WO2020135715A1 - Composé pour immunité tumorale et son application - Google Patents

Composé pour immunité tumorale et son application Download PDF

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Publication number
WO2020135715A1
WO2020135715A1 PCT/CN2019/129201 CN2019129201W WO2020135715A1 WO 2020135715 A1 WO2020135715 A1 WO 2020135715A1 CN 2019129201 W CN2019129201 W CN 2019129201W WO 2020135715 A1 WO2020135715 A1 WO 2020135715A1
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Prior art keywords
alkyl
alkoxy
alkylthio
alkylamino
pharmaceutically acceptable
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PCT/CN2019/129201
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English (en)
Chinese (zh)
Inventor
郭淑春
刘洋
彭建彪
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上海济煜医药科技有限公司
江西济民可信集团有限公司
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Priority to CN201980009297.9A priority Critical patent/CN111655712B/zh
Publication of WO2020135715A1 publication Critical patent/WO2020135715A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
    • C07F9/6574—Esters of oxyacids of phosphorus
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate

Definitions

  • the present invention relates to the compound represented by formula (I), its optical isomer and its pharmaceutically acceptable salt, and the use of the compound as a STING agonist.
  • STING is activated in three ways: 1) by binding exogenous (3', 3') cyclic dinucleotides (c-diGMP, c-diAMP and c-GAMP) released by invading bacteria or archaea ) Activation, which shows that STING has the role of innate immune activation in anti-infection; 2) by binding (2', 3') cyclic guanosine monophosphate adenosine monophosphate (2', 3'c-GAMP) Activation, which is induced by the presence of circular GMP-AMP dinucleotide synthetase (cGAS) in the presence of foreign double-stranded DNA (eg, released by invading bacteria, viruses, or protozoa) or self-DNA in mammals Endogenous circular dinucleotide, which shows that STING has the effect of innate immunity induced by endogenous or exogenous DNA; 3) activation by binding synthetic ligands.
  • exogenous 3',
  • STING acts as a receptor for DNA in the cytoplasm, and its activation can lead to the activation of two downstream pathways, IRF3 and NF- ⁇ B, to activate the immune system.
  • Activation of the NF- ⁇ B pathway leads to the activation of a series of proinflammatory cytokines downstream, while activation of the IRF3 pathway leads to the activation of type I interferon (IFN- ⁇ / ⁇ ), dendritic cells, cytotoxic cells, NK cells, etc. Activation, thereby exerting an anti-tumor effect.
  • IFN- ⁇ / ⁇ type I interferon
  • the DNA in the human body usually does not activate the STING protein, because under normal circumstances DNA can only exist in the nucleus (except mitochondrial DNA). But if DNA leaks into the cytoplasm, it will activate STING and trigger an immune response. Recently, it was found that radiotherapy and chemotherapy can also activate STING, which may also be caused by DNA leakage in dead tumor cells.
