Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/06—Peri-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/06—Peri-condensed systems

Definitions

• the present invention belongs to the filed of medicine and in particular relates to new tricyclic compounds as agonists of stimulator of interferon genes (STING) useful for the treatment of STING-mediated diseases or disorders, and preparation methods thereof.
• STING stimulator of interferon genes
• Innate immunity has no antigen specificity and executes the defense mechanisms immediately after an antigen's appearance in the body.
• Adaptive immunity requires time to generate a full response, but it is antigen- specific and long lasting.
• the adaptive immune system utilizes a set of immune cells specifically designed to attack that antigen. During the course of an adaptive immune response, memory immune cells are generated which allow for a more rapid and effective response to re-exposure to antigens.
• the innate immune system is required to activate our adaptive immune system. Numerous molecules and cells involved in innate immunity and adaptive immunity function cooperatively ( Shanker A. and Marincola F., Cancer Immunol. Immunother., 2011, 60: 1061-1074).
• PAMPs pathogen-associated molecular patterns
• PRRs pattern recognition receptors
• DAMPs damage-associated molecular patterns
• the free cytosolic DNA from pathogens and abnormal cells can be recognized by DNA sensors.
• cGAS cyclic GMP-AMP Synthase
• Stimulator of interferon genes is a signaling molecule associated with the endoplasmic reticulum (ER).
• ER endoplasmic reticulum
• CDNs cyclic dinucleotides
• c-di-AMP bacterial cyclic di- AMP
• c-di-GMP c-di-GMP
• TBK1 also phosphorylates residues on the protein I/cB, leading to its degradation, which causes the activation and translocation of NF-/cB to the nucleus and the transcription of pro-inflammatory cytokines such as TNFa, IL-6 and IL-Ib (Aim J. and Barber G., Current Opinion in Immunology 2014, 31:121-126).
• STING-dependent signaling is critical in promoting antitumor immunity.
• STING deficient mice have decreased tumor rejection observed when compared with wild type mice (Woo S. et al, Immunity, 2014, 41:830-842). Activation of STING significantly suppressed the growth of multiple types of mouse tumors (Corrales et al, Cell Reports, 2015, 11:1018-1030).
• type I IFNs IFNa/b
• IFNa/b type I IFNs
• IFNa/b receptor activates a cascade of events and induces the transcription of a wide variety of genes regulated by IFN-stimulated response elements (ISRE), thus modulating multiple types of immune cells.
• IFN-stimulated response elements IFN-stimulated response elements
• Type I IFNs contribute to antitumor immunity in various types of cancer (Parker B. etal, Nat Rev Cancer, 2016, 16:131- 144). TNFa may be another important contributor to the therapeutic effect observed with the activation of STING (Francica B. et al, Cancer Immunol Res., 2018, 6: 1-12).
• the antitumor function of STING signaling has been well-established.
• the compounds of this invention stimulate the function of STING and accordingly may have a beneficial impact on cancer therapy.
• the present invention in one aspect, provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis- or trans isomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof:
• G 1 , G 2 , G la and G 2a are identical or different, and each is independently N or CR 6 ;
• G 3 and G 3a are identical or different, and each is independently O, NR S , or CR 7 R 8 ;
• L is selected from the group consisting of alkylene, alkenylene, alkynylene, alkylene- Q-alkylene, alkylene-O-alkylene, alkylene-NH-alkylene, alkylene-S(0) m -alkylene, alkylene- C(0)-alkylene, alkylene-C(0)NH-alkylene, alkylene-NHC(0)-alkylene, and alkylene- HNC(0)NH-alkylene, wherein the alkylene, alkenylene, and alkynylene each is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R c is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl;
• R s is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkenyl; wherein the alkyl, cycloalkyl or alkenyl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 3 , R 4 , R 3a and R 4a are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 5 and R 5a are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, and cyano;
• R 6 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 7 and R 8 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 9 and R 10 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R m is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• Q is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; m is 0, 1 or 2;
• n 0, 1, 2 or 3;
• s 0, 1, 2 or 3.
• the present invention provides a pharmaceutical composition, comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.
• the present invention provides a method for treating a STING- mediated disease or disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodmg thereof.
• the present invention relates to use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodmg thereof, in the manufacture of a medicament for treatment of a STING-mediated disease or disorder, wherein the disease or disorder is selected from a cancer, a pre-cancerous syndrome, and viral infections, preferably a cancer and a pre-cancerous syndrome.
• this invention provides a method for preparing a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodmg thereof, the method comprising a step of reacting a compound of formula (IA) with a compound of formula (IB) to obtain the compound of formula (I):
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 1 to R 5 , R la to R 5a , R c , G 1 to G 3 , G la to G 3a , n and s are each as defined in formula (I).
• this invention provides a method for preparing a compound of formula (IG), or a pharmaceutically acceptable salt, solvate, or prodmg thereof, the method comprising a step of reacting a compound of formula (IK) with a compound of NHR 9 R 10 to obtain the compound of formula (I):
• R m is hydrogen or alkyl
• R 2 to R 4 , R 2a to R 4a , G 3 , G 3a , R 9 , R 10 , n and s are each as defined in formula (IG).
• this invention provides a compound of formula (IA) or (IB), used as an intermediate for preparing the compound of formula (I) :
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 1 to R 5 , R la to R 5a , R c , G 1 to G 3 , G la to G 3a , n and s are each as defined in formula (I).
• the present invention relates to a new class of tricyclic compounds useful as STING agonists, preparation methods thereof, and their use as therapeutic agents for treatment of STING- mediated diseases or disorders.
