WO2020151682A1 - Immunomodulateur macrocyclique - Google Patents

Immunomodulateur macrocyclique Download PDF

Info

Publication number
WO2020151682A1
WO2020151682A1 PCT/CN2020/073333 CN2020073333W WO2020151682A1 WO 2020151682 A1 WO2020151682 A1 WO 2020151682A1 CN 2020073333 W CN2020073333 W CN 2020073333W WO 2020151682 A1 WO2020151682 A1 WO 2020151682A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
halogen
substituted
compound
Prior art date
Application number
PCT/CN2020/073333
Other languages
English (en)
Chinese (zh)
Inventor
李进
张登友
潘飞
马荣
朱文吉
吕开智
陈欣
张毅
Original Assignee
成都先导药物开发股份有限公司
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 成都先导药物开发股份有限公司 filed Critical 成都先导药物开发股份有限公司
Publication of WO2020151682A1 publication Critical patent/WO2020151682A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/06—Peri-condensed systems
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles 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
    • A61K31/435—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
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • 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
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/06—Peri-condensed systems

Definitions

  • the invention belongs to the field of medicine and relates to a macrocyclic immunomodulator.
  • the human immune system can generally be divided into “innate immunity” and “adaptive immunity” systems.
  • the innate immune system plays an important role in fighting infections, inhibiting tumor growth, and the pathogenesis of autoimmune diseases. It mainly recognizes pathogenic microorganisms and cancer cell components through pattern recognition receptors, initiates downstream signaling pathways, and finally induces cytokine expression. Kill pathogenic microorganisms and cancer cell components, and adapt to the immune system to promote the production of antibodies and specific T lymphocytes.
  • STING interferon gene stimulating factor, TMEM173, MITA, etc.
  • TMEM173, MITA interferon gene stimulating factor
  • Compounds that induce human interferon can be used to treat various diseases, including allergic diseases and other inflammatory diseases, allergic rhinitis and asthma, infectious diseases, neurodegenerative diseases, precancerous syndromes and cancer, and can also be used as immunity Composition or vaccine adjuvant. Therefore, activation of STING is a potential method for treating related type 1 IFN pathway diseases (including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes).
  • the present invention provides a compound represented by formula I or its tautomers, enantiomers, or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof:
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 is selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen
  • R 4 is selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen or none;
  • R 5 is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • X 2 is selected from C or N;
  • Ring B is selected from a benzene ring substituted with 0 to 4 Ra, and a 5- to 6-membered aromatic heterocyclic ring substituted with 0 to 4 Ra;
  • R a is selected from halogen, hydroxy, amino, and C 1 to C 6 alkyl optionally substituted by 0 to 4 R b ;
  • R b is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkoxy;
  • X is selected from -O-, -S-, -S(O) n -or none; n is 1 or 2;
  • L 1, L 2 are each independently selected from 0 to 4 substituents R i is C 1 ⁇ C 10 alkylene group, and is substituted with 0 to 4 R i alkenylene substituted C 2 ⁇ C 10, wherein, when R i when there are at least two, L 1, L R i 2 may be linked to form a 3 to 10-membered ring;
  • R i is selected from -OR j , halogen, -CN, C 1 ⁇ C 6 alkyl;
  • R j is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • Z is selected from -O-, -C(O)-,
  • R c and R d are independently selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, -C(O)R k or none, or R c and Rd are connected to them nitrogen atom to form a substituted 0-4 R e 3 to 8-membered heterocyclic ring optionally alkane, substituted with 0 to 4 R e 3-10-membered heteroaryl ring;
  • R k is selected from 0 to 4 R m substituted 5- to 6-membered cycloalkyl, substituted with 0 to 4 R m substituted 5- to 6-membered heterocyclic group;
  • R m is selected from C 1 ⁇ C 6 alkyl , C 1 ⁇ C 6 alkyl substituted by halogen;
  • R g and R h are independently selected from -C(O)-, -C(O)O- or none;
  • R e is selected from -OR f -, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R f is selected from hydrogen, C 1 to C 6 alkyl, and halogen substituted C 1 to C 6 alkyl.
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 is selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen
  • R 4 is selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen or none;
  • R 5 is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • X 2 is selected from C or N;
  • Ring B is selected from a benzene ring substituted with 0 to 4 Ra, and a 5- to 6-membered aromatic heterocyclic ring substituted with 0 to 4 Ra;
  • R a is selected from C 1 to C 6 alkyl groups optionally substituted by 0 to 4 R b ;
  • R b is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkoxy;
  • X is selected from -O-, -S- or none
  • L 1, L 2 are each independently selected from 0 to 4 substituents R i is C 1 ⁇ C 10 alkylene group, wherein, when at least two R i, L 1, L R i 2 may be connected Form a 3-10 membered ring;
  • R i is selected from -OR j , halogen, -CN, C 1 ⁇ C 6 alkyl;
  • R j is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • Z is selected from -O-, -C(O)-,
  • R c and R d are independently selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl or none, or R c and R d are connected to the nitrogen atom to which they are connected to form a 0 ⁇ 4 R e is optionally substituted 3 to 8-membered heterocyclic ring alkane, substituted with 0 to 4 R e 3-10-membered heteroaryl ring;
  • R g and R h are independently selected from -C(O)-, -C(O)O- or none;
  • R e is selected from -OR f -, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R f is selected from hydrogen, C 1 to C 6 alkyl, and halogen substituted C 1 to C 6 alkyl.
  • Ring B is selected from
