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WO2018198084A1 - Composés di-nucléotidiques cycliques avec des nucléobases tricycliques - Google Patents

Composés di-nucléotidiques cycliques avec des nucléobases tricycliques Download PDF

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Publication number
WO2018198084A1
WO2018198084A1 PCT/IB2018/052936 IB2018052936W WO2018198084A1 WO 2018198084 A1 WO2018198084 A1 WO 2018198084A1 IB 2018052936 W IB2018052936 W IB 2018052936W WO 2018198084 A1 WO2018198084 A1 WO 2018198084A1
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Prior art keywords
purin
formula
oxo
dihydro
alkyl
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Inventor
Neelima Sinha
Navnath Popat Karche
Sanjay Pralhad KURHADE
Ganesh Rajaram Jadhav
Anil Kashiram HAJARE
Nishant Ramniwasji GUPTA
Baban Rupaji THUBE
Javed Shafi SHAIKH
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Ltd
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Lupin Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • 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

Definitions

  • the present invention relates to cyclic di-nucleotide compounds containing tricyclic heterocycles as nucleobase and having the general Formula (I), (II) and (III) and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, and their combination with suitable medicament, corresponding processes for the synthesis and pharmaceutical compositions and uses of compounds containing the present invention.
  • Stimulator of interferon genes is a signaling molecule that in humans is encoded by TMEM173 gene.
  • STING is protein with 379 amino acids, consisting of several transmembrane regions. STING protein is expressed in several endothelial and epithelial cell types, as well as in haematopoietic lineage, such as T cells, dendritic cells (DCs) including plasmacytoid dendritic cells (pDCs) and macrophages.
  • DCs dendritic cells
  • pDCs plasmacytoid dendritic cells
  • STING is associated with endoplasmic reticulum (ER) in the cell and has a major role in controlling the transcription of numerous host defence genes, including type I interferons (IFNs) and pro-inflammatory cytokines.
  • IFNs type I interferons
  • STING has been shown to undergo single nucleotide polymorphisms which gives rise to variants that have been characterized in humans: R71H-G230A-R293Q (HAQ), R232H, G230A-R293Q, R293Q and I200N (PLoS ONE 2013, 8(10): e77846; J Inflamm (Lond), 2017, 7, 14:11).
  • Cytosolic DNA species can activate STING signaling following binding to cyclic GMP–AMP synthase (cGAS). Binding of cytosolic DNA to cGAS catalyses the production of a type of CDN known as cGAMP (cyclic GMP–AMP), which contains one 2 ⁇ ,5 ⁇ - phosphodiester linkage and a canonical 3 ⁇ ,5 ⁇ linkage (c[G(2 ⁇ ,5 ⁇ )pA(3 ⁇ ,5 ⁇ )p]). The binding of cGAMP and other bacterial CDNs induce changes in the conformation of STING protein and facilitates the binding of TANK-binding kinase 1 (TBK1).
  • cGAMP cyclic GMP–AMP
  • STING-TBK1 complex further transposes to perinuclear regions of the cell to transport TBK1 to endolysosomal compartments where it phosphorylates the transcription factors like, interferon regulatory factor 3 (IRF3).
  • IRF3 interferon regulatory factor 3
  • STAT6 and nuclear factor- ⁇ B also get activated downstream to STING activation.
  • mice have shown that type I IFN signaling plays an important role in tumor-initiated T cell priming and tumor control (J. Exp. Med.2011, 208, 1989–2003).
  • Mice lacking the IFN- ⁇ / ⁇ receptor in dendritic cells (DCs) failed to reject immunogenic tumors, and CD8 ⁇ + DCs from these mice are defective in antigen cross-presentation to CD8+ T cells.
  • DCs dendritic cells
  • Numerous studies have demonstrated that activation of the STING pathway in tumor-resident host APCs is required for induction of a spontaneous CD8+ T cell response against tumor-derived antigens in vivo (Immunity, 2014, 41, 830–842).
  • TILs tumor-infiltrating lymphocytes
  • STING activation partially contributing to the antitumor activity of chemotherapeutic agents as well as radiotherapy (Immunity, 2014, 41, 843–852). Further, STING activation and signaling has been discovered to be essential for protection against the development of cancer by promoting antitumor immune responses.
  • STING mediated activation of innate immunity also primes promotes adaptive immune activation, enhanced systemic immune surveillance leading to abscopal effect, or the regression of distant, untreated tumors (J Immunother Cancer, 2014, 2(Suppl 3): P158).
  • MDSCs myeloid derived suppressor cells
  • STING activation is also known to effectively restrict the migration and metastasis of breast cancer and brain metastatic cancer via.
  • NF- ⁇ B signaling induced cell death (Cancer Lett., 2017, 28, 402:203-212). So activation of STING represents a potential immunotherapy approach for cancer treatment.
  • the present invention relates to compounds of general Formula (I), Formula (II) or Formula (III), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, hydrate, solvate, or its prodrug
  • B1 and B2 are independently selected from formula (i)-(xviii) provided that at least one of B1 or B2 is selected from formula (i)-(vi)
  • X is selected from the group consisting of CR or N ;
  • Xb is -NR8c-
  • Xc is selected from the group consisting of -O- or -S-;
  • X1 and X2 are independently selected from the -O-, -C-, or -S-;
  • X3 is selected from the group consisting of -O- , -S- , -OR9, and -SR9;
  • X4 and X5 are selected from the group consisting of O or S;
  • Y is selected from the group consisting of -O-, -S-, -C(R10)2-, and -CF2-;
  • ring A is selected from substituted- or unsubstituted five to eight membered heterocycle or heteroaryl
  • ring B is selected from substituted- or unsubstituted- aryl, substituted- or unsubstituted- five to six membered heteroaryl, substituted- or unsubstituted five to eight membered carbocycle, and substituted- or unsubstituted five to eight membered heterocycle;
  • R1 and R1a are independently selected from hydrogen, perhaloalkyl, and substituted- or unsubstituted- alkyl;
  • R6 and R6a are independently selected from hydrogen, halogen, -OR8b, perhaloalkyl, and substituted- or unsubstituted- alkyl;
  • R8a is selected from substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocycle;
  • R8b is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, substituted- or unsubstituted- heterocycle, or when two R8b groups are attached to the nitrogen atom they can form a substituted- or unsubstituted- heterocycle;
  • R8c is selected from hydrogen, substituted- or unsubstituted- alkyl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocycle;
  • R9 is selected from hydrogen, and substituted- or unsubstituted- alkyl
  • R10 is selected from hydrogen, substituted- or unsubstituted- alkyl, or two R10 groups together with the carbon atom to which they are attached form a substituted- or unsubstituted- carbocycle
  • n is an integer selected from 1, 2, or 3;
  • each R11 is independently selected from hydrogen, alkyl, and cycloalkyl
  • each R11a is independently selected from alkyl, perhaloalkyl and cycloalkyl; R11b is selected from hydrogen, alkyl, perhaloalkyl, and cycloalkyl.
  • the invention relates to a compound of Formula (I), Formula (II) or Formula (III), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, hydrate, solvate, or its prodrug
  • B1 and B2 are independently selected from formula (i), (vii), (viii) and (xi) provided that at least one of B1 or B2 is formula (i)
  • Xa, Xb , X1, X2 ,X3 ,X4, Y, ring A, R1, R1a , R2, R2a, R3, R4, R4a, R5, R6, R6a and R7 are as defined above.
  • the invention relates to a compound of Formula (I), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, hydrate, solvate, or its prodrug
  • B1 and B2 are independently selected from formula (i), (vii), (viii) and (xi) provided that at least one of B1 or B2 is formula (i)
  • the invention relates to a compound of Formula (II), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, hydrate, solvate, or its prodrug
  • B1 and B2 are independently selected from formula (i), (vii), and (viii) provided that at least one of B1 or B2 is formula (i) X5 is O;
  • Xa, Xb , X1, X2 ,X3 ,X4, Y, ring A, R1, R1a , R2, R2a, R3, R4, R4a, R5, R6, R6a and R7 are as defined above.
  • the invention provides a compound of Formula (I), Formula (II) and Formula (III), or its pharmaceutically acceptable salt , wherein at least one of B1 or B2 are independently selected from
  • the invention provides a compound of formula (I), (II) and (III), or its pharmaceutically acceptable salt, wherein R3 is hydrogen, halogen, -OTBS, -OR8b, or substituted- or unsubstituted- alkyl.
  • the invention provides a compound of formula (I), (II) and (III), or its pharmaceutically acceptable salt, wherein R4, R4a or R5are hydrogen, halogen, -OTBS, -OR8b, or substituted- or unsubstituted- alkyl.
  • the invention provides a compound of formula (I), (II) and (III), or its pharmaceutically acceptable salt, wherein R1, R1a, R6 or R6a are hydrogen.
  • R2a is hydrogen or halogen
  • R3 is hydrogen, halogen, -OTBS, -OR8b, or substituted- or unsubstituted- alkyl
  • R4, R4a or R5 are hydrogen, halogen, -OTBS, -OR8b, or substituted- or unsubstituted- alkyl
  • R1, R1a, R6 or R6a are hydrogen and B1 and B2 are independently selected from formula (i), (vii), (viii) and (xi) provided that at least one of B1 or B2 is formula (i)
  • R2a is hydrogen or halogen
  • R3 is hydrogen, halogen, -OTBS, -OR8b, or substituted- or unsubstituted- alkyl
  • R4 or R4a are hydrogen, halogen, -OR8b, or substituted- or unsubstituted- alkyl
  • R1, R1a, R6 or R6a are hydrogen and B1 and B2 are independently selected from formula (i), (vii), and (viii) provided that at least one of B1 or B2 is formula (i)
  • w eren s ; a s– - or– - an s - c-, w eren c is hydrogen.
  • the invention provides a compound of Formula (I), Formula (II) or Formula (III), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, hydrate, solvate, or its prodrug, wherein the compound is selected from: ’ ’
  • the invention provides a compound of Formula (I), Formula (II) or Formula (III), its tautomeric form, its stereoisomer, its pharmaceutically acceptable salt, hydrate, solvate, or its prodrug, wherein the compound is selected from:
  • the present invention provides a pharmaceutical composition comprising a compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof and one or more of pharmaceutically acceptable excipients.
  • the present invention provides a compound of Formula (I), Formula (II) and Formula (III), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition in which activation of STING is beneficial.
  • the present invention provides the use of a compound or pharmaceutical composition of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or condition in which activation of STING is beneficial.
  • the present invention provides a method of treatment of a disease or condition in which activation of STING is beneficial in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (II) and Formula (III) or its pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment of disease or condition selected from cancer and infectious diseases, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), Formula (II) and Formula (III) or its pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment of cancer such as solid tumors, leukemias and lymphomas.
  • the invention provides a method of treatment of infectious diseases such as viral infection or bacterial infection.
  • the invention provides a composition comprising compound of Formula (I), Formula (II) and Formula (III), or its pharmaceutically acceptable salt thereof, and one or more additional therapies.