• the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, including tautomers, cis- or trans isomers, mesomers, racemates, enantiomers, diastereomers, and mixtures thereof:
• G 1 , G 2 , G la and G 2a are identical or different, and each is independently N or CR 6 ;
• G 3 and G 3a are identical or different, and each is independently O, NR S , or CR 7 R 8 ;
• L is selected from the group consisting of alkylene, alkenylene, alkynylene, alkylene- Q-alkylene, alkylene-O-alkylene, alkylene-NH-alkylene, a]kylene-S(0) m -aIkylene, alkylene- C(0)-alkylene, alkylene-C(0)NH-alkylene, alkylene-NHC(0)-alkylene, and alkylene- HNC(0)NH-alkylene, wherein the alkylene, alkenylene, and alkynylene each is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R c is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkenyl, and alkynyl;
• R s is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkenyl; wherein the alkyl, cycloalkyl or alkenyl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; R 1 and R la are identical or different, and each is independently selected from the group consisting of -C(0)NR 9 R 10 , -C(0)OR m , hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy,
• R 2 and R 2a are identical or different, and each is independently selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 3 , R 4 , R 3a and R 4a are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 5 and R 5a are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, and cyano;
• R 6 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 7 and R 8 are identical or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R 9 and R 10 are identical or different, and each is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• R m is selected from the group consisting of hydrogen, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• Q is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; m is 0, 1 or 2;
• n 0, 1, 2 or 3;
• s 0, 1, 2 or 3.
• L is selected from the group consisting of alkylene, alkenylene, alkynylene, alkylene-O-alkylene, alkylene-NH-alkylene, alkylene-S(0) m -alkylene, alkylene-C(0)-alkylene, alkylene- C(0)NH- alkylene, alkylene-NHC(0)-alkylene, and alkylene-HNC(0)NH-aIkylene, wherein the alkylene or alkenylene each is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino
• R 1 and R la are identical or different, and each is independently selected from the group consisting of - C(0)NR 9 R 10 , -C(0)OR m , hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alk
• the compound of formula (I) is a compound of formula (IM),
• R 1 to R 5 , R la to R 5a , R c , G 1 to G 3 , G la to G 3a , L, n and s are each as defined in formula
• the compound of formula (I), when R c is hydrogen, is a compound of formula (G),
• R 1 to R 5 , R la to R 5a , G 1 to G 3 , G la to G 3a , L, n and s are each as defined in formula (I).
• the compound of formula (I), when R c is hydrogen, is selected from a compound of formula (I”),
• R 1 to R 5 , R la to R 5a , G 1 to G 3 , G la to G 3a , L, n and s are each as defined in formula (I).
• G 1 , G 2 , G la and G 2a are identical or different, and each is CR 6 , wherein R 6 is as defined in formula (I).
• R 2 and R 2a are identical or different, and each is independently selected from the group consisting of aryl and heteroaryl; wherein the aryl or heteroaryl is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
• R 5 and R 5a are each hydrogen.
• the compound of formula (I) is a compound of formula (II),
• ring A is selected from the group consisting of aryl and heteroaryl
• R 11 is each identical or different, and each is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• t 0, 1, 2, 3 or 4;
• R 1 , R la , R c , R 3 , R 4 , R 3a , R 4a , G 3 , G 3a , L, n and s are each as defined in formula (I).
• R 1 and R la are identical or different, and each is independently -C(0)NR 9 R 10 , wherein R 9 and R 10 are each as defined in formula (I).
• R 1 and R la are identical or different, and each is independently selected from the group consisting of - C(0)NR 9 R 10 and -C(0)OR m , R 9 , R 10 and R m are each as defined in claim 1.
• R c is hydrogen
• the compound of formula (I) is a compound of formula (IG) :
• R 2 to R 4 , R 2a to R 4a , R 9 , R 10 , G 3 , G 3a , L, n and s are each as defined in formula (I).
• the compound of formula (I) is a compound of formula (IG) :
• R m is hydrogen or alkyl
• R 2 to R 4 , R 2a to R 4a , G 3 , G 3a , L, n and s are each as defined in formula (I).
• the compound of formula (I) is a compound of formula (III) :
• ring A is selected from the group consisting of aryl and heteroaryl;
• R 11 is each identical or different, and each is independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• t 0, 1, 2, 3 or 4;
• R 3 , R 4 , R 3a , R 4a , R 9 , R 10 , G 3 , G 3a , L, n and s are each as defined in formula (I).
• R 3 , R 4 , R 3a and R 4a are each hydrogen.
• G 3 and G 3a are identical or different, and each is independently O or NH.
• G 3 and G 3a are identical or different, and each is independently O or NR S , R s each is identical or different, and each is hydrogen or alkyl, wherein alkyl is unsubstituted or substituted with one or more alkoxy.
• R 9 and R 10 are each hydrogen.
• the compound of formula (I) is a compound of formula (IV) :
• G 3 and G 3a are identical or different, and each is independently O or NR S ;
• R 12 and R 13 are identical or different, and each is independently selected from hydrogen and alkyl
• R s , L, n and s are each as defined in formula (I).
• the compound of formula (IV) is a compound of formula (IV’):
• G 3 , G 3a , R 12 , R 13 , L, n and s are each as defined in formula (IV).
• the compound of formula (IV) is a compound of formula (IV”):
• G 3 , G 3a , R 12 , R 13 , L, n and s are each as defined in formula (IV).
• the compound of formula (III) is a compound of formula (IVM),
• R 12 and R 13 are identical or different, and each is independently selected from hydrogen and alkyl
• L, n and s are each as defined in formula (I).
• L is selected from the group consisting of alkylene, alkenylene, and alkylene-O-alkylene, wherein the alkylene or alkenylene each is unsubstituted or substituted with one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydroxyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl.
• L is selected from the group consisting of alkylene, alkenylene, alkynylene, alkylene- Q- alkylene, and alkylene-O-alkylene, wherein the alkylene, alkenylene and alkynylene each is unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, amino, nitro, hydroxy, hydro xyalkyl, cyano, cycloalkyl, heterocyclyl, aryl, and heteroaryl;
• Q is selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl.
• Representative compounds of the present invention or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or a mixture thereof include, but are not limited to, the compounds listed in Table 1 below. Table 1. Certain exemplified compounds.
