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WO2018153326A1 - Composé de sulfonyle hydrazine et son utilisation - Google Patents

Composé de sulfonyle hydrazine et son utilisation Download PDF

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Publication number
WO2018153326A1
WO2018153326A1 PCT/CN2018/076728 CN2018076728W WO2018153326A1 WO 2018153326 A1 WO2018153326 A1 WO 2018153326A1 CN 2018076728 W CN2018076728 W CN 2018076728W WO 2018153326 A1 WO2018153326 A1 WO 2018153326A1
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compound
group
substituted
alkyl
unsubstituted
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Chinese (zh)
Inventor
王喆
王晓光
卢涔宾
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Shanghai Longwood Biopharmaceuticals Co Ltd
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Shanghai Longwood Biopharmaceuticals Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D515/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention pertains to the field of medicine, and in particular, to a sulfonyl hydrazide compound for the treatment of hepatitis B and uses thereof.
  • Hepatitis B virus is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene.
  • the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed.
  • the pre-genomic RNA which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.
  • HBV has caused epidemics in parts of Asia and Africa, and it is endemic in China. HBV has infected about 2 billion people worldwide, and about 350 million of them have developed chronic infectious diseases. The virus causes hepatitis B disease and chronic infectious diseases are associated with a high increased risk of development of cirrhosis and liver cancer.
  • the spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum.
  • heteroaryldihydropyrimidines have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) .
  • a sulfamoyl-arylamide involving anti-HBV activity is also disclosed in WO 2013/006394 (published on Jan. 10, 2013) and WO 2013/096744 (published on June 27, 2013).
  • a compound of the formula A or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,
  • R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 3 -C 10 cycloalkyl, substituted or unsubstituted, having 1-3 selected from N, a 3-10 membered heterocycloalkyl group of a hetero atom of S and O, a substituted or unsubstituted C 6 -C 10 aryl group, and a substituted or unsubstituted hetero atom having 1-3 selected from N, S and O a 5-10 membered heteroaryl; wherein in R 1 the substitution is substituted with one or more (eg 1, 2, 3, 4 or 5) substituents selected from the group consisting of: -OH, Halogen, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -O-;
  • Y is a substituted or unsubstituted C 1 -C 7 alkylene group or a C 2 -C 7 alkenylene group; in the Y, the substitution means one or more selected from the group consisting of (for example, 1, 2) , 3, 4 or 5) substituted by a substituent: C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, -OH (preferably C 1 -C 4 alkyl or -OH);
  • W is selected from the group consisting of -SO 2 -, -CO-;
  • Ring C is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O; in said ring C, said substitution refers to a group selected from the group consisting of Or a plurality of (for example 1, 2, 3, 4 or 5, etc.) substituents substituted: C 1 -C 3 alkyl (preferably methyl), C 1 -C 3 haloalkyl, C 3 -C 4 -cycloalkyl, -CN or halogen;
  • Ring B is a substituted or unsubstituted C 6 -C 10 aryl group, or a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from N, S and O; Wherein said substitution is substituted with one or more (e.g., 1, 2, 3, 4 or 5) substituents selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 3 -C 4 cycloalkyl, -CN or halogen;
  • n 0, 1 or 2;
  • p 0, 1 or 2;
  • Z is selected from the group consisting of NH, O or none;
  • Z is selected from the group consisting of: halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10, OR 9 or H.
  • the compound is a compound selected from the group consisting of:
  • R 1 , X, Y, Z, W, ring C, ring B, Ra, Rb, Rc, Rd, n, p are as defined above.
  • -(N) 2 (R 1 )- represents a structure: -NH-N(R 1 )-.
  • R 1 is H, unsubstituted C 1 -C 10 alkyl, -OH, -O- or halogen-substituted C 1 -C 10 alkyl.
  • R 3 is selected from the group consisting of H, substituted or unsubstituted C 1 -C 10 alkyl, preferably H, substituted or unsubstituted C 1 -C 6 alkyl, more preferably The ground is H or methyl.