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, and C 1 to C 6 alkyl optionally substituted with 0 to 4 R b ;
  • R b is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkoxy;
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 and R 4 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 is selected from hydrogen, C 1-6 alkyl
  • L 1, L 2 are each independently selected from 0 to 4 substituents R i is C 1 ⁇ C 10 alkylene group, wherein, when at least two R i, L 1, L R i 2 may be connected Form a 3-10 membered ring;
  • R i is selected from -OR j , halogen, -CN, C 1 ⁇ C 6 alkyl;
  • R j is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • Z is selected from -O-, -C(O)-, -C(O)NR-, -NR-,
  • R is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl or none, or R c and R d are connected with the nitrogen atom to which they are attached to form 3-8 optionally substituted with 0-4 R e Membered heterocyclic alkane, 3-10 membered heteroaromatic ring optionally substituted by 0-4 R e ;
  • R e is selected from -OR f -, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R f is selected from hydrogen, C 1 to C 6 alkyl, and halogen substituted C 1 to C 6 alkyl.
  • the Z is -O-.
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 and R 4 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 is selected from hydrogen, C 1-6 alkyl
  • Ring B is selected from
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, and C 1 to C 6 alkyl optionally substituted with 0 to 4 R b ;
  • R b is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkoxy;
  • R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl or none, or R c and R d are connected with the nitrogen atom to which they are attached to form an optionally substituted with 0 to 4 R e 0-4 is optionally substituted with R e 0-4 is optionally substituted with R e
  • R g and R h are independently selected from -C(O)-, -C(O)O- or none;
  • L 1, L 2 are each independently selected from 0 to 4 substituents R i is C 1 ⁇ C 10 alkylene group, wherein, when at least two R i, L 1, L R i 2 may be connected Form a 3-10 membered ring;
  • R i is selected from -OR j , halogen, -CN, C 1 ⁇ C 6 alkyl;
  • R j is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R e is selected from -OR f -, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R f is selected from hydrogen, C 1 to C 6 alkyl, and halogen substituted C 1 to C 6 alkyl.
  • Ring B is selected from
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, and C 1 to C 6 alkyl optionally substituted with 0 to 4 R b ;
  • R b is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkoxy;
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 and R 4 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L 1, L 2 are each independently selected from 0 to 4 substituents R i is C 1 ⁇ C 10 alkylene group, wherein, when at least two R i, L 1, L R i 2 may be connected Form a 3-10 membered ring;
  • R i is selected from -OR j , halogen, -CN, C 1 ⁇ C 6 alkyl;
  • R j is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • Z is selected from -O-, -C(O)-, -C(O)NR-, -NR-,
  • R is selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R c and R d are independently selected from hydrogen, C 1 -C 6 alkyl or none, or R c and R d are connected with the nitrogen atom to which they are attached to form 3-8 optionally substituted with 0-4 R e Membered heterocyclic alkane, 3-10 membered heteroaromatic ring optionally substituted by 0-4 R e ;
  • R e is selected from -OR f -, C 1 ⁇ C 6 alkyl, and halogen substituted C 1 ⁇ C 6 alkyl;
  • R f is selected from hydrogen, C 1 to C 6 alkyl, and halogen substituted C 1 to C 6 alkyl.
  • Ring B is selected from
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, and C 1 to C 6 alkyl optionally substituted with 0 to 4 R b ;
  • R b is selected from halogen, hydroxyl, amino, C 1 ⁇ C 6 alkoxy;
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 and R 4 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L 1, L 2 are each independently selected from 0 to 4 substituents R i is C 1 ⁇ C 10 alkylene group, wherein, when at least two R i, L 1, L R i 2 may be connected Form a 3-10 membered ring;
  • R i is selected from -OR j , halogen, -CN, C 1 ⁇ C 6 alkyl;
  • R j is selected from hydrogen, C 1 to C 6 alkyl, and halogen substituted C 1 to C 6 alkyl.
  • Ring B is selected from a 5-membered nitrogen-containing aromatic heterocyclic ring substituted with 0 to 3 Ra;
  • R a is selected from halogen, hydroxyl, amino, and C 1 to C 6 alkyl optionally substituted by 0 to 3 R b ;
  • R b is selected from halogen and hydroxyl
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 6 alkyl groups
  • R 3 and R 4 are each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, and halogen;
  • R 5 is selected from hydrogen, C 1 ⁇ C 6 alkyl
  • L 1, L 2 are each independently selected from substituted with 0 to 4 R i C 1 ⁇ C 6 alkylene group, and is substituted with 0 to 4 R i substituents of C 2 ⁇ C 6 alkenylene group,
  • R i is selected from halogen, -CN, C 1 ⁇ C 6 alkyl
  • X is selected from -O-, -S-, -S(O) n -or none, n is 1 or 2;
  • Z is selected from -O-, -C(O)-,
  • R c, R d each independently selected from hydrogen, C 1 ⁇ C 6 alkyl, halo-substituted C 1 ⁇ C 6 alkyl, -C (O) R k, or no;
  • R K is selected from 0 to 4 R m substituted 5- to 6-membered cycloalkyl, 5- to 6-membered heterocycloalkyl substituted with 0 to 4 R m ;
  • R m is selected from C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkane base;
  • R g and R h are independently selected from -C(O)-, -C(O)O- or none.
  • Ring B is selected from
  • R 6 , R 7 , and R 8 are each independently selected from hydrogen, halogen, hydroxyl, amino, and C 1 ⁇ C 2 alkyl optionally substituted with 0 to 3 R b ;
  • R b is selected from halogen and hydroxyl
  • R 1 and R 2 are each independently selected from hydrogen and C 1 ⁇ C 3 alkyl groups
  • R 3 and R 4 are each independently selected from hydrogen, C 1 ⁇ C 3 alkyl, and halogen;
  • R 5 is selected from hydrogen, C 1 ⁇ C 3 alkyl
  • L 1, L 2 are each independently selected from substituted with 0 to 2 R i C 1 ⁇ C 3 alkylene group, and is substituted with 0 to 2 substituents R i of C 2 ⁇ C 3 alkenylene group,
  • R i is selected from halogen, -CN, C 1 ⁇ C 3 alkyl
