WO2021000770A1 - Composé hétérocyclique capable d'améliorer l'activité immunitaire, son procédé de préparation et son application en médecine - Google Patents

Composé hétérocyclique capable d'améliorer l'activité immunitaire, son procédé de préparation et son application en médecine Download PDF

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WO2021000770A1
WO2021000770A1 PCT/CN2020/097941 CN2020097941W WO2021000770A1 WO 2021000770 A1 WO2021000770 A1 WO 2021000770A1 CN 2020097941 W CN2020097941 W CN 2020097941W WO 2021000770 A1 WO2021000770 A1 WO 2021000770A1
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general formula
cancer
alkyl
methyl
alkylene
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PCT/CN2020/097941
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English (en)
Chinese (zh)
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邓永奇
孙健
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凯复制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • 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

Definitions

  • the present invention relates to the field of medicine, and relates to a compound represented by the general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially its use as an STING modulator and treatment of STING-mediated Use of diseases or conditions, such as inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes.
  • diseases or conditions such as inflammation, allergic and autoimmune diseases, infectious diseases, cancer, precancerous syndromes.
  • the human immune system can generally be divided into two types of systems, called “innate immunity” and “adaptive immunity”.
  • the innate immune system of the immune system is mainly responsible for the passage of many soluble factors (including the complement system and chemokine/cytokine system); these factors act on many different cell types, including mast cells, macrophages, dendritic cells and natural Kill cells to resist various pathogens such as viruses, bacteria, fungi and parasites.
  • the adaptive immune system involves delayed and longer-lasting antibody responses and CD8 + and CD4 + T cell responses that play a key role in immune memory to antigens.
  • the innate immune system has no antigen specificity, but it does respond to multiple effect mechanisms.
  • the mechanism by which the innate immune system mediates its response includes phagocytosis, activation of the complement system, and the production of soluble biologically active molecules such as cytokines or chemokines.
  • DAMP damage-related molecular patterns
  • PAMP pathogen-related molecular patterns
  • the innate immune system can provide extensive protection to the body to resist a wide range of threats to the host.
  • the innate immune system can detect free cytoplasmic DNA and RNA in PAMP and DAMP. It has recently been demonstrated that the main sensor for cytosolic DNA is cGAS (cyclic GMP-AMP synthase).
  • CDN cyclic dinucleotide 2'-3'cGAMP
  • type I interferon has antiviral activity and can inhibit the replication of human hepatitis B virus and hepatitis C virus.
  • type I interferons and compounds that can induce the production of type I interferons can be used to treat human cancers. Such molecules may be used as anticancer agents with multiple active pathways. Interferon can directly inhibit the proliferation of human tumor cells and can act synergistically with various approved chemotherapeutics. Type I interferon can significantly enhance the anti-tumor immune response by inducing the activation of adaptive and innate immune cells. Finally, by regulating the expression of enzymes related to tissue remodeling, interferon can inhibit tumor invasiveness.
  • STING is considered to be the key adaptor protein in the cGAS-STING-IFN cascade, and the role of STING in the activation of the innate immune system against tumors has also been recognized.
  • Xiang Zhou et al. STING-mediated DNA sensing in cancer immunotherapy, Science China Life Sciences, Vol. 60, No. 6, pp563-574
  • STING-mediated DNA sensing in cancer immunotherapy Science China Life Sciences, Vol. 60, No. 6, pp563-574
  • tumor-derived DNA is present in the cytoplasm of certain antigen-presenting cells (such as tumor-infiltrating dendritic cells), which may be produced by tumor cell stress or cell death.
  • This tumor-derived DNA is known to activate cGAS, which leads to the production of cyclic nucleotides that have been shown to activate STING, leading to the production of related type 1 interferons such as interferon beta (Woo, SR et al., Immunity (2014) 41: 830 -842).
  • the downstream signal transduction pathways stimulated and produced by STING may also contribute to the recruitment of effector T cells into the inflamed tumor microenvironment (Woo, S.R. Trends in Immunol (2015) 36: 250-256).
