WO2019134707A1 - Immunomodulateur - Google Patents

Immunomodulateur Download PDF

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WO2019134707A1
WO2019134707A1 PCT/CN2019/070791 CN2019070791W WO2019134707A1 WO 2019134707 A1 WO2019134707 A1 WO 2019134707A1 CN 2019070791 W CN2019070791 W CN 2019070791W WO 2019134707 A1 WO2019134707 A1 WO 2019134707A1
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mmol
compound
substituted
methyl
alkyl
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PCT/CN2019/070791
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Chinese (zh)
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李进
张登友
潘飞
冯静超
李应飞
朱文吉
李偲
张毅
魏用刚
陈伟
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成都先导药物开发股份有限公司
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Publication of WO2019134707A1 publication Critical patent/WO2019134707A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
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    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/10—Anti-acne agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 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
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • 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
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to an immunomodulator.
  • the body's immune system can usually be divided into “natural immune” and “adaptive immune” systems.
  • the natural immune system plays an important role in the fight against infection, inhibition of 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 ultimately induces cytokine expression. Kill pathogenic microorganisms and cancer cell components, as well as adapt to the immune system to promote antibody and specific T lymphocyte production.
  • STING interferon gene stimulating factor, TMEM173, MITA, etc.
  • TMEM173, MITA interferon gene stimulating factor
  • STING is a key node molecule for intracellular response to DNA invasion. Under cytoplasmic DNA stimulation, recognition of cytoplasmic DNA receptor signaling plays a key role in the process of inducing interferon production. . After the host cell's DNA recognition receptor recognizes the exogenous or endogenous "non-self" DNA, it transmits a signal to the node molecule STING, which then rapidly dimerizes and transfers from the endoplasmic reticulum to the nuclear peripheral body. Activation of STING leads to upregulation of the IRF3 and NK ⁇ B pathways, resulting in the induction of interferon- ⁇ and other cytokines.
  • the CDN was first discovered to be the second messenger responsible for controlling prokaryotic cell responses. Direct activation of bacterial CDN by STING has been verified by X-ray crystallography (Burdette DL et al. Nature Immunolog, 2013 (14): 19-26). The new CDN signal transduction molecule cGAMP has been found to activate STING, and its interaction with STING has also been verified by X-ray crystallography (Cai X et al. Molecular Cell, 2014 (54): 289-296).
  • Compounds that bind to STING and act as agonists have been shown to induce type 1 interferons and other cytokines when incubated with human PBMC.
  • Compounds that induce human interferon can be used to treat various conditions, such as treating allergic diseases and other inflammatory conditions, such as allergic rhinitis and asthma, treating infectious diseases, neurodegenerative diseases, precancerous syndromes, and cancer, or Used as an immunological composition or vaccine adjuvant.
  • Activation of STING may be a potential method for treating diseases associated with type 1 IFN pathways including inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndrome, or as an immunological combination Or vaccine adjuvant.
  • the present invention provides a compound of formula I, and tautomers, enantiomers thereof, or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof:
  • s is 0 or 1;
  • Ring B is substituted with 0 to 4 R 5 5 ⁇ 6 membered aromatic ring, substituted with 0 to 4 R 5 5 ⁇ 6 membered aromatic heterocyclic ring;
  • R 5 is independently selected from C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -(CH 2 ) n NR a C(O)R b , -(CH 2 ) n C(O)NR a R b , -(CH 2 ) n C(O)OR a , -(CH 2 ) n OC(O)R a ;
  • R 8 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl
  • R 4 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl
  • R 2 is selected from -CONR a R b ;
  • R 1 and R 3 are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