  • the invention provides a composition comprising compound of Formula (I), Formula (II) and Formula (III), or a pharmaceutically acceptable salt thereof, and one or more additional therapies such as chemotherapy, immunotherapy or radiotherapy.
  • the invention provides a vaccine adjuvant comprising a compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof.
  • the invention provides a vaccine composition comprising compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof, and an antigen or antigen composition.
  • DMOCP 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane-2-oxide
  • the abbreviated monomers can be prepared using their respective protected mononers by methods known in the art.
  • IUPAC names of the compounds were derived using ACD Labs name, software module: ACD name, version: 2017.2.1.
  • a compound of Formula (I), Formula (II) and Formula (III), or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or condition in which activation of STING is beneficial.
  • a method of the treatment of a disease or condition in which activation of STING is beneficial in a subject comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (II) and Formula (III) or its pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment of disease or condition selected from cancer and infectious diseases, in a mammal in need thereof, which comprises administering to such mammal a therapeutically effective amount of a compound of Formula (I), Formula (II) and Formula (III) or its pharmaceutically acceptable salt thereof.
  • the invention provides a method of treatment cancer such as solid tumors, leukemias and lymphomas.
  • the invention provides a method of treatment of infectious diseases such as viral infection or bacterial infection.
  • solid tumors which may be treated with the compounds of present invention include, but are not limited to, breast cancer, pancreatic cancer, lung cancer, colon cancer, coloretal cancer, brain cancer, renal cancer, testicular cancer, cancer of urethra, rectal cancer, cancer of fallopian tubes, penile cancer, vaginal cancer, stomach cancer, skin cancer, melanoma, liver cancer, gastrointestinal stromal tumors, urothelial cancer, thyroid cancer, parathyroid gland cancer, adrenal cancer, bone cancer, oral cancer, ovarian cancer, uterine cancer, head and neck sqamous cell carcinoma, endometrial cancer, gall bladder cancer, bladder cancer, orophyrangeal cancer, lymph node cancer, glioblastoma, astrocytoma, glioblastoma multiforme or sarcomas of soft tissue, fibrosarcoma, chondrosarcoma, hemangioma
  • leukemia which may be treated with the compounds of present invention include, but are not limited to Lymphoblastic T cell leukemia, Chronic myelogenous leukemia, Acute lymphoblastic T cell leukemia, Acute myelobastic leukemia, Hairy-cell leukemia, Chronic neutrophilic leukemia, Mantle cell leukemia, Acute megakaryocytic leukemia, Multiple myeloma, Megakaryoblastic leukemia, Erythroleukemia, Plasmacytoma, Promyelocytic leukemia, Chronic myelomonocytic leukemia, Myelodysplastic syndrome, Myelofibrosis, Chronic myelogenous leukemia, Polycythemia vera, Thrombocythemia, Chronic lymphocytic leukemia, Prolymphocytic leukemia, Hairy cell leukemia, Waldenstrom's macroglobulinemia, Castleman's disease, Chronic neutrophilic leukemia, Immunoblastic large
  • lymphoma which may be treated with the compounds of present invention include, but are not limited to, Hodgkin’s disease, non-Hodgkin’s lymphoma, Follicular lymphoma, Mantle cell lymphoma, Burkitt’s lymphoma, Lymphoblastic T-cell lymphoma, Marginal zone lymphoma, Cutaneous T cell lymphoma, CNS lymphoma, Small lymphocytic lymphoma, Lymphoplasmacytic lymphoma, Diffuse large B-cell lymphoma (DLBCL), Peripheral T-cell lymphoma, Anaplastic large cell lymphoma, Primary mediastinal lymphoma, Mycosis fungoides, Small non-cleaved cell lymphoma, Lymphoblastic lymphoma, Immunoblastic lymphoma, Primary effusion lymphoma and HIV associated (or AIDS related) lymphomas.
  • Hodgkin’s disease non-Hodgkin’
  • viral infection examples include, but are not limited to, human immune deficiency virus (HIV), Human papillomavirus(HPV), hepatitis C virus (HCV), hepatitis B virus (HBV), Influenza (Orthomyxoviridae), Alphavirus, Rotavirus, Sendai, vaccinia, respiratory synctical virus, Lassa virus (Arenaviridae), Rabies virus (Rhabdoviridae), West nile virus, Dengue virus, Japanese encephalitis virus, and other Flaviviridae, RNA virus, DNA virus, virus belonging to the family of Alphaflexiviridae, Astroviridae, Alphatetraviridae, Alvernaviridae, Asfarviridae, Ampullaviridae, Adenoviridae, Ascoviridae, Betaflexiviridae, Bromoviridae, Barnaviridae, Bicaudaviridae.
  • HCV human immune deficiency virus
  • Baculoviridae Closteroviridae Closteroviridae, Caliciviridae, Carmotetraviridae, Clavaviridae, Corticoviridae, Dicistroviridae, Endornaviridae, Filoviridae, Globuloviridae, Guttaviridae, Geminiviridae, Hytrosaviridae, Leviviridae, Luteoviridae, Lipothrixviridae, Mesoniviridae, Marnaviridae, Metaviridae, Malacoherpesviridae, Nodaviridae, Nyamiviridae, Nimaviridae, Nanoviridae, Piconaviridae, Partitiviridae, Picobirnaviridae, Paramyxoviridae, Poxviridae, Pandoraviridae, Polymaviridae, Phycodnaviridae, Papillomaviridae, Polyd
  • bacterial infection which may be treated with the compounds of present invention include, but are not limited to, infections caused by bacteria belonging to Brucella, Clostridium, Clostrodium, Campylobacter, Enterococcus, Fransicella, Listeria, Legionella, Mycobacteria, Pseudomonas, Salmonella, Staphylococcus, Yersinia genus.
  • the invention provides a composition comprising compound of Formula (I), Formula (II) and Formula (III), or its pharmaceutically acceptable salt thereof, and one or more additional therapies.
  • the invention provides a composition comprising compound of Formula (I), Formula (II) and Formula (III), or a pharmaceutically acceptable salt thereof, and one or more additional therapies such as chemotherapy, immunotherapy or radiotherapy.
  • Chemotherapy comprises administering one or more additional chemotherapeutic agents that may be used in combination with the compounds of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof.
  • chemotherapeutic agents that may be used in combination includes topoisomerase II inhibitors, anti-tumor antibiotics, anti-metabolites, retinoids, antiviral agents, abiraterone acetate, altretamine, anhydrovinblastine, auristatin, bexarotene, bicalutamide, BMS 184476, 2,3,4,5,6- pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide, bleomycin, N,N- dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly- 1-Lproline-tbutylamide, cachectin, cemadotin, chlorambucil, cycl
  • Immunotherapy comprises administering one or more additional immunostimulatory agents that may be used in combination with the compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof.
  • Immunostimulatory agents that may be used in combination herein includes vaccine adjuvants, such as Toll-like receptor agonists, T-cell checkpoint blockers, CTLA4, PD-1, PD-L1, TIM3, OX40, LAG3, B7-H3, GITR, 4-1BB, ICOS, CD40 and KIR antibody.
  • vaccine adjuvants such as Toll-like receptor agonists, T-cell checkpoint blockers, CTLA4, PD-1, PD-L1, TIM3, OX40, LAG3, B7-H3, GITR, 4-1BB, ICOS, CD40 and KIR antibody.
  • CTLA-4 and PD-1 antagonists include, but are not limited to, ipilimumab, tremelimumab, nivolumab, pembrolizumab, CT-011, AMP-224, and MDX- 1106.
  • the invention provides a vaccine adjuvant comprising a compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof.
  • the invention provides a vaccine composition
  • a vaccine composition comprising compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof, and an antigen or antigen composition.
  • Antigens and adjuvants that may be used in combination with the compound of Formula (I), Formula (II) and Formula (III) or a pharmaceutically acceptable salt thereof disclosed herein include B7 costimulatory molecule, interleukin-2, interferon- ⁇ , GM-CSF, CTLA-4 antagonists, OX-40 agonist, CD40 agonist, sargramostim, levamisol, vaccinia virus, Bacille Calmette-Guerin (BCG), liposomes, alum, Freund's complete or incomplete adjuvant, detoxified endotoxins, mineral oils, surface active substances such as lipolecithin, pluronic polyols, polyanions, peptides, and oil or hydrocarbon emulsions.
  • BCG Bacille Calmette-Guerin
  • Adjuvants such as aluminum hydroxide or aluminum phosphate
  • Adjuvants can be added to increase the ability of the vaccine to trigger, enhance, or prolong an immune response.
  • Additional materials such as cytokines, chemokines, and bacterial nucleic acid sequences, like CpG, a toll-like receptor (TLR) 9 agonist as well as additional agonists for TLR 2, TLR 4, TLR 5, TLR 7, TLR 8, TLR9, including lipoprotein, LPS, monophosphoryllipid A, lipoteichoic acid, imiquimod, resiquimod, and in addition retinoic acid- inducible gene I (RIG-I) agonists such as poly I:C, used separately or in combination with the described compositions are also potential adjuvants.
  • TLR toll-like receptor
  • compositions may be administered by a variety of means including non-parenterally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • Intra-tumoral directly into the tumor mass
  • peri-tumoral around the tumor mass
  • administration of the compounds of the present invention can be defined as follows; however, the meaning stated should not be interpreted as limiting the scope of the term per se.
  • alkyl refers to an alkane derived hydrocarbon radical that includes solely carbon and hydrogen atoms in the backbone, contains no unsaturation, has from one to six carbon atoms, and is attached to the remainder of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1- dimethylethyl (t- butyl) and the like. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkenyl refers to a hydrocarbon radical containing from 2 to 10 carbon atoms and including at least one carbon-carbon double bond.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l- propenyl, 1-butenyl, 2-butenyl and the like. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • alkynyl refers to a hydrocarbon radical containing 2 to 10 carbon atoms and including at least one carbon- carbon triple bond.
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, butynyl and the like. Unless set forth or recited to the contrary, all alkynyl groups described or claimed herein may be straight chain or branched, substituted or unsubstituted.
  • the term‘perhaloalkyl’, as used herein, means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen.
  • the perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl, and the like.
  • cycloalkyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
  • cycloalkenyl refers to a non-aromatic mono or multicyclic ring system having 3 to 12 carbon atoms and including at least one carbon-carbon double bond, such as cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.
  • aryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • heteroaryl refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1-4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic.
  • heterocycle refers to substituted or unsubstituted non-aromatic 3- to 15- membered ring which consists of carbon atoms and with one or more (e.g., 2 or 3) heteroatom(s) independently selected from N, O or S.
  • O divalent oxygen
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone, and the like.
  • the compounds of the present invention may have one or more chiral centers.
  • the absolute stereochemistry at each chiral center may be‘R’ or‘S’.
  • the compounds of the invention include all diastereomers and enantiomers and mixtures thereof. Unless specifically mentioned otherwise, reference to one stereoisomer applies to any of the possible stereoisomers. Whenever the stereoisomeric composition is unspecified, it is to be understood that all possible stereoisomers are included.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations.