  • X is selected from -O-, -S-, -S(O) n -or none, n is 1 or 2;
  • Z is selected from -O-, -C(O)-, Preferably, Z is -O-;
  • R c, R d each independently selected from hydrogen, C 1 ⁇ C 3 alkyl group, halogen-substituted C 1 ⁇ C 3 alkyl, -C (O) R k, or no;
  • R K is selected from 0 to 2 R m substituted 5- to 6-membered cycloalkyl, piperidine ring substituted with 0 to 2 R m ;
  • R m is selected from C 1 ⁇ C 3 alkyl, halogen substituted C 1 ⁇ C 3 alkyl;
  • R g and R h are independently selected from -C(O)-, -C(O)O- or none.
  • B ring is preferably substituted with from 0 to 4 substituents R a nitrogen-containing aromatic 5-membered heterocyclic ring
  • R a is selected from halogen, halo substituted with 0 to 4
  • Substituted C 1 ⁇ C 6 alkyl group L 1 is selected from C 2 ⁇ C 6 alkylene, C 2 ⁇ C 6 alkenylene group, L 2 is selected from C 2 ⁇ C 6 alkylene
  • Z is selected From -O-, -C(O)-, -NHC(O)O-, -NR c -, -C(O)NH-
  • R c is selected from hydrogen, C 1 ⁇ C 6 alkyl, halogen substituted C 1 ⁇ C 6 alkyl, -C (O) R k
  • R k is selected from substituted with 0 to 2 R m 5 to 6-membered cycloalkyl, substituted with 0 to 2 substituents R
  • the compound of Formula I, B is more preferably a ring substituted with 0-3 R a pyrrole, substituted with 0 to 3 R a substituted pyrazole, substituted with 0 to 3 R a substituted imidazole, substituted with 0 to 3 R a substituted thiazole is substituted with 0 to 3 R a substituted isothiazole, substituted with 0 to 3 R a substituted oxazole, substituted with 0 to 3 R a is isoxazole, R a is selected from halo, substituted with 0 to 3 halo C 1 ⁇ C 6 alkyl group.
  • the present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite in the preparation of activating STING drugs .
  • the present invention also provides the compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite for preparing and treating diseases related to STING activity Use in medicine.
  • the diseases related to STING activity are one or more of diseases related to inflammatory, autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.
  • the present invention also provides the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite for preparing treatment of inflammation, autoimmunity Use in medicine for diseases, infectious diseases, cancer or precancerous syndromes.
  • the present invention also provides the use of the aforementioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite in the preparation of an immune adjuvant.
  • the present invention also provides a drug, which is based on the above-mentioned compound, or its stereoisomer, or its pharmaceutically acceptable salt, or its solvate, or its prodrug, or its metabolite A preparation prepared with pharmaceutically acceptable excipients.
  • the compound of the present invention can effectively bind to STING and has a good STING protein agonistic function. Therefore, the compounds of the present invention can be used as STING agonists and used to treat various related diseases.
  • the compound provided by the present invention has very good application prospects in the preparation of drugs for treating diseases related to STING activity, especially in the preparation of drugs for treating inflammatory, autoimmune diseases, infectious diseases, cancer or precancerous syndromes.
  • the diseases related to STING activity defined in the present invention are diseases in which STING plays an important role in the pathogenesis of the disease.
  • Diseases related to STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, and precancerous syndromes.
  • Cancer or “malignant tumor” refers to any of a variety of diseases characterized by uncontrolled abnormal proliferation of cells, the ability of affected cells to spread to other locations locally or through the bloodstream and lymphatic system The body (i.e. metastasis) and any of many characteristic structural and/or molecular characteristics.
  • Cancer cells refer to cells that undergo the early, middle or late stages of tumor progression in multiple steps. Cancers include sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer and prostate cancer.
  • the compound of formula I is used to treat a cancer selected from colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma.
  • the cancer is selected from melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
  • the cancer being treated is a metastatic cancer.
  • Inflammatory diseases include a variety of conditions characterized by histopathological inflammation.
  • inflammatory diseases include acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, vasculitis, Airway inflammation and interstitial cystitis caused by house dust mites.
  • Some embodiments of the present invention relate to the treatment of the inflammatory disease asthma.
  • the immune system is usually involved in inflammatory diseases, which are manifested in allergic reactions and some myopathy. Many immune system diseases lead to abnormal inflammation.
  • the compounds and derivatives provided in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming system.
  • substitution refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.
  • the minimum and maximum content of carbon atoms in a hydrocarbon group are indicated by prefixes.
  • the prefixes Ca to Cb alkyl groups indicate any alkyl groups containing "a" to "b" carbon atoms.
  • a C 1 to C 6 alkyl group refers to an alkyl group containing 1 to 6 carbon atoms.
  • alkyl refers to a saturated hydrocarbon chain having a specified number of member atoms.
  • the C 1 to C 6 alkyl group refers to an alkyl group having 1 to 6 carbon atoms.
  • Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein.
  • Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl) Base) and hexyl.
  • the alkyl group may also be part of another group, such as a C 1 to C 6 alkoxy group.
  • the C a -C b alkoxy group refers to a group obtained by connecting an alkyl group containing "a" to "b" carbon atoms to the corresponding oxygen atom.
  • C 1 ⁇ C 10 alkylene group refers to a divalent having 1 to 10 carbon atoms, saturated aliphatic hydrocarbon.
  • Alkylene groups include branched and straight chain hydrocarbyl groups.
  • (C 1 -C 6 )alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene and the like.
