WO2021057994A1 - Composé pyrazole et son utilisation - Google Patents

Composé pyrazole et son utilisation Download PDF

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WO2021057994A1
WO2021057994A1 PCT/CN2020/118261 CN2020118261W WO2021057994A1 WO 2021057994 A1 WO2021057994 A1 WO 2021057994A1 CN 2020118261 W CN2020118261 W CN 2020118261W WO 2021057994 A1 WO2021057994 A1 WO 2021057994A1
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optionally substituted
compound
alkyl
formula
substituted
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PCT/CN2020/118261
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English (en)
Chinese (zh)
Inventor
彭程
张绍云
沈微
赖小刚
刘奉友
吕遐师
周杨
邹罡
袁海卿
邬征
Original Assignee
苏州爱科百发生物医药技术有限公司
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Publication of WO2021057994A1 publication Critical patent/WO2021057994A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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

Definitions

  • the invention belongs to the field of medicine, and relates to a pyrazole compound, a preparation method thereof, and application in the prevention and/or treatment of hepatitis B.
  • Hepatitis B virus infection can not only cause acute hepatitis, but may also lead to chronic hepatitis, induce cirrhosis and eventually lead to liver cancer. HBV can infect the human body through a variety of ways, causing the spread of liver disease. Every year, the number of deaths due to acute or chronic hepatitis B infection is approximately 800,000. Hepatitis B virus infection has become one of the major diseases affecting human health.
  • Hepatitis B virus is a circular double-stranded DNA virus containing a part of a single-stranded region, with a genome length of about 3.2 kb, belonging to the family of hepadnavividae.
  • the nucleotide sequence heterogeneity of the whole HBV gene is about 8%.
  • S gene region nucleotide sequence heterogeneity of 4.2% as the standard, HBV genotypes can be divided into 8 types, including A-H.
  • the distribution of HBV genotypes has racial and regional differences.
  • the B and C genotypes are mainly distributed in Asia.
  • the A and D genotypes are often distributed in Africa, Europe and the Indian peninsula.
  • the E type is distributed in West Africa, the F type is distributed in Central and South America, and the G genotype is often distributed in France. , Germany and North America.
  • the genome of hepatitis B virus contains four open reading frames, encoding core protein, polymerase, membrane protein and X protein.
  • the infection of hepatitis B virus relies on the sodium ion-taurocholic acid-cotransporter (NTCP) receptor on the liver cell membrane. After hepatitis B virus infects liver cells, part of the double-stranded viral DNA is transported to the nucleus and forms a covalent closure.
  • NTCP sodium ion-taurocholic acid-cotransporter
  • Circular DNA (covalently closed circular DNA, cccDNA), cccDNA is the transcription template of hepatitis B virus pregenomic RNA (pgRNA) and subgenomic RNA.
  • the core protein contains pgRNA and polymerase together for replication (Lamontagne R.J., et al., Hepatoma. Res., 2016, 2:163-186).
  • the hepatitis B virus has a 7nm outer membrane protein layer containing phospholipids, which is called hepatitis B surface antigen (HBsAg).
  • HBsAg hepatitis B surface antigen
  • Membrane proteins are divided into three types (large, middle, and small HBsAg). They are encoded by the S gene of HBV, but their transcription start sites are different. Among them, the C end of the S area is the same area.
  • Membrane proteins are integrated into the endoplasmic reticulum membrane under the guidance of the N-terminal signal sequence. On the one hand, membrane protein will become an important structural protein of mature hepatitis B virus particles; on the other hand, membrane protein will form spherical or filamentous subviral particles (SVPs).
  • SVPs subviral particles
  • the content of subviral particles is usually more than 1000 times that of mature virus particles.
  • the hepatitis B surface antigen positive for more than 6 months is a sign of chronic HBV infection.
  • subviral particles are not infectious, they have an important impact on the host's immune response.
  • Hepatitis B surface antigen can inhibit the activation of monocytes in the innate immune system (Vanlandschoot P., et al., J. Gen.
  • Interferons include ordinary interferon and peginterferon.
  • Lamivudine Adefovir Entecavir Telbivudine Tenofovir Interferon can activate immune cells by regulating the host immune system and induce the production of a variety of antiviral factors to achieve control of HBV.
  • anti-virus can also improve the body's immunity, the effect is relatively long-lasting, and can reduce the incidence of liver cirrhosis and liver cancer.