  • the R 2 and R 3 together with an adjacent C atom constitute a substituted or unsubstituted 3-7 membered impurity having 1-3 hetero atoms selected from N, S and O.
  • Ring C is a substituted or unsubstituted 5- or 6-membered heteroaryl group, said substitution being one or more selected from the group consisting of (eg 1, 2, 3, 4 or 5) Etc.) Substituted by a substituent: methyl, -CN or halogen.
  • ring C is a substituted or unsubstituted 5-6 membered heteroaryl group having 1-3 N, and in said ring C, said substitution refers to one or two selected from the group consisting of Substituted by a substituent: C 1 -C 3 alkyl (preferably methyl), halogen, -CN.
  • Ring B is phenyl or a substituted or unsubstituted 6-membered heteroaryl group, preferably a phenyl or pyridyl group.
  • Ring B is phenyl or 6-membered heteroaryl.
  • the R a , R b , R c and R d are each independently selected from the group consisting of H, halogen, —CHF 2 , —CF 2 —methyl, —CH 2 F, —CF. 3 , -OCF 3 , -CN, -C 3 -C 4 cycloalkyl, -C 1 -C 4 alkyl.
  • the ring C is or among them
  • R 4 is H, -C 1 -C 3 alkyl (preferably methyl), -C 3 -C 4 cycloalkyl;
  • R 6 is selected from H, methyl, -CN or halogen.
  • Z is O or not.
  • the R 7 is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-2 hetero atoms selected from N, S and O.
  • the compound of formula A is selected from the compounds listed in Table 1.
  • the compound of formula A is selected from the compounds prepared in Examples 1-49.
  • the method of the formula A compound is a compound of formula IX-1, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
  • n is an integer from 0-8.
  • a compound, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the first aspect of the invention is provided
  • the method of formula A is a compound of formula VIII-2, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
  • n is an integer from 0-8.
  • the method of formula A is a compound of formula V-3, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
  • the method of formula A is a compound of formula VI-4, the method comprising the steps of:
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H.
  • a pharmaceutical composition comprising (1) a compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable thereof a salt, hydrate or solvate; and (2) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference) Au- ⁇ ) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).
  • an immunomodulator eg, interferon- ⁇ (IFN- ⁇ ), PEGylation interference
  • Au- ⁇ e.g, PEGylation interference
  • a stimulant of the innate immune system such as Toll-like receptor 7 and/or 8 agonists
  • the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.
  • R1, ring C are as defined in relation to the first aspect of the invention.
  • Z is selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 haloalkyl, -NR 9 R 10 , OR 9 or H;
  • n is an integer from 0-8.
  • a hepatitis B virus inhibitor comprising the compound according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutical thereof An acceptable salt, hydrate or solvate.
  • a method for preventing and/or treating hepatitis B comprising the steps of: administering a compound according to the first aspect of the present invention, or a stereoisomer thereof or a mutual An isomer, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the sixth aspect of the invention.
  • a method for inhibiting hepatitis B in vitro comprising the steps of: the compound of the first aspect of the invention, or a stereoisomer or tautomer thereof, or A pharmaceutically acceptable salt, hydrate or solvate is contacted with hepatitis B virus to inhibit hepatitis B.
  • the inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B.
  • the compound of the present invention has a novel mother nucleus in structure, especially a structural moiety having a sulfonyl hydrazide, and therefore, not only has excellent anti-HBV activity, but also has lower cytotoxicity (especially for liver cells), and is superior in medicine. It has the advantages of generational kinetics, improved solubility, and so on, so it has better drug-forming properties. On this basis, the inventors completed the present invention.
  • alkyl as used herein includes a straight or branched alkyl group.
  • C 1 -C 8 alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.
  • alkenyl as used herein, includes a straight or branched alkenyl group.
  • C 2 -C 6 alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.
  • alkynyl includes a straight or branched alkynyl group.
  • C 2 -C 6 alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.
  • C 3 -C 10 cycloalkyl means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.