  • the term "propylene” can be exemplified by the following structure:
  • the term “dimethyl butylene” can be exemplified by any of the following structures, for example:
  • the term "(C 1 -C 6 )alkylene” is meant to include such branched hydrocarbon groups, such as cyclopropylmethylene, which can be exemplified by the following structure:
  • C 2 -C 10 alkenylene refers to an aliphatic hydrocarbon group having 2 to 10 carbon atoms and containing one or more carbon-carbon double bonds.
  • Alkenylene groups include branched and straight chain groups.
  • the carbon-carbon double bonds in the alkenylene group include cis double bonds and trans double bonds.
  • halogen means a halogen group: fluorine, chlorine, bromine or iodine.
  • pharmaceutically acceptable means that a certain carrier, carrier, diluent, excipient, and/or the formed salt is usually chemically or physically compatible with other ingredients constituting a certain pharmaceutical dosage form, and physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salts” refer to the above-mentioned compounds or their stereoisomers, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also include zwitterionic salts (internal Salt), also includes quaternary ammonium salts, such as alkyl ammonium salts. These salts can be directly obtained in the final isolation and purification of the compound. It can also be obtained by mixing the above-mentioned compound, or its stereoisomers, with a certain amount of acid or base appropriately (for example, equivalent).
  • salts may form a precipitate in the solution and be collected by filtration, or recovered after evaporation of the solvent, or prepared by freeze-drying after reaction in an aqueous medium.
  • the salt in the present invention can be the hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, butane Acid salt, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
  • one or more compounds of the present invention may be used in combination with each other.
  • the compound of the present invention can be used in combination with any other active agent to prepare drugs or pharmaceutical compositions for regulating cell functions or treating diseases. If a group of compounds are used, these compounds can be administered to the subject simultaneously, separately or sequentially.
  • the raw materials and equipment used in the present invention are all known products and can be obtained by purchasing commercially available products.
  • the structure of the compound of the present invention was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR is measured with (Bruker AvanceIII 400 and Bruker Avance 300) nuclear magnetometer, and the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ,
  • the internal standard is tetramethylsilane (TMS).
  • the LC-MS measurement uses Shimadzu LC-MS 2020 (ESI).
  • Shimadzu high pressure liquid chromatograph (Shimadzu LC-20A) was used for HPLC measurement.
  • Gilson GX-281 reverse-phase preparative chromatography was used for reverse-phase preparative chromatography.
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, and the specifications for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • the known starting materials of the present invention can be synthesized by or according to methods known in the art, or can be purchased from Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Bailingwei Technology and other companies.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.
  • the hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature.
  • M is mole per liter.
  • Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C.
  • DCM refers to dichloromethane
  • DMF refers to N,N-dimethylformamide.
  • DMSO refers to dimethyl sulfoxide
  • DIPEA refers to diisopropylethylamine.
  • HATU refers to 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • Pd(dppf)Cl 2 refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
  • TFA refers to trifluoroacetic acid.
  • NBS refers to N-bromosuccinimide
  • 1-Ethyl-3-methyl-1H-pyrazole-5-carboxylic acid (4g, 25.9mmol) was dispersed in dry DCM (80mL), and oxalyl chloride (3.9g, 31.1 mmol) and a catalytic amount of DMF. After reacting for 1 hour at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20mL) was added to the crude product, and the solvent was removed by rotary evaporation to obtain 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl chloride (4.46g, 100% yield), which was used directly in the next step reaction.
  • 4-ethyl-2-methylthiazole-5-carboxylic acid (2g, 11.7mmol) was dispersed in dry DCM (40ml), and oxalyl chloride (1.9g, 15.1mmol) and Catalytic amount of DMF. After reacting for 1 hour at room temperature, the volatiles were removed by rotary evaporation under reduced pressure. DCM (20ml) was added to the crude product, and the solvent was removed by rotary evaporation to obtain 4-ethyl-2-methylthiazole-5-carboxylic acid chloride (2.2g, 100% yield), which was directly used in the next reaction.
  • Step 3 Synthesis of 4-ethyl-2-methyloxazole-5-carboxylic acid methyl ester
  • Methyl 2-acetoxy-3-oxopentanoate (3.0 g, 15.9 mmol) was dissolved in acetic acid (50 mL), and then ammonium acetate (9.8 g, 127.6 mmol) was added. The mixture was heated to 120°C and stirred at this temperature for 4 hours.
  • Methyl 4-chloro-3-methoxy-5-nitrobenzoate (10g, 40.7mmol) was dispersed in anhydrous dichloromethane (100mL), and boron tribromide ( 40.8g, 162.8mmol), after dripping, slowly rise to room temperature and stir overnight. After the reaction was completed, methanol was slowly added dropwise to quench under an ice bath, and then it was spin-dried. Methanol (100 mL) and concentrated sulfuric acid (0.2 mL) were added thereto, and the reaction solution was heated to 75° C. and stirred overnight. After cooling, the solvent was removed by concentration under reduced pressure, and 150 mL of water was added. After ultrasonic dispersion, filtration, the solid was washed with water again, and the solid was dried to obtain methyl 4-chloro-3-hydroxy-5-nitrobenzoate (8.89g , 38.4mmol, yield 94%).
  • Step 3 Synthesis of methyl 3-bromo-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)-5-nitrobenzoate
