2-b]pyridine, furan[
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy as used herein alone or in combination refers to -OH.
  • cyano as used herein alone or in combination refers to -CN.
  • methanesulfonyl as used herein alone or in combination refers to -S(O) 2 - CH3 .
  • substituted or “substituted by” means that one or more hydrogens on a particular atom are designated Groups (such as halogen, alkyl, etc.) are substituted. If the normal valency of the specified atom is not exceeded under the existing circumstances, then the result after substitution is a stable compound.
  • the term "pharmaceutically acceptable” refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing adverse effects biologically react or interact in an adverse manner with any component contained in the composition.
  • composition refers to a biologically active compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to a carrier, a stabilizer, Diluents, dispersants, suspending agents, thickeners and/or excipients.
  • carrier refers to a relatively nontoxic chemical compound or agent that facilitates the introduction of a compound into cells or tissues.
  • stereoisomer as used herein includes, but is not limited to, enantiomers, cis-trans isomers, and the like.
  • enantiomers used herein refers to compounds with the same molecular formula that are enantiomers of each other due to the isomerism phenomenon caused by the different spatial arrangements of atoms or atomic groups (groups). Two compounds are mirror images of each other and cannot be superimposed.
  • cis-trans isomers used herein generally refers to the diastereomeric stereoisomerism phenomenon that occurs due to the different arrangement of each group in space due to the restriction of free rotation in the compound molecule.
  • Organic molecules containing such isomers, such as alkenes, azo compounds, alicyclic hydrocarbons, etc., are regarded as cis-trans isomers.
  • cis-trans isomerism is mainly reflected in the form of alicyclic hydrocarbons.
  • cis-trans isomerism occurs when cyclohexane is substituted by two substituents.
  • the two substituents are substituted on the same side of the ring, it is the "cis” isomer, and when the two substituents are substituted on the same side of the ring, it is the "trans” isomer.
  • Formula isomer.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the present invention are contemplated, including, but not limited to, diastereoisomers, enantiomers, steric and geometric (conformational) isomers, and mixtures thereof , such as racemic mixtures, are within the scope of the present invention.
  • the structures described herein also include all isomers of this structure (e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformations) Isomeric forms), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, and steric isomers of biphenyl structures Structure (see Basic Organic Chemistry (Second Edition), Volume 1, Xing Qiyi et al., p104-105); PAC, 1996, 68, 2193.
  • isomers of this structure e.g., diastereomers, enantiomers, cis-trans isomers, steric isomers, geometric (conformations) Isomeric forms
  • R and S configurations of each asymmetric center for example, R and S configurations of each asymmetric center, (Z) and (E) double bond
  • optional groups for each group may be:
  • Ring A is 5-10 membered heteroaryl.
  • the heteroaryl group can be in the form of a single ring or a branched ring.
  • Ring A is respectively connected to ring B through covalent bonds and connected to R 1 through L 1 , and is optionally substituted by 1 to 3 R 3s . If there is no special explanation, R 3 can be connected to ring A by replacing the H atom of any link atom of ring A, including C and N.
  • ring A is a monocyclic ring
  • a 6-membered heteroaryl group is more preferred