• this invention provides a compound of formula (IA) or (IB), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, used as an intermediate for preparing a compound of formula (I), wherein:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 1 to R 5 , R la to R 5a , R c , G 1 to G 3 , G la to G 3a , n and s are each as defined in formula (I).
• Representative intermediates of the present invention include, but are not limited to, the compounds listed in Table 2 below. Table 2. Certain exemplified intermediate compounds.
• this invention provides a preparation process of a compound of formula (I), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 1 to R 5 , R la to R 5a , R c , G 1 to G 3 , G la to G 3a , n and s are each as defined in formula (I).
• this invention provides a preparation process of a compound of formula (IM), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 1 to R 5 , R la to R 5a , R c , G 1 to G 3 , G la to G 3a , n and s are each as defined in formula
• this invention provides a preparation process of a compound of formula (II), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 1 , R la , R c , R 3 , R 4 , R 3a , R 4a , R 11 , G 3 , G 3a , t, n and s are each as defined in formula
• this invention provides a preparation process of a compound of formula (III), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 3 , R 4 , R 3a , R 4a , R 9 to R 11 , G 3 , G 3a , t, n and s are each as defined in formula (III).
• this invention provides a preparation process of a compound of formula (IG), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R m is hydrogen or alkyl
• R 2 to R 4 , R 2a to R 4a , G 3 , G 3a , R 9 , R 10 , n and s are each as defined in formula (IG).
• this invention provides a preparation process of a compound of formula (III), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R m is hydrogen or alkyl
• Ring A, R 3 , R 4 , R 3a , R 4a , G 3 , G 3a , R 9 ⁇ R n , t, n and s are each as defined in formula (III).
• this invention provides a preparation process of a compound of formula (IV), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1 , 2 or 3;
• p 2 is 0, 1 , 2 or 3;
• R 12 , R 13 , G 3 , G 3a , n and s are each as defined in formula (IV).
• this invention provides a preparation process of a compound of formula (IVM), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the preparation process comprising a step of:
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 12 , R 13 , G 3a , n and s are each as defined in formula (IVM).
• the present invention also provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, cis- or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, together with one or more pharmaceutically acceptable carriers, diluents, and/or other excipients.
• a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, cis- or trans isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, together with one or more pharmaceutically acceptable carriers, diluents, and/or other excipients.
• the present invention also relates to use of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, in the preparation of a medicament for use as STING agonist.
• the present invention also relates to use of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment of a STING-mediated disease or disorder.
• a compound of formula (I) in any embodiment disclosed herein, or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for the treatment of a STING-mediated disease or disorder.
• the present invention relates to a method for stimulating STING, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), in any embodiment disclosed herein, or a tautomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition containing the same.
• a compound of formula (I) in any embodiment disclosed herein, or a tautomer, racemate, enantiomer, diastereoisomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition containing the same.
• the present invention relates to a method for treating a STING-mediated disease or disorder, comprising a step of administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same.
• a compound of formula (I) or a tautomer, cis- or trans- isomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or a pharmaceutical composition comprising the same.
• the disease or disorder is selected from a cancer, a pre-cancerous syndrome and viral infections, preferably a cancer and a pre-cancerous syndrome.
• the disease or disorder is brain cancer, leukemia, skin cancer (e.g., melanoma), prostate cancer, thyroid cancer, colon cancer, lung cancer, breast cancer, or sarcoma.
• the cancer is selected from the group consisting of glioma, glioblastoma multiforme, paraganglioma, suprantentorial primordial neuroectodermal tumors, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasm (MPN), angioimmunoblastic lymphoma, melanoma, breast, prostate, thyroid, colon, lung, central chondrosarcoma, central and periosteal chondroma tumors, fibrosarcoma, and cholangiocarcinoma.
• AML acute myeloid leukemia
• MDS myelodysplastic syndrome
• CML chronic myelogenous leukemia
• STING agonist compounds for example, STING agonist compounds, anti-viral agents, anti-cancer agents, antigens, adjuvants, CTLA-4, LAG-3 and PD-1 pathway antagonists, cytotoxic agents, chemotherapeutic agents, checkpoint inhibitors, vascular endothelial growth factor (VEGF) receptor inhibitors, alkylating
• compositions of this invention can be formulated by conventional methods using one or more pharmaceutically acceptable carriers.
• the active compounds of this invention can be formulated as various dosage forms for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), rectal administration, inhalation or insufflation administration ⁇
• the compounds of this invention can also be formulated as sustained release dosage forms.
• Oral compositions include a tablet, troche, lozenge, aqueous or oily suspension, dispersible powder or granule, emulsion, hard or soft capsule, or syrup or elixir.
• Oral compositions can be prepared according to any known method in the art for the preparation of pharmaceutical compositions. Such compositions can contain one or more additives selected from the group consisting of sweeteners, flavoring agents, colorants and preservatives, in order to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient and nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients can be inert excipients, granulating agents, disintegrating agents, and lubricants.
• the tablet can be uncoated or coated by means of a known technique to mask the taste of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract, thereby providing sustained release over an extended period.
• a known technique to mask the taste of the drug or delay the disintegration and absorption of the drug in the gastrointestinal tract, thereby providing sustained release over an extended period.
• water soluble taste masking materials can be used.
• Oral formulations can also be provided as soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or the active ingredient is mixed with a water soluble carrier.
• An aqueous suspension contains the active ingredient in admixture with excipients suitable for the manufacture of an aqueous suspension.
• excipients are suspending agents, dispersants or humectants, and can be naturally occurring phospholipids.
• the aqueous suspension can also contain one or more preservatives, one or more colorants, one or more flavoring agents, and one or more sweeteners.
• An oil suspension can be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil.
• the oil suspension can contain a thickener.
• the aforementioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding an antioxidant.