  • the present invention provides the compound represented by formula (I), its optical isomer and its pharmaceutically acceptable salt,
  • L 1 and L 2 are independently selected from -O-, -N(R)- and -C(RR)-;
  • L 3 is selected from
  • R 1 and R 1a are independently selected from H, halogen, OH, NH 2 , CN, N 3 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1- 6 alkylamino and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 2-6 alkynyl Optionally substituted by 1, 2 or 3 R;
  • R 2 and R 2a are independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino And C 2-6 alkynyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, or C 2-6 alkynyl is optionally substituted 1, 2, or 3 R substitutions;
  • R 3 and R 3a are independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino And C 2-6 alkynyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, or C 2-6 alkynyl is optionally substituted 1, 2, or 3 R substitutions;
  • R 4 and R 4a are independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino And C 2-6 alkynyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, or C 2-6 alkynyl is optionally substituted 1, 2, or 3 R substitutions;
  • R 5 and R 5a are independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino And C 3-6 cycloalkyl, wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 3-6 cycloalkyl Choose to be replaced by 1, 2 or 3 R;
  • X 1 is selected from BH 3 - and -S(R 6 );
  • R 6 is selected from H, CH 2 OC( ⁇ O)R 7 , CH 2 OC( ⁇ O)OR 7 , CH 2 CH 2 SC( ⁇ O)R 7 and CH 2 CH 2 SSCH 2 R 7 ;
  • R 7 is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 1-6 heterocycloalkyl and C 1 - 20 alkyl group, wherein the C 1 - 20 alkyl optionally substituted with 1,2 , 3, 4 or 5 C 6-10 aryl, C 3-10 cycloalkyl, OH and F substitutions;
  • R 1 and R 4 are connected together to form a 5-6 membered heterocycloalkyl
  • R 1a and R 4a are joined together to form a 5-6 membered heterocycloalkyl
  • R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, and C 1-6 alkyl-(C ⁇ O)NH-, wherein the C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino or C 1-6 alkyl-(C ⁇ O)NH- is optionally substituted by 1, 2 or 3 R'substitution;
  • R' is selected from F, Cl, Br, I, OH, NH 2 and CH 3 ;
  • the above R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, Where Me, It can be optionally substituted with 1, 2 or 3 R', and other variables are as defined in the present invention.
  • the above R is independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, Me, Other variables are as defined in the present invention.
  • R 1 and R 1a are independently selected from H, F, Cl, Br, OH, NH 2 , CN, N 3 , C 1-3 alkyl, and C 1-3 alkoxy , C 1-3 alkylthio, C 1-3 alkylamino and C 2-3 alkynyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, C The 1-3 alkylamino group or C 2-3 alkynyl group is optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.
  • R 1 and R 1a are independently selected from H, F, Cl, Br, OH, NH 2 , CN, N 3 , Me and Other variables are as defined in the present invention.
  • R 5 and R 5a are independently selected from H, F, Cl, Br, OH, NH 2 , CN, N 3 , C 1-3 alkyl, and C 1-3 alkoxy , C 1-3 alkylthio, C 1-3 alkylamino and C 3-6 cycloalkyl, wherein the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylthio, The C 1-3 alkylamino group or C 3-6 cycloalkyl group is optionally substituted with 1, 2, or 3 R, and other variables are as defined in the present invention.
  • R 5 and R 5a are independently selected from H, F, Cl, Br, OH, NH 2 , CN, N 3 , Me, Other variables are as defined in the present invention.
  • L 1 and L 2 are independently selected from -O-, -NH- and -CH 2- , and other variables are as defined in the present invention.
  • the above L 3 is selected from Other variables are as defined in the present invention.
  • the above compound, its optical isomer and its pharmaceutically acceptable salt are selected from
  • X 1 , R 1 , R 1a , R 4 , R 4a , R 5 , R 5a , L 1 , L 2 , L 3 are as defined above.
  • the present invention provides compounds of the following formula, their optical isomers and their pharmaceutically acceptable salts, which are selected from
  • the present invention also provides a pharmaceutical composition containing the above compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition in the preparation of a medicament for preventing and/or treating STING-related diseases.
  • the aforementioned STING-related diseases are selected from the group consisting of lymphoma, melanoma, colorectal cancer, breast cancer, acute myeloid leukemia, colon cancer, liver cancer, prostate cancer, pancreatic cancer, renal cancer, and glioma , Bladder cancer, pleural effusion, malignant pleural effusion, head and neck cancer, fibrosarcoma, renal cell carcinoma, lung cancer, malignant ascites, gastric cancer, ovarian cancer, uterine cancer, optic neuroblastoma, bone cancer, rhabdomyosarcoma and esophageal cancer.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Bisulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and other similar acids; also includes salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can be converted to any
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl. All these isomers and mixtures thereof are included in the scope of the present invention.