  • the number of heteroatoms is preferably 1-3
  • the heteroatoms are preferably N.
  • Non-limiting examples thereof include, but are not limited to, pyridine, pyrazine, pyrimidine, pyridazine, and triazine.
  • the connection sites of ring A, ring B and L 1 may be ortho, meta or para.
  • ring A When ring A is a cyclic ring, it is preferably a 5-6 cyclic ring or a 6-6 cyclic ring, and forms a conjugated bicyclic aryl group.
  • the number of heteroatoms is preferably 1-3, and the heteroatom is preferably N.
  • L 1 and ring B are respectively connected to different rings in the parallel ring A.
  • ring B When ring B is a heterocycloalkyl group, it preferably contains 1 heteroatom optionally selected from N, O, and S.
  • non-limiting examples of ring A include, but are not limited to, the following structures:
  • non-limiting examples of the group R3 substituted on ring A include, but are not limited to, halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, preferably cyano, amino, methyl .
  • L 1 is connected to R 1 through a covalent bond linking ring A, or L 1 itself is a chemical bond.
  • L include, but are not limited to, imino, carbonyl, -CO-NH-,
  • R 1 is selected from C 1-6 alkyl, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl, and is optionally substituted by 1-3 R 5 , wherein Cycloalkyl or heterocycloalkyl includes but is not limited to monocyclic, paracyclic, spirocyclic and bridged ring forms, preferably 4-6 membered cycloalkyl or 4-6 membered containing 1-2 selected from N, O, S heteroatom heterocycloalkyl.
  • R 1 is a cycloalkyl or heterocycloalkyl group, it is preferably a 5-7 membered monocyclic ring, or a 7-9 membered bridged ring or spirocyclic ring.
  • the 7-9 membered spirocyclic form has a similar Structure, the dotted line represents the 4-6-membered cycloalkyl group (including the spiro atom) connected to the spiro atom. Any atom can be replaced with a heteroatom if it complies with the valency code of the compound.
  • R include, but are not limited to, cyclobutane, cyclopentyl, cyclohexyl, cycloheptyl, Methyl, ethyl, propyl, isopropyl.
  • R 1 is an asymmetric group, or the substitution site of R 5 is not on the symmetry axis or center of R 1 , different spatial isomers may appear, including enantiomers and cis-trans isomers. It should be noted that both enantiomers and cis-trans isomers have ALK2 inhibitory activity, but the inhibitory activities of different isomers may be different.
  • R 5 is OH, halogen, C 1-6 alkyl, -(CR a R b ) n -OH.
  • R a and R b are preferably H or C 1-3 alkyl, and n is preferably 1-3.
  • Non-limiting examples of R5 include, but are not limited to, hydroxyl, F, Cl, methyl, ethyl, propyl, isopropyl, -CH2OH , -C( CH3 ) 2OH .
  • Ring B is a 6-15 membered ring group, and optionally 1-3 ring carbon atoms are substituted by oxygen; Ring B is optionally substituted by 1-3 R4 .
  • Ring B may be in the form of a single ring, a double ring, or a tricyclic ring. When Ring B is a double ring or a tricyclic ring, the connection form between the rings may be a parallel ring, a spiro ring, or a bridged ring. Unless otherwise specified, at least one ring in Ring B is an aromatic or heteroaromatic ring, the other rings are saturated or unsaturated cycloalkyl or heterocycloalkyl, or the other rings are parallel aromatic or heterocyclic rings. aromatic ring. If there is no special explanation, R 4 can be connected to ring B by replacing the H atom of any link atom of ring B, including C and N.
  • ring B is a monocyclic ring, it is more preferably a 6-membered aryl group or a heteroaryl group, and the number of heteroatoms is preferably 0-3, and the heteroatoms are preferably N.
  • Non-limiting examples thereof include, but are not limited to, benzene, pyridine, pyrazine, pyrimidine, pyridazine, and triazine.
