WO2019134705A1 - Immunomodulateur - Google Patents

Immunomodulateur Download PDF

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WO2019134705A1
WO2019134705A1 PCT/CN2019/070743 CN2019070743W WO2019134705A1 WO 2019134705 A1 WO2019134705 A1 WO 2019134705A1 CN 2019070743 W CN2019070743 W CN 2019070743W WO 2019134705 A1 WO2019134705 A1 WO 2019134705A1
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alkyl
group
hydrogen
substituted
optionally substituted
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PCT/CN2019/070743
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Chinese (zh)
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李进
张登友
魏用刚
潘飞
马荣
李应飞
李偲
张毅
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 WO2019134705A1 publication Critical patent/WO2019134705A1/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
    • 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
    • A61K31/435—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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to an immunomodulator, and in particular to a compound which activates STING and its use as an immunomodulator in the preparation of a medicament.
  • 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 an immunomodulator.
  • the present invention provides a compound of Formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof:
  • X 1 , X 2 , X 3 , X 4 , X 1 ' , X 2 ' , X 3 ' , X 4 ' are each independently selected from C or N;
  • B ring is selected from
  • Ring C is selected from 0 to 4 R 5 'is an optionally substituted benzene ring, substituted with 0 to 4 R 5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;
  • R 4 and R 4' are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and halogen;
  • R 5 , R 6 and R 7 are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl;
  • R 1 , R 2 , R 3 , R 1 ' , R 2 ' , R 3 ' and R 5 ' are each independently selected from the group consisting of hydrogen, -OR d , -NR d R e , halogen, -CN, C(O)OR d , C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl, -C(O)NR a R b or none;
  • R a , R b , R d , R e are each independently selected from hydrogen, C 1 -C 6 alkyl;
  • L is selected from R n 0-4 alkylene group optionally substituted with a C 4 ⁇ C 6, and 0 to 4 being optionally substituted with R n C 4 ⁇ C 6 alkenylene group, substituted with 0 to 4 R n optionally substituted C 4 -C 6 alkynylene; wherein optionally substituted C 4 -C 6 alkylene, optionally substituted C 4 -C 6 alkenylene, optionally substituted
  • the carbon atom in the alkynylene group of C 4 to C 6 may be substituted by -O-, -S-, -NR m - ;
  • R m is selected from the group consisting of hydrogen, C 1 -C 6 alkyl
  • R n is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl;
  • R s and R t are each independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl optionally substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g , -NR f C(O)R g or none;
  • R t is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl optionally substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g , -NR f C(O)R g or none;
  • R s is selected from When m is 0, A is a ring selected from 0-4 R c optionally substituted 3- to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl 0-4 R c is optionally substituted; when m is 1,2,3,4,5,6, a ring is optionally selected from 0-4 R c substituted 3-6 membered cycloalkyl, optionally zero to four substituents R c 4 Metaheterocycloalkyl;
  • R f and R g are each independently selected from hydrogen, a C 1 -C 6 alkyl group optionally substituted by 0 to 4 R h , a benzene ring optionally substituted by 0 to 4 R i , and 0 to 4 R i is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R i optionally 3 to 6-membered cycloalkyl, optionally 0-4 R i is 3 to 6-membered heterocyclic ring alkyl;
  • R h is selected from the group consisting of halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R j , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i optionally substituted benzene ring, substituted with 0 to 4 R i optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R i is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R i ;
  • R i is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl, cyano;
  • R j and R k are each independently selected from hydrogen and a C 1 -C 6 alkyl group.
  • B ring is selected from C ring selected from
  • R 15 , R 16 , R 17 , R 15 ' , R 16 ' and R 17 ' are each independently selected from hydrogen, C 1 -C 6 alkyl, halogen-substituted C 1 -C 6 alkyl;
  • R 14 and R 14 ' are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R 11 and R 13 are each independently selected from the group consisting of hydrogen, -OR d , halogen, -CN, C(O)OR d , and C 1 -C 6 alkyl;
  • R 11 ' and R 13 ' are each independently selected from the group consisting of hydrogen, -OR d , halogen, -CN, C(O)OR d , C 1 -C 6 alkyl or none;
  • R 12 is selected from the group consisting of hydrogen and -C(O)NR a R b ;
  • R 12 ' is selected from hydrogen, -C(O)NR a R b or not;
  • R a , R b , and R d are each independently selected from hydrogen, C 1 -C 6 alkyl;
  • R t1 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl
  • R f is selected from hydrogen, substituted with 0 to 4 R h is an optionally substituted C 1 ⁇ C 6 alkyl, substituted with 0 to 4 R i optionally substituted benzene ring, substituted with 0 to 4 R i optionally substituted 5 to 6-membered aromatic heterocyclic ring, substituted with 0 to 4 R i optionally 3 to 6-membered cycloalkyl, substituted with 0 to 4 R i optionally substituted 3- to 6-membered heterocyclic group;
  • R h is selected from the group consisting of halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R j , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i optionally substituted benzene ring, substituted with 0 to 4 R i optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R i is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R i ;
  • R i is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl, cyano;
  • R j and R k are each independently selected from hydrogen, C 1 -C 6 alkyl
  • L is selected from the group consisting of C 4 to C 6 alkenylene groups.