  • R t is selected from 0 to 2 substituents
  • R f is C 1 ⁇ C 6 alkenyl group, substituted with 0 to 2 substituents
  • R f is C 1 ⁇ C 6 alkynyl group, - (CH 2) m R g, -O ( CH 2 ) m R g , -S(CH 2 ) n R f ;
  • R f is selected from -OR a , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -C(O)NR a R b , -C(O)OR a, -OC (O) R a , -OC (O) NR a R b, substituted with 0-4 R c 3 ⁇ 10 membered cycloalkyl, substituted with 0 to 4 substituents R c of 4 to 10-membered Heterocycloalkyl;
  • Each m, n is independently 0, 1, 2, 3, 4, 5 or 6;
  • R g is selected from 0 to 4 substituents
  • R c is 3 to 10-membered cycloalkyl, substituted with 0 to 4 R c 3 to 10-membered heterocycloalkyl;
  • R g is selected from 0 to 4 substituents R c of 3 to 6-membered cycloalkyl, substituted with 0 to 4 R c substituted 4-membered heterocyclic ring An alkyl group, a 7-10 membered heterocycloalkyl group substituted by 0 to 4 R c ;
  • R d and R e are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • B ring is substituted with 0 to 2 R 5 5 to 6-membered aromatic ring is substituted with 0 to 2 R 5 substituted 5- to 6-membered aromatic heterocyclic ring;
  • R t is selected from 0 or 1 R f is substituted with C 1 ⁇ C 6 alkenyl group, substituted with 0 or 1 R f is substituted with C 1 ⁇ C 6 alkynyl group, - (CH 2) m R g, -O ( CH 2 ) m R g , -S(CH 2 ) n R f ;
  • R f is selected from -OR a , -NR a R b , -NR a C(O)R b , -NR a C(O)OR b , -C(O)NR a R b , -C(O)OR a, -OC (O) R a , -OC (O) NR a R b, substituted with 0 to 2 R c 3 ⁇ 10 membered cycloalkyl, substituted with 0 to 2 substituents R c of 4 to 10-membered Heterocycloalkyl;
  • Each m, n is independently 0, 1, 2, 3, 4, 5 or 6;
  • R g is selected from 0 to 2 substituents
  • R c is 3 to 10-membered cycloalkyl, substituted with 0 to 2 R c 3 to 10-membered heterocycloalkyl;
  • R g is selected from 0 to 2 substituents R c of 3 to 6-membered cycloalkyl, substituted with 0 to 2 substituents R c 4 membered heterocyclic ring An alkyl group having 7 to 10 membered heterocycloalkyl groups substituted with 0 to 2 R c groups.
  • Ring B is selected from 0 to 2 R 5
  • R 5 is independently selected from C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, -(CH 2 ) n OR a , -(CH 2 ) n NR a R b , -(CH 2 ) n NR a C(O)R b , -(CH 2 ) n C(O)NR a R b , -(CH 2 ) n C(O)OR a , -(CH 2 ) n OC(O)R a ;
  • X' is selected from O, alkynylene, S or none;
  • n 1 0, 1, 2,
  • R S is selected from the group consisting of a 3- to 6-membered cycloalkyl group, a 4-membered heterocycloalkyl group, and a 7- to 10-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of hetero atoms is 1, 2;
  • n 1 0, 1, 2,
  • R S is selected from -OR a , -NR a C(O)OR b , 4 to 10 membered heterocycloalkyl; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of heteroatoms is 1, 2;
  • R a and R b are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • n 1 0, 1, 2,
  • R S is selected from a 4-membered heterocycloalkyl group and a 7- to 10-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of heteroatoms is 1, 2;
  • n 1 0, 1, 2,
  • R S is selected from the group consisting of -OH, -OCH 3 , -NHC(O)OCH 3 , and a 4- to 6-membered heterocycloalkyl group; wherein the hetero atom of the heterocycloalkyl group is O, N, and the number of hetero atoms is 1, 2.
  • the 7-10 membered heterocycloalkyl group is a spiro ring; wherein the spiro ring is
  • B ring is selected from
  • n 0, 1, 2, 3, 4, 5, 6;
  • A is a ring selected from 0-4 R c substituted 3- to 6-membered cycloalkyl, substituted with 0 to 4 R c 3 to 6-membered heterocycloalkyl;
  • a ring is selected from substituted with 0 to 4 R c 3 ⁇ 6 membered cycloalkyl, substituted with 0-4 R c 4 membered heterocyclic ring
  • An alkyl group; R c is selected from the group consisting of hydrogen, C 1 -C 6 alkyl;
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl;
  • R 2 is selected from -CONR a R b ; wherein R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl.
  • R 1 , R 3 , R 7 and R 8 are selected from hydrogen.
  • R 5 and R 6 are each independently selected from a C 1 -C 6 alkyl group and a halogen-substituted C 1 -C 6 alkyl group.
  • R 2 is selected from -CONR a R b ; wherein R a and R b are each independently selected from hydrogen.
  • R 4 is selected from a C 1 -C 6 alkyl group.
  • the 3- to 6-membered heterocycloalkyl group substituted by 0 to 4 R c is selected from heterocycloalkyl groups containing nitrogen, oxygen and sulfur; and R c is selected from hydrogen.