  • the connection point between ring A and L2 on ring B can be ortho, meta or para.
  • Ring B When ring B is a parallel ring, it is form, which is preferably 5-6 cyclic ring or 6-6 cyclic ring, Y 1 , Y 2 , Y 3 are independently selected from CH or N.
  • Ring C is a 5-6 membered ring group, preferably a parallel cycloalkyl group, heterocycloalkyl group, aryl group or heteroaryl group. Ring C optionally contains 1-3 N atoms, and the carbon atoms therein are optionally oxo-substituted to form a carbonyl group.
  • L 2 and ring A are respectively the same as those in parallel ring B. Different rings are connected.
  • Ring B can also be a tricyclic group, one of which is a benzene ring.
  • Ring B is r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH and Z 5 is CH or N; optionally one carbon atom in ring B is substituted by oxygen; ring B is optionally substituted by 1-2 R 4s .
  • Z 5 is defined as CH 2 or CH
  • Z 6 is defined as N and connected to L 2
  • p is 2.
  • ring B is r is an integer from 1 to 2, be a single bond or a double bond.
  • Non-limiting examples of Ring B include, but are not limited to, the following structures: Usually, the 6-membered aromatic ring or heteroaromatic ring is connected to (that is, the bond above ring B) is connected to ring A, and the other (i.e. the bond below ring B) is connected to L 2 .
  • non-limiting examples of the group R4 substituted on ring B include, but are not limited to, halogen, hydroxyl, nitro, cyano, amino, C 1-6 alkyl, preferably cyano, methyl, tri Fluoromethyl.
  • L 2 connects ring B and R 2 through a covalent bond, or L 2 itself is a chemical bond.
  • L 2 is defined as -(CR a R b ) n - , wherein Ra and R b are independently selected from H or C 1-3 alkyl, or Ra and R b are The attached carbon atoms form a 3-6 membered cycloalkyl group.
  • n can be an integer from 1 to 3.
  • L2 is -CR a R b -CR a 'R b '-.
  • R a , R b , R a ', and R b '- can be independent.
  • R a and R b , or R a ' and R b ' can form a 3-6 membered cycloalkyl group with the carbon atoms they are jointly connected to, such as
  • non-limiting examples of L include, but are not limited to, chemical bonds, methylene,
  • R 2 is optionally substituted by 1-2 R 6 , wherein heterocycloalkyl includes but is not limited to monocyclic, spirocyclic Formula, preferably a 4-6 membered cycloalkyl group or a 4-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, and S. .
  • R 2 is a heterocycloalkyl group, it is preferably a 5-7-membered monocyclic ring, or a 7-9-membered bridged ring or spirocyclic ring.
  • the 7-9 membered spirocyclic form has a similar Structure, the dotted line represents the 4-6-membered cycloalkyl group (including the spiro atom) connected to the spiro atom. Any atom can be replaced with a heteroatom if it complies with the valency code of the compound.
  • 7-9 membered bridged ring form that is, two non-adjacent atoms on the ring base are connected by a covalent bond or one or more atoms.
  • R include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl,
  • R 2 is an asymmetric group, or the substitution site of R 6 is not on the symmetry axis of R 2 , different spatial isomers may appear, including enantiomers and cis-trans isomers. It should be noted that both enantiomers and cis-trans isomers have ALK2 inhibitory activity, but the inhibitory activities of different isomers may be different.
  • R 6 is selected from hydroxyl, -CO-R c , -CO-NR c R d , -SO 2 -R c , or R 6 is selected from C 1-6 alkyl, 4-8 1-membered cycloalkyl, 4-8 membered heterocycloalkyl, optionally substituted by 1-3 Re .
  • R c and R d are independently selected from H, halogen, hydroxyl, nitro, cyano, amino or C 1-6 alkyl;
  • R e is selected from halogen, hydroxyl, nitro, cyano, amino, C 1- 6 alkoxy.