  • a solid wedge key And wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys And straight dotted keys Represents the relative configuration of the three-dimensional center, with wavy lines Represents a solid wedge key Or wedge-shaped dashed key Or with wavy lines Represents a straight solid line key And straight dotted keys Dotted line Indicates the site to be connected.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can quickly convert to each other. If tautomers are possible (as in solution), the chemical equilibrium of tautomers can be achieved.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as ketone-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers (valence tautomer) include some recombination of bond-forming electrons for mutual conversion.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “isomer enriched”, “rich in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or pairs
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the excess of isomer or enantiomer (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide pure The desired enantiomer.
  • a diastereomer salt is formed with an appropriate optically active acid or base, and then by conventional methods known in the art The diastereomers are resolved and the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography that uses a chiral stationary phase and is optionally combined with chemical derivatization methods (eg, amino groups from amines) Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes in one or more atoms constituting the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • the hydrogen can be replaced by heavy hydrogen to form a deuterated drug.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have lower toxicity and increase drug stability. , Strengthen efficacy, prolong the biological half-life of drugs and other advantages.
  • the conversion of all isotopic compositions of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.
  • “Optional” or “optionally” means that the subsequently described event or condition may, but need not necessarily occur, and the description includes situations where the event or condition occurs and conditions where the event or condition does not occur.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include heavy hydrogen and hydrogen variants, as long as the valence state of the particular atom is normal and the compound after substitution is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical realization.
  • any variable (such as R) appears more than once in the composition or structure of a compound, its definition in each case is independent.
  • R in each case has independent options.
  • substituents and/or variants thereof are only allowed if such combinations will produce stable compounds.
  • connection direction is arbitrary, for example,
  • the linking group L in the middle is -MW-, then -MW- can be formed by connecting the benzene ring and cyclopentane in the same direction as the reading order from left to right It can also be formed by connecting the benzene ring and cyclopentane in the opposite direction to the reading order from left to right
  • Combinations of the linking group, substituents, and/or variants thereof are only allowed if such a combination will produce a stable compound.
  • the number of atoms on a ring is usually defined as the number of members of the ring.
  • “5-6 membered ring” refers to a “ring” with 5-6 atoms arranged around it.
  • 5-6 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl consisting of 5 to 6 ring atoms Radical or heteroaryl.
  • the ring includes a single ring, and also includes a bicyclic ring system such as a spiro ring, a parallel ring, and a bridge ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 5-6 member ring includes 5 member, 6 member ring and the like.
  • 5-6 membered ring includes, for example, phenyl, pyridyl, piperidinyl, and the like; on the other hand, the term “5-6 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, where each "ring” independently conforms to the above definition.
  • C 1-20 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 20 carbon atoms.
  • the C 1-20 alkyl group includes C 1-10 , C 1-9 , C 1-8 , C 1-6 , C 1-5 , C 1-14 , C 1-3 , C 1-2 , C 2-16 , C 2-4 , C 10 , C 8 , C 7 , C 6 and C 5 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent ( Such as methine).
  • C 1-20 alkyl groups include but are not limited to methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, heptyl, octyl and so on.
  • Me methyl
  • Et ethyl
  • propyl including n-propyl and isopropyl
  • butyl including n-butyl, isobutyl , S-butyl and t-butyl
  • pentyl including n-pentyl, isopentyl and neopentyl
  • hexyl heptyl, octyl and so on.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups; etc.; Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and so on.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • heteroalkyl by itself or in combination with another term means a stable linear or branched alkyl radical consisting of a certain number of carbon atoms and at least one heteroatom or heteroatom group or a combination thereof.
  • the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • the heteroalkyl is C 1-6 heteroalkyl; in other embodiments, the heteroalkyl is C 1-3 heteroalkyl.
  • the heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including the attachment position of the alkyl group to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkane Oxygen) is a conventional expression and refers to those alkyl groups that are connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through one oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • C 1- 6 alkoxy groups include but are not limited to methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, etc.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule by one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through an amino group.
  • the C 1-6 alkylamino group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkyl amino groups Wait.
  • C 1-6 alkylamino examples include but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 ) ( CH 2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3, etc.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include but are not limited to -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 ,- NHCH 2 (CH 3 ) 2 etc.