  • enantiomer refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another.
  • chiral center refers to a carbon atom to which four different groups are attached.
  • diastereomers refers to stereoisomers which are not enantiomers.
  • racemate or “racemic mixture” refer to a mixture of equal parts of enantiomers.
  • treating or “treatment” of a state, disease, disorder, condition or syndrome includes: (a) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder, condition or syndrome developing in a subject that may be afflicted with or predisposed to the state, disease, disorder, condition or syndrome but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder, condition or syndrome; (b) inhibiting the state, disease, disorder, condition or syndrome, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof; c) lessening the severity of a disease disorder or condition or at least one of its clinical or subclinical symptoms thereof; and/or (d) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.
  • a “therapeutically effective amount” refers to the amount of a compound that, when administered to a subject in need thereof, is sufficient to cause a desired effect.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, age, weight, physical condition and responsiveness of the subject to be treated.
  • Compounds disclosed herein and their tautomeric forms, stereoisomers, prodrugs may be prepared, for example, by techniques well known in the organic synthesis and familiar to a practitioner ordinarily skilled in art of this invention.
  • the processes described herein may enable the synthesis of the compounds of the present invention. However, these may not be the only means by which the compounds described in the invention may be synthesized. Further, the various synthetic steps described herein may be performed in alternate sequences in order to furnish the desired compounds.
  • Scheme 1 shows a method of preparation of the compound of the formula (5), (5a), (5b), (5c), and (7), wherein R3’ is -OTBS or -OCH3; R2a is H.
  • the compound of the formula (11) is reacted with di-t-butylsilylbis(trifluoromethane sulfonate) and t-butyl dimethyl silyl chloride in presence of a suitable base such as imidazole, pyridine, dimethyl amino pyridine in a suitable solvent such as DMF, THF, DCM, chloroform, carbon tetrachloride to form a compound of formula (2).
  • a suitable base such as imidazole, pyridine, dimethyl amino pyridine in a suitable solvent such as DMF, THF, DCM, chloroform, carbon tetrachloride
  • the compound of formula (2) further reacted with 1-bromopropan-2-one in presence of sodium hydride in a suitable solvent such as DMSO, DMF to form a compound of formula (5b).
  • a suitable solvent such as DMSO, DMF
  • the compound of formula (5b) reacts with methyl iodide in presence of suitable base such as potassium carbonate and suitable solvent such as DMSO, DMF to form a compound of formula (5c).
  • the compound of the formula (2) is reacted with 1, 1-dimethoxy-N,N- dimethylmethanamine in a suitable solvent such as methanol, dimethyl formamide, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride to form a compound of formula (3) (wherein R3’ is -OTBS).
  • a suitable solvent such as methanol, dimethyl formamide, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride
  • the compound of formula (3) further reacted with 2-(bromomethyl)-1,3-dioxolane or 2- (iodomethyl)-1,3-dioxolane in presence of a suitable base such as potassium carbonate, cesium carbonate and suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, dioxane to form a compound of formula (4).
  • a suitable base such as potassium carbonate, cesium carbonate
  • suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, dioxane
  • the compound of formula (4) further reacted with acetic acid or hydrochloric acid or trifluoroacetic acid in water or chlorinated solvent, to form a compound of formula (5).
  • the compound of formula (3) is reacted with 3-bromopropane-1,2-diyl diacetate in presence of a suitable base such as potassium carbonate and a suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide to form a compound of formula (4a).
  • a suitable base such as potassium carbonate
  • a suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide
  • the compound of formula (4a) further reacted with ammonia in methanol, to form a compound of formula (4a’).
  • the compound of formula (4a’) reacted with sodium periodate in a suitable solvent such as acetonitrile, tetrahydrofuran or chlorinating solvents such as chloroform, dichloromethane followed by treatment with acetic acid to obtain the compound of formula (5).
  • the compound of formula (5) reacts with methyl iodide in presence of suitable base such as potassium carbonate and suitable solvent
  • Compound of formula (3) is reacted with ethyl bromoacetate in presence of a suitable a base such as potassium carbonate, cesium carbonate and suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, dioxane to form a compound of formula (6).
  • a suitable a base such as potassium carbonate, cesium carbonate and suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, dioxane
  • the compound of formula (6) reacted with ammonia in methanol or water, to form a compound of formula (7).
  • the compound of the formula (2a) prepared as disclosed in Tetrahedron Letters 2016, vol 57, # 3, 268-271) is reacted with t-butyl dimethyl chlorosilane and in presence of a suitable base such as imidazole, pyridine or dimethyl amino pyridine to form a compound of formula (2b).
  • a suitable base such as imidazole, pyridine or dimethyl amino pyridine
  • the compound of the formula (2b) is reacted with 1, 1-dimethoxy-N,N- dimethylmethanamine in a suitable solvent such as methanol, dimethyl formamide, tetrahydrofuran, dichloromethane, chloroform, carbon tetrachloride to form a compound of formula (3a).
  • the compound of formula (3a) is further reacted with 2-(bromomethyl)-1,3- dioxolane or 2-(iodomethyl)-1,3-dioxolane in presence of a suitable base such as potassium carbonate, cesium carbonate and suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, dioxane to form a compound of formula (4b).
  • a suitable base such as potassium carbonate, cesium carbonate
  • suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, dioxane
  • the compound of formula (4b) further reacted with trifluoroacetic acid acetic acid in the presence of chlorinated solvent dichloromethane to form a compound of formula (4c).
  • the compound of formula (4c) reacts triethylamine trihydrogenfluoride (TEA.3HF) in presence of suitable solvent such as triethylamine and pyridine to form a compound of formula (4d).
  • TEA.3HF triethylamine trihydrogenfluoride
  • suitable solvent such as triethylamine and pyridine
  • the compound of formula (4d) is reacted with 4,4'- (chloro(phenyl)methylene)bis(methoxybenzene) in the presence of suitable solvent such as pyridine to form a compound of formula (5d).
  • the compound of the formula (2) is reacted with trimethyl silyl bromide and tert- butylnitrite in a suitable solvent such as dibromomethane to form a compound of formula (8).
  • the compound of formula (8) is further reacted with hydrazine hydrate in presence of suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, water, ethanol to form a compound of formula (9).
  • suitable solvent such as dimethyl formamide, tetrahydrofuran, dimethyl sulphoxide, water, ethanol.
  • the compound of formula (9) further reacted with triethoxymethane or 1,1,1-triethoxyethane in dimethyl formamide, to form a compound of formula (10) [where R7– H, methyl]
  • the compound of formula (8) is further reacted with (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)acrylate in presence of potassium phosphate, dibasic and Tetrakis(triphenylphosphine)palladium in suitable solvent(s) such as 1,4 dioxane and water, to form a compound of formula (8A).
  • suitable solvent(s) such as 1,4 dioxane and water
  • suitable solvent(s) such as 1,4 dioxane and water
  • the compound of formula (8A) was treated with sodium borohydride and lithium borohydride in the presence of suitable solvent such as THF to form compound of formula (9A).
  • the compound of formula (9A) was further reacted with triphenylphosphine and Diethyl azodicarboxylate (DEAD), in presence of suitable solvent such as THF to form a compound of formula (10A).
  • the compound of the formula (11) is reacted with amino methyl hydrogen sulphate in presence of a base such as sodium hydroxide in water to form a compound of formula (12).
  • the compound of the formula (12) is further reacted with di-t- butylsilylbis(trifluoromethanesulfonate) and t-butyldimethylchlorosilane in a suitable solvent such as dimethyl formamide in presence of a base such as imidazole to form a compound of formula (13).
  • the compound of formula (13) is further reacted with formamide to form a compound of formula (14).
  • Scheme 4 shows a method of preparation of the compound of the formula (18), when R3’is -OTBS.
  • the compound of the formula (15) is reacted with di-t- butylsilylbis(trifluoromethanesulfonate) and t-butyldimethylchlorosilane in a suitable solvent such as dimethyl formamide in presence of a base such as imidazole to form a compound of formula (16).
  • the compound of formula (16) is further reacted with hydrazine hydrate in suitable solvent such as methanol, ethanol, to form a compound of formula (17).
  • the compound of formula (17) further reacted with triethyl orthoformate in presence of acid such as acetic acid to form a compound of formula (18).
  • the compound of the formula (19) [prepared according to procedure reported in the European Journal of Organic Chemistry 2000, 12, (2315-2323)] is treated with dimethoxy trityl chloride (DMT-Cl) in presence of a base like pyridine to obtain the compound of formula (20).
  • DMT-Cl dimethoxy trityl chloride
  • the compound of formula (20) treated with t-butyl dimethyl silyl chloride in presence of a base such as pyridine to obtain the compounds of formula (21A) and (21B) after column purification.
  • the compound of formula (21A) and (21B) can be converted to compound of formula (22A) and (22B) by reaction with phosphorus trichloride, 4- methylmorpholine, and 1, 2, 4-triazole in a suitable solvent such as chloroform, dichloromethane acetonitrile, tetrahydrofuran followed by treatment with dichloroacetic acid in dichloromethane and water.
  • a suitable solvent such as chloroform, dichloromethane acetonitrile, tetrahydrofuran followed by treatment with dichloroacetic acid in dichloromethane and water.
  • compound of formula (21A) and (21B) can be converted to compound of formula (22A) and (22B) by reaction with salicyl chlorophosphite (SalPCl) in a suitable solvent such as 1, 4-dioxane and a suitable base such as pyridine followed by treatment with dichloroacetic acid in dichloromethane and water.
  • SalPCl salicyl chlorophosphite
  • Step H When R3’ is -OTBS and R2a is H
  • the compound of formula (23) is reacted with HF-Pyridine in a suitable solvent such as acetonitrile, tetrahydrofuran or chlorinating solvent such as chloroform, dichloromethane followed by treatment with dimethoxy trityl chloride (DMT-Cl) in presence of a base such as pyridine to obtain the compound of formula (24A).
  • a suitable solvent such as acetonitrile, tetrahydrofuran or chlorinating solvent such as chloroform, dichloromethane
  • DMT-Cl dimethoxy trityl chloride
  • the compound of formula (24A) further treated with sodium bicarbonate (NaHCO3) (pH 9) to form a compound of formula (24B).
  • NaHCO3 sodium bicarbonate
  • the compound of formula (24A) and (24B) further converted to compound of formula (25A) and (25B) respectively by following similar method as described above in Scheme 5, for the conversion of compound of formula (
  • the compound of formula (24A) and (24B) is reacted with 3-((chloro(diisopropylamino) phosphino)oxy)propanenitrile in presence of a base such as pyridine, imidazole, di- isopropyl ethyl amine and 1-methyl imidazole and solvent such as acetonitrile, tetrahydrofuran, or chlorinating solvents such as chloroform, dichloromethane to obtain the compound of formula (25C) and (25D) respectively.