  • n 0, 1, 2, 3, 4, 5, 6;
  • n 0, 1, 2, 3;
  • p 0, 1, 2, 3, 4;
  • R 1 , R 3 , R 7 , and R 8 are each independently selected from hydrogen;
  • R 4 is selected from C 1 -C 6 alkyl
  • R 5 and R 6 are each independently selected from a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group;
  • R 2 is selected from -CONR a R b ; wherein R a , R b are each independently selected from hydrogen;
  • R c is independently selected from hydrogen, C 1 -C 6 alkyl.
  • p 0, 1, 2, 3, 4;
  • R 1 , R 3 , R 7 , and R 8 are each independently selected from hydrogen;
  • R 4 is selected from C 1 -C 6 alkyl
  • R 5 and R 6 are each independently selected from a C 1 -C 6 alkyl group, a halogen-substituted C 1 -C 6 alkyl group;
  • R 2 is selected from -CONR a R b ; wherein R a , R b are each independently selected from hydrogen;
  • X selects -O-, -NR d -, -S-;
  • R c is independently selected from hydrogen, C 1 -C 6 alkyl.
  • the present invention also provides the use of the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, for the preparation of a STING agonist.
  • the present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of a therapeutic or prophylactically related to STING activity
  • the use of the disease in medicine The use of the disease in medicine.
  • the present invention also provides the aforementioned compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, in the preparation of an immunological composition or vaccine adjuvant Use in.
  • the experimental results show that the compound of the present invention can effectively bind to STING, and the compound of the present invention can be used as a STING agonist for the treatment of various diseases, especially for leukemia.
  • the disease associated with STING activity as defined in the present invention is a disease in which STING plays an important role in the pathogenesis of the disease.
  • Diseases associated with STING activity include inflammatory, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndrome.
  • Cancer refers to any of a variety of diseases characterized by abnormal proliferation of uncontrolled cells, the ability of affected cells to spread locally or through the bloodstream and lymphatic system to other sites. The body (ie, metastasis) and any of a number of characteristic structures and/or molecular features.
  • Cell cancer cells refers to cells that undergo early, intermediate or late stages of multi-step tumor progression. Cancer includes sarcoma, breast cancer, lung cancer, brain cancer, bone cancer, liver cancer, kidney cancer, colon cancer, and prostate cancer.
  • the compound of Formula I is for use in treating a cancer selected from the group consisting of colon cancer, brain cancer, breast cancer, fibrosarcoma, and squamous cell carcinoma.
  • the cancer is selected from the group consisting of melanoma, breast cancer, colon cancer, lung cancer, and ovarian cancer.
  • the cancer 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 invention relate to the treatment of inflammatory diseases and asthma.
  • the immune system usually involves inflammatory diseases, which are manifested in allergic reactions and some myopathy, and many immune system diseases cause abnormal inflammation.
  • the compounds and derivatives provided in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
  • substitution means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
  • the minimum and maximum values of the carbon atom content in the hydrocarbon group are represented by a prefix, for example, the prefix (C a - C b ) alkyl group indicates any alkyl group having "a" to "b” carbon atoms.
  • (C 1 -C 4 )alkyl means an alkyl group containing from 1 to 4 carbon atoms.
  • C a to C b alkoxy, C a to C b alkyl ester group, C a to C b alkylamino group, and C a to C b acyl group respectively mean "a" to "b" carbon atoms. a group obtained by linking an alkyl group to a corresponding oxygen atom, ester group, amino group, or acyl group.
  • cycloalkane or “cycloalkyl group” in the present invention means a saturated ring or a non-aromatic unsaturated ring formed by linking carbon atoms, and includes a monocyclic ring, a ring or a spiro ring.
  • Heterocycle means a saturated saturated ring or a non-aromatic unsaturated ring containing at least one hetero atom, including a monocyclic ring, a cyclic ring or a spiro ring.
  • the hetero atom is a nitrogen atom, an oxygen atom or a sulfur atom.
  • aromatic ring and “aryl group” mean an aromatic unsaturated ring formed by linking carbon atoms.
  • aromatic heterocyclic ring and “aromatic heterocyclic group” in the present invention means an aromatic unsaturated ring containing at least one hetero atom, wherein the hetero atom means a nitrogen atom, an oxygen atom or a sulfur atom.