  • STING activation in the tumor microenvironment can induce an adaptive immune response, leading to anti-tumor activity. Therefore, in those STING-deficient tumors, by activating antigen-presenting cells and dendritic cells (APC and DC) and inducing adaptive immune responses, these tumors still have anti-tumor activity. With more and more data showing that the cGAS-STING cytosolic DNA sensory pathway has a significant ability to induce type I interferons, the development of STING activators has rapidly occupied an important position in the field of anti-tumor therapy today.
  • CDN cyclic dinucleotides Due to easy hydrolysis in the body and very low permeability, natural cyclic dinucleotides (CDN) are not suitable for clinical development.
  • Aduro Company modified the natural cyclic dinucleotide structure and replaced the phosphoric acid ester with phosphorothioate to obtain the compound ADU-S100 with higher druggability.
  • the object of the present invention is to provide a compound represented by general formula (I):
  • X is selected from O, NR a and C(R a )(R b );
  • Y is selected from N and CR a ;
  • U, V, and W are each independently selected from N, O and C;
  • R 1 and R 2 are each independently selected from a hydrogen atom, a cyano group, and -CON(R m )(R n );
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen atom, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro, cyano,- C(O)R m , -OC(O)R m , -SR m , -S(O)R m , -S(O) 2 R m , -S(O) 2 N(R m )(R n ), -N(R m )(R n ), -N(R m )-C(O)R n , -C(O)-N(R m )(R n ), -(C 1 -C 6 Al
  • R 7 and R 8 together with the connected atoms form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted by one or more R c ;
  • one of R 7 and R 8 is selected from -(C 1 -C 6 alkylene) -N(R m )-S(O)-N(R m )(R n ), -(C 1 -C 6 alkylene)-N(R m )-S(O) 2 -N(R m )(R n ), -(C 2 -C 6 alkenylene)-N(R m )-S(O) -N (R m) (R n ), - (C 2 -C 6 alkynylene) -N (R m) -S ( O) -N (R m) (R n), - (C 2 -C 6 alkenylene) -N (R m) -S ( O) 2 -N (R m) (R n), - (C 2 -C 6 alkenylene) -N (R m) -S ( O) 2 -N (R m
  • R a and R b are each independently selected from hydrogen atom, halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 3-6 membered heterocyclic, nitro and cyano;
  • R c is selected from hydrogen atom, halogen, hydroxyl, amino, -N (R m ) (R n ), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -6 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 heterocyclic, amino, nitro and cyano; and
  • R m and R n are each independently selected from hydrogen atom, halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 6-10 aryloxy, 5-10 membered heteroaryl, 5-10 heterocyclic, nitro and cyano;
  • R m and R n together with the attached nitrogen atom form a 5-7 membered heterocyclic group, wherein the 5-7 membered heterocyclic group is optionally substituted with one or more R c .
  • the compound represented by general formula (I) is a compound of general formula (I-1) and a compound of general formula (I-2):
  • X, Y, R 1 -R 3 , R 5 , R 7 and R 8 are as defined in the general formula (I).
  • the compound represented by general formula (I) is a compound of general formula (I-1a) and a compound of general formula (I-2a):
  • R 3 , R 5 , R 7 and R 8 are as defined in the general formula (I).
  • one of R 7 and R 8 is selected from -(C 1 -C 6 alkylene)-N(R m )-S (O) 2 -N(R m )(R n ) and -(C 1 -C 6 alkylene)-3-6-membered heterocyclic ring-S(O) 2 -N(R m )(R n ),
  • the other of R 7 and R 8 is selected from a C 1 -C 6 alkyl group, wherein R m and R n are each independently selected from a hydrogen atom and a C 1 -C 6 alkyl group, or R m and R n are connected to The nitrogen atoms of together form a 5-7 membered heterocyclic group, preferably a 5-membered heterocyclic group or a 6-membered heterocyclic group, more preferably a pyrrolidinyl group or a morpholinyl group.
  • R 3 is selected from C 1 -C 6 alkyl and halo C 1 -C 6 alkyl.
  • R 5 is selected from C 1 -C 6 alkyl and C 1 -C 6 alkoxy.