  • C 1 -C 8 alkylamino refers to an amine group substituted by a C 1 -C 8 alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.
  • C 1 -C 8 alkoxy refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.
  • the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from N, S and O” means having from 3 to 10 atoms and wherein 1-3 of the atoms are selected from A saturated or partially saturated cyclic group of a hetero atom of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.
  • C 6 -C 10 aryl refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.
  • the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from N, A cyclic aromatic group of a hetero atom of S and O. It may be a single ring or a fused ring.
  • Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.
  • the groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C 1 -C 6 alkyl-amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, halogenated C 1 - C 6 alkyl, halo C 2 -C 6 alkenyl, halo C 2 -C 6 alkynyl, halo C 1 -C 6 alkoxy, allyl, benzyl, C 6 -C 12 aryl , C 1 -C 6 alkoxy-C 1 -C 6 alkyl, C 1 -C 6 alkoxy-carbonyl, phenoxycarbonyl, C 2 -C 6 alkynyl-carbonyl
  • halogen or halogen atom refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo” means substituted with an atom selected from the group consisting of F, Cl, Br, and I.
  • the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond.
  • a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.
  • tautomer means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other.
  • proton tautomers ie, proton shifts
  • proton transfer such as 1H-carbazole and 2H-carbazole.
  • Valence tautomers include interconversion through some bonding electron recombination.
  • solvate refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.
  • hydrate refers to a complex formed by the coordination of a compound of the invention with water.
  • a compound of the invention refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A).
  • pharmaceutically acceptable salt refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament.
  • Pharmaceutically acceptable salts include inorganic and organic salts.
  • a preferred class of salts are the salts of the compounds of the invention with acids.
  • Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
  • Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid,
  • the pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer.
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
  • safe and effective amount it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.
  • vegetable oil such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifier such as Tween
  • a wetting agent such as sodium lauryl sulfate
  • a coloring agent such as a flavoring agent, a stabilizer, an antioxidant, a preservative
  • the mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • other pharmaceutically acceptable compounds e.g., anti-HBV agents.
  • the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents).
  • one or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound e.g, an anti-HBV agent
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.
  • the compounds of the invention are very toxic to normal cells.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.
  • the compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).
  • hepatitis B virus-related diseases for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • step 1
  • the preparation of the compound 6e was carried out in the same manner as in the step 1-4 of Example 1, except that in the step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
  • the compound 6e is used instead of the compound 6, and the 3-chloro-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • n-heptane: ethyl acetate 2:1
  • the preparation of the compound 6f was carried out by referring to the step 1-4 of Example 1, except that in the step 1, 1-allyl-1-isopropylindole was used instead of 1-allyl-1-methylindole.
  • the compound 6f is used instead of the compound 6, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • the preparation of the compound 6f is carried out in the same manner as in the step 1-4 of the first embodiment except that 2-methyl-1-allyl-1-isopropylindole is used in place of 1-allyl-1-methyl. Hey.
  • the compound 6f is used instead of the compound 6, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • the preparation of the compound 26b was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-cyclopropyl hydrazine was replaced by 1-allyl-1-cyclopropyl hydrazine in the step 21.
  • the compound 26d was prepared by referring to Step 21-24 of Example 13, except that in Step 21, 1-(1-allylhydrazo)ethanol was used instead of 1-allyl-1-methyloxime.
  • the preparation of the compound 26e was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-isopropylindole was replaced with 1-allyl-1-isopropylindole in the step 21.
  • the preparation of the compound 26f was carried out by referring to the step 21-24 of Example 13, except that the 1-allyl-1-isopropylindole was replaced with 1-allyl-1-isopropylindole in the step 21.
  • step 25 of the embodiment 13 it is only necessary to replace the compound 26 with the compound 26f, and to replace the 3,4-difluoro-1-aniline with 3-cyano-4-fluoro-1-aniline, and the other conditions are unchanged.
  • the preparation of the compound 45b is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
  • the compound 45c was prepared by following the procedure of Steps 41 to 43 of Example 25 except that 1-tert-butoxycarbonyl-1-tert-butylindole was used in place of 1-tert-butoxycarbonyl-1-isopropylindole.