• the active ingredient and the dispersants or wetting agents, suspending agent or one or more preservatives can be prepared as a dispersible powder or granule suitable for the preparation of an aqueous suspensionn by adding water. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavoring agents and colorants, can also be added. These compositions can be preserved by adding an antioxidant such as ascorbic acid.
• the present pharmaceutical composition can also be in the form of an oil-in-water emulsion.
• the oil phase can be a vegetable oil, or a mineral oil, or mixture thereof.
• Suitable emulsifying agents can be naturally occurring phospholipids. Sweeteners can be used.
• Such formulations can also contain moderators, preservatives, colorants and antioxidants.
• the pharmaceutical composition can be in the form of a sterile injectable aqueous solution.
• the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
• the sterile injectable preparation can also be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
• the injectable solution or microemulsion can be introduced into an individual’s bloodstream by local bolus injection. Alternatively, it can be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the present compound. In order to maintain such a constant concentration, a continuous intravenous delivery device can be utilized. An example of such a device is Deltec CADD- PLUS. TM.
• the pharmaceutical composition can be in the form of a sterile injectable aqueous or oily suspension for intratumoral, intramuscular and subcutaneous administration.
• a suspension can be formulated with suitable dispersants or wetting agents and suspending agents as described above according to known techniques.
• the sterile injectable preparation can also be a sterile injectable solution or suspension prepared in a nontoxic parenterally acceptable diluent or solvent.
• sterile fixed oils can easily be used as a solvent or suspending medium, and fatty acids can also be used to prepare injections.
• the present compound can be administered in the form of a suppository for rectal administration ⁇
• These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures, but liquid in the rectum, thereby melting in the rectum to release the drug.
• compositions can be formulated as tablets or lozenges by conventional means.
• the active compounds of the present invention are conveniently delivered in the form of a solution or suspension released from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray released from a pressurized container or nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit can be determined by providing a valve to deliver a metered amount.
• the pressurized container or nebulizer can contain a solution or suspension of the active compound.
• Capsules or cartridges for example, made from gelatin
• for use in an inhaler or insufflator can be formulated
• the dosage of a drug depends on a variety of factors, including but not limited to, the following factors: activity of the specific compound, age, weight, general health, behavior, diet of the patient, administration time, administration route, excretion rate, drug combination and the like.
• the best treatment such as treatment mode, daily dose of the compound of formula ( I ) or the type of pharmaceutically acceptable salt thereof can be verified by traditional therapeutic regimens.
• Alkyl refers to a saturated aliphatic hydrocarbon group including C1-C20 straight chain and branched chain groups.
• an alkyl group is an alkyl having 1 to 12, sometimes preferably 1 to 6, sometimes more preferably 1 to 4, carbon atoms.
• Representative examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl,
• an alkyl group is a lower alkyl having 1 to 6 carbon atoms.
• Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2- dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, l-ethyl-2-methylpropyl,
• alkyl group can be substituted or unsubstituted.
• the substituent group(s) can be substituted at any available connection point, preferably the substituent group(s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
• substituent group(s) is one or more substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl,
• Alkenyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, for example, vinyl, 1-propenyl, 2- propenyl, 1-, 2-, or 3- butenyl, etc., preferably C2-20 alkenyl, more preferably C2-12 alkenyl, and most preferably C2-6 alkenyl.
• the alkenyl group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
• Alkynyl refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3- butynyl etc., preferably C2-20 alkynyl, more preferably C2-12 alkynyl, and most preferably C2-6 alkynyl.
• the alkynyl group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
• Alkylene refers to a saturated linear or branched aliphatic hydrocarbon group, wherein having 2 residues derived by removing two hydrogen atoms from the same carbon atom of the parent alkane or two different carbon atoms.
• the straight or branched chain group containing 1 to 20 carbon atoms preferably has 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms.
• alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (- CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (-CH2CH2CH2-), 1,4- butylidene (-CH2CH2CH2CH2-) etc.
• the alkylene group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
• Alkenylene refers to an alkylene defined as above that has at least two carbon atoms and at least one carbon-carbon double bond, preferably C2-20 alkenylene, more preferably C2-12 alkenylene, and most preferably C2-6 alkenylene.
• the alkenylene group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalky lthio and heterocylic alkylthio.
• Alkynylene refers to an alkynyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, preferably C2-20 alkynylene, more preferably C2-12 alkynylene, and most preferably C2-6 alkynylene.
• alkenylene groups include, but are not limited to, -CHoCH-, -CHoCHCH 2 -, -CHoCHCH 2 CH 2 -, - CH2CHoCHCH2- etc.
• the alkynylene group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalky lthio and heterocylic alkylthio.
• Cycloalkyl refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 10 carbon atoms, and most preferably 3 to 8 carbon atoms or 3 to 6 carbon atoms.
• Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.
• Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, lused ring or bridged ring.
• “Spiro Cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
• a spiro cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered.
• a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably refers to a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5- membered, 4-membered/6-membered, 5 -membered/5 -membered, or 5-membered/6- membered mono-spiro cycloalkyl.
• Representative examples of spiro cycloalkyl include, but are not limited to the following substituents:
• “Fused Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
• a fused cycloalkyl group is 6 to 14 membered, more preferably 7 to 10 membered.
• fused cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic lused cycloalkyl, and preferably refers to a bicyclic or tricyclic fused cycloalkyl, more preferably 5-membered/5- membered, or 5-membered/6-membered bicyclic fused cycloalkyl.
• Representative examples of fused cycloalkyls include, but are not limited to, the following substituents:
• “Bridged Cycloalkyl” refers to a 5 to 20 membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings can have one or more double bonds, but have no completely conjugated pi-electron system.
• a bridged cycloalkyl is 6 to 14 membered, and more preferably 7 to 10 membered.
• bridged cycloalkyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably refers to a bicyclic, tricyclic or tetracyclic bridged cycloalkyl, more preferably a bicyclic or tricyclic bridged cycloalkyl.
• Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:
• the cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl, wherein the ring bound to the parent structure is cycloalkyl.
• Representative examples include, but are not limited to indanylacetic, tetrahydronaphthalene, benzocycloheptyl and so on.
• the cycloalkyl is optionally substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.
• “Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S(0) m (wherein m is 0,1 or 2) as ring atoms, the remaining ring atoms being C, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system.
• a spiro heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
• spiro heterocyclyl is divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or poly-spiro heterocyclyl, and preferably refers to mono- spiro heterocyclyl or di-spiro heterocyclyl, more preferably 4-membered/4-membered, 4- membered/5-membered, 4-membered/6-membered, 5 -membered/5 -membered, or 5- membered/6-membered mono-spiro heterocyclyl.
• Representative examples of spiro heterocyclyl include, but are not limited to the following substituents:
• “Fused Heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with the other ring, wherein one or more rings can contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more, sometimes preferably one to five, sometimes more preferably one to three, heteroatoms selected from the group consisting of N, O, and S(0) p (wherein p is 0, 1, or 2) as ring atoms, the remaining ring atoms being C.
• a fused heterocyclyl is 6 to 14 membered, and more preferably 7 to 10 membered.
• lused heterocyclyl is divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably refers to bicyclic or tricyclic fused heterocyclyl, more preferably 5-membered/5-membered, or 5-membered/6- membered bicyclic lused heterocyclyl.
• fused heterocyclyl include, but are not limited to, the following substituents:
• the ring of said heterocyclyl can be fused to the ring of an aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl.
• Representative examples include, but are not limited to the following substituents: etc.
• Aryl refers to a 6 to 14 membered all-carbon monocyclic ring or a polycyclic lused ring (a "fused" ring system means that each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group, and has a completely conjugated pi-electron system.
• aryl is 6 to 10 membered, such as phenyl and naphthyl, most preferably phenyl.
• the aryl can be lused to the ring of heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Representative examples include, but are not limited to, the following substituents:
• the aryl group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NR 9 R 10 .
• the heteroaryl group can be substituted or unsubstituted.
• the substituent group(s) is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NR 9 R 10 .
• Alkoxy refers to both an -O-(alkyl) and an -0-(unsubstituted cycloalkyl) group, wherein the alkyl is defined as above. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
• the alkoxyl can be substituted or unsubstituted.
• the substituent is preferably one or more, sometimes preferably one to five, sometimes more preferably one to three, substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.
• “Bond” refers to a covalent bond using a sign of“—”.
• Hydroalkyl refers to an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.
• Haldroxy refers to an -OH group.
• Halogen refers to fluoro, chloro, bromo or iodo atoms.
• Amino refers to a -NH2 group.
• Cyano refers to a -CN group.
• Carboxyl refers to a -C(0)0H group.
• Alkoxycarbonyl refers to a -C(0)0(alkyl) or (cycloalkyl) group, wherein the alkyl and cycloalkyl are defined as above.
• “Optional” or “optionally” means that the event or circumstance described subsequently can, but need not, occur, and the description includes the instances in whichthe event or circumstance may or may not occur.
• “the heterocyclic group optionally substituted by an alkyl” means that an alkyl group can be, but need not be, present, and the description includes the case of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
• “Substituted” refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents exist in their only possible chemical position. The person skilled in the art is able to determine if the substitution is possible or impossible without paying excessive efforts by experiment or theory. For example, the combination of amino or hydroxyl group having free hydrogen and carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
• A“pharmaceutical composition” refers to a mixture of one or more of the compounds described in the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.
• Suitable pharmaceutically acceptable excipients include, but are not limited to, diluents, lubricants, binders, disintegrants, fillers, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, flavor masking agents, coloring agents, anti-caking agents, hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants, and buffering agents.
• a pharmaceutical composition is to facilitate administration of a compound to an organism, which is conducive to the absorption of the active ingredient and thus displaying biological activity.
• “Pharmaceutically acceptable salts” refer to salts of the compounds of the invention, such salts being safe and effective when used in a mammal and have corresponding biological activity.
• the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid.
• Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• the cations of pharmaceutically acceptable salts include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetrameth yl am mon i u m , tetraeth y I am mo n i u m , methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, and N-methylmorpholine.
• nontoxic quaternary amine cations such as ammonium, tetrameth yl am mon i u m , tetraeth y I am mo n i u m , methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributy
• solvate means a physical association of a compound of this invention with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art. “Prodrug” refers to compounds that can be transformed in vivo to yield the active parent compound under physiological conditions, such as through hydrolysis in blood.
• a prodrug may also be formed by acylation of an amino group or a nitrogen atom in a heterocyclyl ring structure, which acyl group can be hydrolyzed in vivo.
• acyl group includes, but is not limited to, a C 1 -C 6 acyl, preferably C 1 -C 4 acyl, and more preferably C 1 -C 2 (formyl or acetyl) group, or benzoyl.
• subject or “patient” includes both human and other mammals, especially domestic animals, for example, dogs, cats, horses, or the like, sometimes preferably a human.
• treating refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.
• the compounds of present invention may be used for their prophylactic effects in preventing a disease, disorder or condition from occurring in a subject that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it.
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• the catalyst includes, but is not limited to, Hoveyda-Grubbs 2nd Gen Catalyst, Grubbs Catalyst (1 st gen, 2 nd gen, 3 rd gen, etc).
• reaction is preferably in solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, A,A-dimethylformamide and the mixture thereof .
• solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, A,A-dimethylformamide and the mixture thereof .
• p 1 is 0, 1 , 2 or 3;
• reaction is preferably in solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, /V-dimethylformamide and the mixture thereof .
• solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, /V-dimethylformamide and the mixture thereof .
• R 1 , R la , R c , R 3 , R 4 , R 3a , R 4a , R 11 , G 3 , G 3a , t, n and s are each as defined in formula
• the catalyst includes, but is not limited to, Hoveyda-Grubbs 2nd Gen Catalyst, Grubbs Catalyst (1 st gen, 2 nd gen, 3 rd gen, etc).