  • a base such as pyridine, imidazole, di- isopropyl ethyl amine and 1-methyl imidazole and solvent such as acetonitrile, tetrahydrofuran, or chlorinating solvents such as chloroform, dichloromethane
  • a base such as pyridine, imidazole, di- isopropyl ethyl amine and 1-methyl imidazole
  • solvent
  • Step I When R3’is -OCH3 and R2a is H
  • the compound of formula (23) is reacted with HF-Pyridine in a suitable solvent such as tetrahydrofuran or chlorinating solvent such as chloroform, dichloromethane in presence of a base such as pyridine to obtain the compound of formula (24C).
  • a suitable solvent such as tetrahydrofuran or chlorinating solvent such as chloroform, dichloromethane in presence of a base such as pyridine
  • the compound of formula (24D) is converted to compound of formula (25E) by reaction with phosphorus trichloride, 4-methylmorpholine, and 1, 2, 4-triazole in a suitable solvent such as chloroform, dichloromethane, acetonitrile, tetrahydrofuran followed by treatment with triethylammoniumformate buffer (pH6).
  • a suitable solvent such as chloroform, dichloromethane, acetonitrile, tetrahydrofuran followed by treatment with triethylammoniumformate buffer (pH6).
  • Step I When R3’is–H and R2a is F
  • the compound of formula (24A) is converted to compound of formula (25F) by reaction with phosphorus trichloride, 4-methylmorpholine, and 1, 2, 4-triazole in a suitable solvent such as chloroform, dichloromethane, acetonitrile, tetrahydrofuran followed by treatment with triethylammoniumformate buffer (pH6).
  • a suitable solvent such as chloroform, dichloromethane, acetonitrile, tetrahydrofuran followed by treatment with triethylammoniumformate buffer (pH6).
  • Chem.2015, 80, 4835 ⁇ 4850] is reacted with 3-((chloro(diisopropylamino)phosphino)oxy)propanenitrile in presence of a base such as pyridine, imidazole, di-isopropyl ethyl amine and 1-methyl imidazole and solvent such as acetonitrile, tetrahydrofuran, or chlorinating solvents such as chloroform, dichloromethane to obtain the compound of formula (27).
  • a base such as pyridine, imidazole, di-isopropyl ethyl amine and 1-methyl imidazole and solvent such as acetonitrile, tetrahydrofuran, or chlorinating solvents such as chloroform, dichloromethane
  • solvent such as acetonitrile, tetrahydrofuran, or chlorinating solvents such as chloroform, dichloromethane
  • compound of formula (26) reacted with phosphorus trichloride, 4- methylmorpholine, and 1,2,4-triazole in a suitable solvent such as chloroform, dichloromethane acetonitrile, tetrahydrofuran followed by treatment with dichloroacetic acid in dichloromethane and water to form a compound of formula (27A).
  • compound of formula (26) can be converted to compound of formula (27A) by reaction with salicyl chlorophosphite (SalPCl) in a suitable solvent such as 1, 4-dioxane and a suitable base such as pyridine followed by treatment with dichloroacetic acid in dichloromethane and water.
  • the compound of formula (26) is reacted with 4-oxopentanoic anhydride in the presence of a base such as pyridine and solvent such as tetrahydrofuran or dichloromethane followed by N,N dimethyl amino pyridine to obtain the compound of formula (27B).
  • a base such as pyridine
  • solvent such as tetrahydrofuran or dichloromethane followed by N,N dimethyl amino pyridine
  • the compound of formula (24B) is further reacted with triethylsilane in the presence of a solvent such as dichloromethane followed by dichloroacetic acid to form a compound of formula (27C).
  • compound of the formula (26A) reacted with phosphorus trichloride, 4- methylmorpholine, and 1,2,4-triazole in a suitable solvent such as chloroform, dichloromethane acetonitrile, tetrahydrofuran followed by treatment with dichloroacetic acid in dichloromethane and water to form a compound of formula (27A’).
  • a suitable solvent such as chloroform, dichloromethane acetonitrile, tetrahydrofuran followed by treatment with dichloroacetic acid in dichloromethane and water
  • compound of formula (26A) can be converted to compound of formula (27A’) by reaction with salicyl chlorophosphite (SalPCl) in a suitable solvent such as 1, 4-dioxane and suitable a base such as pyridine followed by treatment with dichloroacetic acid in dichloromethane and water.
  • SalPCl salicyl chlorophosphite
  • activator such as 5-[3,5-bis(trifluoromethyl)phenyl]-1H-tetrazole (Activator 42) or pyridinium trifluoroacetate (Py.TFA) or 1-(cyanomethyl)pyrrolidin-1-ium trifluoromethanes
  • DMOCP 2-chloro-5,5-dimethyl-1,3,2- dioxaphosphorinane-2-oxide
  • the compound of formula (29A) can be form by reacting compound of formula (25C) and formula (27A) by following similar synthetic process as disclosed above for the conversion of compound of formula (25A) to compound of formula (29).
  • the compound of the formula (29) and compound formula (29A) is reacted with solution of methylamine in alcohol or aqueous ammonia in methanol to obtain the compound of formula (30).
  • solution of methylamine in alcohol or aqueous ammonia in methanol Preferably 30-35% solution of methyl amine in ethanol was used for the reaction at room temperature to 60°C.
  • the compound of formula (30) was purified by preparative HPLC using triethyl ammonium acetate as a volatile buffer.
  • the compound of the formula (31) as triethyl ammonium salt obtained is treated with aqueous sodium hydroxide on cation exchange resin to obtain the compounds of the formula (Ia) as di-sodium salt.
  • the compound of formula (36) is further reacted with hydrazine hydrate in the presence of pyridine:acetic acid in suitable solvent such as acetonitrile, followed by addition of pentane-2,4-dione and aquoeus citric acid solution to form a compound of formula (37).
  • the compound of formula (37) is converted to compound of formula (38) by reaction with phosphorus trichloride, 4-methylmorpholine, and 1, 2, 4-triazole in a suitable solvent such as chloroform, dichloromethane, acetonitrile, tetrahydrofuran followed by treatment with triethylammoniumformate buffer in presence of acid such as dichloroacetic acid or acetic acid.
  • a base such as pyridine
  • activator such as
  • DMOCP 2-chloro-5,5- dimethyl-1,3,2-dioxaphosphorinane-2-oxide
  • diphenyl chlorophosphonate or pivaloyl chloride in presence of a base such as pyridine
  • reaction mixture was cooled to 0-5 °C, and to this 3-((chloro(diisopropylamino)phosphino)oxy)propanenitrile (0.64 g, 2.71 mmol) was added in 5 minutes. Reaction mixture was stirred at 0-5 °C for 30 minutes and at room temperature for 2 hrs. Progress of reaction was monitored by TLC. After completion, reaction mixture was quenched by addition of methanol (3 mL) and concentrated under reduced pressure to get crude sticky compound, which was purified by column chromatography. The desired product was eluted in 80 to 90% ethyl acetate in hexane to afford the title compound.
  • Step-5 Synthesis of (2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)- 5-(6-methyl-9-oxo-5,9-dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • Step-4 1.1 g, 1.17 mmol was dissolved in acetonitrile (50 mL). To this solution were added water (0.04 mL, 2.34 mmol) and pyridinium trifluoroacetate (0.36 g, 1.87 mmol) and the resulting mixture was stirred for 15 minutes at room temperature.
  • reaction mixture was cooled to 0-5 °C, and to this 3- ((chloro(diisopropylamino)phosphino)oxy)propanenitrile (6.61 g, 27.9 mmol) was added in 5 minutes. Reaction mixture was stirred at 0-5 °C for 30 minutes and at room temperature for 2 hr. Progress of reaction was monitored by TLC. After completion, reaction mixture was quenched by addition of methanol (3 mL) and concentrated under reduced pressure to get crude sticky compound, which was purified by column chromatography. The desired product was eluted in 45 to 50% ethyl acetate in hexane to get title compound as off-white solid. [Yield: 12.10 gm (87%)]
  • Step-7 Synthesis of (2R,3R,4R,5R)-2-((((((2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9- yl)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(2- cyanoethoxy)phosphoryl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(6-methyl-9- oxo-5,9-dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • Reaction mixture was stirred at room temperature for 16 hr.
  • 5.5 M solution of t-butyl hydroperoxide (0.42 mL, 2.30 mmol) was added and stirred for 3 hrs at room temperature.
  • Progress of reaction was monitored by TLC.
  • the solution was filtered, and the molecular sieves were washed with dichloromethane (2 x 20 mL).
  • the filtrate was concentrated under reduced pressure and co-evaporated with acetonitrile three times.
  • the residue was treated with 3% dichloroacetic acid in dichloromethane (60 mL), in the presence of water (0.32 mL) for 15 minutes at room temperature.
  • Step-1 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy) tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-5,6-dimethyl- 3,5-dihydro-9H-imidazo[1,2-a]purin-9-one
  • the Compound 2 was prepared from Step-1 product (Example 2) according to the procedure (Step-3 to Step-11) analogous to those outlined in Example 1 above using appropriate monomers, described as preparations in the coupling step.
  • Step-1 Synthesis of (E)-N'-(9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl) oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-6-oxo-6,9- dihydro-1H-purin-2-yl)-N,N-dimethylformimidamide
  • reaction mixture was diluted by dichloromethane (100 mL) and washed with water (2 x 30 mL). Organic layer was separated, dried over sodium sulphate and evaporated to get crude product. The crude product is used without purification for step-2.
  • Step-2 Synthesis of 3-(9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-2-((E)- ((dimethylamino)methylene)amino)-6-oxo-6,9-dihydro-1H-purin-1-yl)propane-1,2-diyl diacetate
  • Step-4 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-3,5-dihydro-9H- imidazo[1,2-a]purin-9-one
  • reaction mixture was diluted by dichloromethane (500 mL) and washed by water (2 x 200 mL). Organic layer was separated, dried over sodium sulphate and evaporated to get crude product. Reaction mass was passed through silica gel and eluted using 6-7% methanol in dichloromethane. The eluted mixture was concentrated under reduced pressure to obtain intermediate aldehyde.
  • Step-5 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-5-methyl-3,5- dihydro-9H-imidazo[1,2-a]purin-9-one
  • the Compound 3 was prepared from Step-5 product (Example 3) according to the procedure analogous to those outlined in Example 1 above using appropriate monomers, described as preparations in the coupling step.
  • Step-1 Synthesis of (E)-N'-(1-((1,3-dioxolan-2-yl)methyl)-9-((4aR,6R,7R,7aR)-2,2-di- tert-butyl-7-((tert-butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6- yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)-N,N-dimethylformimidamide
  • Step-2 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy) tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-3,5-dihydro-9H- imidazo[1,2-a]purin-9-one
  • Step-3 Synthesis of 3-((2R,3R,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-3-((tert-butyldimethylsilyl)oxy)-4- hydroxytetrahydrofuran-2-yl)-3H-imidazo[1,2-a]purin-9(5H)-one
  • reaction mixture was stirred at 0 °C for 1 hr. Reaction mixture was quenched carefully with saturated sodium bicarbonate solution until neutral pH was attained and then extracted using ethyl acetate (3 x 50 mL). Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude intermediate. Crude intermediate was dissolved in pyridine (50 mL) at 0 °C and 1-[chloro-(4-methoxyphenyl)-phenylmethyl]-4-methoxybenzene (3.02 g, 8.90 mmol) was added. The reaction mixture was stirred overnight at room temperature. Progress of the reaction was monitored by TLC.