  • Halogen is fluorine, chlorine, bromine or iodine.
  • Alkenyl in the present invention means a hydrocarbon group containing at least one carbon-carbon double bond.
  • alkynyl group in the present invention means a hydrocarbon group containing at least one carbon-carbon triple bond.
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients that constitute a pharmaceutical dosage form, and is physiologically Compatible with the receptor.
  • salts and “pharmaceutically acceptable salt” refer to the above-mentioned compounds or stereoisomers thereof, acid and/or basic salts formed with inorganic and/or organic acids and bases, and also includes zwitterionic salts (within Salts) also include quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. It can also be obtained by mixing the above compound, or a stereoisomer thereof, with a certain amount of an acid or a base as appropriate (for example, an equivalent amount).
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • one or more compounds of the invention may be used in combination with one another.
  • the compounds of the invention may be used in combination with any other active agent for the preparation of a medicament or pharmaceutical composition that modulates cellular function or treats a disease. If a group of compounds is used, the compounds can be administered to the subject simultaneously, separately or sequentially.
  • the structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS).
  • the NMR shift ( ⁇ ) is given in units of 10-6 (ppm).
  • the NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl 3 ), deuterated methanol (CD3OD), internal standard. It is tetramethylsilane (TMS).
  • the LC-MS was measured using a Shimadzu LC-MS 2020 (ESI).
  • the HPLC was measured using Shimadzu High Pressure Liquid Chromatograph (Shimadzu LC-20A).
  • Reverse phase preparative chromatography was performed using a Gilson GX-281 reverse phase preparative chromatograph.
  • the thin layer chromatography silica gel plate is separated from the Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate by thin layer chromatography, and the specification is 0.4mm to 0.5mm.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from companies such as Anike Chemical, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • M is a mole per liter.
  • the room temperature is an optimum reaction temperature of 20 ° C to 30 ° C.
  • DMF means N,N-dimethylformamide.
  • DMSO refers to dimethyl sulfoxide
  • DIPEA refers to diisopropylethylamine.
  • Boc refers to tert-butyloxycarbonyl.
  • TFA refers to trifluoroacetic acid.
  • DBU 1,8-diazabicycloundec-7-ene.
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • Methyl 4-chloro-3-methoxy-5-nitrobenzoate (10 g, 40.7 mmol) was dissolved in anhydrous dichloromethane (100 mL), and boron tribromide was slowly added dropwise in an ice bath ( 40.8 g, 162.8 mmol), and slowly added to room temperature after stirring, and the reaction was stirred overnight. After the reaction was completed, it was quenched by slowly dropwise adding methanol under an ice bath, and then it was dried. Methanol (100 mL) and concentrated sulfuric acid (0.2 mL) were added thereto, and the reaction mixture was heated to 75 ° C and stirred overnight.
  • Step 2 Synthesis of methyl 4-chloro-3-nitro-5-(2-(oxetan-3-yl)ethoxy)benzoate
  • Step 3 Synthesis of methyl 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate
  • Step 4 Synthesis of methyl 3-amino-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate
  • Methyl 3-nitro-5-(2-(oxetan-3-yl)ethoxy)-4-(propylamino)benzoate (1.28 g, 3.8 mmol) in methanol (15 mL)
  • 10% Pd/C (0.13g)
  • Methyl 4-(propylamino)benzoate (1.1 g, 3.5 mmol) was used directly in the next step.
  • Step 5 Synthesis of methyl 2-amino-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxylate
  • Step 3 Synthesis of methyl 4-ethyl-2-methyloxazole-5-carboxylate
  • 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). The mixture was warmed to 120 ° C and stirred at this temperature for 4 hours. After concentrating the reaction mixture, it was diluted with water and extracted with ethyl acetate. The separated organic layer was washed with water and brine, then dried over anhydrous sodium sulfate, and the filtrate was evaporated to dryness. Agent: petroleum ether / ethyl acetate, 90/10) gave 4-ethyl-2-methyloxazole-5-carboxylic acid methyl ester (0.52 g, 3.1 mmol).
  • Methyl 4-ethyl-2-methyloxazole-5-carboxylate (323 mg, 1.9 mmol) was dissolved in THF / MeOH (10 mL / 5 mL), and hydrated lithium hydroxide (160 mg, 3.8 mmol). Stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. EtOAc (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated tolululululululululululu
  • the yellow oil was dissolved in dry acetone (10 ml) and added dropwise to a solution of potassium thiocyanate (276 mg, 2.84 mmol) in acetone (15 ml), and stirred at room temperature for 3 h.