  • B ring is selected from
  • Ring C is selected from 0 to 4 R 5 'is an optionally substituted benzene ring, substituted with 0 to 4 R 5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;
  • R 21 , R 23 , R 24 , R 25 , R 26 and R 27 are each independently selected from hydrogen, C 1 -C 6 alkyl;
  • R 22 is selected from the group consisting of -C(O)NR a R b , -C(O)OR d ;
  • R 21 ' , R 23 ' and R 5 ' are each independently selected from the group consisting of hydrogen, -OR d , -NR d R e , halogen, C 1 -C 6 alkyl;
  • R 24 ' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl
  • R a , R b , R d , R e are each independently selected from hydrogen, C 1 -C 6 alkyl;
  • R 22 ' is selected from the group consisting of hydrogen, -OR d , -NR d R e , halogen, -CN, C(O)OR d , C 1 -C 6 alkyl, -C(O)NR a R b ;
  • R t2 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl optionally substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -C(O) OR f , -CONR f R g , -NR f COR g ;
  • R f and R g are each independently selected from hydrogen, a C 1 -C 6 alkyl group optionally substituted by 0 to 4 R h , a benzene ring optionally substituted by 0 to 4 R i , and 0 to 4 R i is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R i optionally 3 to 6-membered cycloalkyl, optionally 0-4 R i is 3 to 6-membered heterocyclic ring alkyl;
  • R h is selected from the group consisting of halogen, -OR j , -NR j R k , -COR j , -CO 2 R j , -CONR j R k , -NR j COR k , benzene optionally substituted by 0 to 4 R i ring substituted with 0 to 4 R i optionally aromatic 5 to 6-membered heterocyclic ring, substituted with 0 to 4 R i optionally 3 to 6-membered cycloalkyl, optionally zero to four substituents R i 3- to 6-membered heterocycloalkyl;
  • R i is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl, cyano;
  • R j and R k are each independently selected from hydrogen, C 1 -C 6 alkyl
  • L is selected from R n 0-4 alkylene group optionally substituted with a C 4 ⁇ C 6, and 0 to 4 being optionally substituted with R n C 4 ⁇ C 6 alkenylene group, substituted with 0 to 4 R n optionally substituted C 4 -C 6 alkynylene; wherein optionally substituted C 4 -C 6 alkylene, optionally substituted C 4 -C 6 alkenylene, optionally substituted C The carbon atom in the alkynylene group of 4 to C 6 may be substituted by -O-, -S-, or -NR m - ;
  • R m is selected from the group consisting of hydrogen, C 1 -C 6 alkyl
  • R n is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl.
  • R 21 , R 23 , R 24 , and R 27 are each independently selected from hydrogen;
  • R 25 and R 26 are each independently selected from a C 1 -C 6 alkyl group
  • R a and R b are each independently selected from hydrogen
  • s 0, 1, 2, 3;
  • R 21 ' , R 23 ' and R 5 ' are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R 24' is selected from hydrogen
  • R 22 ' is selected from -C(O)NR a R b ;
  • R t2 is selected from the group consisting of hydrogen and -OR f ;
  • R f is selected from a C 1 -C 6 alkyl group optionally substituted by 0 to 4 R h , a 3 to 6 membered cycloalkyl group optionally substituted by 0 to 4 R i , and is optionally substituted with 0 to 4 R i a substituted 3-6-membered heterocycloalkyl group;
  • R h is selected from 0 to 4, optionally substituted with R i is 3 to 6-membered cycloalkyl, substituted with 0 to 4 R i optionally substituted 3- to 6-membered heterocyclic group;
  • R i is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl, cyano;
  • L is selected from 0-4 R n optionally substituted C 4 ⁇ C 6 alkylene group, and is substituted with 0 to 4 R n is C alkylene optionally substituted alkenyl group of 4 ⁇ C 6;
  • R n is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl.
  • R 21 , R 23 , R 24 and R 27 are each independently selected from hydrogen;
  • R 25 and R 26 are each independently selected from a C 1 -C 6 alkyl group
  • R 22 ' is selected from -C(O)NR a R b ;
  • R a and R b are each independently selected from hydrogen
  • X selects -C-, -O-, -NR z -, -S-;
  • R z is selected from the group consisting of hydrogen, C 1 -C 6 alkyl
  • n 0, 1, 2, 3, 4, 5, 6;
  • n 1, 2, 3, 4;
  • p 0, 1, 2, 3, 4.
  • R 21 , R 23 , R 24 and R 27 are each independently selected from hydrogen;
  • R 25 and R 26 are each independently selected from a C 1 -C 6 alkyl group
  • R a and R b are each independently selected from hydrogen.