  • Non-limiting examples of R include - but are not limited to H, F, methyl, ethyl, isopropyl, hydroxyl,
  • Some of the compounds in this application can be divided into paracyclic compounds and tricyclic compounds according to different ring Bs. These compounds have better ALK2 inhibitory activity and cell activity, and have better selectivity than existing compounds.
  • ring B has the following structure: Among them, Y 1 , Y 2 and Y 3 are independently selected from CH or N, and ring C is a parallel 5-6 membered ring group.
  • ring C can be a 5- to 6-membered saturated or unsaturated cycloalkyl or heterocycloalkyl group, as well as an aryl or heteroaryl group.
  • the C atoms of ring C can be substituted by oxygen to form a carbonyl group.
  • Ring B has the following structure: Among them, Ring C can be further preferably a parallel 5-membered cycloalkyl group, nitrogen-containing heterocycloalkyl group, or nitrogen-containing heteroaryl group, for example
  • R 1 can be a 4-6 membered cycloalkyl group or a heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, etc., such as cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , tetrahydrofuryl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, morpholine; further, R 1 can be optionally substituted by 1-2 R 5 , and R 5 can be It is hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  • connection sites of L 1 and R 5 on R 1 do not limit the connection sites of L 1 and R 5 on R 1 , so the two connection sites can be ortho, meta or para, preferably meta or para.
  • the substituent and the substitution site stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R 1 is R 5 is hydroxyl or unsubstituted.
  • L 2 is selected from a chemical bond or a simple ()alkylene group, connecting R 2 and Ring B.
  • R 2 is usually a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 , for example, R 2 can be L 2 is connected to any position of R 2 by replacing the hydrogen atom on R 2 .
  • R 6 can be something like halogen, hydroxyl, amino, cyanide
  • the simple substituent of the base can also be a 4-7-membered cycloalkyl group optionally substituted by R e , a 4-7-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, C 1 -3 alkyl.
  • connection sites of L 2 and R 6 on R 4 can be ortho, meta or para, preferably meta or para.
  • stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R e is usually halogen, and can also be other simple substituents similar to hydroxyl, amino or cyano. Also depending on its substitution position, it may form stereoisomerism with R 6 , including cis-trans isomerism and para-isomerism. Isomerism.
  • ring B has the following structure: r, p, and q are integers from 1 to 3; Z 1 , Z 2 , and Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O, Z 5 is CH 2 or NH; when When it is a double bond, Z 4 is CH, Z 5 is CH or N; Z 6 is NH or O; any one carbon atom in ring B is replaced by oxygen.
  • the C atom of ring B can be replaced by oxygen to form a carbonyl group.
  • Ring B is r or q is an integer from 1 to 3; Z 1 , Z 2 or Z 3 are independently selected from CH or N, and at most one is N; is a single bond or a double bond; when When it is a single bond, Z 4 is CH 2 or O; when When it is a double bond, Z 4 is CH; Ring B is optionally replaced by 1-2 R 4 ;
  • Ring B has the following structure: Among them, r takes 1 or 2, for example When ring B is further for When, the first end is usually connected to ring A, and the upper end is connected to L 2 .
  • R 1 can be a 4-6 membered cycloalkyl group or a heterocycloalkyl group containing 1-2 heteroatoms selected from N, O, etc., such as cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl , tetrahydrofuryl, tetrahydropyranyl, azetidinyl, tetrahydropyrrolyl, hexahydropyridyl, morpholine; further, R 1 can be optionally substituted by 1-2 R 5 , and R 5 can be It is hydroxyl, halogen, C 1-3 alkyl, -CH 2 OH, -C(CH 3 ) 2 OH.