• reaction is preferably in solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, A,/V-dirnethylformamide and the mixture thereof .
• solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, A,/V-dirnethylformamide and the mixture thereof .
• R m is hydrogen or alkyl
• R 2 to R 4 , R 2a to R 4a , G 3 , G 3a , R 9 , R 10 , n and s are each as defined in formula (IG).
• the reagents that provide an alkaline condition include organic bases and inorganic bases.
• the organic bases include, but are not limited to triethylamine, N,N- diisopropylethylamine, n-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide.
• the inorganic bases include, but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide.
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 1 is 0, 1, 2 or 3;
• p 2 is 0, 1, 2 or 3;
• R 3 , R 4 , R 3a , R 4a , R 9 to R 11 , G 3 , G 3a , t, n and s are each as defined in formula (III).
• reaction is preferably in solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, A,A-dimethylformamide and the mixture thereof .
• solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, A,A-dimethylformamide and the mixture thereof .
• R m is hydrogen or alkyl
• Ring A, R 3 , R 4 , R 3a , R 4a , G 3 , G 3a , R 9 ⁇ R n , t, n and s are each as defined in formula (III).
• the reagents that provide an alkaline condition include organic bases and inorganic bases.
• the organic bases include, but are not limited to triethylamine, N,N-diisopropylethylamine, n- butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide.
• the inorganic bases include, but are not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and lithium hydroxide.
• p 1 is 0, 1 , 2 or 3;
• p 2 is 0, 1 , 2 or 3;
• the catalyst includes, but is not limited to, Hoveyda-Grubbs 2nd Gen Catalyst, Grubbs Catalyst (1 st gen, 2 nd gen, 3 rd gen, etc).
• reaction is preferably in solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, V,V-dimethylformamide and the mixture thereof .
• solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, V,V-dimethylformamide and the mixture thereof .
• R e and R f are identical or different, and each is independently selected from the group consisting of hydrogen and alkyl;
• p 2 is 0, 1 , 2 or 3;
• R 12 , R 13 , G 3a , n and s are each as defined in formula (IVM).
• the catalyst includes, but is not limited to, Ho veyda- Grubbs 2nd Gen Catalyst, Grubbs Catalyst (1 st gen, 2 nd gen, 3 rd gen, etc).
• reaction is preferably in solvent, wherein solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, V,V-dimethylformamide and the mixture thereof.
• solvent used herein includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydroluran, dichlorome thane, dimethylsulfoxide, 1,4-dioxane, water, V,V-dimethylformamide and the mixture thereof.
• each compound was indentifiedby nuclear magnetic resonsance (NMR) and/or mass spectrometry (MS). NMR chemical shifts (d) were given in 10 6 (ppm). NMR was determined by Bruker AVANCE-300, AVANCE-400 or AVANCE-500 machine. The solvents were deuterated-dimethyl sulfoxide (DMSO- ⁇ 3 ⁇ 4), deuterated-chloroform (CDCh) and deuterated-methanol (CD3OD).
• DMSO- ⁇ 3 ⁇ 4 deuterated-dimethyl sulfoxide
• CDCh deuterated-chloroform
• CD3OD deuterated-methanol
• HPLC High performance liquid chromatography
• the average rates of kinase inhibition, and the IC50 values were determined by Microplate reader (BMG company, Germany).
• the known starting material of the invention can be prepared by the conventional synthesis method in the prior art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc or Dari chemical Company, etc.
• argon atmosphere or“nitrogen atmosphere” means that a reaction flask was equipped with a balloon having 1 L of argon or nitrogen.
• hydrox atmosphere means that a reaction flask was equipped with a balloon having 1 L of hydrogen. High pressure hydrogenation reactions were performed with a Parr 3916EKX hydrogenation apparatus and clear blue QL-500 hydrogen generator or HC2-SS hydrogenation apparatus.
• Microwave reactions were performed with a CEM Discover-S 908860 microwave reactor.
• the solution used in following reactions refers to an aqueous solution.
• reaction temperature in the following reactions was room temperature.
• the reaction process is monitored by thin layer chromatography (TLC), and the developing solvent system includes: A: dichloromethane and methanol, B: hexane and ethyl acetate.
• the ratio of the volume of the solvent can be adjusted according to the polarity of the compounds.
• the elution system for purification of the compounds by column chromatography, thin layer chromatography and ComhlFlash flash rapid preparation instrument includes: A: dichloromethane and methanol, B: hexane and ethyl acetate.
• the ratio of the volume of the solvent can be adjusted according to the polarity of the compounds, and sometimes a small amount of basic reagent such as ammonia or acidic reagent such as acetic acid can be added.
• Hoveyda-Grubbs 2nd Gen Catalyst is (l,3-Bis-(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(o-isopropoxyphenylmethylene)ruthenium (Sigma- Aldrich),
• Grubb's (II) catalyst is (l,3-Bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium,
• HATU is l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphate
• HBTU 0-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
• DCM dichloromathene
• DMF is N,N-dimethylformamide
• DMSO dimethyl sulfoxide
• DEAD is diethyl azodiformate
• DIAD is diisopropyl azodicarboxylate
• EDCI is N-Ethyl-N' -(3-dimethylaminopropyl)carbodiimide hydrochloride
• EtOAc is ethyl acetate
• Prep HPLC is Prepative High performance liquid chromatography.