  • the inorganic salt was removed by filtration and washed with n-hexane.
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-yloxy)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(cyclopropylmethoxy)-1-propyl-1H-benzo[d Synthesis of imidazole-5-carboxamide
  • Step 3 Synthesis of 3-amino-5-(N-tert-butoxycarbonylazetidin-3-ylmethoxy)-4-(propylamino)benzamide
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(N-tert-butoxycarbonylazetidin-3-ylmethoxy) Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • N-tert-butoxycarbonylazetidin-3-ethanol 1.0 g, 4.9 mmol
  • p-toluenesulfonyl chloride 1.0 g, 5.3 mmol
  • Alkyl-3-ylethyl p-benzenesulfonate (1.38 g, 3.9 mmol) was used directly in the next step.
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(N-tert-butoxycarbonylazetidin-3-ylethoxy) Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1 - Synthesis of propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 Synthesis of 2-(3-methyloxetan-3-yl)acetic acid ethyl acetate
  • Step 7 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(3-methyloxetan-3-yl)ethoxylate Synthesis of 1-propyl-1H-benzo[d]imidazole-5--carboxamide
  • Step 2 Synthesis of methyl 1-(2-hydroxyethyl)-3-methyl-1H-pyrazole-5-carboxylate
  • Step 3 Synthesis of methyl 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylate
  • Step 6 2-(1-(2-Fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)B Synthesis of oxy)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 4 2-(1-(2,2-Difluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetane-3- Synthesis of ethoxy)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 Synthesis of 2-chloro-6-ethyl isonicotinic acid methyl ester
  • Methyl 2,6-dichloronicotinate (544 mg, 2.64 mmol) and diethyl zinc (2.64 mL, 2.64 mmol) were added to 1,4-dioxane (8 mL) at room temperature under nitrogen. Thereafter, Pd(dppf)Cl 2 (70 mg, 0.264 mmol) was added, and the mixture was heated to 70 ° C under nitrogen to stir the reaction for 16 hours. After the reaction was completed, it was cooled to room temperature, and then extracted with ethyl acetate (20 mL ⁇ 3), and the organic phase was combined and washed with water and brine, dried over anhydrous sodium sulfate and filtered.
  • Lithium aluminum hydride (71 mg, 1.87 mmol) was added to methyl 2-chloro-6-ethylisonicotinate (305 mg, 1.53 mmol) in tetrahydrofuran (3 mL). After the completion of the reaction, the mixture was quenched with EtOAc EtOAc (EtOAc) -Chloro-6-ethylpyridin-4-yl)methanol (Compound 12b) (200 mg, 1.17 mmol), yield 75%.
  • tert-Butyldimethylchlorosilane 210 mg, 2.55 mmol was added to (2-chloro-6-ethylpyridin-4-yl)methanol (195 mg, 1.16 mmol), imidazole (159 mg, 2.34).
  • Step 4 2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-ethylpyridin-2-yl)amino)-7-(2-(oxa) Synthesis of Methylcyclobutane-3-yl)ethoxy)-1-propyl-1H-methyl-benzo[d]imidazole-5-carboxylate
  • Step 5 2-((6-Ethyl-4-(hydroxymethyl)pyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 6 2-((6-ethyl-4-(hydroxymethyl)pyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 2-((4,6-Dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H Synthesis of benzo[d]imidazol-5-carboxylic acid methyl ester
  • Step 3 2-((4,6-Dimethylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 1 2-((4-(((tert-butyldimethylsilyl)oxy)methyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxa) Synthesis of Ethylcyclobutane-3-yl)ethoxy)-1-propyl-1H-methyl-benzo[d]imidazole-5-carboxylate
  • Step 2 2-((4-(Hydroxymethyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 3 2-((4-(Hydroxymethyl)-6-methylpyridin-2-yl)amino)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 2 N-(5-carbamoyl-7-(oxetan-3-yloxy)-1-propyl-1H-benzo[d]imidazol-2-yl)-4-ethyl Synthesis of benzyl-2-methyloxazole-5-carboxamide
  • reaction solution was purified by reverse phase HPLC to give N-(5-carbamoyl-7-(oxetan-3-yloxy)-1-propyl-1H-benzo[d]imidazol-2-yl 4-ethyl-2-methylthiazole-5-carboxamide (34.3 mg, yield 34%), white solid.