  • connection sites of L 1 and R 5 on R 1 can be ortho, meta or para, preferably para.
  • substituent and the substitution site stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R 1 is R 5 is hydroxyl or unsubstituted, and the substitution position is para-substitution.
  • L 2 is selected from a chemical bond or a simple ()alkylene group, connecting R 2 and Ring B.
  • R 2 is usually a 5-6 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N and O, optionally substituted by 1-2 R 6 , for example, R 2 can be R 6 is preferably a simple substituent of halogen, hydroxyl, amino, or cyano, and may not be substituted.
  • This scheme does not limit the connection sites of L 2 and R 6 on R 4 , so the two connection sites can be ortho, meta or para, preferably para.
  • substituents and substitution sites stereoisomerism may exist, including cis-trans isomerism and enantiomerism.
  • R2 is H or
  • Preparation Pre-HPLC conditions: Instrument: GILSON-GX281; Wavelength: 220nm&254nm; Column model: Waters X-bridge (30 ⁇ 100mm, 10 ⁇ m) or Luna C18 (30 ⁇ 75mm, 3 ⁇ m) or Luna C18 (30 ⁇ 75mm, 3 ⁇ m) ;Mobile phase: A: 10mM ammonium bicarbonate or H 2 O (0.1% formic acid) or H 2 O (0.1% trifluoroacetic acid), B: acetonitrile; running time: 15min; flow rate: 25mL/min.
  • Reverse column purification uses a C18 reverse silica gel column (Spherical C18, 40-60 ⁇ m, 40g-120g), with water/acetonitrile (95/5 ⁇ 30/70) as the mobile phase.
  • the synthesis of intermediate 1 refers to the synthesis steps of intermediate A3 in Example 34 of patent CN109641871B.
  • the reaction solution was cooled to room temperature, diluted with ethyl acetate (5 mL), filtered through diatomaceous earth, the filter cake was washed with ethyl acetate (3 mL x 2), and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • N,N-dimethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piper Azine-1-carboxamide (40 mg, 0.11 mmol) and intermediate 3 (40 mg, 0.11 mmol) were dissolved in a mixed solvent of 1,4-dioxane and water (10 mL/2 mL), and PdCl 2 (dppf) was added (8mg, 0.01mmol) and potassium carbonate (30mg, 0.22mmol).
  • the reaction solution was heated to 100°C under nitrogen protection and stirred overnight.
  • the reaction solution was spun to dryness, dissolved in methanol, filtered, and concentrated under reduced pressure.
  • step (2) of Example 16 6-(4-(4-(dimethylcarbamoyl)piperazin-1-yl)phenyl)pyrazine-2-carboxylic acid (30 mg, 0.08 mmol ) and 4-aminobicyclo[2.2.2]octan-1-ol hydrochloride (11 mg, 0.08 mmol) were used as raw materials to obtain the title compound (13 mg, white solid), yield: 32.5%.
  • N-(4-hydroxybicyclo[2.2.2]oct-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (45mg, 0.1mmol) was dissolved in a mixed solvent of 1,4-dioxane and water (5mL/1mL), and 4 -(6-bromopyridin-3-yl)-N,N-dimethylpiperazine-1-carboxamide (41 mg, 0.13 mmol), potassium carbonate (45 mg, 0.33 mmol) and Pd(dppf)Cl 2 (50 mg ). The reaction solution was stirred under reflux overnight under nitrogen.
  • step (2) of Example 10 use 2-amino-5-bromo-N-((3R,6S)-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)nicotinamide (108 mg, 329umol, Example 32 step 1) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Benzyl)morpholine (100 mg, 329umol) was used as raw material to obtain the title compound (71.2 mg, white solid), yield: 50.62%.
  • step (2) in Example 10 use 3-amino-6-bromo-N-(tetrahydro-2H-pyran-4-yl)pyrazine-2-carboxamide (70 mg, 232.45umol) and 4 -(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (90mg, 296.83umol) as raw material, The title compound (34.6 mg, light yellow solid) was obtained, yield: 37.45%. MS (ESI): m/z 398.3[M+H] + .