  • B ring is selected from
  • a ring is selected from 0-4 optionally substituted by R c 3 to 6-membered cycloalkyl, substituted with 0 to 4 R c optionally having 3 to 6-membered heterocyclic group;
  • A is a ring selected from substituted with 0 to 4 R c optionally 3 to 6-membered cycloalkyl, substituted with 0-4 R c optionally 4-membered heterocycloalkyl;
  • R 31 , R 33 and R 34 are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
  • R 35 , R 36 and R 37 are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R 32 is selected from -CONR a R b ;
  • R a and R b are each independently selected from hydrogen, C 1 -C 6 alkyl
  • R d and R e are each independently selected from hydrogen, C 1 -C 6 alkyl
  • Ring C is selected from 0 to 4 R 5 'is an optionally substituted benzene ring, substituted with 0 to 4 R 5' is an optionally substituted 5 to 6 membered aromatic heterocyclic ring;
  • R 31 ' , R 33 ' and R 5 ' are each independently selected from the group consisting of hydrogen, -OR d , -NR d R e , halogen, C 1 -C 6 alkyl;
  • R 34 ' is selected from the group consisting of hydrogen and C 1 -C 6 alkyl
  • R 32 ' is selected from the group consisting of hydrogen, -OR d , -NR d R e , halogen, -CN, C(O)OR d , C 1 -C 6 alkyl, -C(O)NR a R b ;
  • R t3 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl optionally substituted by 0 to 4 R h , -OR f , -NR f R g , -C(O)R f , -CO 2 R f , -C(O)NR f R g , -NR f C(O)R g ;
  • R f and R g are each independently selected from hydrogen, a C 1 -C 6 alkyl group optionally substituted by 0 to 4 R h , a benzene ring optionally substituted by 0 to 4 R i , and 0 to 4 R i is an optionally substituted 5 to 6 membered aromatic heterocyclic ring, substituted with 0 to 4 substituents R i optionally 3 to 6-membered cycloalkyl, optionally 0-4 R i is 3 to 6-membered heterocyclic ring alkyl;
  • R h is selected from the group consisting of halogen, -OR j , -NR j R k , -C(O)R j , -CO 2 R j , -C(O)NR j R k , -NR j C(O)R k , substituted with 0 to 4 R i optionally substituted benzene ring, substituted with 0 to 4 R i optionally aromatic 5 to 6-membered heterocyclic ring, optionally zero to four R i is a substituted 3 to 6-membered cycloalkoxy a 3- to 6-membered heterocycloalkyl group optionally substituted by 0 to 4 R i ;
  • R i is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl, cyano;
  • R j and R k are each independently selected from hydrogen, C 1 -C 6 alkyl
  • L is selected from R n 0-4 alkylene group optionally substituted with a C 4 ⁇ C 6, and 0 to 4 being optionally substituted with R n C 4 ⁇ C 6 alkenylene group, substituted with 0 to 4 R n optionally substituted C 4 -C 6 alkynylene; wherein optionally substituted C 4 -C 6 alkylene, optionally substituted C 4 -C 6 alkenylene, optionally substituted C The carbon atom in the alkynylene group of 4 to C 6 may be substituted by -O-, -S-, or -NR m - ;
  • R m is selected from the group consisting of hydrogen, C 1 -C 6 alkyl
  • R n is selected from the group consisting of halogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, halogen-substituted C 1 -C 6 alkyl.
  • R 31 , R 33 and R 34 are each independently selected from hydrogen and halogen;
  • R 37 is independently selected from hydrogen
  • R 35 and R 36 are each independently selected from a C 1 -C 6 alkyl group
  • R a and R b are each independently selected from hydrogen
  • the A ring is selected from a 3- to 6-membered cycloalkyl group or a 4-membered heterocycloalkyl group optionally substituted by 0 to 4 R c ;
  • s 0, 1, 2, 3;
  • R 31 ' , R 33 ' and R 35 ' are each independently selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
  • R 34 ' is selected from hydrogen
  • R 32 ' is selected from -NR d R e , -C(O)NR a R b ;
  • R t3 is selected from the group consisting of hydrogen and -OR f ;
  • R f is selected from a C 1 -C 6 alkyl group optionally substituted by 0 to 4 R h , a 3 to 6 membered cycloalkyl group optionally substituted by 0 to 4 R i , and is optionally substituted with 0 to 4 R i a substituted 3-6-membered heterocycloalkyl group;
  • R h is selected from -OR j, substituted with 0 to 4 R i optionally 3 to 6-membered cycloalkyl, substituted with 0 to 4 R i optionally substituted 3- to 6-membered heterocyclic group;
  • L is selected from R n 0-4 alkylene optionally substituted C 4 ⁇ C 6, and is 0 to 4 R n is C alkylene optionally substituted alkenyl group of 4 ⁇ C 6.
  • R 31 , R 33 , R 34 and R 37 are each independently selected from hydrogen;
  • R 35 and R 36 are each independently selected from a C 1 -C 6 alkyl group
  • R a and R b are each independently selected from hydrogen
  • n 0, 1, 2, 3, 4, 5, 6;
  • n 0, 1, 2, 3;
  • p 0, 1, 2, 3, 4;
  • R d and R e are each independently selected from hydrogen and C 1 -C 6 alkyl.
  • R 31 , R 33 and R 34 are each independently selected from hydrogen and halogen
  • R 37 is independently selected from hydrogen
  • R 35 and R 36 are each independently selected from a C 1 -C 6 alkyl group
  • R a and R b are each independently selected from hydrogen
  • X selects -O-, -NR y -, -S-;
  • NR y is selected from the group consisting of hydrogen and C 1 -C 6 alkyl
  • p 0, 1, 2, 3, 4;
  • R d and R e are each independently selected from hydrogen and 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 medicament for activating STING .
  • 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, for the preparation of a disease associated with STING activity Use of the drug.
  • the disease associated with STING activity is one or more of diseases associated with inflammatory, autoimmune diseases, infectious diseases, cancer, precancerous syndrome.
  • 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 inflammatory, autoimmune Use in medicines for diseases, infectious diseases, cancer or precancerous syndrome.
  • 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, in the preparation of an immunoadjuvant.
  • the present invention also provides a drug which is a compound of the foregoing, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug thereof, or a metabolite thereof, A preparation prepared from a pharmaceutically acceptable excipient.
  • 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 disease 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.
  • 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 present invention discloses a compound of the formula I, and discloses the use of the compound for the preparation of a medicament for treating a disease associated with STING activity, in particular for the preparation of a medicament for the treatment of inflammatory, allergic, autoimmune diseases, infectious diseases Use in drugs for cancer, cancer or precancerous syndrome, and in the preparation of immunological adjuvants.
  • a new option for drugs for clinical screening and/or preparation of diseases associated with STING activity is provided.
  • Figure 1 is a graph showing the effect of different concentrations of the compounds prepared in Example 2 on CT-26 tumor volume.
  • Figure 2 is a graph showing the effect of the compound prepared in Example 2 at a concentration of 1 mg/kg on the CT-26 tumor volume.