  • Step 4 7-(2-oxaspiro[3.3]hept-6-yloxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1- Synthesis of propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 1-propyl-7-((tetrahydrofuran-3-yl)thiomethylmethyl)-1H-benzo[d]imidazole-5-carboxylate
  • Step 2 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydrofuran-3-yl)thio)-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 3 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydrofuran-3-yl)thio)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 Synthesis of methyl 3-bromo-5-nitro-4-(propylamino)benzoate
  • Step 2 Synthesis of methyl 3-amino-5-bromo-4-(propylamino)benzoate
  • Step 4 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-A Synthesis of Methyl Amido)-1-propyl-1H-benzo[d]imidazole-5-carboxylate
  • Step 5 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylate
  • Step 6 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 7 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-hydroxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 8 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((2-hydroxyethyl)thio)-1-propyl-1H-benzene And [d] Synthesis of imidazole-5-carboxamide
  • Step 1 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylate
  • Step 2 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 3 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-methoxyethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((2-methoxyethyl)thio)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 1 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 1-propyl-7-((tetrahydro-2H-pyran-4)yl)thio)-1H-benzo[d]imidazole-5-carboxylate
  • Step 2 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydro-2H-pyran-4-)yl)thio)-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 3 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-((tetrahydro-2H-pyran-4-yl)thio)-1H-benzo[d]imidazole-5-carboxamide
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-((tetrahydro-2H-pyran-4-yl)sulfide Synthesis of -1H-benzo[d]imidazole-5-carboxamide
  • Step 1 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of methyl 7-((2-morpholinoethyl)thio)-1-propylmethyl-1H-benzo[d]imidazole-5-carboxylate
  • Step 2 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-morpholinoethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 3 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 7-((2-morpholinoethyl)thio)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 4 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-((2-morpholinoethyl)thio)-1-propyl-1H -Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 1 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-vinyl-1H-benzo[d]imidazole-5-carboxylic acid (Compound 25a)
  • Step 2 2-(1-Ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carboxamido)- Synthesis of 1-propyl-7-vinyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25b)
  • NMO 561.6 mg, 4.8 mmol
  • potassium citrate dihydrate 88.3 mg, 0.24 mmol
  • 5 mL of water was added to compound 25b (1.2 g, 2.4 mmol) of acetonitrile
  • the solution was diluted with water and extracted with dichloromethane (10 mL ⁇ 2).
  • the organic phase was washed with saturated brine (10 mL ⁇ 1), dried over anhydrous sodium sulfate
  • This intermediate was dissolved in dichloromethane (15 mL) then aqueous sodium iodate (1.0 g, 4.8 mmol) (6 mL) was added at room temperature. The mixture was reacted at room temperature for about 1.5 hours.
  • Step 5 7-(2-oxa-6-azaspiro[3.3]hept-6-ylmethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 25)
  • 6-oxa-2-azaspiro[3.4]octane 39.6 mg, 0.35 mmol was added to a solution of compound 25e (160 ⁇ 70% mg, 0.29 mmol) in methanol (10 mL) After adding acetic acid (100 uL) for 1 h, sodium cyanoborohydride (54.8 mg, 0.87 mmol) was added and stirring was continued at room temperature for 3 h.
  • Step 1 7-Bromo-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-A Synthesis of Amido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid methyl ester (Compound 28b)
  • Step 2 7-(3-((tert-Butoxycarbonyl)amino)prop-1-yn-1-yl)-2-(1-ethyl-3-methyl-N-((2-(3) Methylsilyl)ethoxy)methyl)-1H--pyrazole-5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid (compound 28c) synthesis
  • Step 3 tert-Butyl (3-(5-carbamoyl-2-(1-ethyl-3-methyl-N-((2-(trimethylsilyl)ethoxy)methyl)) -1H-pyrazole-5-carboxamido)-1-propyl-1H--benzo[d]imidazol-7-yl)prop-2-yn-1-yl)carbamic acid tert-butyl ester (Compound 28d )Synthesis
  • Step 4 7-(3-Aminoprop-1-yn-1-yl)-2-(((1-ethyl-3-methyl-1H-pyrazol-5-yl)methyl)amino)- Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide (Compound 28e)
  • Step 5 Methyl (3-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H-benzo[ Synthesis of d]imidazolium-7-yl)prop-2-yn-1-yl)carbamic acid (Compound 28)
  • Step 1 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-methylcarboxylate
  • Step 2 2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy)-1 Synthesis of -propyl-1H-benzo[d]imidazole-5-methylcarboxylic acid
  • Step 3 2-(1-Ethyl-3-methyl-1H-pyrazole-5-formylamino)-N-methyl-7-(2-(oxetan-3-yl)B Synthesis of oxy)-1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy Synthesis of methyl-1-propyl-1H-benzo[d]imidazole-5-carboxylate
  • Step 2 2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxylic acid
  • Step 4 2-(1-Ethyl-N,3-dimethyl-1H-pyrazole-5-carboxamido)-7-(2-(oxetan-3-yl)ethoxy Synthesis of 1-propyl-1H-benzo[d]imidazole-5-carboxamide
  • This experiment evaluates the function of sting agonists by detecting changes in CXCL10 (IP10) cytokines produced by compounds that stimulate human peripheral blood mononuclear cell line THP1 cells (Shanghai Cell Bank).