  • Step 4 (E)-3-(3-(tert-butoxy)-3-oxoprop-1-en-1-yl)-4-((3-((tert-butoxycarbonyl)amino) Synthesis of propyl)amino)-5-methylnitrobenzene
  • Step 5 3-Amino-5-(3-(tert-butoxy)-3-oxopropyl)-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)benzoic acid Synthesis of methyl ester
  • Step 6 7-(3-(tert-butoxy)-3-oxopropyl)-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-methyl)carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester
  • compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate 80mg, 0.41mmol was added dropwise to compound 1e (180mg, 0.399mmol) in DMF (3mL ) In the solution, react for 0.5h. Then HATU (160mg, 0.421mmol) and N,N-diisopropylethylamine (110mg, 0.851mmol) were added to the reaction solution, and stirring was continued at room temperature for 3h.
  • Step 7 3-(1-(3-Aminopropyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5-(methoxycarbonyl)- Synthesis of 1H-Benzo[d]imidazol-7-yl)propionic acid
  • Step 8 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo-7,8,9,10,11,12-hexahydro-6H- Synthesis of 2,9,12a-triazepane[cd]]indene-4-carboxylic acid methyl ester
  • Step 9 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo 7,8,9,10,11,12 hexahydro-6H-2, Synthesis of 9,12a-triazacyclodecane benzo[cd]indene-4-carboxylic acid
  • Step 10 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-oxo 7,8,9,10,11,12 hexahydro-6H-2, Synthesis of 9,12a-triazacyclodecane benzo[cd]indene-4-carboxamide
  • Step 1 Synthesis of tert-butyl (3-(3-(benzyloxy)propoxy)propyl)carbamate
  • Step 2 Synthesis of tert-butyl (3-(3-hydroxypropoxy)propyl)carbamate
  • Step 3 Synthesis of (3-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propoxy)propyl) tert-butyl carbamate
  • Step 6 10-Amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxacycloundecane-12-carboxamide synthesis
  • Step 7 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-6,10-dioxa Synthesis of 2,13a-diazacycloundecanebenzo[cd]indene-4-carboxamide
  • Step 1 Synthesis of tert-butyl (3-(2-(benzyloxy)ethoxy)propyl)carbamate
  • Step 2 Synthesis of tert-butyl (3-(2-hydroxyethoxy)propyl)carbamate
  • Step 3 Synthesis of (tert-butyl(3-(2-(5-carbamoyl-2-chloro-3-nitrophenoxy)ethoxy)propyl)carbamate
  • Step 7 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12tetrahydro-7H-6,9-dioxa2,12a Synthesis of -diazadecane benzo[cd]indene-4-carboxamide
  • compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate 80mg, 0.41mmol
  • compound 7f 108mg, 0.407mmol
  • DMF 3mL
  • HATU 160mg, 0.421mmol
  • N,N-diisopropylethylamine 105mg, 0.814mmol
  • Step 1 Synthesis of 2-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl methanesulfonate
  • Step 2 Synthesis of S-(2-(3-((tert-butoxycarbonyl)amino)propoxy)ethyl)ethanethiol ester
  • Step 4 Synthesis of methyl 4-((3-(2-(acetylthio)ethoxy)propyl)amino)-3-bromo-5-nitrobenzoate
  • Step 5 Synthesis of methyl 3-bromo-4-((3-(2-mercaptoethoxy)propyl)amino)-5-nitrobenzoate
  • Step 6 Synthesis of 9-nitro-2,3,5,6,7,8-hexahydrobenzo[e][1,4,7]oxathiacridine-11-carboxylic acid methyl ester
  • Step 7 Synthesis of 9-amino-2,3,5,6,7,8-hexahydrobenzo[e][1,4,7]oxythiazine-11-carboxylic acid methyl ester
  • Step 8 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxa-6-thia Synthesis of -2,12a-Diazacyclodecene[cd]indene-4-carboxylic acid ethyl ester
  • Step 9 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxa-6-thia Synthesis of -2,12a-diazacyclodecene[cd]indene-4-carboxylic acid
  • Step 10 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxa-6-thia Synthesis of -2,12a-diazacyclodecene[cd]indene-4-carboxamide
  • Step 2 Synthesis of tert-butyl (3-((4-((tert-butyldimethylsilyl)oxy)but-2-yl)oxy)propyl)carbamate
  • Step 3 Synthesis of tert-butyl (3-((4-hydroxybut-2-yl)oxy)propyl)carbamate
  • Step 4 Synthesis of tert-butyl (3-((4-(5-carbamoyl-2-chloro-3-nitrophenoxy)but-2-yl)oxy)propyl)carbamate
  • Step 7 10-Amino-4-methyl-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaundecane-12 -Synthesis of formamide
  • Step 8 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl 7,8,9,11,12,13 hexahydro-6,10- Synthesis of Dioxa-2,13a-Diazacycloundecane[CD]Indene-4-Carboxamide
  • Step 2 Synthesis of 1-tert-butyldimethylsilyl-3-((4-(trityloxy)butan-2-yl)oxy)propan-1-ol
  • Step 4 Synthesis of 3-((4-(trityloxy)butan-2-yl)oxy)propan-1-ol p-toluenesulfonate
  • Step 5 Synthesis of tert-butyl (3-(((4-(trityloxy)butan-2-yl)oxy)propyl)carbamic acid
  • Step 6 Synthesis of tert-butyl (3-((4-hydroxybut-2-yloxy)propyl)carbamic acid
  • Step 7 Synthesis of methyl 3-(3-(3-(((tert-butoxycarbonyl)amino)propoxy)butoxy)-4-chloro-5-nitrobenzoate
  • Step 8 Synthesis of methyl 3-(3-(3-aminopropoxy)butoxy)-4-chloro-5-nitrobenzoate
  • Step 10 (S)-4-Methyl-10-amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxazepine Synthesis of Heteroundecene-12-Methyl Carboxylate
  • Step 11 (S)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Methyl Hydro-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylate
  • Step 12 (S)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylic acid
  • Step 13 (S)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxamide
  • Step 3 (R)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Methyl Hydro-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylate
  • Step 4 (R)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxylic acid
  • Step 5 (R)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexa Synthesis of Hydrogen-6,10-Dioxa-2,13a-Diazacyclobenzo[cd]indan-4-carboxamide
  • Step 1 Synthesis of methyl 3-amino-5-bromo-4-((3-((tert-butoxycarbonyl)amino)propyl)amino)benzoate
  • Step 2 7-Bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido) Synthesis of -1H-benzo[d]imidazole-5-carboxylic acid methyl ester
  • Step 3 7-Bromo-1-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-N-((2-(trimethylform Synthesis of (silyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester
  • Step 4 (E)-7-(4-(tert-butoxy)-4-oxobut-1-en-1-yl)-1-(3-((tert-butoxycarbonyl)amino)propane Yl)-2-(1-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester
  • Step 5 (E)-4-(1-(3-aminopropyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-5-(methoxy Carbonyl)-1H-benzo[d]imidazol-7-yl)but-3-enoic acid