  • the raw materials and equipment used in the specific embodiments of the present invention are known products and are obtained by purchasing commercially available products.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS).
  • NMR shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD).
  • the internal standard is tetramethylsilane (TMS).
  • the LC-MS was measured by 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.
  • the overnight stay was 12 ⁇ 1 h.
  • PE petroleum ether
  • EA means ethyl acetate
  • DCM means dichloromethane
  • MeOH means methanol
  • DMF means N,N-dimethylformamide
  • DMSO means dimethyl sulfoxide
  • DMAP means 4-dimethylaminopyridine
  • DIPEA means diisopropylethylamine
  • Boc means t-butyloxycarbonyl
  • TFA means trifluoroacetic acid
  • DBU means 1,8-diazabicycloundecene- 7-ene
  • HATU means 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.
  • Step 1 Synthesis of (trans)-tert-butyl(4-(4-carbamoyl-2-methoxy-6-nitrophenyl)amino)-n-but-2-enyl)carbamate
  • Step 2 Synthesis of (trans)-tert-butyl(4-((2amino-4carbamoyl-6-methoxyphenyl)amino)-n-but-2-enyl)carbamate
  • Step 3 (trans)-tert-Butyl (4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-methoxy Synthesis of -1H-benzimidazolyl)-n-but-2-enyl)carbamate
  • Step 4 (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of methoxy-l-hydrogen-benzimidazole-5-carboxamide
  • Step 5 (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-yloxy)phenyl)amino)-n-but-2- Synthesis of alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • Step 6 (trans)-1-(4-(2-Amino-4-carboxamido-6-(oxetan-3-yloxy)phenyl)-n-but-2-enyl) Synthesis of -2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • aqueous ammonia (0.08 mL, 0.56 mmol) was added dropwise to a solution of compound 1f (38 mg, 0.05 mmol) in methanol (5 mL), and the mixture was stirred for 5 min. The aqueous solution (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 h. Diluted with water, filtered, and the filtrate was evaporated to dryness.
  • Step 7 (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxa) Synthesis of cyclobutane-3-yloxy)phenyl)-1hydro-imidazole-5-carboxamide-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • Step 1 (trans)-tert-butyl(4-(4-carbamoyl-2-oxetanyloxy-6-nitrophenyl)amino)n-but-2-enyl)aminocarbyl Acid ester synthesis
  • Step 3 (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-oxocycle Synthesis of butanoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate
  • Step 4 (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of -oxetanyloxy-1hydro-benzimidazole-5-carboxamide
  • Step 5 (trans)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)-n-but-2-enyl)-2-(1-ethyl-3-A Synthesis of yl-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide
  • Step 6 (trans)-1-(4-(2-amino-4-carboxamidophenyl)-n-but-2-enyl)-2-(1-ethyl-3-methyl-1 hydrogen Synthesis of pyrazole-5-carboxamido-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide
  • aqueous ammonia (0.17 mL, 1.3 mmol) was added dropwise to a solution of compound 2f (80 mg, 0.13 mmol) in methanol (5 mL), and the mixture was stirred for 5 min. The aqueous solution (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirred for 1 h.
  • Step 7 (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[ d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxyheterocycle Synthesis of butane-3-yloxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 (trans)-tert-butyl(4-(4-carbamoyl-2-cyclopropylmethoxy-6-nitrophenyl)amino)-n-but-2-enyl)carbamic acid Ester synthesis
  • Step 2 Synthesis of (trans)-tert-butyl(4-((2amino-4carbamoyl-6cyclopropylmethoxyphenyl)amino)-n-but-2-enyl)carbamate
  • Step 3 (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-cyclopropyl Synthesis of methoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate
  • Step 4 (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 -Synthesis of cyclopropylmethoxy-1hydro-benzimidazole-5-carboxamide
  • Step 5 (trans)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropyl
  • (trans)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropyl A Synthesis of oxy)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide
  • Step 6 (trans)-1-(4-((4-carbamoyl-2-aminophenyl)amino)butyl-2-en-1-yl)-7-(cyclopropyl A Synthesis of oxy)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide
  • aqueous ammonia (0.5 mL, 4.87 mmol) was added dropwise to a solution of compound 3f (300 mg, 0.487 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL), and the mixture was stirred for 5 min. (425 mg, 2.44 mmol) aqueous solution (3 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was spun dry.
  • Step 7 (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxa) Synthesis of cyclobutane-3-yloxy)phenyl)-1hydro-imidazole-5-carboxamide-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • Step 1 (trans)-1-(4-((4-carbamoyl-2-nitro-6(oxetan-3-methyloxy)phenyl)amino)-n-butyl-2 Synthesis of 2-alkenyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • Step 2 (trans)-1-(4-(2-Amino-4-carboxamido-6-(oxetan-3-methyloxy)phenyl)-n-but-2-enyl Synthesis of 2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • aqueous ammonia (0.43 mL, 3.0 mmol) was added dropwise to a solution of Compound 4a (180 mg, 0.05 mmol) in methanol (5 mL). The mixture was stirred for 5 min. The aqueous solution (5 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 h.
  • Step 3 (trans)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxa) Synthesis of cyclobutane-3-methyloxy)phenyl)-1hydro-imidazole-5-carboxamide-7-methoxy-1hydro-benzimidazole-5-carboxamide
  • Example Compound 4 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-yl) Oxy)phenyl)-1 hydrogen-imidazole-5-carboxamide)-7-methoxy-1 hydrogen-benzimidazole-5-carboxamide (Example Compound 4) (39 mg, yield 31%) White solid.