  • IP10 CXCL10
  • the ELISA plate was coated according to the IP10 ELISA test kit (BD, #550926).
  • the compound DMSO was dissolved into a stock solution, and diluted with a medium to a working concentration of 2X, and added to a 96-well plate at 100 ⁇ L per well; the THP1 cells in the logarithmic growth phase were counted and diluted to a concentration of 2*10 6 /mL, and the above-mentioned inclusion was added.
  • the compounds of the present invention are capable of effectively binding to STING, and the compounds of the present invention are useful as STING agonists for the treatment of various conditions, particularly for leukemia.

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Abstract

Composé de formule (I), son tautomère et son enantiomère, ou son sel pharmaceutiquement acceptable, sa forme cristalline, son hydrate ou son solvate. Le composé de formule (I) peut se combiner efficacement avec STING et tenir lieu d'agoniste STING pour le traitement de diverses maladies associées à STING
PCT/CN2019/070791 2018-01-08 2019-01-08 Immunomodulateur WO2019134707A1 (fr)

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WO2020042995A1 (fr) * 2018-08-29 2020-03-05 杭州阿诺生物医药科技有限公司 Composé agoniste de protéine sting à activité élevée
TWI716976B (zh) * 2018-08-24 2021-01-21 大陸商杭州阿諾生物醫藥科技有限公司 高活性sting蛋白激動劑
CN112279835A (zh) * 2019-07-24 2021-01-29 中国医学科学院药物研究所 芳环或芳杂环并咪唑类化合物，其制备方法及制药用途
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

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WO2021098844A1 (fr) * 2019-11-20 2021-05-27 成都先导药物开发股份有限公司 Immunomodulateur
CN112824399B (zh) * 2019-11-20 2022-04-12 成都先导药物开发股份有限公司 一种免疫调节剂
CN112940004B (zh) * 2019-12-11 2022-07-12 中国科学院上海药物研究所 一种杂环化合物及其用途

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WO2015077354A1 (fr) * 2013-11-19 2015-05-28 The University Of Chicago Utilisation d'un agoniste de sting en tant que traitement anti-cancéreux
CN106459131A (zh) * 2014-06-04 2017-02-22 葛兰素史克知识产权开发有限公司 作为sting调节剂的环状二核苷酸
WO2017175156A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
WO2017175147A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine

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WO2015077354A1 (fr) * 2013-11-19 2015-05-28 The University Of Chicago Utilisation d'un agoniste de sting en tant que traitement anti-cancéreux
CN106459131A (zh) * 2014-06-04 2017-02-22 葛兰素史克知识产权开发有限公司 作为sting调节剂的环状二核苷酸
WO2017175156A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
WO2017175147A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI716976B (zh) * 2018-08-24 2021-01-21 大陸商杭州阿諾生物醫藥科技有限公司 高活性sting蛋白激動劑
WO2020042995A1 (fr) * 2018-08-29 2020-03-05 杭州阿诺生物医药科技有限公司 Composé agoniste de protéine sting à activité élevée
CN112279835A (zh) * 2019-07-24 2021-01-29 中国医学科学院药物研究所 芳环或芳杂环并咪唑类化合物，其制备方法及制药用途
CN112279835B (zh) * 2019-07-24 2022-07-22 中国医学科学院药物研究所 芳环或芳杂环并咪唑类化合物，其制备方法及制药用途
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

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