  • Typical compounds of the present invention include but are not limited to:
  • the present invention also relates to a method for preparing the compound represented by general formula (I), which comprises:
  • X, Y, R 1 -R 8 are as defined in the general formula (I).
  • the compound of general formula (IA) and the compound of general formula (IB) undergo a condensation reaction in the presence of a condensing agent to obtain a compound of general formula (IC).
  • a condensing agent is selected from 2-(7).
  • HATU hexafluorophosphate
  • N,N'-dicyclohexylcarbodiimide N,N'-diisopropylcarbodiimide
  • O-benzotriazole-N,N,N',N' -Tetramethylurea tetrafluoroborate 1-hydroxybenzotriazole, 1-hydroxy-7-azobenzotriazole, O-benzotriazole-N,N,N',N' -Tetramethylurea hexafluorophosphate
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate benzotriazole-1- Tris(dimethylamino)phosphonium hexafluorophosphate
  • the present invention also relates to a method for preparing the compound represented by general formula (I), which comprises:
  • q is an integer of 1-6
  • L is a halogen, preferably a chlorine atom
  • R 8 is -(C 1 -C 6 alkylene) -N(R m )-S(O) 2 -N(R m ) (R n )
  • X, Y, R 1 -R 7 , R m and R n are as defined in the general formula (I).
  • the present invention also relates to a method for preparing the compound represented by general formula (I), which comprises:
  • q is an integer of 1-6
  • L is halogen, preferably the chlorine atom
  • R 7 is -(C 1 -C 6 alkylene) -N(R m )-S(O) 2 -N(R m )( R n )
  • X, Y, R 1 -R 6 , R 8 , R m and R n are as defined in the general formula (I).
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, enantiomers, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to the use of the compound represented by the general formula (I) or the pharmaceutical composition containing the same in the preparation of a medicine for the treatment of STING-mediated diseases or disorders.
  • the STING-mediated disease or condition is selected from inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.
  • the present invention also relates to the use of the compound represented by the general formula (I) or the pharmaceutical composition containing the same in the preparation of a medicine for treating cancer.
  • the cancer is selected from breast cancer, cervical cancer, colorectal cancer, and intrauterine cancer.
  • the present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used as a medicine.
  • the present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, which is used to treat STING-mediated diseases or conditions.
  • the STING-mediated disease or condition is selected from inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.
  • the present invention also relates to the compound represented by the general formula (I) or its tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition containing the same, for the treatment of cancer, preferably, the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, Head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer.
  • the cancer is selected from breast cancer, cervical cancer, colorectal cancer, endometrial cancer, glioblastoma, Head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer and urethral cancer.
  • the present invention also relates to a method for treating STING-mediated diseases or conditions, which comprises administering a therapeutically effective amount of a compound represented by the general formula (I) or its tautomers, mesosomes, or exogenous compounds to a desired patient. Rotates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the STING-mediated disease or condition is selected from inflammatory diseases, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes.
  • the present invention also relates to a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by general formula (I) or its tautomers, mesosomes, racemates, enantiomers to a desired patient Constructs, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.
  • the cancer is selected from breast cancer, cervical cancer, colorectal cancer, and uterine cancer. Endometrial cancer, glioblastoma, head and neck cancer, kidney cancer, liver cancer, lung cancer, medulloblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, and urethral cancer.
  • the compounds according to the present invention can be administered orally, sublingually, intraperitoneally, parenterally, subcutaneously, intramuscularly, intravenously, transdermally, topically, or rectally.
  • the active ingredient may be the same as conventional
  • the pharmaceutical carriers are mixed together and administered to animals or humans in the form of administration units.
  • Suitable administration unit forms include oral forms such as tablets, gel capsules, powders, granules and oral solutions or suspensions, sublingual or oral administration forms, parenteral, subcutaneous, intramuscular, intravenous, and nasal Intra or intraocular administration form and rectal administration form.
  • the main active ingredient is mixed with pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
  • pharmaceutical carriers such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like.