  • Step 1 Synthesis of ethyl 3-(toluenesulfonyloxy)cyclobutanecarboxylate
  • Step 2 Synthesis of ethyl 3-(5-carbamoyl-2-chloro-3-nitrophenoxy)cyclobutanecarboxylate
  • Step 3 (E)-3-(5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[[d]imidazol-1-yl)but-2-en-1-yl)amino)-3-nitrophenoxy)cyclobutanecarboxylic acid Synthesis of ethyl ester
  • Step 4 (E)-3-(3-Amino-5-carbamoyl-2-((4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole) -5-formylamino)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)phenoxy)cyclobutanecarboxylate Synthesis
  • aqueous ammonia (0.3 mL, 2.0 mmol) was added dropwise to a solution of compound 5d (143 mg, 0.20 mmol) in methanol (5 mL), and the mixture was stirred for 5 min. The aqueous solution (2 mL) was slowly added. The reaction mixture was slowly warmed to room temperature and stirring was continued for 3 h.
  • Step 5 (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H- Synthesis of Ethyl Pyrazole-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylate
  • Step 1 (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridyl Synthesis of oxazol-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylic acid
  • Step 1 (E)-3-((5-carbamoyl-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Amido)-7-methoxy-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyridyl Synthesis of Isoazol-5-carboxamido)-1H-benzo[d]imidazol-7-yl)oxy)cyclobutanecarboxylic acid isopropyl ester
  • Step 1 (S,E)-(4-((4-carbamoyl-2-nitro-6-((tetrahydrofuran-3-yl)oxy)phenyl)amino)but-2-ene-1 Synthesis of tert-butyl carbamate
  • Step 2 (S,E)-(4-((2-Amino-4-carbamoyl-6-((tetrahydrofuran-3-yl)oxy)phenyl)amino)but-2-en-1- Synthesis of tert-butyl carbamate
  • Step 3 ((S,E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-7-((tetrahydrofuran) Synthesis of tert-butyl ester of -3-yl)oxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-ylcarbamate
  • Step 4 (S,E)-1-(4-Aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide) Synthesis of -7-((tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 5 (S,E)-1-(4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)-2-(1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-carboxamido)-7-((tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 6 (S,E)-1-(4-((2-Amino-4-carbamoylphenyl)amino)but-2-en-1-yl)-2-(1-ethyl-3 Synthesis of -methyl-1H-pyrazole-5-carboxamido)-7-((tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 7 (S,E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo [d]imidazol-1-yl)butyr-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(( Synthesis of Tetrahydrofuran-3-yl)oxy)-1H-benzo[d]imidazole-5-carboxamide
  • Example 9 The starting material used in Example 9 was the reverse of the configuration of Example 8 as (S)-3-hydroxytetrahydrofuran, and the operation of the experimental procedure was the same. Finally, Example Compound 9 (25.5 mg) was obtained.
  • Step 1 (E)-1-(4-((2-Nitro-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl) Amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)- Synthesis of 1H-benzo[d]imidazole-5-carboxamide
  • Step 2 (E)-1-(4-((2-Amino-6-(3-((tert-butyldimethylsilyl)oxy)propoxy)-4-carbamoylphenyl) Amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H -Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 3 (E)-7-(3-((tert-Butyldimethylsilyl)oxy)propoxy)-1-(4-(5-carbamoyl-7-(cyclopropyl) Oxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-1H-benzo[d]imidazol-1-yl)but-2-ene-1- Synthesis of 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H--benzo[d]imidazole-5-carboxamide
  • Step 4 (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-7-(3-hydroxyl) Propoxy)-1H-benzo[d]imidazolazine-1-yl)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl- Synthesis of 3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 Synthesis of (E)-(4-((4-carbamoyl-2-nitrophenyl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester
  • Step 2 Synthesis of (E)-(4-((2-amino-4-carbamoylphenyl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester
  • Step 3 (E)-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole Synthesis of -1-yl)but-2-en-1-yl)carbamic acid tert-butyl ester
  • Step 4 (E)-1-(4-Aminobut-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H -Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 5 (E)-1-(4-((4-carbamoyl-2-nitro-6-(2-(oxetan-3-yl)ethoxy)phenyl)amino)) But-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide synthesis
  • Step 6 (E)-1-(4-((2-Amino-4-carbamoyl-6-(2-(oxetan-3-yl)ethoxy)phenyl)amino) Synthesis of 2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide
  • Step 7 (E)-1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d] Imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(2-(oxygen) Synthesis of Heterocyclobutane-3-yl)ethoxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 Synthesis of tert-butyl (4-fluoro-3-nitrophenyl)carbamate
  • Step 2 (E)-(4-((4-(5-carbamoyl-7-(cyclopropylmethoxy))-2-(1-ethyl-3-methyl-1H-pyrazole- Synthesis of tert-butyl 5-formylamino)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)-3-nitrophenyl)carbamate
  • Step 3 (E)-(3-Amino-4-((4-(5-carbamoyl-7-(cyclopropylmethoxy))-2-(1-ethyl-3-methyl-1H) Synthesis of tert-butyl ester of pyrazole-5-formylamino)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)amino)phenyl)carbamate
  • Step 4 (E)-(1-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5) -carboxamide)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Synthesis of Formamide--1H-Benzo[d]imidazol-5-yl)carbamic acid tert-butyl ester
  • Step 5 (E)-1-(4-(5-Amino-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole -1-yl)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide Synthesis of -1H-benzo[d]imidazole-5-carboxamide