  • the aqueous layer was extracted with dichloromethane (3 x 20 mL), the combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield intermediate as a semisolid compound.
  • the semisolid compound was treated with a 3% solution of dichloroacetic acid in dichloromethane (20 mL) and water (10 equivalent) for 15 min. Progress of reaction was monitored by TLC. The reaction was quenched with methanol (5 mL) and pyridine (5 mL). The solvents were removed in vacuum to get crude product. Crude product was purified by flash chromatography using methanol in dichloromethane. The product was eluted in 25% methanol in dichloromethane. Fractions were concentrated under reduced pressure to afford the desired product.
  • Reaction mixture was stirred at room temperature for 16 hrs.
  • 5.5 M solution of t-butyl hydroperoxide (0.30 mL, 1.64 mmol) was added and stirred for 3 hrs at room temperature.
  • Progress of reaction was monitored by TLC.
  • the solution was filtered and the molecular sieves were washed with dichloromethane (2 x 20 mL).
  • the filtrate was concentrated under reduced pressure and co-evaporated thrice with acetonitrile.
  • the residue was treated with 3% dichloroacetic acid in dichloromethane (60 mL), in the presence of water (0.32 mL) for 15 minutes at room temperature.
  • the reaction was quenched with methanol (20 mL) and pyridine (20 mL). The solvents were removed under reduced pressure to get the residue, and the residue was purified by silica-gel column chromatography, using 15 to 60% methanol in dichloromethane as eluent to obtain the title compound.
  • Step-7 product (0.45 g, 0.48 mmol) was co-evaporated in 10 mL dry acetonitrile, and to this (3.00 mL) dry pyridine was added and solution was heated to 50 °C and triethylamine trihydrofluoride (3.50 mL, 21.60 mmol) and triethylamine (6.0 mL) were added to a stirring reaction mixture. Reaction mixture was stirred at 50 °C for 2 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Reaction mixture was poured in to chilled solution of 1M solution triethylammonium bicarbonate (40 mL) and submitted for preparative HPLC for filtration through c-18 column using triethyl ammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get oily compound as Bis triethylammonium salt.
  • SOte Sp-1 S Ny N HntNhe Ns Nis N of O (2 NR N,3R y) phosphorroth N, iH4R,5R)-2-((((((2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9- yl)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(2- cyanoethox oyl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(9-oxo- 5,9-dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • Step-4A TBS deprotection of isolated peak 1 (Diastereomer 1) of step 3
  • Reaction mixture was poured in to chilled solution of 1M solution triethylammonium bicarbonate (40 mL) and submitted for preparative HPLC for filtration through C-18 column using triethylammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get oily compound as Bis triethylammonium salt.
  • Step-4C TBS deprotection of isolated peak 3 (Diastereomer 3) of step 3
  • Diastereomer 4 of step-3 (0.20 g, 0.20 mmol) was co-evaporated in dry acetonitrile (10 mL) and to this dry pyridine (3.0 mL) was added and solution was heated to 50 °C and triethylamine trihydrofluoride (1.53 mL, 9.38 mmol) and triethylamine (3.0 mL) were added to a stirring reaction mixture. Reaction mixture was stirred at 50 °C for 2 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Step-5D Synth Oesi Os of (2’, 3’)Cyclic-AIPM(PS)2 (Compound 8-Diastereomer 4)
  • Step-1 Synthesis of 2-bromo-9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert-butyldimethyl)
  • reaction mixture was quenched slowly on vigorously stirred mixture of aqueous bicarbonate solution (300 mL) and dichloromethane (300 mL). Two layers were separated; aqueous layer was extracted with dichloromethane (1 x 200 mL). Combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to get crude product; which was purified on flash using 35-45% ethyl acetate in hexane as eluent to afford desired product.
  • Step-3 Synthesis of 8-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert-butyldimethylsilyl) oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-1,8-dihydro-5H-[1,2,4]triazolo[4,3- a] purin-5-one
  • Step-1 Synthesis of ethyl (E)-3-(9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-6-oxo-6,9- dihydro-1H-purin-2-yl)acrylate.
  • Step-1 Product of Example 6, 34.0 g, 56.5 mmol) in 1,4 dioxane (300 ml) was added (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (15.33 g, 67.8 mmol), Potassium Phosphate, dibasic (19.68 g, 113 mmol) and water (10 mL).
  • Step-2 Synthesis of 9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-2-(3- hydroxypropyl)-1,9-dihydro-6H-purin-6-one.
  • Step-3 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-3,5,6,7- tetrahydro-9H-pyrrolo[1,2-a]purin-9-one.
  • Step-4 Synthesis of 3-((2R,3R,4R,5R)-3-((tert-butyldimethylsilyl)oxy)-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-3,5,6,7-tetrahydro-9H-pyrrolo[1,2-a]purin-9-one.
  • reaction mixture was stirred at 0 °C for 1 hr.
  • Reaction mixture was quenched carefully with saturated aqueous sodium bicarbonate solution (up to neutral pH) and extracted using ethyl acetate (3 x 50 mL).
  • Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain crude residue.
  • the residue was purified by column chromatography employing ethyl acetate in hexane as eluent. The title compound eluted in 90% ethyl acetate in hexane.
  • Step-5 Synthesis of 3-((2R,3R,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-3-((tert-butyldimethylsilyl)oxy)-4- hydroxytetrahydrofuran-2-yl)-3,5,6,7-tetrahydro-9H-pyrrolo[1,2-a]purin-9-one.
  • step-4 1.9 g, 4.50 mmol
  • pyridine 30.0 mL
  • 1-[chloro-(4-methoxyphenyl)- phenylmethyl]-4-methoxybenzene (1.52 g, 4.50 mmol).
  • TLC TLC-(4-methoxyphenyl)- phenylmethyl]-4-methoxybenzene
  • Step-6 Synthesis (2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)-5- (9-oxo-5,6,7,9-tetrahydro-3H-pyrrolo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate.
  • reaction was quenched by adding water (10 mL) and the solvent was evaporated under reduced pressure. Residue was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution (2 x 50 mL) and with brine (75 mL). The organic layer was dried over sodium sulphate filtered and concentrated to yield crude compound.
  • Reaction mixture was stirred at room temperature for 16 hrs.
  • 5.5 M solution of t-butyl hydroperoxide (0.27 mL, 1.53 mmol) was added and stirred for 3 hrs at room temperature.
  • Progress of reaction was monitored by TLC.
  • the solution was filtered, and the molecular sieves were washed with dichloromethane (2 x 20 mL).
  • the filtrate was concentrated under reduced pressure and co-evaporated with acetonitrile three times.
  • the residue was treated with 3% dichloroacetic acid in dichloromethane (60 mL) in the presence of water (0.32 mL) for 15 minutes at room temperature.
  • Step-6 product (0.12 g, 0.13 mmol) was co-evaporated in 10 mL dry acetonitrile, and to this (3.00 mL) dry pyridine was added and solution was heated to 50°C and triethylamine trihydrofluoride (1.35 mL, 13.10 mmol) and triethylamine (1.9 mL) were added to a stirring reaction mixture. Reaction mixture was stirred at 50°C for 2 hrs. Progress of reaction was monitored by LCMS and HPLC. Reaction mix was poured in to chilled solution of 1M solution triethylammonium bicarbonate (40 mL) and submitted for preparative HPLC for filtration through C-18 column using triethyl ammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get oily compound as Bis triethylammonium salt. [Yield- 0.06 gm]
  • step-7 product (0.06 g) in 10 mL of deionized water was loaded in to the column.
  • Column was eluted with 50 mL of deionized water; each 5 mL fractions were collected. The fractions those which show UV activity on TLC, were mixed and concentrated under reduced pressure to get the title compound as disodium salt.
  • Step-1 Synthesis of 8-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy) tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-3-methyl-1,8- dihydro-5H-[1,2,4]triazolo [4,3-a]purin-5-one
  • Ote O O Pp- N1 Fa O O N S Ny Han2Nth Ne Os Nis OH of O (2R,3S,4S,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((bis(4-methoxy phenyl)(phenyl)methoxy)methyl)-4-fluorotetrahydrofuran-3-yl(2-cyanoethyl)diisopropyl phosphoramidite
  • reaction mixture was stirred at 0-5 °C for 30 minutes and at room temperature for 2 hrs. Progress of reaction was monitored by TLC. After completion, reaction mixture was quenched by addition of methanol (3 mL) and concentrated under reduced pressure to get crude sticky compound, which was purified by column chromatography. The desired product was eluted in 45 to 50% ethyl acetate in hexane to get title compound as off-white solid.
  • Step-1 Synthesis of ethyl 2-(9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-2-(((E)- (dimethyl amino)methylene)amino)-6-oxo-6,9-dihydro-1H-purin-1-yl)acetate
  • reaction mixture was stirred for 10 min, and then ethyl 2-bromoacetate (1.183 g, 7.08 mmol) was added to the reaction mixture.
  • Reaction mixture was heated at 75 °C for 16 hrs. Progress of the reaction was monitored by TLC. Reaction was quenched by water (250 mL), resulting yellow solid was filtered and taken in dichloromethane (300 mL). Organic layer was washed with water (2 x 100 mL), separated organic layer was dried over sodium sulphate and evaporated to get crude product. Crude product was purified by flash chromatography using ethyl acetate in hexane. The product was eluted at 80% of ethyl acetate in hexane.
  • Step-2 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy) tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-3,5-dihydro-9H- imidazo[1,2-a]purine-6,9(7H)-dione
  • Example 13 was prepared from Step-2 product (Example 11) according to the procedure (Step-3 to Step-9) analogous to those outlined in Example 4 above using appropriate monomers, described as preparations in the coupling step.
  • Example 11 (2’, 3’) cyclic-AIPDMP (Compound 13)
  • the Compound 14 was prepared from Step-2 product (Example 8) and commercially available (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4- methoxyphenyl)(phenyl)methoxy) methyl)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-3-yl (2-cyanoethyl) diisopropyl phosphoramidite, according to the procedure (Step-3 to Step-8) analogous to those outlined in Example 8 above using appropriate monomers, described as preparations in the coupling step.
  • Step-1 Synthesis of 1,2-diamino-9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6-one
  • Step-2 Synthesis of 1,2-diamino-9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethyl silyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-1,9-dihydro-6H- purin-6-one
  • Step-1 1,2 diamino-9-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydrofuran-2-yl)-1H-purin-6(9H)-one (Step-1, 15.0 g, 50.3 mmol) in dimethyl formamide (150 ml) was added di-t-butylsilylbis(trifluoromethanesulfonate) (19.69 mL, 60.4 mmol) in 15 minutes at 0 °C . The reaction mixture was stirred at 0 °C for 30 minutes.