  • step (2) of Example 10 use 2-amino-5-bromo-N-((3R,6S)-6-(2-hydroxypropan-2-yl)tetrahydro-2H-pyran-3 -Nicotinamide (35.4 mg, 98.9umol, step 1 of Example 10) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboroheterocycle) Pentan-2-yl)benzyl)morpholine (30.0 mg, 98.9umol) was used as raw material to obtain the title compound (19.2 mg, yellow solid), yield: 42.69%. MS (ESI): m/z 455.2[M+H] + .
  • step (3) of Example 36 use 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30 mg, 95.85umol, step 2 of Example 36) and piperidine- Using 4-alcohol (11 mg, 105.43umol) as raw material, the title compound (14.2 mg, yellow solid) was obtained, yield: 37.4%. MS (ESI): m/z 397.3[M+H] + .
  • step (3) of Example 36 use 2-amino-5-(4-(morpholinomethyl)phenyl)nicotinic acid (30 mg, 95.85umol, step 2 of Example 36) and piperidine- 4-ylmethanol (12 mg, 105.43umol) was used as raw material to obtain the title compound (16.9 mg, yellow oil), yield: 43.0%.
  • intermediate 5 33.29 mg, 97.84umol
  • 1-(1-(oxetan-3-yl)piperidin-4-yl)-5-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 45 mg, 117.40umol
  • 1,4-dioxane 0.5 mL
  • sodium carbonate 31.11 mg, 293.51 umol
  • Pd(dppf)Cl 2 7.16 mg, 9.78 umol
  • reaction solution was heated to 100°C and stirred for 12 hours. After the reaction solution cooled to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by Prep-TLC to obtain the title compound (90.0 mg, yellow oil), yield: 67.8%. MS(ESI):m/z 422.3[M+H] + .
  • reaction solution was replaced with nitrogen gas, then the temperature was raised to 110°C and stirred under nitrogen protection for 16 hours.
  • the reaction solution was cooled to room temperature, concentrated, diluted with methanol (2 mL), and filtered through a syringe filter.
  • step (2) of Example 50 4-(2-amino-5-bromopyridin-3-yl)benzoic acid methyl ester (500 mg, 1.63 mmol, step 1 of Example 50) and 4-(4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (592.31 mg, 1.95 mmol) was used as raw material to obtain the title Compound (600 mg, orange solid), yield: 91.4%. MS(ESI):m/z 404.3[M+H] + .
  • step (3) of Example 50 use 4-(2-amino-5-(4-(morpholinomethyl)phenyl)pyridin-3-yl)benzoate methyl ester (350 mg, 867.47umol) As raw material, the title compound (300 mg, orange solid) was obtained, and the crude product was used directly in the next step without purification. MS(ESI):m/z390.3[M+H] + .
  • step (4) of Example 50 use 4-(6-(4-morpholinophenyl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (3 mg, 7.49umol) As raw material, the title compound (1 mg, yellow solid) was obtained, yield: 30.44%. MS (ESI): m/z 439.2[M+H] + .
  • step 1 4-bromo-3-fluorobenzaldehyde and (R)-2-methylpyrrolidine were used as raw materials, and the title compound (13.0 mg, white solid) was obtained through similar steps.
  • step 4 5-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-2-aminonicotinic acid (35 mg, 0.11 mmol) and tetrahydro-2H-pyran-4-amine (34 mg, 0.34 mmol) were used as raw materials to obtain the title compound (15 mg, light yellow solid), yield: 34.6%.
  • the first step uses 4-bromo-3-fluorobenzaldehyde and (R)-2-methylpyrrolidine as raw materials
  • the third step uses (R)-2-amino-5-(2 -Fluoro-4-((2-methylpyrrolidin-1-yl)methyl)phenyl)nicotinic acid and ((2S,5R)-5-aminotetrahydro-2H-pyran-2-yl)methanol Hydrochloride was used as raw material, and the title compound (10.0 mg, white solid) was obtained through similar steps.
  • reaction solution was heated to 80°C under nitrogen protection and stirred for 18 hours.
  • the crude product was further purified by Prep-HPLC to obtain the title compound (210 mg, light yellow oil), yield: 30 %.
  • 6-Bromo-2-(tetrahydro-2H-pyran-4-yl)-1,2,3,4-tetrahydroisoquinoline 250 mg, 0.85 mmol
  • (6-amino-5-(methyl Oxycarbonyl)pyridin-3-yl)boronic acid (236mg, 0.85mmol)
  • PdCl 2 (dppf) 65mg, 0.08mmol
  • potassium carbonate 234mg, 1.7mmol