• NMR is proton nuclear magnetic resonance
• Step 6 (S)-methyl 3-allyl-2-(l-ethyl-3-methyl-l//-pyrazole-5-carboxamido)-3, 4-dihydro- 5-oxa-l,2a-diazaacenaphthylene-7-carboxylate li
• Step 7 (S)-3-allyl-2-(l-ethyl-3-methyl-l/ -pyrazole-5-carboxamido)-3,4-dihydro-5-oxa- l,2a-diazaacenaphthylene-7-carboxylic acid lj
• Step 8 (S)-3-allyl-2-(l-ethyl-3-methyl-l/7-pyrazole-5-earboxamido)-3,4-dihydro-5-oxa- l,2a-diazaacenaphthylene-7-carboxamide lk
• Example 1 (Shorter retention time on reverse phase HPLC) (35,3"5)-3,3"-((£')-but-2- ene- 1 ,4-diyl)bis(2-(l-ethyl-3-methyl- 177-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa- 1 ,2a- diazaacenaphthylene-7-carboxamide) MS m/z (ESI): 761 [M+l]; 1 H NMR (300 MHz, Methanol-i 4 ) d 7.60 (d, 2H), 7.31 (d, 2H), 6.62 (s, 2H), 5.63-5.69 (m, 2H), 4.73 - 4.49 (m, 6H), 4.44 (d, 2H), 4.24 - 4.13 (m, 2H), 2.54-2.64 (m, 4H), 2.21 (s, 6H), 1.35 (t, 6H).
• Example 2 Longer retention time on reverse phase HPLC (35,3"5)-3,3"-((Z)-but-2- ene- 1 ,4-diyl)bis(2-(l-ethyl-3-methyl- 177-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa- 1 ,2a- diazaacenaphthylene-7-carboxamide) MS m/z (ESI): 761 [M+l]; 1 H NMR (300 MHz, Methanol-i 4) d 7.52 (d, 2H), 7.28 (d, 2H), 6.45 (s, 2H), 5.85-5.91 (m, 2H), 4.67 - 4.52 (m, 6H), 4.21 (m, 2H), 2.89-2.99 (m, 2H), 2.34 (s, 2H), 1.88 (s, 6H), 1.43 (t, 6H), 1.31 (s, 2H).
• Example 3 Longer retention time on reverse phase HPLC
• the crude stuff was purified on a silica gel column, eluting with 60% ethyl acetate in hexanes, to get the title compound, dimethyl 5,5'-(((25,75,£)-2,7-bis((tert-butoxycarbonyl)amino)oct-4- ene-l,8-diyl)bis(oxy))bis(4-chloro-3-nitrobenzoate) 3d (9.0 g, 84.1%) .
• Step 8 l-ethyl-3-methyl-l//-pyrazole-5-carboxylic pivalic anhydride 3j
• Step 9 (3S,3"S)-dimethyl 3,3"-((E)-but-2-ene- 1 ,4-diyl)bis(2-( 1 -ethyl-3-methyl- 177- pyrazole-5-carboxamido)-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylene-7-carboxylate)
• the second polar product was identified by 1 H NMR, 13 C NMR and LCMS as (S)- methyl 2-(l-ethyl-3-methyl-l /-pyrazole-5-carboxamido)-3-((£)-4-((5)-7-(methoxycarbonyl)- 2-pivalamido-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylen-3-yl)but-2-en-l-yl)-3,4-dihydro-5- oxa-l,2a-diazaacenaphthylene-7-carboxylate 31 (1.01 g, 44% yield).
• the least polar product was identified by 1 H NMR, 13 C NMR and LCMS as (3S,3"S)- dimethyl 3,3"-((7?)-but-2-ene- 1 ,4-diyl)bis(2-pivalamido-3,4-dihydro-5-oxa- 1 ,2a- diazaacenaphthylene-7-carboxylate) 3m (0.56 g, 37% yield).
• Step 1 (S)-3-((£)-4-((S)-7-carboxy-2-(l-ethyl-3-methyl-l -pyrazole-5-carboxamido)-3,4- dihydro-5-oxa-l,2a-diazaacenaphthylen-3-yl)but-2-en-l-yl)-2-pivalamido-3,4-dihydro-5- oxa-l,2a-diazaacenaphthylene-7-carboxylic acid 4a
• the title compound can be prepared by the same method as step 2 in example 4.
• Step 1 (Z)-l,4-bis((2S,5/?)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)but-2-ene 2b
• Step 4 di-tert-butyl ((25,75,Z)-l,8-dihydroxyoct-4-ene-2,7-diyl)dicarbamate 2e
• the filtrate was concentrated and purified on a silica gel column, eluting with 60 % ethyl acetate in hexanes to get di-tert-butyl ((25,75, Z)-l,8-dihydroxyoct-4-ene-2,7- diyl)dicarbamate 2e (3.1 g, 63.7 % yield).
• Step 5 dimethyl 5 '-(((25,75,Z)-2,7-bis((tert-butoxycarbonyl)amino)oct-4-ene-l,8 - diyl)bis(oxy))bis(4-chloro-3-nitrobenzoate) 2f
• Step 6 dimethyl 5,5'-(((25,75,Z)-2,7-diaminooct-4-ene-l,8-diyl)bis(oxy))bis(4-chloro-3- nitrobenzoate) 2g
• Step 9 (3S,3'S)-dimethyl 3,3'-((Z)-but-2-ene-l,4-diyl)bis(2-amino-3,4-dihydro-5-oxa-l,2a -diazaacenaphthylene-7 -carboxylate) 2j
• Step 10 (3S,3'S)-dimethyl 3,3'-((Z)-but-2-ene- 1 ,4-diyl)bis(2-( 1 -ethyl-3-methyl- 1//- pyrazole-5-carboxamido)-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylene-7-carboxylate)
• Step 11 (3S y 3'S)-3,3'-((Z)-but-2-ene-l,4-diyl)bis(2-(l-ethyl-3-methyl-lH-pyrazole-5- carboxamido)-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylene-7-carboxylic acid) 21
• Step 12 (3S,3"S)-3,3"-((Z)-but-2-ene-l,4-diyl)bis(2-(l-ethyl-3-methyl-li/-pyrazole-5- carboxamido)-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylene-7-carboxamide) 2
• Step 2 (2S,7S)-dimethyl 2,7-bis((tert-butoxycarbonyl)amino)oct-4-ynedioate 6c
• Zinc dust (662 mg, 10.1 mmol) was weighed into a round bottomed flask. Iodine (24 mg, 0.1 mmol) was added and the flask was heated with a heat gun, under vacuum for tenminutes and then flushed with argon. The flask was vacuumed and flushed with argon a further three times and cooled to 0°C.