  • C 1-6 alkylthio refers to those alkyl groups containing 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom.
  • the C 1-6 alkylthio group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkane Sulfur-based.
  • Example C 1- 6 alkylthio include, but are not limited to, -SCH 3, -SCH 2 CH 3, -SCH 2 CH 2 CH 3, -SCH 2 (CH 3) 2 and the like.
  • C 1-3 alkylthio refers to those alkyl groups containing 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 and the like.
  • C 2-6 alkynyl is used to denote a linear or branched hydrocarbon group consisting of at least one carbon-carbon triple bond consisting of 2 to 6 carbon atoms, a carbon-carbon triple bond It can be located anywhere on the group.
  • the C 2-6 alkynyl group includes C 2-4 , C 2-3 , C 4 , C 3 and C 2 alkynyl groups. It can be monovalent, divalent or multivalent. Examples of C 2-6 alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms Are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms, wherein nitrogen atoms are optionally quaternized, and nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p Is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro ring, parallel ring and bridge ring.
  • the hetero atom may occupy the connection position of the heterocyclic alkyl group to the rest of the molecule.
  • the 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.) , Tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -Piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydr
  • C 6-10 aromatic ring and “C 6-10 aryl group” of the present invention may be used interchangeably.
  • the term “C 6-10 aromatic ring” or “C 6-10 aryl group” means A cyclic hydrocarbon group consisting of 6 to 10 carbon atoms with a conjugated ⁇ -electron system. It can be a monocyclic ring, fused bicyclic ring or fused tricyclic ring system, where each ring is aromatic. It may be monovalent, divalent, or polyvalent, and C 6-10 aryl groups include C 6-9 , C 9 , C 10, and C 6 aryl groups. Examples of C 6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl, 2-naphthyl, etc.).
  • 5-10 membered heteroaryl ring and “5-10 membered heteroaryl group” of the present invention may be used interchangeably.
  • the term “5-10 membered heteroaryl group” means from 5 to 10 rings Atom-containing cyclic groups with a conjugated ⁇ -electron system. 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. It can be a monocyclic ring, fused bicyclic ring or fused tricyclic ring system, where each ring is aromatic.
  • nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or carbon atom.
  • the 5-10 membered heteroaryl group includes 5-8 membered, 5-7 membered, 5-6 membered, 5 membered, and 6 membered heteroaryl groups.
  • Examples of the 5-10 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyryl Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazoly
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-6 includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 , including any range from n to n+m, for example, C 1-6 includes C 1-3 , C 1-6 , C 1-4 , C 3-6 , C 3- 5 , C 2- 5 and C 1-5, etc.; in the same way, n to n+m means that the number of atoms in the ring is n to n+m, for example, 5-6 member ring includes 5 member ring and 6 member ring .
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination with other chemical synthesis methods and well known to those skilled in the art Equivalently, preferred embodiments include but are not limited to the embodiments of the present invention.
  • CDCl 3 stands for deuterated chloroform
  • CD 3 OD stands for deuterated methanol
  • DMSO-d 6 stands for deuterated dimethyl sulfoxide
  • Bz stands for benzoyl
  • TBS stands for tert-butyl dimethyl Silyl
  • DMTr stands for 4,4'-bismethoxytrityl
  • CE stands for cyanoethyl
  • BSA stands for N,O-bistrimethylsilylacetamide
  • DMTrCl stands for 4,4'-bismethoxytris Benzyl chloride
  • DIAD stands for diisopropyl azodicarboxylate
  • DDTT stands for (E)-N,N-dimethyl-N'-(3-thio-3H-1,2,4-dithiazole -5-yl)formamidine
  • ADDP stands for azodicarbonyl dipiperidine.
  • HPLC Column: YMC-Pack ODS-A 150*4.6mm, 5um, mobile phase: water (0.06875% trifluoroacetic acid)-acetonitrile (0.0625% trifluoroacetic acid); flow rate: 1.0mL/min; detection wavelength: UV 220nm&215nm&254nm; column temperature: 40°C.