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un inhibiteur de kinase ALK2 tel que représenté par la formule générale (I), une composition pharmaceutique de celui-ci, un procédé de préparation associé et l'utilisation de l'inhibiteur de kinase ALK2 dans la préparation d'un médicament pour la prévention et/ou le traitement d'indications associées à la voie de signalisation ALK2. Un composé selon la présente invention est un inhibiteur de kinase ALK2 à haute activité idéal, et peut être utilisé pour traiter et/ou prévenir des maladies, y compris l'anémie, l'inflammation, les tumeurs et certaines maladies rares, telles que la fibrodysplasie ossifiante progressive, le gliome pontique intrinsèque diffus, l'anémie ferriprive réfractaire au fer, l'anémie inflammatoire, le syndrome myélodysplasique et le myélome multiple, et peut également être combiné à un inhibiteur de JAK2 pour traiter l'anémie liée à MPN.
PCT/CN2023/087857 2022-04-13 2023-04-12 Inhibiteur de kinase alk2 WO2023198114A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202210388938.X 2022-04-13
CN202210388938 2022-04-13
CN202210936456.3 2022-08-05
CN202210936456 2022-08-05

Publications (1)

Publication Number Publication Date
WO2023198114A1 true WO2023198114A1 (fr) 2023-10-19

Family

ID=87217109

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/087857 WO2023198114A1 (fr) 2022-04-13 2023-04-12 Inhibiteur de kinase alk2

Country Status (2)

Country Link
CN (1) CN116478145B (fr)
WO (1) WO2023198114A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024044848A1 (fr) * 2022-08-29 2024-03-07 Mindset Pharma Inc. Dérivés d'indazole en tant qu'agents sérotoninergiques utiles pour le traitement de troubles associés

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018183633A1 (fr) * 2017-03-29 2018-10-04 University Of Houston System Compositions destinées à être utilisées dans des procédés d'inhibition de protéines kinases
CN109641871A (zh) * 2016-07-20 2019-04-16 诺华股份有限公司 氨基吡啶衍生物及其作为选择性alk-2抑制剂的用途
WO2019236631A1 (fr) * 2018-06-05 2019-12-12 Rapt Therapeutics, Inc. Composés de pyrazolo-pyrimidin-amino-cycloalkyle et leurs utilisations thérapeutiques
CN110913855A (zh) * 2017-06-15 2020-03-24 拜奥克里斯特制药公司 含咪唑的alk2激酶抑制剂
CN111164083A (zh) * 2017-04-27 2020-05-15 布里格姆妇女医院股份有限公司 用于抑制bmp信号传导的新型alk2抑制剂和方法
WO2022184152A1 (fr) * 2021-03-03 2022-09-09 劲方医药科技(上海)有限公司 Composé hétérocyclique à six chaînons substitué par un cycle condensé, son procédé de préparation et son utilisation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20210023837A (ko) * 2018-05-25 2021-03-04 실버백 테라퓨틱스, 인크. 아미노-피라진카복사미드 화합물, 접합체, 및 그의 용도
IL293085A (en) * 2019-11-22 2022-07-01 Incyte Corp Combined treatment that includes an alk2 inhibitor and a jak2 inhibitor
US20230235036A1 (en) * 2020-06-05 2023-07-27 The J. David Gladstone Institutes, a testamentary trust established under the Will of J. David Glads Acvr1 (alk2) receptor inhibition to treat neurological diseases
TW202214239A (zh) * 2020-06-16 2022-04-16 美商英塞特公司 用於治療貧血之alk2抑制劑

