WO2021104470A1 - Composé de 1,7-naphtyridine anti-vhb - Google Patents

Composé de 1,7-naphtyridine anti-vhb Download PDF

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Publication number
WO2021104470A1
WO2021104470A1 PCT/CN2020/132344 CN2020132344W WO2021104470A1 WO 2021104470 A1 WO2021104470 A1 WO 2021104470A1 CN 2020132344 W CN2020132344 W CN 2020132344W WO 2021104470 A1 WO2021104470 A1 WO 2021104470A1
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Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
group
alkyl
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PCT/CN2020/132344
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English (en)
Chinese (zh)
Inventor
吴立方
孙飞
丁照中
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202080082572.2A priority Critical patent/CN114761405A/zh
Publication of WO2021104470A1 publication Critical patent/WO2021104470A1/fr

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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicine, in particular to a new class of anti-HBV 1,7-naphthyridine compounds or pharmaceutically acceptable salts thereof, a preparation method thereof, and application thereof in the preparation of drugs for treating hepatitis B.
  • hepatitis B virus hepatitis B virus
  • HBv hepatitis B virus
  • Hepatitis B virus is the pathogen that causes hepatitis B (hepatitis B for short) and belongs to the family of hepatotropic DNA viruses. After HBV adheres to the surface of liver cells, it enters the cell through viral endocytosis mediated by sodium ion-taurocholic acid transporter polypeptide (NTCP), releases the capsid in the cytoplasm, and enters the nucleus and transforms into a covalently closed loop DNA (cccDNA). All subgenomic RNA (sgRNA) and pregenomic RNA (pgRNA) are formed by cccDNA transcription.
  • sgRNA subgenomic RNA
  • pgRNA pregenomic RNA
  • sgRNA After exiting the nucleus, sgRNA is translated into X protein and three other envelope proteins, and pgRNA is translated into core protein and viral polymerase. pgRNA and core protein self-assemble under the action of polymerase to form RNA that wraps the nucleocapsid. In the nucleocapsid, pgRNA is reverse-transcribed into negative-strand DNA, and the positive strand of DNA is further synthesized from this to form rcDNA.
  • the rcDNA wrapped by nucleocapsid re-uncoated into the nucleus to further amplify the cccDNA; on the other hand, it recombines with the envelope protein and releases the cell through the endoplasmic reticulum to form a new HBV.
  • cccDNA has a high degree of stability and is a template for HBV to replicate continuously. It exists in the form of minichromosomes in the nucleus of the host liver cell, and it is difficult to completely remove it with current treatment methods. This is also the main reason why hepatitis B is difficult to cure at present.
  • nucleoside (acid) compounds and interferons. Nucleoside (acid) drugs, such as lamivudine, entecavir, tenofovir (ester), etc., can effectively inhibit HBV DNA replication, but these drugs cannot eliminate cccDNA, and the disease often rebounds after stopping the drug.
  • Interferon drugs can partially activate the patient's immune system and inhibit hepatitis B virus through the body's autoimmune effect.
  • these drugs have relatively large side effects and are not well tolerated by patients. What is more serious is the response rate of different populations to interferon therapy. Significant differences, but overall the response rate is low (usually less than 30%) (Nat. Rev. Gastro. Hepat. 8 (2011), 275-284).
  • Existing clinical treatment programs have a low functional cure rate, and there is still a large unmet clinical need for hepatitis B treatment.
  • the present invention provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof,
  • R 1 is selected H, F, and C 1 ⁇ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br and CF 3 ;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ⁇ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b is substituted;
  • L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;
  • L 1 is selected from -C(R 7 ) 2 -;
  • L 2 is selected from -C(R 7 ) 2 -;
  • R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;
  • T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;
  • R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;
  • n is selected from 1, 2, 3 and 4;
  • R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;
  • R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;
  • the C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected H, F, and C 1 ⁇ 3 alkyl group, the optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br and CF 3 ;
  • R 3 , R 4 , R 5 and R 6 are each independently selected from H, F, Cl, Br, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3 ⁇ 6-membered heterocycloalkyl, the C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally selected by 1, 2, or 3 R b is substituted;
  • L is selected from -O-, -S-, -SO 2 -, -N(R 7 )- and -C(R 7 ) 2 -;
  • L 1 is selected from -C(R 7 ) 2 -;
  • L 2 is selected from -C(R 7 ) 2 -;
  • R 7 is each independently selected from H, F, Cl, Br, I, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, so The C 1-6 alkyl group, C 3-6 cycloalkyl group, C 1-6 heteroalkyl group and 3-6 membered heterocycloalkyl group are optionally substituted with 1, 2 or 3 R c ;
  • T, T 1 , T 2 , and T 3 are independently selected from CR 8 and N;
  • R 8 is selected from H, F, Cl, Br, I, CN, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 heteroalkyl and 3-6 membered heterocycloalkyl are optionally substituted with 1, 2 or 3 R d ;
  • n is selected from 1, 2, 3 and 4;
  • R 9 is each independently selected from H, F, Cl, Br, I, and C 1-3 alkyl groups, the C 1-3 alkyl groups are optionally substituted with 1, 2 or 3 R e ;
  • R a, R b, R c , R d and R e are each independently selected from F, Cl, Br, I, OH, CN, NH 2, COOH, CF 3, -CHF 2, -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl;
  • the C 1-6 heteroalkyl group and 3-6 membered heterocycloalkane each independently include 1, 2, 3, or 4 atoms or heteroatom groups independently selected from O, N, S, and NH.