  • the tablets may be coated with sucrose or other suitable materials or processed in such a way that they have prolonged or delayed activity and continuously release a predetermined amount of active ingredient.
  • a gel capsule preparation is obtained by mixing the active ingredient with a diluent and by pouring the obtained mixture into soft or hard capsules.
  • Preparations in the form of syrups or tinctures may contain the active ingredient together with sweetening agents, preservatives, and flavoring agents and appropriate coloring agents.
  • the water-dispersible powders or granules may contain active ingredients mixed with dispersing agents, wetting agents or suspending agents, and with flavoring or sweetening agents.
  • Suppositories are used for rectal administration and are prepared with adhesives that melt at rectal temperature, for example, cocoa butter or polyethylene glycol.
  • Aqueous suspension, isotonic physiological saline solution or sterile and injectable solution which contains pharmacologically compatible dispersing agent and/or wetting agent for parenteral, intranasal or intraocular Apply.
  • the active ingredient (possibly with one or more additive carriers) can also be formulated as microcapsules.
  • the compound of the present invention can be used at a dose between 0.01 mg/day and 1000 mg/day, provided in a single dose/day or administered in several doses throughout the day, for example, the same dose twice a day .
  • the daily dose administered is advantageously between 0.1 mg and 1000 mg, even more advantageously between 2.5 mg and 50 mg. It may be necessary to use dosages outside of these ranges, and those skilled in the art themselves will be aware of this.
  • the pharmaceutical composition may also be formulated for external administration. It can be introduced into the usual forms of the application type (ie, in particular lotions, foams, gels, dispersions, sprays), which have excipients, in particular It can penetrate the skin to improve the properties and accessibility of active ingredients.
  • these compositions usually further comprise a physiologically acceptable medium, which usually comprises water or a solvent, for example, alcohol, ether or glycol.
  • the composition may also include surfactants, preservatives, stabilizers, emulsifiers, thickeners, other active ingredients that produce complementary effects or possible synergistic effects, trace elements, essential oils, fragrances, colorants, collagen, Chemical or mineral filter.
  • stereoisomers refer to geometric isomers (or configuration isomers) or optical isomers.
  • “Geometric isomers” are caused by substituents at different positions on the double bond, which can then have the Z or E configuration, also called cis or trans.
  • Optical isomers are caused in particular by substituents at different steric positions on carbon atoms, said carbon atoms containing four different substituents. This carbon atom constitutes the chiral center or asymmetric center.
  • Optical isomers include diastereomers and enantiomers.
  • Optical isomers that are non-superimposable mirror images of each other are called “enantiomers”.
  • Optical isomers that are not superimposable mirror images of each other are called "diastereomers”.
  • racemic mixture A mixture containing equal amounts of two separate enantiomeric forms of opposite chirality is called a "racemic mixture.”
  • tautomers refer to structural isomers of compounds obtained by proton transfer rearrangement (prototropie), that is, by the migration of hydrogen atoms and the change of the position of the double bond.
  • the different tautomers of the compound are generally mutually convertible and exist in the solution in a balanced manner in proportions, which may vary according to the solvent used, temperature or pH.
  • pharmaceutically acceptable is understood to mean that it is used to prepare pharmaceutical compositions, which are generally safe, non-toxic, biologically or otherwise satisfying and the combination The drug can be accepted for veterinary and human drug use.
  • the "pharmaceutically acceptable salt” of the compound is understood to refer to the following salt, which is a pharmaceutically acceptable (as defined herein) salt and which possesses the expected pharmacological activity of the parent compound.
  • This salt includes:
  • alkali metal ions such as Na + , K + or Li +
  • alkaline earth metal ions such as Ca 2+ or Mg 2+
  • aluminum ions or the salt formed when coordinated with an organic base or an inorganic base.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.
  • Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.
  • halogen means fluorine, bromine, chlorine or iodine atom.
  • C 1-6 alkyl refers to a saturated straight or branched hydrocarbon chain containing 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2 -Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc.
  • C 1-6 alkylene refers to a divalent hydrocarbon chain containing 1 to 6 carbon atoms.