  • the preparation of the compound 45d is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-hydroxyisopropyl hydrazine is used instead of 1-tert-butoxycarbonyl-1-isopropyl hydrazine. .
  • step 41 The preparation of compound 45e is carried out by referring to steps 41-43 of Example 25, except that in step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group.
  • the preparation of the compound 45f is carried out by referring to the steps 41-43 of Example 25, except that in the step 41, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
  • the compound 45f is used instead of the compound 45, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • the preparation of the compound 55b is carried out by referring to the steps 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is substituted for 1-tert-butoxycarbonyl-1-isopropyl group in the step 51. Hey.
  • the compound 55c was prepared by referring to the procedures 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-tert-butylindole was used in the step 51 instead of 1-tert-butoxycarbonyl-1-isopropylindole.
  • the preparation of the compound 55d is carried out by referring to the steps 51-53 of Example 31, except that in the step 41, 1-tert-butoxycarbonyl-1-hydroxyisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl hydrazine. .
  • the compound 55d was used instead of the compound 55, and the other conditions were unchanged.
  • the preparation of the compound 55e is carried out by referring to the steps 51-53 of Example 31, except that in the step 51, 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is used in place of 1-tert-butoxycarbonyl-1-isopropyl group. Hey.
  • the preparation of the compound 55f is carried out by referring to the steps 51-53 of Example 31 except that 1-tert-butoxycarbonyl-1-trifluoroisopropyl hydrazine is substituted for 1-tert-butoxycarbonyl-1-isopropyl group in the step 51.
  • reaction solution A) is dropped into the reaction liquid B), and the reaction system is controlled to about 0 degree, and after the completion of the dropwise addition, the reaction is carried out at 0 degree for 0.5 hour.
  • Step 62
  • Compound 64c was prepared as described in steps 61-63 of Example 38, except that in step 62, t-butyloxazolidinone was used in place of isopropyloxazolidinone.
  • the compound 64d was used instead of the compound 64, and the other conditions were unchanged.
  • reaction solution A) was dropped into the reaction liquid B), and the reaction system was controlled to about 0 degree, and the reaction was carried out at 0 degree for 0.5 hour after the completion of the dropwise addition.
  • Step 74
  • the compound 74b was used instead of the compound 74, and the other conditions were unchanged.
  • Column chromatography (n-heptane: ethyl acetate 1:3) of the desired product 80b (5 mg).
  • the compound 74c was prepared by following the procedures 71-73 of Example 44, except that in step 72, t-butyloxazolidinone was used in place of the isopropyloxazolidinone.
  • the compound 74d was prepared by following the procedures 71-73 of Example 44, except that in step 72, hydroxyisopropyloxazolidinone was used in place of the isopropyloxazolidinone.
  • the compound 74d was used instead of the compound 74, and the other conditions were unchanged.
  • the compound 74f was prepared by following the procedures 71-73 of Example 44, except that in step 71, trifluoroisopropyloxazolidinone was used in place of the isopropyloxazolidinone.
  • the compound 74f is used instead of the compound 74, and the 3-cyano-4-fluoro-1-aniline is substituted for the 3,4-difluoro-1-aniline.
  • [C150Bo] (A280- x1300M -1 ) / 60,900M -1 ;
  • [C150Bo] represents the concentration of a fluorescently labeled protein
  • A504 represents an absorbance value of a wavelength of 504 nM
  • A280 represents an absorption value of a wavelength of 280 nM
  • M -1 represents the reciprocal of the molar concentration.
  • the mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 ⁇ M with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.
  • C150Bo was diluted to 2 ⁇ M with 50 mM HEPES. 37.5 ⁇ L of C150Bo and 2.5 ⁇ L of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 ⁇ l of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.
  • Control wells were assembled with 0% protein, 10 ⁇ L of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.
  • Control wells were assembled with 100% protein and 10 ⁇ L of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.