  • R 1 is selected from H, F and CH 3, said optionally substituted with 1, 2 or 3 R a.
  • R 1 is selected from H and CH 3 .
  • R 1 is selected from H.
  • R 2 is selected from Cl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from H.
  • R 7 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 R c .
  • the above-mentioned R 7 is selected from H, F, Cl, Br, I, CF 3 , -CHF 2 , -CH 2 F, -OCH 3 , CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 , -NHCH 3 , -N(CH 3 ) 2 and cyclopropyl.
  • the aforementioned L is selected from -O-, -S-, -SO 2 -, -NH- and -CH 2 -.
  • the above-mentioned L is selected from -O-.
  • the aforementioned L 1 is selected from -CH 2 -, -CHF- and -CF 2 -.
  • the aforementioned L 2 is selected from -CH 2 -, -CHF- and -CF 2 -.
  • the above-mentioned R 8 is selected from H, F, Cl, Br, I, -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl, the -OCH 3 , CH 3 , -CH 2 CH 3 , -NHCH 3 and cyclopropyl are optionally substituted with 1, 2 or 3 Rd .
  • R 8 is selected from H.
  • R 9 is independently selected from H.
  • the above-mentioned compound is selected from
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , T, T 1 , T 2 , T 3 , L 1 , L 2 and m are as defined in the present invention.
  • the above-mentioned compound is selected from
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are as defined in the present invention.
  • the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof, and the compound is selected from
  • the present invention also provides the application of the above-mentioned compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating hepatitis B virus.
  • the present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt in the preparation of a medicine for inhibiting the activity of cccDNA.
  • the compound of the present invention exhibits significant cccDNA inhibitory activity on HepDES19 cell lines, and exhibits low clearance and high plasma exposure in mouse pharmacokinetic studies.
  • the compounds of the present invention can be used for diseases caused by HVB infection, such as the treatment of hepatitis B.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid.
  • Certain specific compounds of the present invention contain basic and acidic functional groups
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key And straight dashed key
  • the term “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refers to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0 alkyl-A means that the structure is actually -A.
  • the substituent can be bonded with any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. .
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
  • Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms.
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-6 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 6 carbon atoms.
  • the C 1-6 alkyl group includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl groups, etc.; it may Is monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • C 1-6 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • heteroalkyl by itself or in combination with another term means a stable linear or branched alkyl group or combination thereof composed of a certain number of carbon atoms and at least one heteroatom or heteroatom group.
  • the heteroatoms are selected from B, O, N, and S, wherein nitrogen and sulfur atoms are optionally oxidized, and nitrogen heteroatoms are optionally quaternized.
  • the heteroalkyl is a C 1-6 heteroalkyl; In other embodiments, the heteroalkyl is a heteroalkyl C 1- 3.
  • heteroatom or heteroatom group can be located in any internal position of the heteroalkyl group, including the position of attachment of the alkyl group to the rest of the molecule.
  • alkoxy "alkylamino” and “alkylthio” (or thioalkoxy) are customary expressions and refer to those connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
  • Alkyl group is customary expressions and refer to those connected to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively.
  • Up to two heteroatoms can be continuous
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic ring system, and the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • 3-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms.
  • a heteroatom may occupy the connection position of the heterocycloalkyl group with the rest of the molecule.
  • the 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4-membered, 5-membered and 6-membered heterocycloalkyl group.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithiazinyl, isoxazolidinyl, isothiazo
  • C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, where n and m are natural numbers, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, such as C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.
  • n-membered to n+m-membered means that the number of atoms in the ring is from n to n+m.
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, and a 7-membered ring.