  • Step-3 Synthesis of 3-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy) tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-3,5-dihydro-9H- [1,2,4]triazolo[1,5-a]purin 9-one
  • Step-2 1,2-diamino-9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-1H-purin-6(9H)- one (Step-2, 15.0 g, 27.1 mmol) was dissolved in formamide (100 mL) and reaction mixture was stirred at 180°C for 2.5 hrs. Reaction mixture was cooled to room temperature, water (100 mL) was added and the reaction mixture was extracted with ethyl acetate (2 x 150 mL).
  • Step-1 Synthesis of 6-chloro-9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert-butyldimethyl silyl)oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-9H-purine
  • Step-2 Synthesis of 9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert- butyldimethylsilyl)oxy) tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-6-hydrazinyl- 9H-purine
  • Step-3 Synthesis of 7-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-((tert-butyldimethylsilyl) oxy)tetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-7H-[1,2,4]triazolo[3,4-i]purine
  • the Compound 16 was prepared from Step-3 product (Example 14) according to the procedure (Step-3 to Step-8) analogous to those outlined in Example 8 above using appropriate monomers, described as preparations in the coupling step.
  • the Compound 17 was synthesized according to the procedure (Step-1 to Step-8) analogous to those outlined in Example 8 above using appropriate monomers, described as preparations in the coupling step.
  • Step-1 Synthesis of (2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxy methyl)- 2-(2-isobutyramido-6-oxo-1H-purin-9(6H)-yl)tetrahydrofuran-3-yl hydrogen phosphonate.
  • Step-2 Synthesis of (2R,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl) methoxy) methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(9-oxo-5,9-dihydro-3H-imidazo[1,2-a]purin-3- yl) tetrahydrofuran-3-yl (2-cyanoethyl) diisopropylphosphoramidite.
  • reaction mixture was cooled to 0-5 °C, and to this 3-((chloro(diisopropyl amino)phosphino)oxy)propanenitrile (3.31 g, 13.98 mmol) was added in 5 minutes. Reaction mixture was stirred at 0-5 °C for 30 minutes and at room temperature for 2 hrs. Progress of reaction was monitored by TLC. After completion, reaction mixture was quenched by addition of methanol (10 mL) and concentrated under reduced pressure to get sticky compound which was purified by column chromatography. The desired product was eluted in 80% ethyl acetate in hexane. Fractions were concentrated to obtain title compound as white solid.
  • reaction mixture was stirred at room temperature for 16 hrs.
  • 2- phenylacetic dithioperoxyanhydride (2.84 g, 9.41 mmol) was added and the reaction mixture was stirred for another 2 hrs at room temperature.
  • Progress of reaction was monitored by TLC.
  • the reaction mixture was filtered, and the molecular sieves were washed with dichloromethane (2 x 50 mL).
  • the filtrate was concentrated under reduced pressure and coevaporated three times with acetonitrile.
  • the residue was treated with 10% dichloroacetic acid in dichloromethane (100 mL) in the presence of water (2 mL) for 15 minutes at room temperature.
  • the reaction was quenched with solution of methanol (10 mL) in pyridine (10 mL). The solvents were removed under reduced pressure to get the residue.
  • the crude product was purified using silica gel column chromatography, using 0- 100% ethyl acetate in hexane and then 20-60% methanol in dichloromethane as eluent to obtain the desired compound.
  • Diastereomer 1 of step-5 (150 mg, 0.154 mmol) was co-evaporated three times with dry acetonitrile (10 mL). To this was added dry pyridine (2 mL) and triethylamine (2 mL) and the solution was heated to 60 °C. To the stirring reaction mixture was added triethylamine trihydrofluoride (1.503 mL, 9.23 mmol). Reaction mixture was stirred at 50 °C for 3 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Reaction mixture was poured into chilled solution of 1M solution of triethylammonium bicarbonate (50 mL) and submitted for preparative HPLC for filtration through C-18 column using triethylammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get oily compound as Bis triethylammonium salt.
  • Step-6D TBS deprotection of isolated diastereomer 4 of step 5
  • Step 7A Synthesis of (2’, 3’) cyclic-GIPM(PS)2 (Compound 18-Diastereomer 1)
  • Step-1 Synthesis of (2R,3R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)- 2-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • the compounds 22, 23 and 24 were prepared from Step-1 product (Example 17) according to the procedures (Step-2 to Step-7) analogous to those outlined in Example 16 above using appropriate monomer.
  • Step-1 Synthesis of (2R,3R,5S)-2-(6-benzamido-9H-purin-9-yl)-5-((((((2R,3R,4R,5R)-4- ((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)-5-(9-oxo-5,9-dihydro-3H-imidazo[1,2- a]purin-3-yl)tetrahydrofuran-3-yl)oxy)(2-cyanoethoxy)phosphorothioyl)oxy)methyl) tetrahydrofuran-3-yl hydrogen phosphonate
  • the filtrate was concentrated under reduced pressure and co- evaporated three times with acetonitrile.
  • the residue was treated with 10% dichloroacetic acid in dichloromethane (100 mL), in the presence of water (2 mL) for 15 minutes at room temperature.
  • the red colored reaction mixture was quenched with methanol (10 mL) and pyridine (10 mL).
  • the solvents were removed under reduced pressure to get the crude residue.
  • the crude compound was purified by silica-gel column chromatography, using (20 - 100%) methanol in dichloromethane as eluent to obtain the title compound.
  • Step 1 Synthesis of (2R,3R,4R,5R)-2-((((((2R,3S,4S,5R)-2-(6-benzamido-9H-purin-9- yl)-4-fluoro-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(2- cyanoethoxy)phosphorothioyl) oxy) methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(9-oxo- 5,9-dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • reaction mixture was stirred at room temperature for 16 hrs. Progress of reaction was monitored by TLC.
  • 2-phenylacetic dithioperoxyanhydride (2.18 g, 7.21 mmol) in anhydrous pyridine (9.3 mL, 115 mmol) was added and the reaction mixture was stirred for another 2 hrs at room temperature. Progress of reaction was monitored by TLC. After completion, the solution was filtered, and the molecular sieves were washed with dichloromethane (2 x 30 mL). The filtrate was concentrated under reduced pressure and co- evaporated with acetonitrile (three times).
  • Step-4A TBS deprotection of isolated peak 1 (Diastereomer 1) of step 3
  • Diastereomer 1 of step-3 (0.030 g, 0.035 mmol) was co-evaporated in dry acetonitrile (10 mL), and to this (2.00 mL) dry pyridine was added and the solution was heated to 60 °C and triethylamine trihydrofluoride (0.34 mL, 2.126 mmol) and triethylamine (2.0 mL) were added to a stirring reaction mixture. Reaction mixture was stirred at 60 °C for 3 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Diastereomer 2 of step 3 (0.050 g, 0.059 mmol) was co-evaporated in dry acetonitrile (10 mL), and to this dry pyridine (2.0 mL) was added and solution was heated to 60 °C and triethylamine trihydrofluoride (0.577 mL, 3.54 mmol) and triethylamine (2.0 mL) were added to a stirring reaction mixture. Reaction mixture was stirred at 60 °C for 3 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Step-4C TBS deprotection of isolated peak 3 (Diastereomer 3) of step 3
  • Diastereomer 3 of step 3 (0.050 g, 0.059 mmol) was co-evaporated in dry acetonitrile (10 mL), and to this dry pyridine (2.0 mL) was added and solution was heated to 60 °C and triethylamine trihydrofluoride (0.577 mL, 3.54 mmol) and triethylamine (2.0 mL) were added to a stirring reaction mixture. Reaction mixture was stirred at 60 °C for 3 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Step-5B (2’, 3’) cyclic-3’- ⁇ FAIPM(PS)2 (Compound 29-Diastereomer 2)
  • the compounds 31 and 32 were prepared from corresponding monomers according to the procedures analogous to those outlined in Example 19 above.
  • Step-1 Synthesis of N-(3-((2R,3R,4S,5R)-5-((bis(4-methoxyphenyl)(phenyl) methoxy) methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl) benzamide:
  • reaction mass was diluted with ethyl acetate (200 mL) and quenched with saturated aqueous solution of sodium bicarbonate (100 mL). Organic layer was washed with water and brine. Separated organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain crude mass. Crude mass was purified by column chromatography using 10% methanol in dichloromethane to obtain title compound. (Yield: 11 g, 67.4 % yield).
  • step-1 N-(3-((2R,3R,4S,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-3,4-dihydroxytetrahydrofuran-2-yl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-7-yl)benzamide (step-1, 11 g, 16.30 mmol) in pyridine (110 mL) was added imidazole (5.55 g, 82 mmol) followed by t-butyl dimethyl silyl chloride (2.95 g, 19.56 mmol) at room temperature and the reaction mixture was stirred for 16 hrs. The progress of the reaction was monitored by TLC.
  • This compound is prepared from step 2 product by following analogous procedure of step 6 of example 1.
  • the compounds 34 and 35 were synthesized by using appropriate monomers, (2R,3R,4R,5R)-5-(6-benzamido-9H-purin-9-yl)-2-((bis(4-methoxyphenyl) (phenyl) methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-3-yl(2-cyanoethyl) diisopropylphosphoramidite) (Prepared according to the procedure reported in the literature, Journal of Organic Chemistry, 1991 , vol.56, # 15 p.4608– 4615) and Step 4 product of example 4 by following analogous procedures (Step-1 to Step-5) those outlined in example 5.
  • Step-1 Synthesis of 3-((2R,3R,4S,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-3- hydroxytetrahydrofuran-2-yl)-3,5-dihydro-9H-imidazo[1,2-a]purin-9-one
  • reaction mixture was stirred at 0 °C for 1 hr. White solid separates out.
  • reaction mixture was quenched carefully with saturated sodium bicarbonate solution (up to pH 9), and the basic reaction mixture was stirred for 2 hrs at room temperature.
  • the solid was filtered.
  • the filtered solid was dissolved in methanol in dichloromethane (1:1), dried over anhydrous sodium sulphate and evaporated under reduced pressure to obtain crude mass.
  • reaction mixture was stirred at room temperature for 16 hrs. Progress of reaction was monitored by TLC. After 16 hrs, tert-butyl hydroperoxide (0.300 mL, 1.648 mmol) 5.5M was added to the reaction mixture and stirred for another 3 hrs. Progress of reaction was monitored by TLC. After completion, the solution was filtered through celite pad, and the molecular sieves were washed with dichloromethane (2 x 30 mL). The filtrate was concentrated under reduced pressure and co- evaporated three times with acetonitrile. The residue was treated with 10% dichloroacetic acid in dichloromethane (60 mL), in the presence of water (0.148 mL, 8.24 mmol) for 15 minutes at room temperature.
  • the red coloured reaction mixture was quenched with methanol (20 mL) and pyridine (20 mL). The solvents were removed under reduced pressure to get the crude residue.
  • the crude compound was purified by silica-gel column chromatography, using 15 - 60% methanol in dichloromethane as eluent to obtain the title compound.
  • e compoun was prepare rom corresponding monomers (Step 2 product of Example 16 and Step 2 product of Example 23) according to the procedures (Step 5 to Step 9) analogous to those outlined in Example 4.