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109641871A (zh) * 2016-07-20 2019-04-16 诺华股份有限公司 氨基吡啶衍生物及其作为选择性alk-2抑制剂的用途
WO2018183633A1 (fr) * 2017-03-29 2018-10-04 University Of Houston System Compositions destinées à être utilisées dans des procédés d'inhibition de protéines kinases
CN111164083A (zh) * 2017-04-27 2020-05-15 布里格姆妇女医院股份有限公司 用于抑制bmp信号传导的新型alk2抑制剂和方法
CN110913855A (zh) * 2017-06-15 2020-03-24 拜奥克里斯特制药公司 含咪唑的alk2激酶抑制剂
WO2019236631A1 (fr) * 2018-06-05 2019-12-12 Rapt Therapeutics, Inc. Composés de pyrazolo-pyrimidin-amino-cycloalkyle et leurs utilisations thérapeutiques
WO2022184152A1 (fr) * 2021-03-03 2022-09-09 劲方医药科技(上海)有限公司 Composé hétérocyclique à six chaînons substitué par un cycle condensé, son procédé de préparation et son utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AGUSTIN H MOHEDAS ET AL.: "Structure-Activity Relationship of 3,5-Diaryl-2-aminopyridine ALK2 Inhibitors Reveals Unaltered Binding Affinity for Fibrodysplasia Ossificans Progressiva Causing Mutants", J. MED. CHEM., vol. 57, no. 19, 7 August 2014 (2014-08-07), XP055227623, ISSN: 0022-2623, DOI: 10.1021/jm501177w *

Also Published As

Publication number Publication date
CN116478145A (zh) 2023-07-25
CN116478145B (zh) 2024-02-02

Similar Documents

Publication Publication Date Title
WO2021031952A1 (fr) Composé de pyrimidine cyclique à six chaînons substitué par oxygène, son procédé de préparation et son utilisation médicale
CN112437772A (zh) Bcl-2抑制剂
WO2021239058A1 (fr) Composé tricyclique condensé, composition pharmaceutique associée et son utilisation
WO2022228568A1 (fr) Composé pyridino- ou pyrimido-cyclique, son procédé de préparation et son utilisation médicale
CN115073474A (zh) 作为HPK1抑制剂的吡咯并[2,3-b]吡嗪及其用途
CN114929689A (zh) Bcl-2抑制剂
CN103038233A (zh) 吡啶酮和氮杂吡啶酮化合物及使用方法
CN110678461B (zh) Syk抑制剂及其使用方法
CN112538072A (zh) 新型氨基嘧啶类egfr抑制剂
CN112566905A (zh) 取代的苯基丙烯基吡啶类衍生物，其制法与医药上的用途
WO2021115457A9 (fr) Composé de pyrazolo[1,5-a]pyridine, son procédé de préparation et son utilisation
CN114341127A (zh) 作为hpk1抑制剂的氨基吡嗪化合物及其用途
WO2023061294A1 (fr) Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
CN111925367A (zh) 稠环类衍生物抑制剂、其制备方法和应用
WO2021190417A1 (fr) Nouvel inhibiteur aminopyrimidine d'egfr
CN114127080A (zh) 作为激酶抑制剂的杂环化合物、包括该杂环化合物的组合物、及其使用方法
CN115335376A (zh) 通过缀合btk抑制剂与e3连接酶配体降解布鲁顿氏酪氨酸激酶（btk）及其使用方法
KR20210125983A (ko) 피라졸일-아미노-피리미딘일 유도체의 벤즈아미드, 이의 조성물 및 방법
WO2021249475A1 (fr) Dérivé de quinazoline condensé, son procédé de préparation et son application en médecine
WO2021208918A1 (fr) Composés tricycliques servant d'inhibiteurs d'egfr
CN115485278A (zh) 通过缀合btk抑制剂与e3连接酶配体降解布鲁顿氏酪氨酸激酶(btk)及其使用方法
CN114163444A (zh) 一种用于雄激素受体蛋白靶向降解的嵌合体化合物、其制备方法及其在医药上的应用
CN112979655A (zh) 三唑并哒嗪类衍生物、其制备方法、药物组合物和用途
WO2022166860A1 (fr) Inhibiteur de pim kinase
WO2022194269A1 (fr) Nouvel agent de dégradation de l'egfr

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23787757

Country of ref document: EP

Kind code of ref document: A1