  • Step 1 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-1 -yl)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(oxetan-3-yloxy)-1H- Synthesis of benzo[d]imidazole-5-carboxamide
  • Step 1 1-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-1 -yl)butyl)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d] Synthesis of imidazole-5-carboxamide
  • Step 1 trans-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-((3) Synthesis of 1-nitropyridin-2-yl)amino)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide
  • Step 2 (E)-1-(4-((3-Aminopyridin-2-yl)amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-( Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide
  • Step 3 (E)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2) -(1-ethyl-3-methyl-1H-pyrazole-5-formylamino)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl Synthesis of -1H-benzo[d]imidazole-5-carboxamide
  • Step 1 Synthesis of (E)-(4-((3-nitropyridin-2-yl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester
  • Step 2 Synthesis of (E)-(4-((3-aminopyridin-2-yl)amino)but-2-en-1-yl)carbamic acid tert-butyl ester
  • Step 5 (E)-N-(3-(4-((4-carbamoyl)-2-(2-methoxyethoxy)-6-nitrophenyl)amino)but-2-ene Synthesis of -1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 6 (E)-N-(3-(4-((2-Amino-4-phenyl)-6-(2-methoxyethoxy)phenyl)amino)but-2-ene- Synthesis of 1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 7 (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(2-methoxy
  • B Synthesis of oxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 (E)-N-(3-(4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)but-2-en-1-yl)-3H Synthesis of imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 2 (E)-N-(3-(4-((2-Amino-4-carbamoyl-6-methoxyphenyl)amino)but-2-en-1-yl)-3H- Synthesis of Imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 1 (E)-N-(3-(4-((4-carbamoyl-2-nitro-6-(oxetan-3-yloxy)phenyl)amino))- Synthesis of 2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 2 ((E)-N-(3-(4-((2-Amino-4-carbamoyl-6-(oxetan-3-yloxy)phenyl)amino))- Synthesis of 2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 3 ((E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-) -1H-pyrazole-5-carboxamido)--3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(oxeidine Synthesis of alk-3-yloxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 (E)-N-(3-(4-((4-carbamoyl-2-nitro-6-(oxetan-3-ylmethoxy)phenyl)amino)) Synthesis of 2--2-enyl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • Step 2 (E)-N-(3-(4-((2-Amino-4-carbamoyl-6-(oxetan-3-ylmethoxy)phenyl)amino))- Synthesis of 2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5-carboxamide
  • aqueous ammonia (0.2 mL, 1.94 mmol) was added dropwise to a solution of compound 19a (100 mg, 0.169 mmol) in methanol (1 mL) and tetrahydrofuran (1 mL). After 5 min, sodium dithionite (100 mg, 0.568 mmol) The aqueous solution (1 mL) was added slowly. The reaction mixture was slowly warmed to room temperature and stirring was continued for 1 h. Diluted with water, filtered, and the filtrate was evaporated to dryness.
  • Step 3 (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(oxetane- Synthesis of 3-ylmethoxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 (E)-N-(3-(4-((4-carboyl-2-nitro-6-(2-(oxetan-3-yl)ethoxy)phenyl) Amino)but-2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5- Amide synthesis
  • Step 2 ((E)-N-(3-(4-((2-Amino-4-carbamoyl-6-(2-(oxetan-3-yl)ethoxy)phenyl) Amino)but-2-en-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)-1-ethyl-3-methyl-1H-pyrazole-5- Amide synthesis
  • Step 3 (E)-2-(1-Ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2-(1-ethyl-3-methyl) -1H-pyrazole-5-carboxamido)-3H-imidazo[4,5-b]pyridin-3-yl)but-2-en-1-yl)-7-(2-(oxo-heterocycle) Synthesis of butane-3-yl)ethoxy)-1H-benzo[d]imidazole-5-carboxamide
  • Step 1 (E)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(( Synthesis of 2-nitropyridin-3-yl)amino)but-2-en-1-yl)-1H-benzo[d]imidazole-5-carboxamide
  • Step 2 (E)-1-(4-((2-Aminopyridin-3-yl)amino)but-2-en-1-yl)-7-(cyclopropylmethoxy)-2-( Synthesis of 1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-benzo[d]imidazole-5-carboxamide
  • Step 3 (E)-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(4-(2) -(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1H-imidazo[4,5-b]pyridin-1-yl)but-2-en-1-yl Synthesis of -1H-benzo[d]imidazole-5-carboxamide
  • Oxalyl chloride (3.4 mL, 40 mmol) was added dropwise to a solution of the crude compound 22b (2.5 g, 13.4 mmol, 60% purity) in dichloromethane, and then DMF (200 uL). After stirring for 2 h in an ice bath. The reaction solution was sparged under reduced pressure, and the residue after spin-drying was dissolved in dichloromethane, and then this dichloromethane solution was added to anhydrous methanol. It was then stirred at room temperature for 1.5 h. Diluted with water and extracted with ethyl acetate (10 mL ⁇ 3). The organic phase was washed with brine (10 mL ⁇ 1), dried over anhydrous sodium sulfate and evaporated to dryness.
  • HNO 3 (1.3 mL) was added dropwise to a solution of compound 6-chloro-2-methoxynicotinic acid methyl ester (1.3 g, 6.5 mmol) in trifluoroacetic acid anhydride (40 mL). Stir in an ice salt bath for 3 h. The reaction solution was slowly poured into ice water, and the pH was adjusted to 7-8 with saturated sodium carbonate to precipitate a yellow solid.
  • Step 4 E)-6-((4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Synthesis of Methylcarboxamide)-1H-benzo[d]imidazole-piperazin-1-yl)but-2-en-1-yl)amino)-2-methoxy-5-nitronicotinate
  • Methyl 6-chloro-2-methoxy-5-nitronicotinate (330 mg, 1.3 mmol) was added to a solution of compound 1e (604 mg, 1.3 mmol) and DIPEA (503 mg, 3.9 mmol) in DMF (10 mL) The reaction mixture was stirred at room temperature for 2 h.