  • compound 1-2 (2g, 2.96mmol) and imidazole (302.25mg, 4.44mmol) were dissolved in N,N-dimethylformamide (10mL), and then tert-butyldimethylchlorosilane was added (669.18mg, 4.44mmol), the reaction system was heated to 25 °C and stirred for 24h.
  • compound 1-1 (2g, 5.36mmol) and imidazole (547.04mg, 8.04mmol) were dissolved in N,N-dimethylformamide (10mL), and tert-butyldimethylchlorosilane ( 888.17mg, 5.89mmol), after addition, the reaction was warmed to 25 °C and stirred for 24h.
  • compound 1-6 (4.8g, 3.61mmol) was dissolved in dichloromethane (50mL), water (650.35mg, 36.10mmol, 650.35 ⁇ L) was added, and then dichloroacetic acid (2.47g, 10.83) was added dropwise mmol) (5% dichloroacetic acid solution), after the addition is complete, the reaction is stirred for 30 min. Triethylsilane (4.20g, 36.10mmol, 5.77mL) was added, and the reaction was continued to stir for 30min.
  • compound 1-7 (386.30mg, 376.04 ⁇ mol) was dissolved in tetrazole in acetonitrile solution (0.45M, 25.00mL), 4A molecular sieve (1g) was added, and then 2- A solution of cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite (226.69 mg, 752.09 ⁇ mol, 238.87 ⁇ L) in acetonitrile (0.5 mL) was stirred and reacted for 2 h. Add DDTT to continue the reaction for 1h.
  • compound 1-8 (450 mg, 388.48 ⁇ mol) was dissolved in tetrahydrofuran (12 mL), and acetic acid (699.87 mg, 11.65 mmol, 666.54 ⁇ L) and tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.17 mL) were added ), the reaction was stirred for 12h.
  • compound 1-9 (300mg, 322.64 ⁇ mol) was dissolved in acetonitrile (3mL), followed by 4A molecular sieve (500mg), tetrazolium (0.45M acetonitrile solution, 14.03mL), then A solution of 2-cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite (145.87 mg, 483.95 ⁇ mol, 153.71 ⁇ L) in acetonitrile (0.5 mL) was added dropwise, and the reaction was stirred for 1 h.
  • compound 1-10 (350mg, 340.18 ⁇ mol) was dissolved in dichloromethane (8mL), followed by 4A molecular sieve (500mg), borane dimethyl sulfide complex (2M di Chloromethane solution, 680.36 ⁇ L), and stirred for 10 min.
  • the reaction was quenched with water (0.5 mL), diluted with dichloromethane (20 mL), filtered, the filtrate was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude product 1-11, without further purification of the product , Directly used in the next reaction.
  • compound 1-3 (7g, 8.86mmol) was dissolved in tetrahydrofuran (70mL), and 1,4-butynediol (1.53g, 17.72mmol) and ADDP (4.47g, 17.72mmol), after addition, tri-tert-butylphosphine (3.59g, 17.72mmol, 4.37mL) was added dropwise, and the temperature was raised to 30°C for 20h.
  • compound 2-1 (4.8g, 5.59mmol) was dissolved in tetrahydrofuran (50mL), and compound 1-5 (3.55g, 7.27mmol) and triphenylphosphine (4.40g, 16.78mmol), after addition, DIAD (3.39g, 16.78mmol, 3.26mL) was added dropwise, and the reaction was carried out at this temperature for 16h.
  • reaction solution was diluted with ethyl acetate (300 mL), washed sequentially with saturated aqueous sodium bicarbonate solution (100 mL x 3), saturated brine (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • compound 2-2 (3.5 g, 2.64 mmol) was dissolved in methylene chloride (40 mL), dichloroacetic acid (1.81 g, 7.91 mmol, 5% methylene chloride solution) was added, and the reaction solution was stirred for 1 h After that, triethylsilane (3.07g, 26.36mmol, 4.21mL) was added, and the reaction system was continued to stir for 15min.