  • Representative examples include, but are not limited to, methylene (-CH 2 -), 1,1-ethylene (-CH(CH 3 )-), 1,2-ethylene (-CH 2 CH 2 )-, 1,1-propylene (-CH(CH 2 CH 3 )-), 1,2-propylene (-CH 2 CH(CH 3 )-), 1,3-propylene (- CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -) and 1,5-butylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), etc.
  • C 2-6 alkenyl refers to a straight or branched hydrocarbon chain having at least one double bond and having 2 to 6 carbon atoms. Representative examples include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
  • C 2-6 alkynyl refers to a straight or branched hydrocarbon chain having at least one triple bond and having 2 to 6 carbon atoms. Representative examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
  • C 1-6 alkoxy refers to -O-(C 1-6 alkyl), wherein the definition of C 1-6 alkyl is as described above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy and the like.
  • halogenated C 1-6 alkyl means that C 1-6 alkyl is substituted by one or more halogens, wherein C 1-6 alkyl and halogen are as defined above.
  • C 3-6 cycloalkyl refers to a saturated or partially unsaturated monocyclic hydrocarbon system containing 3 to 6 carbon atoms. Representative examples include, but are not limited to, cyclohexyl, cyclopentyl, cyclobutyl, Cyclopropyl, cyclohexenyl, etc.
  • 3-6 membered heterocyclyl refers to a heterocyclic group containing 3 to 6 ring atoms, of which 1-3 ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1, or 2) Atomized saturated or partially unsaturated monocyclic hydrocarbon systems, including 3-membered, 4-membered, 5-membered, and 6-membered heterocyclic groups.
  • Representative examples include, but are not limited to, oxirane, pyrrolidinyl, and imidazolidine Group, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, etc.
  • 5-7 membered heterocyclyl refers to a heterocyclic group containing 5 to 7 ring atoms, wherein 1-3 ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is 0, 1, or 2).
  • Atomized saturated or partially unsaturated monocyclic hydrocarbon systems including 5-membered, 6-membered, and 7-membered heterocyclic groups.
  • Representative examples include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, and tetrahydropyran Group, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, etc.
  • C 5-10 aryl refers to a 5- to 10-membered all-carbon monocyclic or fused polycyclic (that is, rings that share adjacent pairs of carbon atoms) groups with a conjugated ⁇ -electron system, including C 6 aryl groups , C 7 aryl, C 8 aryl, C 9 aryl, C 10 aryl, such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring may be fused on a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples of which include:
  • C 6-10 aryloxy refers to -O-(C 6-10 alkyl), wherein the definition of C 6-10 alkyl is as described above.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 10 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen, including 5-membered, 6-membered, 7-membered Member, 8-membered, 9-membered, 10-membered heteroaryl groups, preferably 5-membered or 6-membered heteroaryl groups containing 1 to 2 heteroatoms, such as quinolinyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc.
  • the heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is
  • hydroxyl refers to the -OH group.
  • nitro refers to -NO 2 .
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.
  • the analysis sample was vacuum dried (1-5 mmHg) at room temperature.
  • the monitoring of the reaction progress in the examples adopts thin layer chromatography (TLC).
  • Thin layer chromatography (TLC) was performed on a silica gel plate, and spots were observed by UV light (214 and 254 nm).
  • Column purification and flash chromatography were performed using silica gel (200-300 mesh).
  • the mixed solvent system is reported in volume ratio.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). ( ⁇ ) is given in units of 10 -6 (ppm).
  • the determination solvent is deuterated chloroform (CDCl 3 ), deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) or deuterated acetonitrile (CD 3 CN).
  • the internal standard is tetramethylsilane (TMS).