  • Step 5 (E)-5-Amino-6-((4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-) Synthesis of pyrazole-5-carboxamido)-1H-benzo[methyl]d]imidazol-1-yl)but-2-en-1-yl)amino)-2-methoxynicotinate
  • Step 6 (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Formamide)-1H-benzo[d]imidazol-1-methyl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5 Synthesis of methyl 3-formylamino)-5-methoxy-3H-imidazo[4,5-b]pyridine-6-carboxylate
  • Step 7 (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Formamide)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-A Synthesis of Amido)-5-Methoxy-3H-imidazo[4,5-b]pyridine-6-carboxylic Acid
  • the compound 22h (70mg, 0.09mmol) was dissolved in a mixed solvent of THF (1mL) and methanol (1mL), and a solution of lithium hydroxide (19mg, 0.81mmol) was added at room temperature, stirred at room temperature for 1h, and the reaction solution was added.
  • Step 8 (E)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-) Formamide)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-A Synthesis of Amido)-5-Methoxy-3H-imidazo[4,5-b]pyridine-6--carboxamide
  • Step 2 (trans)-tert-butyl(4-((2-amino-4carbamoyl-6cyclopropylmethoxyphenyl)amino)-n-but-2-enyl)carbamate (compound) Synthesis of 23c)
  • Aqueous ammonia (1.62 mL, 11.80 mmol) was added to a solution of compound 23b (670 mg, 1. After 5 min, an aqueous solution (6 mL) of sodium dithionite (1.22 g, 7.01 mmol) was slowly added dropwise. After 1 h of reaction, the color of the reaction solution changed from orange-red to white. The reaction solution was stirred with methanol, then diluted with water, and extracted with ethyl acetate (30 mL ⁇ 4).
  • Step 3 (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-cyclopropyl Synthesis of methoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (Compound 23d)
  • Step 4 (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of cyclopropylmethoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 23e)
  • Step 5 (trans)-1-(6-((5-nitro-nicotinate methyl)amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy) Synthesis of -2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide (Compound 23f)
  • Step 6 (trans)-1-(6-((5-Amino-methylnicotinate)amino)butyl-2-en-1-yl)-7-(cyclopropylmethoxy) Synthesis of -2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-1hydro-benzo[d]imidazole-5-carboxamide (Compound 23g)
  • Step 7 (trans)-methyl-3-(4-(5-aminoformyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen) -pyrazole-5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1 Synthesis of Hydrogen-pyrazole-5-aminoformyl)-3hydro-imidazole [4,5-pyro]pyridine-6-methyl carbonate (Compound 23h)
  • Step 8 (trans)-3-(4-(5-carbamoyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole- 5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole Synthesis of 5-5-carboxamido)-3hydro-imidazole [4,5-pyro]pyridine-6-carboxylic acid (Compound 23i)
  • Step 9 (trans)-3-(4-(5-aminoformyl-7-(cyclopropylmethoxy)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole) -5-carboxamido)-1hydro-benzene[and]imidazol-1-yl)butyl-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyridyl Synthesis of oxazol-5-carboxamido)-3hydro-imidazole [4,5-pyro]pyridine-6-carboxamide (Compound 23)
  • Step 1 (trans)-methyl-6-((4-((tert-butoxycarbonyl)amino)-n-but-2-yl-1-yl)amino)-5-nitronicotinic acid (Compound 24b) )Synthesis
  • Step 2 Synthesis of (trans)-6-((4-((tert-butoxycarbonyl)amino)-n-but-2-en-1-yl)amino)-5-nitronicotinic acid (Compound 24c)
  • HATU 1406 mg, 3.7 mmol
  • DMF DMF
  • ammonium chloride 900 mg, 18.45 mmol
  • N,N- Diisopropylethylamine 1439 mg, 11.07 mmol
  • the reaction mixture was diluted with water and extracted with ethyl acetate (200 mL ⁇ 3).