  • Step-1 (2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert- butyldimethylsilyl)oxy)tetrahydrofuran-3-yl 4-oxopentanoate
  • reaction mixture was stirred at 25 °C for 2 hour. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was diluted with ethyl acetate and then poured on water. The two layers were separated and the aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over anhydrous sodium sulphate and then concentrated under reduced pressure to obtain desired product in crude form which was directly used for further transformation without purification.
  • Step-2 (2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9-yl)-4-((tert-butyldimethylsilyl)oxy)- 5-(hydroxymethyl)tetrahydrofuran-3-yl 4-oxopentanoate
  • reaction mixture was stirred at 25 °C for 30 minutes. The progress of the reaction was checked by TLC. Upon completion, the reaction mixture was diluted with dichloromethane and washed with water, organic layer was concentrated after drying over anhydrous sodium sulphate to obtain crude mass. The crude mass was purified by column chromatography employing ethyl acetate in hexane as eluent. The desired product eluted in 60-80% ethyl acetate in hexane. The fractions were collected and the solvent was removed under reduced pressure to obtain desired product. [Yield: 8.5 g, (76.50 %) over two steps].
  • Step-3 Synthesis of 2-amino-9-((2R,3S,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert- butyldimethylsilyl)oxy)methyl)-3-fluorotetrahydrofuran-2-yl)-1,9-dihydro-6H-purin-6- one
  • Step-7 Synthesis of 3-((2R,3S,4R,5R)-3-fluoro-4-hydroxy-5- (hydroxymethyl)tetrahydrofuran-2-yl)-3,5-dihydro-9H-imidazo[1,2-a]purin-9-one
  • Step-8 Synthesis of 3-((2R,3S,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-3,5- dihydro-9H-imidazo[1,2-a]purin-9-one
  • Step-9 Synthesis of (2R,3R,4S,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)- 4-fluoro-5-(9-oxo-5,9-dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • the solution was stirred for 30 minutes at same temperature and then, upon completion, was neutralized by addtion of 1M triethylammoniumformate buffer solution (PH 6).
  • the aqueous layer was extracted with dichloromethane, the combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield intermediate as semisolid compound.
  • the semisolid crude compound was treated with 20% solution of dichloroacetic acid in dichloromethane (100 mL) and water (10.0 mL) for 15 min. Progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched with solution of methanol (50 mL) and pyridine (50 mL). The solvents were removed in vacuo and the residue was triturated with methyltertbutylether, followed by acetonitrile to yield the title compound as crude solid.
  • step 13 product 2.2 g, 2.314 mmol
  • 33% methyl amine in ethanol 30 ml
  • Progress of the reaction was monitored by LCMS.
  • the volatiles were removed under reduced pressure.
  • the obtained residue was triturated with acetonitrile to yield desired product as crude solid.
  • Diastereomer 1 of step-14 (50 mg, 0.059 mmol) was co-evaporated three times with dry acetonitrile (10 mL). To this was added dry pyridine (3 mL) and triethylamine (3 mL) and the solution was heated to 60 °C. To the stirring reaction mixture was added triethylamine trihydrofluoride (3 mL). The reaction mixture was stirred at 60 °C for 2 hour. Progress of reaction was monitored by LCMS and HPLC. Reaction mixture was poured into chilled solution of 1M solution of triethylammonium bicarbonate (50 mL) and submitted for preparative HPLC for filtration through C-18 column using triethylammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get desired compound as bis triethylammonium salt.
  • Step 15C TBS deprotection of isolated diastereomer 3 of step 14
  • Step 15D TBS deprotection of isolated diastereomer 4 of step 14
  • Step 16C Synthesis of (2’, 3’) cyclic-A2’- ⁇ FIPM(PS)2 (Compound 40-Diastereomer 3)
  • Step-1 Synthesis of (E)-N'-(9-((4aR,6R,7R,7aR)-2,2-di-tert-butyl-7-methoxytetrahydro- 4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-6-oxo-6,9-dihydro-1H-purin-2-yl)-N,N- dimethylformimidamide.
  • Step-2 Synthesis of (E)-N'-(1-((1,3-dioxolan-2-yl)methyl)-9-((4aR,6R,7R,7aR)-2,2-di- tert-butyl-7-methoxytetrahydro-4H-furo[3,2-d][1,3,2]dioxasilin-6-yl)-6-oxo-6,9-dihydro- 1H-purin-2-yl)-N,N-dimethylformimidamide.
  • reaction mixture was stirred for 10 min, then added 2-(iodomethyl)-1, 3- dioxolane (20.05 mL, 169 mmol).
  • the reaction mixture was heated at 75 °C for 12 hour. Progress of the reaction was monitored by TLC. Upon completion, the reaction was quenched with ice-cold water (1000 mL). Free solid precipitates out, which was filtered and the bed was washed with water (500 mL). The solid compound was dissolved in dichloromethane, dried over sodium sulphate and evaporated to get crude product. The crude product was purified by flash chromatography using methanol in dichloromethane. The product was eluted at 5% of methanol in dichloromethane.
  • Step-3 Synthesis of 3-((4aR,6R,7R,7aS)-2,2-di-tert-butyl-7-methoxytetrahydro-4H- ,2-a]purin-9-one.
  • Step-4 Synthesis of 3-((2R,3R,4R,5R)-4-hydroxy-5-(hydroxymethyl)-3- methoxytetrahydrofuran-2-yl)-3,5-dihydro-9H-imidazo[1,2-a]purin-9-one.
  • Step-5 Synthesis of 3-((2R,3R,4R,5R)-5-((bis(4- methoxyphenyl)(phenyl)methoxy)methyl)-4-hydroxy-3-methoxytetrahydrofuran-2-yl)- 3,5-dihydro-9H-imidazo[1,2-a]purin-9-one.
  • Step-6 Synthesis of (2R,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)- 4-methoxy-5-(9-oxo-5,9-dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate.
  • Step 1 (2R,3R,4R,5R)-2-((bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-4-((tert- butyldimethylsilyl)oxy)-5-(6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydrofuran-3-yl (2- cyanoethyl) diisopropylphosphoramidite
  • Step-1 Synthesis of (2R,3R,4R,5R)-2-((((((2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9- yl)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(2- cyanoethyl) phosphorothioyl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(9-oxo-5,9- dihydro-3H-imidazo[1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • the red coloured reaction mixture was quenched with methanol (20 mL) and pyridine (20 mL). The solvents were removed in vacuo to get the residue.
  • the crude product was purified using silica gel column chromatography, using 0-100% ethyl acetate in hexane and then 20-60% methanol in dichloromethane as eluent to obtain the desired compound.
  • Step-2 Cyclization and oxidation of step 1 product
  • step 2 product (step 2 product, 2.0 g, 1.818 mmol) was treated with 33% methylamine in ethanol (45 mL), and the resulting mixture was stirred at 60 °C in sealed tube for 3 hour. Progress of the reaction was monitored by LCMS. Reaction mixture was cooled to room temperature. The mixture was concentrated, and the resulting residue was dried under reduced pressure to get sticky solid. The solid residue obtained was purified by reverse phase preparative-HPLC (YMC triart C18– 250 x 50 mm x 10 ⁇ m). Eluted with 0-50% acetonitrile in triethylammonium acetate buffer over 25 minutes to obtain two diastereomers
  • Diastereomer 1 of step-3 (120 mg, 0.127 mmol) was co-evaporated three times with dry acetonitrile (10 mL). To this was added dry pyridine (2 mL) and triethylamine (2 mL) and the solution was heated to 60 °C. To the stirring reaction mixture was added triethylamine trihydrofluoride (1.243 mL, 7.64 mmol). Reaction mixture was stirred at 60 °C for 3 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Reaction mixture was poured into chilled solution of 1M solution of triethylammonium bicarbonate (50 mL) and submitted for preparative HPLC for filtration through C-18 column using triethylammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get oily compound as Bis triethylammonium salt.
  • Step-4B TBS deprotection of isolated diastereomer 2 of step 3
  • Step 5A (Compound 49-Diastereomer 1)
  • Step-1 Synthesis of (2R,3R,4R,5R)-2-((((((2R,3R,4R,5R)-2-(6-benzamido-9H-purin-9- yl)-4-((tert-butyldimethylsilyl)oxy)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(2- cyanoethoxy) phosphoryl)oxy)methyl)-4-((tert-butyldimethylsilyl)oxy)-5-(9-oxo-5,9- dihydro-3H-imidazo [1,2-a]purin-3-yl)tetrahydrofuran-3-yl hydrogen phosphonate
  • reaction mixture was stirred at room temperature for 16 hour. Progress of the reaction was monitored by TLC. After 16 hour, tert-butyl hydroperoxide (0.899 mL, 4.94 mmol) 5.5M was added to the reaction mixture and stirred for another 3 hour. Progress of the reaction was monitored by TLC. After completion, the solution was filtered through celite pad, and the molecular sieves were washed with dichloromethane (2 x 30 mL). The filtrate was concentrated under reduced pressure and co-evaporated three times with acetonitrile. The residue was treated with 10% dichloroacetic acid in dichloromethane (60 mL), in the presence of water (0.445 mL, 24.72 mmol) for 15 minutes at room temperature.
  • the red colored reaction mixture was quenched with methanol (10 mL) and pyridine (10 mL). The solvents were removed under reduced pressure to get the crude residue.
  • the crude compound was purified by silica-gel column chromatography, using 25-50 % methanol in dichloromethane as eluent to obtain the title compound.
  • step 2 product (step 2 product, 1.3 g, 1.182 mmol) was treated with 33% methylamine in ethanol (45 mL), and the resulting mixture was stirred at 60 °C in sealed tube for 3 hrs. Progress of reaction was monitored by LCMS. Reaction mixture was cooled to room temperature. The mixture was concentrated, and the resulting residue was dried under reduced pressure to get sticky solid. The solid residue obtained was purified by reverse phase preparative-HPLC (YMC triart C18– 250 x 50 mm x 10 ⁇ m). Eluted with 0-50% acetonitrile in triethylammonium acetate buffer over 25 minutes to obtain two diastereomers
  • Diastereomer 1 of step-3 (90 mg, 0.095 mmol) was co-evaporated three times with dry acetonitrile (10 mL). To this was added dry pyridine (2 mL) and triethylamine (2 mL) and the solution was heated to 60 °C. To the stirring reaction mixture was added triethylamine trihydrofluoride (0.932 mL, 5.73 mmol). Reaction mixture was stirred at 60 °C for 3 hrs. Progress of reaction was monitored by LCMS and HPLC.
  • Reaction mixture was poured into chilled solution of 1M solution of triethylammonium bicarbonate (50 mL) and submitted for preparative HPLC for filtration through C-18 column using triethylammonium acetate buffer. Isolated fraction was concentrated under reduced pressure to get oily compound as Bis triethylammonium salt.
  • Step-4B TBS deprotection of isolated diastereomer 2 of step 3
  • THP1-BlueTM ISG Invivogen, USA
  • B16-BlueTM IFN- ⁇ / ⁇ Invivogen, USA
  • SEAP-based reporter cell lines or HEK-293 cells overexpressing human or mouse STING coupled to Luciferase reporter.