  • 3-12 membered ring includes 3-6 membered ring, 3- 9-membered ring, 5-6 membered ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, 6-10 membered ring, etc.; in particular, C 0 represents not present.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (for example, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (P
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • DMF stands for N,N-dimethylformamide
  • Na 2 CO 3 stands for sodium carbonate
  • K 2 CO 3 stands for potassium carbonate
  • EtOAc stands for ethyl acetate
  • THF stands for tetrahydrofuran
  • MeOH stands for methanol
  • DCM stands for dichloromethane
  • DMSO stands for dimethyl sulfoxide
  • EtOH stands for ethanol
  • CH 3 CN stands for acetonitrile
  • TFA stands for trifluoroacetic acid
  • DIPEA stands for N,N-diisopropylethylamine
  • Tf stands for trifluoromethanesulfonate
  • Pd(PPh 2 )Cl 2 stands for bistriphenylphosphorus palladium dichloride
  • CO 2 stands for carbon dioxide
  • LCMS stands for liquid chromatography mass spectrometry
  • MS stands for mass spectrometry
  • HPLC stands for liquid chromatography
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
  • SXRD single crystal X-ray diffraction
  • the cultured single crystal is collected with the Bruker D8 venture diffractometer to collect the diffraction intensity data
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration
  • the present invention will be described in detail through the following examples, but it is not meant to impose any disadvantageous restriction on the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
  • Step B Dissolve A-2 (1.75 g, 10.79 mmol) in N,N-dimethylformamide (40 mL), cool the solution to 0 degrees Celsius, and add oxalyl chloride (1.78 g, 14.03 mmol) .
  • the reaction mixture was naturally heated to 25 degrees Celsius, and after stirring for 1 hour, methanol (5 mL) and water (50 mL) were added, and the mixture was extracted with 90 mL of ethyl acetate (30 mL/time, 3 times).
  • the combined organic phase was dried over anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure to obtain A-3.
  • Step C Add A-3 (3 g, 16.61 mmol), pyridine (6.57 g, 83.06 mmol), and N,N-diisopropylethylamine (4.72 g, 36.55 mmol) to dichloromethane in sequence (250 ml), after cooling to 0 degrees Celsius, add trifluoroacetic anhydride (37.50 g, 132.90 mmol). After the reaction mixture was naturally heated to 25 degrees Celsius, it was stirred for 3 hours. Then water (200 ml) was added, and extraction was performed with 600 ml of dichloromethane (200 ml/time, 3 times of extraction).
  • 1 H NMR 400 MHz, CDCl 3
  • Step B To a solution of ethyl (cis)-3-hydroxycyclobutyrate (B-3, 5 g, 34.68 mmol) in toluene (150 ml) was added N, N-diisopropylethylamine (8.96 g , 69.36 mmol) and B-2 (17.83 g, 69.36 mmol). The reaction mixture was stirred at 90 degrees Celsius for 12 hours. Then water (300 mL) and ethyl acetate (100 mL) were added to extract and separate the layers. The organic phase was washed once with 100 ml of saturated brine, and then dried over anhydrous sodium sulfate.
  • the preparation of Intermediate E refers to the preparation process of Intermediate B, and the compound (cis)-3-hydroxycyclobutyric acid ethyl ester (B-3) in step B is replaced with 3-hydroxybicyclo[1.1.1]pentane- Methyl 1-carboxylate (E-1).
  • the preparation of intermediate E refers to the preparation process of intermediate B, and the compound (cis)-3-hydroxycyclobutyric acid ethyl ester (B-3) in step B is replaced with 3-hydroxy-1-methylcyclobutyl ester ( F-1).
  • Step A Dissolve 1-1 (200 mg, 896.60 ⁇ mol) and Intermediate B (247.67 mg, 986.26 ⁇ mol) in acetonitrile (3 mL), then add potassium carbonate (185.87 mg, 1.34 mmol) and potassium iodide (14.88 mg, 89.66 micromolar). Under the protection of nitrogen, the reaction mixture was stirred at 85 degrees Celsius for 12 hours. Then water (20 mL) was added, and extraction was performed with 40 mL ethyl acetate (20 mL/time, extraction twice). The organic phase was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product 1-2, which was directly used in the next reaction.
  • Step B Dissolve 1-2 (280 mg, crude product, 711.98 micromolar) and bipartanol borate (216.96 mg, 854.37 micromolar) in anhydrous dioxane (5 mL), and then add Potassium acetate (139.75 mg, 1.42 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (51.10 mg, 71.2 micromoles). Under the protection of nitrogen, the reaction mixture was stirred at 100°C for 12 hours. Then water (20 mL) was added, and extraction was performed with 40 mL ethyl acetate (20 mL/time, extraction twice).