  • Step 4 (trans)-tert-butyl(4-((3-amino-5-carbamoylpyridin-2-yl)amino)butyl-2-en-1-yl)carbamate (compound) Synthesis of 24f)
  • Step 5 (trans)-tert-butyl (4-(6-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-3 hydrogen-imidazole) Synthesis of [4,5-and]pyridin-3-yl)butyl-2-en-1-yl)carbamate (Compound 24g)
  • Step 6 (trans)-3-(4-aminobutyric-2-en-1-yl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carbamoyl Synthesis of -3 hydrogen-imidazole [4,5-pyro]pyridine-6-carbamate (compound 24h)
  • Step 7 (trans)-3-(4-((4-carbamoyl-2-nitrophenyl)amino)-n-but-2-en-1-yl)-2-(1-ethyl- Synthesis of 3-methyl-1hydro-pyrazol-5-carbamoyl)-3hydro-imidazole [4,5-pyro]pyridine-6-carbamate (Compound 24i)
  • Step 8 (trans)-3-(4-((2-amino-4-carbamoylphenyl)amino)-n-but-2-en-1-yl)-2-(1-ethyl-3 Synthesis of -methyl-1 -hydropyrazol-5-carbamoyl)-3hydro-imidazole [4,5-pyro]pyridine-6-carbamate (Compound 24j)
  • Step 9 (trans)-3-(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-1 hydrogen-benzene [ And] imidazol-1-yl)n-but-2-en-1-yl)-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-3 hydrogen-imidazole [ Synthesis of 4,5-and]pyridine-6-carbamate (Compound 24)
  • Step 1 (trans)-tert-butyl(4-(4-carbamoyl-2-oxetanyloxy-6-nitrophenyl)amino)n-but-2-enyl)aminocarbyl Synthesis of acid ester (compound 25b)
  • Step 3 (trans)-tert-butyl(4-(5-carbamoyl-2-(1-ethyl-3-methyl-1 hydrogen-pyrazole-5-carboxamide)-7-oxocycle Synthesis of butanoxy-1H-benzimidazolyl)-n-but-2-enyl)carbamate (Compound 25d)
  • Step 4 (trans)-1-(4-amino-n-but-2-enyl)-2-(1-ethyl-3-methyl-1hydro-pyrazole-5-carboxamido)-7 Synthesis of oxetaneoxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25e)
  • Step 5 (trans)-1-(6-((3-nicotinic acid methyl ester-5-nitropyridine)amino)-n-but-2-enyl)-2-(1-ethyl-3- Methyl-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (compound 25f)
  • Step 6 (trans)-1-(6-((3-nicotinic acid methyl ester-5-aminopyridine)amino)-n-but-2-enyl)-2-(1-ethyl-3-methyl Base-1 hydrogen-pyrazole-5-carboxamido)-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (compound 25g)
  • Step 7 (trans)-1-(6-(3-nicotinylmethyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-pyridine Synthesis of 1-hydrogen-imidazole-5-carboxamide-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide (Compound 25h)
  • Step 8 (trans)-1-(6-(3-carboxylic acid-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-pyridine)-1 Synthesis of hydrogen-imidazole-5-carboxamide-7-oxetanyloxy-1 hydrogen-benzimidazole-5-carboxamide (Compound 25i)
  • the compound 25h (86mg, 0.11mmol) was dissolved in a mixed solvent of THF (2mL) and methanol (2mL), and a solution of lithium hydroxide (9mg, 0.22mmol) was added at room temperature, stirred at room temperature for 1h, and the reaction solution was added 1N.
  • Step 9 (trans)-1-(6-(3-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-pyridine)- Synthesis of 1H-imidazole-5-carboxamide-7-oxetanyloxy-1hydro-benzimidazole-5-carboxamide (Compound 25)
  • the dissolution profile of the protein was determined on a qPCR instrument, and the Tm value was fitted using Protein Thermal Shift Software 1.3 software to calculate the difference in Tm of the protein when different concentrations of the compound were added and when no compound was added, and Kd was fitted according to the change in the concentration of the compound according to ⁇ Tm.
  • the maximum right shift ⁇ Tm of the compound of Example 1 of the present invention was 9.6 °C.
  • test results indicate that the compound of the present invention can interact with STING and may be used for the preparation of a medicament for regulating diseases associated with STING activity.
  • 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.
  • test results indicate that the compound prepared by the present invention has an activating effect on STING and can be used for the preparation of a drug that activates STING or a disease associated with STING activity.
  • CT-26 colon cancer homologous mouse model CT-26 colon cancer cells were inoculated into Balb/C mice, and the compounds prepared in Example 2 were sequentially administered intratumorally for three times on the first, fourth, and seventh days after the tumor volume reached 100 mm 3 .
  • the doses administered per group were 0.01 mg per mouse, 0.03 mg per mouse, and 0.1 mg per mouse. Measurement of tumor volume was performed at the beginning of treatment. After the start of dosing, the mouse tumor gradually subsided to completely disappear. The result is shown in Figure 1.
  • CT-26 colon cancer homologous mouse model CT-26 colon cancer cells were inoculated into Balb/C mice, and 1 mg/kg of the compound prepared in Example 2 was intraperitoneally administered every two days after the tumor volume reached 100 mm 3 , and ML-RR-S2CDA was used as a control. Measurement of tumor volume was performed at the beginning of treatment. After the start of administration, the tumor growth rate of the mice was slowed, and on the 29th day, the tumor growth inhibition was 89%. The results are shown in Figure 2.
  • ADU-S100 is a clinical compound of Aduro Biotech.
  • the present invention discloses a compound of the formula I, and discloses the use of the compound for the preparation of a medicament for treating a disease associated with STING activity, in particular for the preparation of a therapeutic inflammatory, allergic, autoimmune disease, Use in drugs for infectious diseases, cancer or precancerous syndrome, and in the preparation of immunological adjuvants.
  • a new option for drugs for clinical screening and/or preparation of diseases associated with STING activity is provided.

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Abstract

Font l'objet de la présente invention un agent immunomodulateur et, plus particulièrement, un composé activant STING et ses utilisations, ce dernier agissant comme agent immunomodulateur dans la préparation d'un médicament. Fait aussi l'objet de la présente invention un composé représenté par la formule I ou son stéréo-isomère, ou encore son sel pharmaceutiquement acceptable, son solvate, son promédicament ou l'utilisation d'un métabolite dans la préparation d'un médicament activant STING, ledit composé offrant de nouvelles perspectives pour le criblage clinique et/ou la préparation d'un médicament pour le traitement de maladies associées à STING. (I)
PCT/CN2019/070743 2018-01-08 2019-01-08 Immunomodulateur WO2019134705A1 (fr)

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CN115181117A (zh) * 2022-08-08 2022-10-14 中国医学科学院医学生物学研究所 一种s构型手性分子化合物及其制备方法和作为疫苗佐剂的应用
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CN114163420A (zh) * 2021-10-26 2022-03-11 中山大学附属第一医院 一种内质网高尔基体靶向小分子、偶联物及其应用
CN115181117A (zh) * 2022-08-08 2022-10-14 中国医学科学院医学生物学研究所 一种s构型手性分子化合物及其制备方法和作为疫苗佐剂的应用
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