• Step 4 dimethyl 5,5'-(((2S,7S)-2,7-bis((tert-butoxycarbonyl)amino)oct-4-yne-l,8- diyl)bis(oxy))bis(4-chloro-3-nitrobenzoate) 6e
• PPI13 428 mg, 3 eq
• DEAD 257 uL, 3 eq
• Step 7 (3S,3'S)-dimethyl 3, 3'-(but-2-yne-l,4-diyl)bis(5-amino-3, 4-dihydro- 2 H- benzo[b][l,4]oxazine-7-carboxylate) 6h
• Step 9 (3S,3'S)-dimethyl 3,3'-(but-2-yne-l,4-diyl)bis(2-(l-ethyl-3-methyl-l//-pyrazole-5- carboxamido)-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylene-7-carboxylate) 6j
• Step 11 (3S,3"S)-3,3"-(but-2-yne-l,4-diyl)bis(2-(l-ethyl-3-methyl-l/ -pyrazole -5- carboxamido)-3,4-dihydro-5-oxa-l,2a-diazaacenaphthylene-7-carboxamide) 6
• Step 8-15 of Examples 7 was prepared with the similar procedures as Example 1
• Example 7 (Shorter retention time on reverse phase HPLC), 10,10"-(but-2-ene-l,4-diyl)bis(l- ( 1 -ethyl-3-methyl- 17/-pyrazole-5-carboxamido)-7,8,9, 10-tetrahydro-6-oxa-2, 10a- diazacycloocta[c ⁇ i]indene-4-carboxamide) 7 (1.8 mg, 12%) with MS m/z (ESI): 817 [M+l], 815 [M-l]
• Example 8 (Longer retention time on reverse phase HPLC), 10-(4-((5)-7-carbamoyl-2-(l- ethyl-3-methyl- 17/-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa- 1 ,2a-diazaacenaphthylen-3- yl)but-2-en-l-yl)-l-(l-ethyl-3-methyl-lH-pyrazole-5-carboxamido)-7,8,9,10-tetrahydro-6- oxa-2, 10a-diazacycloocta
• Step 4 of Example 9 was prepared with the similar procedures as Example 1.
• Steps 8-12 of Example 9 were prepared with the similar procedures as Example 1.
• step 12 the mixture was purified by prep-HPLC, eluated with ACN/thO/formic acid to give title compound LV)-4-allyl-2-( 1 -ethyl-3-methyl- 1 //-pyrazole-5-carboxamido)- 6- methyl-5,6-dihydro-4 /-imidazo
• Step 13 of Examples 9 and 10 was prepared with the similar procedures as Example 7 and 8.
• Step 1 (S)-methyl 2-allyl-4-(3-methoxypropyl)-8-nitro-l,2,3,4-tetrahydroquinoxaline-6- carboxylate 11a
• Steps 2-6 of Examples 11 and 12 were prepared with the similar procedures as in Example 1.
• Step 7 (4S,4'S)-4,4'-((£)-but-2-ene-l,4-diyl)bis(2-(l-ethyl-3-methyl-li/-pyrazole-5- carboxamido)-6-(3-methoxypropyl)-5,6-dihydro-4//-imidazo[l,5,4-de]quinoxaline-8- carboxamide) 11
• Example 14 (5)-4-((Z)-4-((5)-8-carbamoyl-2-(l-ethyl-3-methyl-l /-pyrazole-5-carboxamido)-6-(3- methoxypropyl)-5,6-dihydro-4//-imidazo[l,5,4-de]quinoxalin-4-yl)but-2-en-l-yl)-2-(l-ethyl- 3 -methyl- 1 H-pyrazole-5-carboxamido)-6-methyl-5 , 6 - d i h yd ro - 4 /- i m i da zo 1 1 ,5 ,4- de]quinoxaline-8-carboxamide 14
• Step 1 of Examples 13 and 14 was prepared with the similar procedures as Example 7 and 8
• the first elute was title compound (5)-4-((£)-4- ((.V)-8-carbamoyl-2-( 1 -ethyl-3 -methyl- 1 H-pyrazole-5-carboxamido)-6-(3-methoxypropyl)- 5,6-dihydro-47/-imidazo
• the compouds 15-20 can be prepared with the similar procedures as illustrated in
• Test Example 1 Thermal shift assay for measuring the relative binding affinity to hSTING R232 c-terminal domain.
• Tm °C melting temperature
• the compounds of the present invention showed binding affinity to a human STING protein.
• Activation of STING in THPl-Dual KI-hSTING-R232 cells was determined by measuring the luminescence signal resulting from the expression of the IRF luciferase reporter gene. All reagent preparation and assay procedures were conducted according to the protocols provided by InvivoGen. In brief, test compounds and cells (1 x 10 5 cells per well) were dispensed into 96- well plates with a final volume per well of 150pl. Plates were incubated in a humidified, 5% CO2 incubator at 37°C for 24 hours. The expression level of the reporter gene was measured by transferring 20m1 of the supernatant to a non-transparent 96-well plate to which 50m1 of QUANTI-LUC was dispensed into each well.
• the resulting luminescence signal was immediately read using a TECAN plate reader.
• the background luminescence signal from media was subtracted.
• the fold induction effect of the luminescence signal at each compound concentration was determined relative to controls that lack compound treatment.
• the plot of fold induction effect versus the log of compound concentration was fit in GraphPad Prism with a 4-parameter concentration response equation to calculate EC50 and Emax.
• PBMCs peripheral blood human mononuclear cells

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