  • borane dimethyl sulfide complex (2M in dichloromethane, 555 ⁇ L) was added dropwise to compound 2-6 (380 mg, 370.06 ⁇ mol) and 4A molecular sieve (0.5 g) in dichloromethane (25 mL) In the solution, the reaction system was added and stirred at 0°C for 15 min.
  • reaction solution was filtered to remove molecular sieves, and the filtrate was washed with saturated sodium bicarbonate solution (50 mL x 3) and saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 2-7, without After further purification, it was directly used in the next reaction.
  • Step 8 Preparation of compounds 2A, 2B, 2C and 2D
  • reaction solution was diluted with ethyl acetate (50 mL), filtered, and the filtrate was washed with saturated sodium bicarbonate solution (50 mL) and saturated brine (50 mL) in this order, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude product 3- 4. Used for the next reaction without further purification.
  • borane dimethyl sulfide complex (2M dichloromethane solution, 272.73 ⁇ L) was added dropwise to compound 3-4 (150 mg, 148.42 ⁇ mol) and 4A molecular sieve (0.2 g) in dichloromethane (4 mL ) In the solution, add the reaction system and stir at 0°C for 10 min.
  • the reaction solution was diluted with dichloromethane (20 mL), filtered to remove the molecular sieve, the filtrate was washed with water (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 3-5, which was directly used in the next step without further purification reaction.
  • Chromatography column Xbridge Prep OBD C18 150*40 mm 10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0%-40%, flow rate: 25mL/min, 25min); 2) Chromatography column: Xbridge, Prep, OBD, C18, 150*40mm, 10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 0%-50%, flow rate: 25mL/min, 30min) ⁇ .
  • compound 1-9 400mg, 430.18umol was added to the mixed solution of 4A molecular sieve (500mg) and tetrazolium (0.45M acetonitrile solution, 9.56mL), and then added dropwise 2- A solution of cyanoethyl N,N,N',N'-tetraisopropylphosphoramidite (259.32 mg, 860.36 umol, 273.26 uL) in acetonitrile (2.0 mL) was stirred and reacted for 2 h. DDTT (264.98mg, 1.29mmol) was added to continue stirring the reaction for 1h.
  • reaction solution was diluted with methylene chloride (100 mL), then washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Fluorescence polarization test (fluorescence polarization assay, FP assay) was used to detect the affinity of compounds for human STING protein. There is a certain amount of fluorescein-labeled c-di-GMP and different concentrations of test compounds in the reaction system. When the recombinant human STING C-terminal protein is added, the two small molecules competitively bind to the protein. The bound fluorescein-labeled c-di-GMP rotates slowly in the liquid phase, and the degree of fluorescence polarization detected is also high at this time. The degree of fluorescence polarization is inversely proportional to the concentration and affinity of the test compound. By detecting the magnitude of polarized light in the reaction system, we can accurately know the affinity of the test compound for human STING.
  • the soluble human STING protein sequence used in the experiment was intercepted from the C-terminal part of human wild-type endoplasmic reticulum binding protein STING, from 140 amino acids to 379 amino acids.
  • Human STING protein has a variety of alleles with different sequence differences. Different alleles have different affinity for CDN (Yi, et.al., "Single Nucleotide Polymorphisms of Human STING can affect immunological responses" to cyclic dinucleotides"PLOSONE.2013, 8(10), e77846). Wild-type STING sequences (G230, R232, R293) account for approximately 57.9% of the total.
  • the N-terminus of the recombinant STING protein is a 6His-SUMO sequence, which facilitates the correct folding and purification of the protein. After protease excision, the C-terminus STING is used for FP testing.
  • a 384-well plate was used, and a 10 ⁇ l reaction system was added with a final concentration of 30 nM fluorescein-labeled c-di-GMP, 10 ⁇ M human STING protein, and different concentrations of reference compound or test compound. Centrifuge at 1000g for 1 minute, incubate at room temperature in the dark for 30 minutes, and read the plate with Envision.