  • Step 6 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo 8,9,10,11,12,13-hexahydro-2,10 Synthesis of ,13a-triazol[cd]indene-4-carboxylic acid methyl ester
  • Step 7 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo 8,9,10,11,12,13-hexahydro-2,10 Synthesis of ,13a-triazol[cd]indene-4-carboxylic acid
  • Step 8 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo 8,9,10,11,12,13-hexahydro-2,10 Synthesis of ,13a-triazol[cd]indene-4-carboxamide
  • Step 9 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-9-oxo-6,7,8,9,10,11,12,13-A Synthesis of hydrogen-2,10,13a-triazacycloaryl[cd]indene-4-carboxamide
  • Step 1 (S)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid methyl ester
  • Step 2 (S)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid
  • Step 3 (S)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxamide
  • Step 1 (R)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid methyl ester
  • Step 2 (R)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxylic acid
  • Step 3 (R)-1-(1-ethyl-4-fluoro-3-methyl-1H-pyrazole-5-carboxamido)-9-methyl-7,8,9,11,12 Synthesis of ,13-hexahydro-6,10-dioxa-2,13a-diaza heterocyclic benzo[cd]indan-4-carboxamide
  • Step 1 (S)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxylate
  • Step 2 (S)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-carboxylic acid
  • Step 3 (S)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxamide
  • Step 1 (R)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxylate
  • Step 2 (R)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-carboxylic acid
  • Step 3 (R)-1-(4-ethyl-2-methylthiazole-5-carboxamido)-9-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxazole-2,13a-Diazol[cd]indene 4-Carboxamide
  • Step 1 Synthesis of methyl 3-bromo-4-((3-hydroxypropyl)amino)-5-nitrobenzoate
  • Step 2 Synthesis of methyl 3-amino-5-bromo-4-((3-hydroxypropyl)amino)benzoate
  • Step 4 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxy Synthesis of Amido)-1-(3-hydroxypropyl)-1H-benzo[d]imidazole 5-carboxylate
  • Step 5 7-(3-((tert-butoxycarbonyl)amino)prop-1-yn-1-yl)-2-(1-ethyl-3-methyl-N-((2-(tri (Methylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)-1-(3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl Synthesis of ester
  • compound 15d (270mg, 0.45mmol) was dissolved in N,N-dimethylformamide (5mL) solution, N-tert-butoxycarbonylpropynamide (106mg, 0.68mmol), Pd(PPh 3 ) 2 Cl 2 (16 mg, 0.02 mmol), tri-tert-butylphosphorus (10% toluene solution, 37 mg, 0.04 mmol), cuprous iodide (8.7 mg, 0.04 mmol) and DIPEA (117 mg, 0.91 mmol). The mixture was replaced with nitrogen for 5 times, heated to 85°C under nitrogen protection and stirred overnight at this temperature.
  • Step 6 7-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethyl (Oxy)methyl)-1H-pyrazole-5-carboxamido-1-(3-hydroxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester
  • Step 7 7-(3-((tert-butoxycarbonyl)amino)propyl)-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethyl Oxy)methyl)-1H-pyrazole-5-carboxamido-1-(3-((((4-nitrophenoxy)carbonyl)oxy)propyl)-1H-benzo(d ] Synthesis of imidazole-5-carboxylic acid methyl ester
  • Step 8 7-(3-Aminopropyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(3-((((4-nitro (Phenoxy)carbonyl)oxy)propyl)-1H-benzo[d]imidazole-5-carboxylic acid methyl ester
  • Step 9 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-10-oxo-6,7,8,9,10,12,13,14-A Synthesis of Methyl Hydro-11-oxa-2,9,14a-triazacyclododecyl[cd]indene-4-carboxylate
  • Step 10 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-10-oxo-6,7,8,9,10,12,13,14-A Synthesis of hydrogen-11-oxa-2,9,14a-triazacyclododecyl[cd]indan-4-carboxylic acid
  • Step 11 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-10-oxo-6,7,8,9,10,12,13,14-A Synthesis of hydrogen-11-oxa-2,9,14a-triazacyclododecyl[cd]indan-4-carboxamide
  • 1,3-butanediol (15g, 167mmol), benzaldehyde (17.7g, 167mmol), anhydrous sodium sulfate (40g, 333mmol), p-toluenesulfonic acid (2.9g, 17mmol) were dissolved in DCM (200mL), react at room temperature for 10h. After the reaction is completed, the inorganic salt is filtered, and the organic phase is spin-dried to obtain 16a (29 g, 163 mmol) with a yield of 97%.
  • Step 3 Synthesis of tert-butyl (3-(3-(benzyloxy)butoxy)propyl)carbamate
  • Step 4 Synthesis of tert-butyl (3-(3-hydroxybutoxy)propyl)carbamate
  • Step 5 Synthesis of (3-(3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propoxy)propyl) tert-butyl carbamate
  • Step 8 2-Methyl-10-amino-3,4,6,7,8,9-hexahydro-2H-benzo[b][1,8,4]dioxaazacycloundecane Synthesis of Alkyl-12-Carboxamide
  • Step 9 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methyl-7,8,9,11,12,13-hexahydro-6, Synthesis of 10-Dioxa-2,13a-Diazacycloundecanebenzo[cd]indene-4-carboxamide
  • compound 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate 35mg, 0.18mmol
  • DMF 3mL
  • HATU 75mg, 0.20mmol
  • N,N-diisopropylethylamine 46mg, 0.36mmol
  • Step 1 1-(4-Ethyl-2-(fluoromethyl)thiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-6,10-dioxazole- Synthesis of 2,13a-diazacyclohexyl[cd]indene 4-carboxamide
  • Step 1 Synthesis of benzyl (3-((tert-butoxycarbonyl)amino)propylbenzyl(3-((tert-butyldimethylsilyl)oxy)propyl)carbamate
  • Step 2 Synthesis of benzyl (3-((tert-butoxycarbonyl)amino)propyl)(3-hydroxypropyl)carbamate
  • Step 4 Synthesis of methyl 3-(3-((3-aminopropyl)((benzyloxy)carbonyl)amino)propoxy)-4-chloro-5-nitrobenzoate
  • Step 5 5-benzyl12-methyl10-nitro-3,4,6,7,8,9-hexahydrobenzo[b][1,4,8] diazacycloundecane -5,12(2H)-Dicarboxylic acid ester synthesis
  • Step 7 10-((Benzyloxy)carbonyl)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13 Synthesis of -hexahydro-7H-6-oxa-2,10,13a-triazaheterocyclyl[cd]indene-4-carboxylic acid methyl ester
  • Step 8 10-((Benzyloxy)carbonyl)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13 Synthesis of -hexahydro-7H-6-oxa-2,10,13a-triazaheterocyclyl[cd]indene-4-carboxylic acid 21g (200mg, 0.34mmol) was dissolved in methanol (3mL) and tetrahydrofuran 3mL) was added hydrated lithium hydroxide (74mg, 1.7mmol). Raise to 75°C and react for 2h. After cooling, the pH was adjusted to about 3 with dilute hydrochloric acid (1M), a solid was precipitated, and the solid was filtered and dried to obtain compound 21h (160 mg, yield 84%).