  • TMS tetramethylsilane
  • the LC/MS instrument used is an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization. Unless otherwise specified, the general LCMS conditions are as follows:
  • Method A Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm ⁇ 4.6 mm ⁇ 3.5 microns); column temperature: 40°C; flow rate: 1.5 mL/min; mobile phase: 95% within 0.8 minutes Change the mixed solvent of [water+0.05% trifluoroacetic acid] and 5% [acetonitrile+0.05% trifluoroacetic acid] to 0% [water+0.05% trifluoroacetic acid] and 100% [CH3CN+0.05% trifluoroacetic acid] Mix the solvent, then keep it under this condition for 0.4 minutes, and finally change it to 95% [water+0.05% trifluoroacetic acid] and 5% [CH3CN+0.05% trifluoroacetic acid], keep it for 0.01 minutes under this condition;
  • Method B Agilent LCMS 1200-6110, column: Waters X-Bridge C18 (50 mm ⁇ 4.6 mm ⁇ 3.5 microns); column temperature: 40°C; flow rate: 2.0 mL/min; mobile phase: 95% within 1.6 minutes Change the mixed solvent of [water+0.05% trifluoroacetic acid] and 5% [acetonitrile+0.05% trifluoroacetic acid] to 0% [water+0.05% trifluoroacetic acid] and 100% [acetonitrile+0.05% trifluoroacetic acid] Mixed solvent, then under this condition for 1.4 minutes, and finally within 0.05 minutes it becomes a mixed solvent of 95% [water+0.05% trifluoroacetic acid] and 5% [acetonitrile+0.05% trifluoroacetic acid], under this condition Hold for 0.7 minutes;
  • Method C Agilent LCMS 1200-6120, column: Waters X-Bridge C18 (50 mm ⁇ 4.6 mm ⁇ 3.5 microns); column temperature: 40°C; flow rate: 2.0 mL/min; mobile phase: 95% within 1.6 minutes [Water+10mM ammonium bicarbonate] and 5% acetonitrile to 0% [water+10mM ammonium bicarbonate] and 100% acetonitrile, then keep under this condition for 1.4 minutes, and finally change to 95% [water+10mM] within 0.1 minutes Ammonium bicarbonate] and 5% acetonitrile and kept under these conditions for 0.7 minutes.
  • Nuclear magnetic resonance instrument Bruker ARX-500 high-resolution mass spectrometer and Bruker ARX-400 high-resolution mass spectrometer.
  • MTT detection instrument Thermo Scientific Multiskan GO full-wavelength microplate reader.
  • the thin layer chromatography silica gel plate uses Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5mm.
  • the reactions are all carried out under an argon atmosphere or a nitrogen atmosphere.
  • the solution in the reaction refers to an aqueous solution.
  • reaction temperature is room temperature.
  • the seventh step 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-3,4-dihydro-5-oxa-1,2a-diazepine Acenaphthylene-7-carboxamide 1
  • the 1-ethyl-3-methyl-1H-pyrazole in the seventh step was replaced by 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid -5-carboxylic acid to obtain compound 2 as a white solid; replace the 1-ethyl-3-methyl- in the seventh step with 3-ethyl-1-methyl-1H-pyrazole-4-carboxylic acid 1H-pyrazole-5-carboxylic acid to obtain compound 3 as a white solid.
  • the sixth step 1-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9-dihydro-7H-6-oxa-2,9a-di Azabenzo[cd]azulene-4-carboxamide 4
  • the fifth step (2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)tert-butyl)ethyl)tert-butyl carbamate 7-5
  • the sixth step 7-(2-aminoethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H- Benzo[d]imidazole-5-carboxamide 7-6
  • the seventh step 7-(2-((N,N-dimethylsulfamoyl)amino)ethoxy)-2-(1-ethyl-3-methyl-1H-pyrazole -5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 7
  • the first step N-(2-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)ethyl)sulfamoyl)tert-butyl carbamate 9-1
  • the second step 2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-7-(2-(sulfamoylamino) Ethoxy)-1H-benzo[d]imidazole-5-carboxamide 9
  • the first step (4-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)butyl) tert-butyl carbamate 10-1
  • the fifth step 1-(4-aminobutyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-7-methoxy-1H-benzene And [d]imidazole-5-carboxamide 10-5
  • the sixth step 1-(4-((N,N-dimethylsulfamoyl)amino)butyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide 10
  • the fifth step (4-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)tert-butyl)butyl)carbamate 13-5
  • the sixth step 7-(4-aminobutoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-propyl-1H- Benzo[d]imidazole-5-carboxamide 13-6
  • the seventh step 7-(4-((N,N-dimethylsulfamoyl)amino)butoxy)-2-(1-ethyl-3-methyl-1H-pyrazole -5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 13
  • the first step (3-(5-carbamoyl-2-chloro-3-nitrophenoxy)propyl) tert-butyl carbamate 15-1
  • 4-chloro-3-hydroxy-5-nitrobenzamide 1-1 (1.0g, 4.62mmol) was dissolved in 15ml DMF, and (1.3mg, 5.54mmol) (5-bromopropyl) tert-butylamino was added Formate, (3.2mg, 23.1mmol) potassium carbonate, heated to 120°C and reacted for 4 hours.