  • the THP1-Dual TM cells (InvivoGen catalog code: thpd-nfis) used in the test were constructed by stably integrating two inducible reporter genes in the human monocyte cell line THP1.
  • the promoter sequence of the secreted embryonic alkaline phosphatase (SEAP) reporter gene consists of an IFN- ⁇ basic promoter and 5 copies of the NF- ⁇ B consensus transcriptional response element upstream (NF- ⁇ B consensus transcriptional response element) And 3 copies of the c-Rel binding site.
  • SEAP secreted embryonic alkaline phosphatase
  • the secreted luciferase (Lucia) reporter gene is driven by five interferon (IFN)-stimulated response elements and an ISG54 basic promoter. This makes it possible to study the two main downstream signaling pathways of STING at the same time: to study the NF ⁇ B pathway by detecting the activity of SEAP: and to study the IRF pathway by evaluating the activity of Lucia luciferas
  • the compound was diluted with PB buffer (50 mM HEPES, 100 mM KCl, 3 mM MgCl2, 0.1 mM DTT, 85 mM Sucrose, 1 mM ATP, 0.1 mM GTP, 0.2% BSA).
  • PB buffer 50 mM HEPES, 100 mM KCl, 3 mM MgCl2, 0.1 mM DTT, 85 mM Sucrose, 1 mM ATP, 0.1 mM GTP, 0.2% BSA.
  • the compounds of the present invention can activate STING and promote the production of interferon beta.
  • the RAW-Dual TM cells (InvivoGen catalog code: rawd-ismip) used in the test were constructed by stably integrating two inducible reporter genes in the mouse macrophage cell line RAW264.7: the NF-KB pathway was studied by detecting SEAP activity, And study the IRF3 pathway by evaluating Lucia luciferase activity.
  • the suspension of cells (50,000 cells per well) was added to a 96-well plate (Corning 3599 flat bottom plate) at 200 ⁇ L per well, and cultured in a 37°C incubator for 18 to 24 hours.
  • the culture medium was discarded, and 200 ⁇ L of the compound solution prepared with the medium was added to each well, incubated at room temperature for 30 minutes, the treatment liquid was aspirated, washed twice with serum-free culture medium, and then 200 ⁇ L of culture medium was added to each well, 37 Cultivate in an incubator for 18 to 24 hours.
  • 20 ⁇ L of supernatant was taken from each well, and the activation of IRF3 pathway was quantified using QUANTI-LucTM according to the manufacturer's instructions.

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Abstract

L'invention concerne un composé représenté par la formule (I), des isomères optiques de celui-ci, des sels pharmaceutiquement acceptables de celui-ci, et une application du composé en tant qu'agoniste de STING. (I)
PCT/CN2019/129201 2018-12-29 2019-12-27 Composé pour immunité tumorale et son application WO2020135715A1 (fr)

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WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018098203A1 (fr) * 2016-11-25 2018-05-31 Janssen Biotech, Inc. Dinucléotides cycliques en tant qu'agonistes de sting
CN108137641A (zh) * 2015-08-13 2018-06-08 默沙东公司 作为sting激动剂的环状双核苷酸化合物
WO2018152450A1 (fr) * 2017-02-17 2018-08-23 Eisai R&D Management Co., Ltd. Composés dinucléotidiques cycliques pour le traitement du cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108137641A (zh) * 2015-08-13 2018-06-08 默沙东公司 作为sting激动剂的环状双核苷酸化合物
WO2018098203A1 (fr) * 2016-11-25 2018-05-31 Janssen Biotech, Inc. Dinucléotides cycliques en tant qu'agonistes de sting
WO2018152450A1 (fr) * 2017-02-17 2018-08-23 Eisai R&D Management Co., Ltd. Composés dinucléotidiques cycliques pour le traitement du cancer

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021206158A1 (fr) 2020-04-10 2021-10-14 小野薬品工業株式会社 Méthode de cancérothérapie

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