  • Step 9 10-((Benzyloxy)carbonyl)-1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13 Synthesis of -hexahydro-7H-6-oxa-2,10,13a-triazaheterocyclyl[cd]indene-4-carboxamide
  • HATU 106 mg, 0.28 mmol
  • DIPEA 108 mg, 0.84 mmol
  • ammonium chloride 74 mg, 1.4 mmol
  • Step 10 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,10,11,12,13-hexahydro-7H-6-oxa-2 Synthesis of ,10,13a-triazaheterocyclyl[cd]indene-4-carboxamide
  • Step 1 Synthesis of tert-butyl (3-(3-(benzyloxy)propoxy)propyl)carbamate
  • Step 2 Synthesis of tert-butyl (3-(3-hydroxypropoxy)propyl)carbamate
  • Step 4 Synthesis of acetic acid-3-(3-tert-butoxycarbonylamino)propoxy)propylthioester
  • Step 5 Synthesis of acetic acid-3-(3-aminopropoxy)propylthioester
  • Step 6 Synthesis of methyl 4-(3-(3-ethylthiopropoxy)propylamino)-3-bromo-5-nitrobenzoate
  • Step 7 Synthesis of methyl 4-(3-(3-mercaptopropoxy)propylamino)-3-bromo-5-nitrobenzoate
  • Step 10 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a Synthesis of Methyl Diazacycloundec[cd]indene-4-carboxylate
  • Step 11 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a Synthesis of -Diazacycloundec[cd]indene-4-carboxylic acid
  • Step 12 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a Synthesis of -Diazacycloundec[cd]indene-4-carboxamide
  • Step 1 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-Diazacycloundec[cd]indene-4-carboxylic acid methyl ester
  • Step 2 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxylic acid
  • Step 3 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxamide
  • Dissolve compound 23b (148mg, 0.334mmol) in DMF (5mL), add N,N-diisopropylethylamine (0.22mL, 1.336mmol), HATU (190mg, 0.501mmol), stir at room temperature for 30 minutes Ammonium chloride (53 mg, 1.00 mmol) was added and stirred overnight at room temperature.
  • Step 1 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a -Diazacycloundec[cd]indene-4-carboxylic acid methyl ester-6,6-dioxide synthesis
  • Step 2 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a -Diazacycloundec[cd]indene-4-carboxylic acid-6,6-dioxide synthesis
  • Step 3 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxo-6-sulfur-2,13a -Diazacycloundec[cd]indene-4-carboxamide-6,6-dioxide synthesis
  • Dissolve compound 24b (25mg, 0.051mmol) in DMF (5mL), add N,N-diisopropylethylamine (0.033mL, 0.204mmol), HATU (29mg, 0.077mmol), stir at room temperature for 30 minutes Ammonium chloride (8mg, 0.152mmol) was added and stirred overnight at room temperature.
  • Step 1 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-Diazacycloundecyl[cd]indene-4-carboxylic acid methyl ester-6-oxide
  • Step 2 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxylic acid-6-oxide
  • Step 3 1-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7,8,9,11,12,13-hexahydro-10-oxy-6-sulfur Synthesis of -2,13a-diazaheteroundec[cd]indene-4-carboxamide-6-oxide
  • Step 1 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxy-6-sulfur-2,12a-di Synthesis of azepine[cd]indene-4-carboxylic acid methyl ester
  • Step 2 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxy-6-sulfur-2,12a-di Synthesis of azepine[cd]indene-4-carboxylic acid
  • Step 3 1-(4-Ethyl-2-methylthiazole-5-carboxamido)-8,10,11,12-tetrahydro-7H-9-oxy-6-sulfur-2,12a-di Synthesis of azepine[cd]indene-4-carboxamide
  • Dissolve compound 26b (80mg, 0.179mmol) in DMF (5mL), add triethylamine (0.1mL, 0.716mmol), HATU (102mg, 0.0.269mmol), stir at room temperature for 30 minutes and add ammonium chloride (29mg , 0.538mmol), stirred overnight at room temperature.
  • the protein thermal transfer test was used to determine the binding affinity of the compound to the Sting protein.
  • Mix 5X SYPRO Orange dyes measure the dissolution curve of the protein on a qPCR instrument, fit the Tm value with the Protein Thermal Shift Software 1.3 software, calculate the difference between the Tm of the protein when different concentrations of compound and no compound are added, according to ⁇ Tm as the compound concentration
  • the change fitting obtains the dissociation constant Kd. The lower the Kd, the stronger the binding affinity of the compound to the Sting protein.
  • the Kd value of each compound is determined according to the following instructions:
  • the compound of the present invention has a good ability to bind to the Sting protein, especially the compounds 2-6, 9, 13, 16, 17, 19, 20, 23, 28. Therefore, the compound of the present invention can be used as an effective STING protein regulator.
  • Test Example 2 Test of the agonistic function of the compound of the present invention on Sting protein
  • the function of sting agonist was evaluated by detecting the changes of CXCL10 (IP10) cytokines produced by THP1 cells (Shanghai Cell Bank) stimulated by compounds in the peripheral blood mononuclear cell line.
  • IP10 CXCL10
  • THP1 cells Sthai Cell Bank
  • the ELISA plate was coated according to the instructions of the IP10 ELISA detection kit (BD, #550926).
  • EC 50 concentration for the half-maximal effect refers to a drug concentration effective to cause 50% of individuals.
  • the EC 50 value of each compound is determined according to the following instructions:
  • the above experimental results show that the compound of the present invention has a good activity of stimulating THP1 cells to produce CXCL10 (IP10) cytokines, and has a good STING protein agonistic function, especially the compound 2, 4, 9-1, 9-2, 11, 12 , 19, 20, 23.
  • the present invention provides a compound with a novel structure shown in formula I.
  • Experimental results show that the compound of the present invention can effectively bind to STING and has a good STING protein agonistic function. Therefore, the compounds of the present invention can be used as STING agonists and used to treat various related diseases.
  • the compound provided by the present invention has a very good application prospect in the preparation of drugs for treating diseases related to STING activity, especially in the preparation of drugs for treating inflammatory, autoimmune diseases, infectious diseases, cancer or precancerous syndromes.