  • Step C Dissolve 1-3 (60 mg, 136.26 micromoles) and Intermediate A (42.6 mg, 136.26 micromoles) in anhydrous tetrahydrofuran (6 mL) and water (1 mL), then add sodium carbonate (28.88) Mg, 272.52 micromoles) and [1,1-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (11.13 mg, 13.63 micromoles). Under the protection of nitrogen, the reaction mixture was stirred at 75 degrees Celsius for 3 hours. Then water (30 mL) was added, and extraction was performed with 40 mL of ethyl acetate (20 mL/time, extraction twice).
  • Step D Add 1-4 (20 mg, 41.93 micromoles) to a mixed solvent of water (1 mL), methanol (1 mL) and tetrahydrofuran (1 mL), and then add lithium hydroxide monohydrate (4.4 mg, 104.83 micromolar). The reaction mixture was stirred at 25 degrees Celsius for 2 hours. After adjusting the pH to about 3 with hydrochloric acid (1 mol/L, 10 mL), it was concentrated under reduced pressure.
  • the preparation of compound 3 refers to the preparation process of compound 1, replacing intermediate B in step A with intermediate D. Separation and purification by preparative HPLC (column: Shim-pack C18 150 ⁇ 25mm ⁇ 10 ⁇ m; mobile phase: phase A: 0.225% aqueous formic acid; phase B: acetonitrile; elution gradient: 48% to 68%; 10 minutes) to obtain compound 3 .
  • the preparation of compound 4 refers to the preparation process of compound 1, replacing intermediate B in step A with intermediate E.
  • preparative HPLC column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; mobile phase: phase A: 0.05% ammonia solution; phase B: acetonitrile; elution gradient: 5% to 35%; 10 minutes) to obtain compound 4.
  • Step A Preparation of Intermediate 7-5 Referring to the preparation process of Compound 1, the compound 6-bromo-2-naphthol (1-1) in Step A is replaced with 3-bromo-7-hydroxyquinoline (5- 1) Replace Intermediate B with Intermediate F.
  • the crude compound 7 was purified by high performance liquid chromatography (column: Unisil 3-100C18, 150 ⁇ 50mm ⁇ 3 ⁇ m; mobile phase: phase A: 0.225% aqueous formic acid, phase B: acetonitrile; elution gradient: 30%-50% , 10 minutes) to obtain compound 7.
  • the HepDES19 cell line contains a 1.1-unit-length HBV genome, and the transcription of pgRNA is controlled by tetracycline. In the absence of tetracycline, the transcription of pgRNA is induced, but because the very short leader sequence before the HBeAg start codon interferes with the promoter, pgRNA cannot produce HBV e antigen (HBeAg). Only after the formation of cccDNA, the missing leader sequence and promoter mutation can be restored, and then HBeAg can be synthesized. Therefore, HBeAg can be used as a surrogate marker for cccDNA.
  • the HBeAg content of HepDES19 cell culture supernatant was detected by enzyme-linked immunosorbent assay (ELISA) to evaluate the compound's inhibitory effect on HBV.
  • ELISA enzyme-linked immunosorbent assay
  • DMEM/F12 medium source: Gibco Cat.11330057
  • 10% fetal bovine serum Fetal Bovine Serum, FBS, source: Clontech
  • 100unis/mL 100 ⁇ g/mL penicillin/streptomycin (Penicillin/streptomycin)
  • Source: Hyclone 2mM GlutaMAX (source: Gibco), 1% non-essential amino acid solution (MEM NEAA, source: Gibco), 0.1mM aminoglycoside antibiotic (Geneticin, source: Gibco), 1 ⁇ g/mL tetracycline hydrochloride (Tetracycline) Hydrochloride, source: Sigma), subcultured and expanded according to the ratio of 1/3, then planted HepDES19 into a T150 culture flask at a cell density of 4 ⁇ 10 6 cells, replaced with a tetracycline-free medium and cultured for 8 days, and finally The cells were collected and cryopreserved in liquid nitrogen (1 ⁇ 10 7
  • HepDES19 cells Resuscitate HepDES19 cells, plant HepDES19 cells in a 96-well plate (6 ⁇ 10 4 cells/well), and incubate overnight at 37 degrees Celsius and 5% CO 2.
  • the compound was diluted to a total of 8 concentrations in 3-fold serial dilutions. Compounds of different concentrations were added to the culture wells, and the wells were duplicated. The final concentration of DMSO in the culture broth is 0.5%.