  • THP1-BlueTM ISG cells or B16-BlueTM IFN- ⁇ / ⁇ cells in 96 well plate were treated with varying concentrations of test and reference compounds and incubated at 37 ⁇ C with 5% CO2 for 18-20 hours. The control untreated cells were also set-up.
  • the cell supernatant was tested for SEAP (Secreted Embryonic Alkaline Phosphatase) activity using the QuantiBlue substrate reagent (Invivogen, USA).
  • SEAP Secreted Embryonic Alkaline Phosphatase
  • the formation of blue coloured product was quantified by measuring absorbance at wavelength of 620 nm using PheraStar reader. Luciferase reporter activity was monitored using Bright- Glo (Promega, USA) or other suitable luciferase detection reagent and luminescence was estimated on Pherastar plate reader. The average of duplicate readouts for each data point was plotted in GraphPad Prism 6 against the concentration of test or reference compound to calculate EC50 value. The fold of SEAP induction or increase in luminescence at different data points was estimated against the un-stimulated cell control set.
  • EC50 (effective concentration) was calculated using 4 parametric nonlinear regression (curve fit) and sigmoidal dose-response (variable slope) using Graph pad prism software. Human IFN ⁇ production was analysed in THP1-BlueTM ISG cells. Cells were treated for 5 h with various concentrations of the test compounds and fold induction of hIFN ⁇ in the supernatant was determined by ELISA (R&D systems).
  • THP1 Blue cells Compounds with 1.1 to 5 fold activation @ 30 ⁇ M (THP1 Blue cells) are grouped under group A, compounds with 5.1 to 10 fold activation @ 30 ⁇ M (THP1 Blue cells) are grouped under group B, and compounds with 10.1 to 25 fold activation @ 30 ⁇ M (THP1 Blue cells) are grouped under group C.
  • compounds of the present invention also activated the various hSTING variants viz. HAQ, H232, AQ and Q.
  • Compounds 8, 22 and 35 showed a significant induction of hIFN ⁇ production in THP1- BlueTM ISG cells.
  • Tumor volume was calculated by using the following formula:
  • mice were randomized into treatment groups based on the tumor volume. Mice were administered with vehicle or the test article by intratumoral route (i.tu.) on defined days, e.g., Day-1, Day-3 and Day-5, and defined dose levels, e.g., 3, 10, 30, 50, 100 or 250 ⁇ g/mouse. Tumor sizes were measured with Vernier caliper twice weekly and body weights of mice were recorded daily.
  • % TGI Percent tumor growth inhibition
  • Tf and Ti are the final and initial test tumor volumes
  • Cf and Ci are the final and initial control mean tumor volumes, respectively.
  • % TR Percent Tumor Regression
  • % TR [(Initial T.V. - Final T.V.)/(Initial T.V.)] ⁇ 100
  • Compounds 8, 22 and 35 showed greater than 95% tumor regression with 50 microgram per mouse dose in 4T1 murine breast cancer allograft model.

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Abstract

La présente invention concerne des composés di-nucléotidiques cycliques contenant des hétérocycles tricycliques en tant que nucléobases et ayant la formule générale (I), (II) et (III) et leurs formes tautomères, leurs stéréoisomères, sels pharmaceutiquement acceptables, ainsi que leur combinaison avec un médicament approprié, des procédés correspondants pour la synthèse, des compositions pharmaceutiques et des utilisations des composés de l'invention.
PCT/IB2018/052936 2017-04-27 2018-04-27 Composés di-nucléotidiques cycliques avec des nucléobases tricycliques Ceased WO2018198084A1 (fr)

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US10246480B2 (en) 2017-02-17 2019-04-02 Eisai R&D Management Co., Ltd. Compounds for the treatment of cancer
WO2019074887A1 (fr) * 2017-10-10 2019-04-18 Bristol-Myers Squibb Company Dinucléotides cycliques utilisés en tant qu'agents anticancéreux
WO2019232392A1 (fr) 2018-06-01 2019-12-05 Eisai R&D Management Co., Ltd. Méthodes de traitement du cancer de la vessie
US10980825B2 (en) 2016-12-01 2021-04-20 Takeda Pharmaceutical Company Limited Cyclic dinucleotide
US11110106B2 (en) 2018-10-29 2021-09-07 Venenum Biodesign, LLC Sting agonists for treating bladder cancer and solid tumors
US11161864B2 (en) 2018-10-29 2021-11-02 Venenum Biodesign, LLC Sting agonists
CN114213491A (zh) * 2021-12-31 2022-03-22 中南民族大学 一类内源性核苷M1dG及其衍生物的合成方法及其应用
CN114213490A (zh) * 2021-12-31 2022-03-22 中南民族大学 一类三环核苷酸类似物及其合成方法和应用
EP3727401A4 (fr) * 2017-12-20 2022-04-06 Merck Sharp & Dohme Corp. Composés dinucléotidiques cycliques utilisés comme agonistes sting
US11299512B2 (en) 2016-03-18 2022-04-12 Immunesensor Therapeutics, Inc. Cyclic di-nucleotide compounds and methods of use
US11400108B2 (en) 2017-02-21 2022-08-02 Board Of Regents, The University Of Texas System Cyclic dinucleotides as agonists of stimulator of interferon gene dependent signalling
US11542293B2 (en) 2017-11-10 2023-01-03 Takeda Pharmaceutical Company Limited Sting modulator compounds, and methods of making and using
US11691990B2 (en) 2018-08-16 2023-07-04 Eisai R&D Management Co., Ltd Salts of compounds and crystals thereof
US11725024B2 (en) 2020-11-09 2023-08-15 Takeda Pharmaceutical Company Limited Antibody drug conjugates
US11787833B2 (en) 2019-05-09 2023-10-17 Aligos Therapeutics, Inc. Modified cyclic dinucleoside compounds as sting modulators
CN120757600A (zh) * 2025-09-10 2025-10-10 天津法尔玛制药有限公司 环二核苷酸2′,3′-cG4′-MeAMP、制备方法及其在制备先天免疫激活剂中的应用

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WO2017027645A1 (fr) * 2015-08-13 2017-02-16 Merck Sharp & Dohme Corp. Composés di-nucléotidiques cycliques en tant qu'agonistes de sting
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WO2016096174A1 (fr) * 2014-12-16 2016-06-23 Invivogen Dinucléotides cycliques fluorés utilisables en vue de l'induction des cytokines
WO2017027645A1 (fr) * 2015-08-13 2017-02-16 Merck Sharp & Dohme Corp. Composés di-nucléotidiques cycliques en tant qu'agonistes de sting
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US11299512B2 (en) 2016-03-18 2022-04-12 Immunesensor Therapeutics, Inc. Cyclic di-nucleotide compounds and methods of use
US11666594B2 (en) 2016-12-01 2023-06-06 Takeda Pharmaceutical Company Limited Antibody-drug conjugates comprising a cyclic dinucleotide
US12171777B2 (en) 2016-12-01 2024-12-24 Takeda Pharmaceutical Company Limited Methods of making a cyclic dinucleotide
US10980825B2 (en) 2016-12-01 2021-04-20 Takeda Pharmaceutical Company Limited Cyclic dinucleotide
US10246480B2 (en) 2017-02-17 2019-04-02 Eisai R&D Management Co., Ltd. Compounds for the treatment of cancer
US10618930B2 (en) 2017-02-17 2020-04-14 Eisai R&D Management Co., Ltd. Compounds for the treatment of cancer
US11339188B2 (en) 2017-02-17 2022-05-24 Eisai R&D Management Co., Ltd. Compounds for the treatment of cancer
US11400108B2 (en) 2017-02-21 2022-08-02 Board Of Regents, The University Of Texas System Cyclic dinucleotides as agonists of stimulator of interferon gene dependent signalling
US12036231B2 (en) 2017-02-21 2024-07-16 Board Of Regents, The University Of Texas System Cyclic dinucleotides as agonists of stimulator of interferon gene dependent signalling
US11660311B2 (en) 2017-10-10 2023-05-30 Bristol-Myers Squibb Company Cyclic dinucleotides as anticancer agents
WO2019074887A1 (fr) * 2017-10-10 2019-04-18 Bristol-Myers Squibb Company Dinucléotides cycliques utilisés en tant qu'agents anticancéreux
US12054512B2 (en) 2017-11-10 2024-08-06 Takeda Pharmaceutical Company Limited Sting modulator compounds, and methods of making and using
US11542293B2 (en) 2017-11-10 2023-01-03 Takeda Pharmaceutical Company Limited Sting modulator compounds, and methods of making and using
EP3727401A4 (fr) * 2017-12-20 2022-04-06 Merck Sharp & Dohme Corp. Composés dinucléotidiques cycliques utilisés comme agonistes sting
US11685761B2 (en) 2017-12-20 2023-06-27 Merck Sharp & Dohme Llc Cyclic di-nucleotide compounds as sting agonists
US12251394B2 (en) 2018-06-01 2025-03-18 Eisai R&D Management Co., Ltd. Methods for the treatment of bladder cancer
WO2019232392A1 (fr) 2018-06-01 2019-12-05 Eisai R&D Management Co., Ltd. Méthodes de traitement du cancer de la vessie
US11691990B2 (en) 2018-08-16 2023-07-04 Eisai R&D Management Co., Ltd Salts of compounds and crystals thereof
US11161864B2 (en) 2018-10-29 2021-11-02 Venenum Biodesign, LLC Sting agonists
US11883420B2 (en) 2018-10-29 2024-01-30 Venenum Biodesign, LLC Sting agonists for treating bladder cancer and solid tumors
US11110106B2 (en) 2018-10-29 2021-09-07 Venenum Biodesign, LLC Sting agonists for treating bladder cancer and solid tumors
US11787833B2 (en) 2019-05-09 2023-10-17 Aligos Therapeutics, Inc. Modified cyclic dinucleoside compounds as sting modulators
US12221460B2 (en) 2020-11-09 2025-02-11 Takeda Pharmaceutical Company Limited Antibody drug conjugates
US11725024B2 (en) 2020-11-09 2023-08-15 Takeda Pharmaceutical Company Limited Antibody drug conjugates
CN114213491A (zh) * 2021-12-31 2022-03-22 中南民族大学 一类内源性核苷M1dG及其衍生物的合成方法及其应用
CN114213490B (zh) * 2021-12-31 2024-04-02 中南民族大学 一类三环核苷酸类似物及其合成方法和应用
CN114213491B (zh) * 2021-12-31 2024-04-02 中南民族大学 一类内源性核苷M1dG及其衍生物的合成方法及其应用
CN114213490A (zh) * 2021-12-31 2022-03-22 中南民族大学 一类三环核苷酸类似物及其合成方法和应用
CN120757600A (zh) * 2025-09-10 2025-10-10 天津法尔玛制药有限公司 环二核苷酸2′,3′-cG4′-MeAMP、制备方法及其在制备先天免疫激活剂中的应用

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