Landscapes

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

Abstract

L'invention concerne un composé représenté par la formule (I), un tautomère ou un énantiomère de celui-ci, ou un sel pharmaceutiquement acceptable, une forme cristalline, un hydrate ou un solvate de celui-ci, en tant qu'immunomodulateur macrocyclique. Les résultats expérimentaux indiquent que le composé selon la présente invention est capable de se lier de manière efficace à STING, et a un bon effet dans l'agonisation d'une protéine STING. Ainsi, le composé selon la présente invention sert d''agoniste de STING et peut être utilisé pour traiter diverses maladies associées. Le composé selon la présente invention a des perspectives prometteuses dans la préparation de médicaments pour le traitement de maladies associées à une activité STING, en particulier dans la préparation de médicaments pour le traitement d'une inflammation, de maladies auto-immunes, de maladies infectieuses, du cancer ou de syndromes précancéreux.
PCT/CN2020/073333 2019-01-23 2020-01-20 Immunomodulateur macrocyclique WO2020151682A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910052988 2019-01-23
CN201910052988.9 2019-01-23

Publications (1)

Publication Number Publication Date
WO2020151682A1 true WO2020151682A1 (fr) 2020-07-30

Family

ID=71736070

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/073333 WO2020151682A1 (fr) 2019-01-23 2020-01-20 Immunomodulateur macrocyclique

Country Status (2)

Country Link
CN (1) CN111471056B (fr)
WO (1) WO2020151682A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie
US11155567B2 (en) 2019-08-02 2021-10-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017175156A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
CN109071514A (zh) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 用作蛋白质调节剂的杂环酰胺

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2851563B1 (fr) * 2003-02-26 2005-04-22 Sod Conseils Rech Applic Nouveaux derives de benzimidazole et d'imidazo-pyridine et leur utilisation en tant que medicament
US20070032469A1 (en) * 2005-08-05 2007-02-08 Astrazeneca Ab Tricyclic benzimidazoles and their use as metabotropic glutamate receptor modulators
AU2007309488B2 (en) * 2006-10-24 2012-10-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
FR2918061B1 (fr) * 2007-06-28 2010-10-22 Sanofi Aventis Derives de 6-cycloamino-3-(pyridin-4-yl)imidazo°1,2-b!- pyridazine,leur preparation et leur application en therapeutique.
TW200942243A (en) * 2008-03-05 2009-10-16 Biocryst Pharm Inc Antiviral therapeutic agents
TW201103941A (en) * 2009-06-10 2011-02-01 Janssen Pharmaceutica Nv Benzimidazole derivatives useful as TRPM8 channel modulators
TW201206946A (en) * 2010-07-15 2012-02-16 Bristol Myers Squibb Co Compounds for the reduction of beta-amyloid production
WO2013104613A1 (fr) * 2012-01-11 2013-07-18 F. Hoffmann-La Roche Ag Amides macrocycliques en tant qu'inhibiteurs de protéase
JP6888000B2 (ja) * 2015-10-08 2021-06-16 バイエル ファーマ アクチエンゲゼルシャフト 新規な修飾された大環状化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017175156A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
CN109071514A (zh) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 用作蛋白质调节剂的杂环酰胺

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11155567B2 (en) 2019-08-02 2021-10-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie

Also Published As

Publication number Publication date
CN111471056A (zh) 2020-07-31
CN111471056B (zh) 2021-07-02

Similar Documents

Publication Publication Date Title
CN110016025B (zh) 一种免疫调节剂
WO2020156363A1 (fr) Immunomodulateur
TWI659957B (zh) 新穎吡唑并［3,4-d］嘧啶化合物或其鹽
WO2018223909A1 (fr) Molécule chimère, préparation et utilisation associées
TWI711619B (zh) 作爲蛋白質激酶抑制劑之胺基噠嗪酮化合物
WO2021218110A1 (fr) Composé de benzothiazolyle biaryle, son procédé de préparation et son utilisation
CN101754966B (zh) 丙型肝炎病毒抑制剂
CN105899490B (zh) 嘧啶fgfr4抑制剂
CN110016021B (zh) 一种免疫调节剂
WO2022166974A1 (fr) Dérivé de pyridopyrimidinone, son procédé de préparation et son utilisation
KR20100016431A (ko) 약학적 화합물
WO2020011246A1 (fr) Composé contenant un cycle benzénique, son procédé de préparation et son utilisation
WO2016169421A1 (fr) Dérivé imidazo isoindole, méthode de préparation correspondante et utilisation médicale correspondante
CN113950481A (zh) 大环化合物
WO2022268230A1 (fr) Composé destiné à être utilisé en tant qu'inhibiteur de kif18a
WO2020151682A1 (fr) Immunomodulateur macrocyclique
WO2020168927A1 (fr) Composé cyclique condensé contenant de l'azote, son procédé de préparation et son utilisation
WO2019228404A1 (fr) Nouveau inhibiteur de phosphoïnositide 3-kinase et procédé de préparation et d'utilisation associé
WO2022166860A1 (fr) Inhibiteur de pim kinase
WO2021063362A1 (fr) Composé de biaryle substitué par sulfo ou sel correspondant, son procédé de préparation et son utilisation
WO2023045960A1 (fr) Dérivé de pyridine et son utilisation
WO2022268209A1 (fr) Dérivé ayant une structure cyclique fusionnée à la pyrimidine, et son utilisation
WO2022161166A1 (fr) Composé chimère de ciblage, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
WO2021114691A1 (fr) Composé à cycles condensés contenant de l'azote, son procédé de préparation et son utilisation
WO2022032484A1 (fr) Composé de pyridazine-3-formamide, son procédé de préparation et son utilisation médicale

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: 20745944

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20745944

Country of ref document: EP

Kind code of ref document: A1