  • the third step (3-(3-amino-5-carbamoyl-2-(propylamino)phenoxy)propyl) tert-butyl carbamate 15-3
  • the fifth step (3-((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H- Benzo[d]imidazol-1-yl)oxy)propyl)tert-butyl carbamate 15-5
  • the sixth step 7-(3-aminopropoxy)-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzene And [d]imidazole-5-carboxamide 15-6
  • the seventh step 7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)-2-(1-ethyl-3-methyl-1H-pyrazole -5-carboxamido)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 15
  • N,N-dimethylsulfamoyl chloride in the seventh step was replaced by pyrrolidine-1-sulfonyl chloride to obtain compound 17 as a pale yellow solid.
  • N,N-dimethylsulfamoyl chloride in the seventh step was replaced by morpholine-4-sulfonyl chloride to obtain compound 18 as a yellow solid.
  • N,N-dimethylsulfamoyl chloride in the seventh step was replaced by methyl(propyl)sulfamoyl chloride to obtain compound 19 as a pale yellow solid.
  • N,N-dimethylsulfamoyl chloride in the seventh step was replaced by diethylsulfamoyl chloride to obtain compound 20 as a white solid.
  • the first step (2-((4-carbamoyl-2-methoxy-6-nitrophenyl)amino)ethyl) tert-butyl carbamate 21-1
  • the third step (2-(2-amino-5-carbamoyl-7-methoxy-1H-benzo[d]imidazol-1-yl)ethylaminomethane Tert-butyl ester 21-3
  • the sixth step 1-(2-((N,N-dimethylsulfamoyl)amino)ethyl)-2-(1-ethyl-3-methyl-1H-pyrazole-5- Carboxamido)-7-methoxy-1H-benzo[d]imidazole-5-carboxamide 21
  • 3-Methyl-1H-pyrazole-5-carboxylic acid methyl ester 24-0 (200mg, 1.4mmol), fluoroethanol (110.7mg, 1.7mmol), triphenylphosphine (550mg, 2.1mmol) were dissolved in tetrahydrofuran ( 20 mL), cool to 0°C, add dimethyl azodicarboxylate (365 mg, 2.1 mmol) dropwise, and stir at room temperature for 12 hours.
  • the obtained 1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxylic acid 24-2 was 220 mg of a white solid with a yield of 59.4%. MS(ESI): 187.2 [M+1] + .