  • the final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 ⁇ M, and the final concentration of C150Bo was 1.5 ⁇ M. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.
  • % protein assembly [1- (sample fluorescence value - 1M NaCl fluorescence value) / (0M NaCl fluorescence value - 1M NaCl fluorescence value)] ⁇ 100.
  • the IC 50 value is calculated by the prism software and the equation is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • Top indicates that Top represents the top of the curve
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • HepG2.2.15 cells (4 x 10 4 cells/well) were plated into 96-well plates and incubated overnight at 37 ° C, 5% CO 2 . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.
  • the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15.
  • the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.
  • the activity calculation formula is as follows:
  • X represents the logarithm of the concentration
  • Y represents the effect value
  • Y is fitted from the bottom to the top with an S-shape
  • HillSlope represents the absolute value of the maximum slope of the curve.
  • test compounds The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.
  • the compound of the present invention has good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and has low cytotoxicity.
  • +++ means IC 50 or EC 50 ⁇ 1 ⁇ M
  • ++ indicates an IC 50 or EC 50 of 1 to 100 ⁇ M
  • control compound is:
  • control group positive control compound
  • Test group Table 2 for each compound, comparing its pharmacokinetic differences.
  • Rats were fed a standard diet and given water. Fasting began 16 hours before the test.
  • the drug was dissolved with PEG400 and dimethyl sulfoxide. Blood was collected from the eyelids at a time point of 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours after administration.
  • Rats were briefly anesthetized after inhalation of ether, and 300 ⁇ L of blood samples were collected from the eyelids in test tubes. There was 30 ⁇ L of 1% heparin salt solution in the test tube. The tubes were dried overnight at 60 ° C before use. After the blood sample collection was completed at a later time point, the rats were anesthetized with ether and sacrificed.
  • Plasma samples were centrifuged at 5000 rpm for 5 minutes at 4 ° C to separate plasma from red blood cells. Pipette 100 ⁇ L of plasma into a clean plastic centrifuge tube to indicate the name and time point of the compound. Plasma was stored at -80 °C prior to analysis. The concentration of the compound of the invention in plasma was determined by LC-MS/MS. Pharmacokinetic parameters were calculated based on the plasma concentration of each animal at different time points.
  • the compound of the present invention has better pharmacokinetics in the animal than the control group, and the compound AUC of the present invention has an average increase of 15-100% and an average Cmax of 10-100% with respect to the control group. ), thus having better pharmacodynamics and therapeutic effects.
  • Test method 50 mg each of compound 10f, 60f and the positive control compound were taken at room temperature (20 ° C), and added to 2 ml of the corresponding solvent. After stirring, the supernatant was taken, and the solubility was measured by HPLC. The results are shown in the following table (unit: Mg/mL):
  • the compound of the present invention is excellent in anti-hepatitis B virus nucleocapsid assembly activity and anti-hepatitis B virus activity in vitro, and has lower cytotoxicity, and the compound of the present invention exhibits superior solubility and good pharmacokinetics of the reference compound. nature.

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Abstract

La présente invention concerne un composé de sulfonyle hydrazine et son utilisation en tant que médicament destiné à être utilisé dans le traitement de l'hépatite B. Plus particulièrement, la présente invention concerne un composé qui peut agir en tant qu'inhibiteur du VHB et qui a la structure représentée par la formule chimique A, ou un stéréoisomère ou un tautomère de celui-ci, ou un sel pharmaceutiquement acceptable, un hydrate ou un solvant dudit composé. Les définitions de chaque groupe, sont telles que décrites dans la description. La présente invention concerne également une composition pharmaceutique comprenant ledit composé et son utilisation dans le traitement de l'hépatite B.
PCT/CN2018/076728 2017-02-22 2018-02-13 Composé de sulfonyle hydrazine et son utilisation Ceased WO2018153326A1 (fr)

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WO2022213870A1 (fr) * 2021-04-06 2022-10-13 上海长森药业有限公司 Médicament et procédé d'inhibition des cellules cd4+treg au moyen d'une administration orale

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