  • the culture medium in the culture well was collected, and the content of hepatitis B virus HBeAg was determined by ELISA. After aspirating the culture medium in the culture wells, add Celltiter-Glo reagent to each well of the 96-well plate, and the microplate reader detects the chemiluminescence value of each well to detect cell viability.
  • ELISA measures the content of hepatitis B virus HBeAg.
  • the specific steps refer to the product manual. The steps are briefly described as follows: Take 50 microliters of sample and standard substance into the reaction plate, and then add 50 microliters of enzyme conjugate to each well, shake and mix. Incubate at 37 degrees Celsius for 60 minutes, then wash the plate with washing solution 6 times, then add 50 microliters of luminescent substrate to each well, mix well, and react for 10 minutes in the dark at room temperature. Finally, check the chemiluminescence intensity with a microplate reader.
  • %Inh. (1-HBeAg value in sample/DMSO control HBeAg value) ⁇ 100.
  • % Cell viability (sample luminescence value-medium control luminescence value) / (DMSO control luminescence value-medium control luminescence value) ⁇ 100%.
  • the compound of the present invention has good anti-HBV activity in vitro.
  • This experiment aims to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection or oral gavage in mice.
  • the compound is formulated as a clear solution of 0.2 mg/mL, and the vehicle: 5% DMSO/5% dodecyl hydroxystearate (solutol)/90% water; orally administered by gavage, the compound is formulated as 0.3 mg /mL suspension, solvent: 0.5% sodium carboxymethyl cellulose/0.2% Tween 80/99.3% water.
  • the sample collection schedule is as follows:
  • the concentration of the compound in plasma was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the retention time of the compound and the internal standard (diclofenac), the collection of chromatograms, and the integration of the chromatograms are processed by the software Analyst (Applied Biosystems), and the data statistics are processed by the software Watson LIMS (Thermo Fisher Scientific) or Analyst (Applied Biosystems).
  • the unit of the analyte concentration in the sample is ng/mL, with 3 significant digits reserved, and all values expressed in percentage (such as% deviation and% coefficient of variation, etc.) are kept to one decimal place.
  • Each calibration curve contains at least 6 concentration levels.
  • the preparation of calibration standards requires stock solutions from different sources from the quality control samples.
  • the standard sample should be rejected in the regression analysis.
  • the rejected calibration standards should be less than 25%, and each calibration curve contains at least 6 calibration standards that meet the acceptance criteria. If the lower limit of quantification and upper limit of quantification need to be rejected, the upper and lower limit of quantification of the analysis batch will be increased and lowered accordingly.
  • the non-compartmental model of WinNonlin TM Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software was used to process the plasma concentration, and the linear logarithmic ladder method was used to calculate the pharmacokinetic parameters.
  • the pharmacokinetic parameters to be calculated include but are not limited to (data permitted) T 1/2 , Vd ss , CL, AUC 0-24h in the intravenous administration (iv) group; oral administration (po) group C max , T max , AUC 0-24h , bioavailability (F%).
  • mice The pharmacokinetic parameters of the examples of the present invention in mice are shown in Table 2 below.
  • the compound of the present invention exhibits a lower clearance rate and a higher plasma exposure of the drug, and has good pharmacokinetic properties.

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Abstract

L'invention concerne un composé de 1,7-naphtyridine, et spécifiquement un composé tel que représenté dans la formule (I') et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2020/132344 2019-11-29 2020-11-27 Composé de 1,7-naphtyridine anti-vhb WO2021104470A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1829709A (zh) * 2003-08-01 2006-09-06 健亚生物科技公司 对抗黄病毒的双环咪唑衍生物
US20090264426A1 (en) * 2005-09-07 2009-10-22 Shunji Sakuraba Bicyclic aromatic substituted pyridone derivative
CN103140474A (zh) * 2010-07-02 2013-06-05 吉里德科学公司 治疗aids的萘-2-基乙酸衍生物
WO2019204614A1 (fr) * 2018-04-19 2019-10-24 Tvardi, Inc. Inhibiteurs de stat3

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0326963D0 (en) * 2003-11-19 2003-12-24 Glaxo Group Ltd Compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1829709A (zh) * 2003-08-01 2006-09-06 健亚生物科技公司 对抗黄病毒的双环咪唑衍生物
US20090264426A1 (en) * 2005-09-07 2009-10-22 Shunji Sakuraba Bicyclic aromatic substituted pyridone derivative
CN103140474A (zh) * 2010-07-02 2013-06-05 吉里德科学公司 治疗aids的萘-2-基乙酸衍生物
WO2019204614A1 (fr) * 2018-04-19 2019-10-24 Tvardi, Inc. Inhibiteurs de stat3

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