  • the third step (3-((5-carbamoyl-2-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl -1H-Benzo[d]imidazol-7-yl)oxy)propyl)tert-butyl carbamate 24-3
  • the fifth step 7-(3-((N,N-dimethylsulfamoyl)amino)propoxy)-2-(1-(2-fluoroethyl)-3-methyl -1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 24
  • Step 2 Tertiary 3-((5-carbamoyl-3-nitro-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid Butyl ester 25-2
  • the third step tertiary 3-((3-amino-5-carbamoyl-2-(propylamino)phenoxy)methyl)pyrrolidine-1-carboxylic acid Butyl ester 25-3
  • the fifth step 3-(((5-carbamoyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamide)-1-propyl-1H-benzene And [d]imidazol-7-yl)oxy)methyl)pyrrolidine-1-carboxylic acid tert-butyl ester 25-5
  • the seventh step 7-((1-(N,N-dimethylsulfamoyl)pyrrolidin-3-yl)methoxy)-2-(1-ethyl-3-methyl -1H-pyrazole-5-carboxamide)-1-propyl-1H-benzo[d]imidazole-5-carboxamide 25
  • Test Example 1 Determination of Stimulating THP1 Cells to Produce Interferon ⁇
  • the compound to be tested is prepared as a 10 mM DMSO solution and diluted 3 times with DMSO to prepare a solution of 3.3 mM, 1.1 mM, 0.4 mM, 0.1 mM, 0.033 mM, 0.0137 mM and 0.0046 mM
  • -Assay medium RPMI1640 medium and 0.5% HIFBS
  • Example 1 Compound EC 50 ( ⁇ M) ADU-S100 4.2 Example 1 42 Example 2 80 Example 3 100 Example 4 12 Example 5 60 Example 6 300 Example 7 12 Example 8 14.6 Example 9 300 Example 10 124 Example 11 300 Example 12 300 Example 13 4.2 Example 14 3.9 Example 15 3.3 Example 16 4.1 Example 17 2.1 Example 18 4.2 Example 19 8.2 Example 20 2.2 Example 21 300 Example 22 12.7 Example 23 300 Example 25 Untested Example 25 1.8
  • the compound of the present invention has excellent activity and can effectively activate and stimulate THP1 cells to produce interferon ⁇ , thereby having excellent anti-inflammatory and anti-tumor activities.
  • the compound of the present invention has good solubility and is beneficial to absorption in the body. More importantly, it can be formulated into a solution for intratumoral injection to improve the efficacy.

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Abstract

Composé hétérocyclique capable d'améliorer l'activité immunitaire, son procédé de préparation et une application en médecine. De façon spécifique, l'invention concerne un composé représenté par la formule générale (I), un procédé de préparation de celui-ci, et une composition pharmaceutique contenant le dérivé, ainsi que son utilisation en tant qu'agent thérapeutique, en particulier en tant que régulateur de STING et pour le traitement de maladies ou de troubles médiés par STING, tels que l'inflammation, les maladies allergiques et auto-immunes, les maladies infectieuses, les cancers et les syndromes précancéreux. (I)
PCT/CN2020/097941 2019-07-02 2020-06-24 Composé hétérocyclique capable d'améliorer l'activité immunitaire, son procédé de préparation et son application en médecine WO2021000770A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112920172A (zh) * 2021-02-01 2021-06-08 厦门大学 一种干扰素刺激蛋白靶向化合物、其放射性标记物、及它们的制备方法与应用
WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie
US11155567B2 (en) 2019-08-02 2021-10-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
CN115572282A (zh) * 2021-07-05 2023-01-06 华东理工大学 含芳杂环结构的吡唑酰胺类化合物及其制备方法和应用

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WO2017175156A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
CN109071514A (zh) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 用作蛋白质调节剂的杂环酰胺
WO2020038387A1 (fr) * 2018-08-24 2020-02-27 杭州阿诺生物医药科技有限公司 Agoniste de protéine sting à haute activité

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017175156A1 (fr) * 2016-04-07 2017-10-12 Glaxosmithkline Intellectual Property Development Limited Amides hétérocycliques utiles en tant que modulateurs de protéine
CN109071514A (zh) * 2016-04-07 2018-12-21 葛兰素史密斯克莱知识产权发展有限公司 用作蛋白质调节剂的杂环酰胺
WO2020038387A1 (fr) * 2018-08-24 2020-02-27 杭州阿诺生物医药科技有限公司 Agoniste de protéine sting à haute activité

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11155567B2 (en) 2019-08-02 2021-10-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
US11939343B2 (en) 2019-08-02 2024-03-26 Mersana Therapeutics, Inc. Sting agonist compounds and methods of use
WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie
CN112920172A (zh) * 2021-02-01 2021-06-08 厦门大学 一种干扰素刺激蛋白靶向化合物、其放射性标记物、及它们的制备方法与应用
CN115572282A (zh) * 2021-07-05 2023-01-06 华东理工大学 含芳杂环结构的吡唑酰胺类化合物及其制备方法和应用

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