  • the disadvantage is that the antiviral effect is not strong, accompanied by more side effects, which may cause flu-like symptoms, muscle pain, thrombocytopenia, hair loss, depression and other symptoms.
  • Lamivudine is a drug that has been used to treat AIDS. It is quickly absorbed after oral administration. It can significantly inhibit the replication of HBV, thereby reducing the total load of the virus. Its effect is strong, safe, and there are few adverse reactions. However, long-term use will produce Resistance.
  • adefovir The therapeutic effect of adefovir is better than that of lamivudine, the antiviral effect is good, and it is still effective for lamivudine-resistant patients, and has good tolerability and safety, but long-term use will cause nephrotoxicity.
  • Long-term treatment with nucleoside drugs can only make 0.5-1% of patients get hepatitis B surface antigen clearance each year (E.Loggi, et al., Dig. Liver. Dis., 2015, 47(10): 836-841) .
  • HBV persists and replicates in liver cells, and HBV will continue to mutate and produce mutations during treatment
  • current antiviral drugs cannot completely eliminate HBV.
  • most patients need long-term treatment, which brings a huge economic and social burden to hepatitis B patients and society.
  • the elimination of hepatitis B surface antigen may break the host's immune tolerance to hepatitis B virus and restore the host's immune response to HBV, thereby achieving the goal of treating hepatitis B and providing a new direction for the treatment of hepatitis B. Therefore, the development of reducing hepatitis B DNA and realizing hepatitis B surface antigen to become negative will have an important impact on the treatment of hepatitis B, and produce huge economic and social benefits.
  • the present invention provides a pyrazole compound with high hepatitis B virus inhibition activity, low cytotoxicity, high safety, good liver selectivity, and high bioavailability.
  • the present invention provides the following technical solutions:
  • R 1 , R 2 and R 3 are each independently selected from H, D, halogen, -CN, -OH, optionally substituted -NH 2 , optionally substituted C 1-6 alkyl, and optionally substituted C 1 -6 alkoxy;
  • B is selected from optionally substituted aryl and optionally substituted heteroaryl
  • Each R 5 is independently selected from H, D, halogen, -CN, -COOH, -OH, -CF 3 , optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted ⁇ C 1-6 alkoxy;
  • R 6 is selected from H, D, optionally substituted C 1-6 alkyl and optionally substituted C 3-7 cycloalkyl;
  • A is selected from O, S and NH;
  • n 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • Q is an optionally substituted group: -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered Heteroaryl, where m is any integer from 1-10.
  • R 1, R 2 and R 3 are each independently selected from H, D, halo, -CN, -OH, optionally substituted substituted -NH 2, optionally substituted C 1- 6 alkyl and optionally ⁇ C 1-6 alkoxy; the optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted C 1-6 alkoxy are unsubstituted or are selected from -NH 2 , C 1-6 alkyl and C 1-6 alkoxy substituted by one or more substituents in C 1-6 alkyl, halogen, -NH 2, -CN or -OH;
  • B is selected from optionally substituted aryl and optionally substituted heteroaryl, said optionally substituted aryl or optionally substituted heteroaryl is unsubstituted or is selected from deuterium, C 1-6 alkane Aryl and heteroaryl substituted by one or more substituents in the group, halogen, -NH 2 , -CN or -OH, preferably the optionally substituted aryl or optionally substituted heteroaryl is unsubstituted Substituted or aryl and heteroaryl substituted with one or more substituents selected from C 1-6 alkyl, halogen, -NH 2, -CN or -OH;
  • Each R 5 is independently selected from H, D, halogen, -CN, -COOH, -OH, -CF 3 , optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted ⁇ C 1-6 alkoxy; the optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted C 1-6 alkoxy are unsubstituted or are selected from -NH 2 , C 1-6 alkyl and C 1-6 alkoxy substituted by one or more substituents in C 1-6 alkyl, halogen, -NH 2, -CN or -OH;
  • R 6 is selected from H, D, optionally substituted C 1-6 alkyl and optionally substituted C 3-7 cycloalkyl; the optionally substituted C 1-6 alkyl and optionally substituted C 3 -7 cycloalkyl is unsubstituted or is selected from a C 1-6 alkyl, halo, -NH 2, -CN or -OH or more substituents, and C 1-6 alkyl C 3-7 cycloalkyl;
  • Q is an optionally substituted group: -(CH 2 ) m -, C 3-7 cycloalkylene or 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered Heteroaryl, where m is any integer from 1 to 10; when substituted, the Q is selected from C 1-6 alkyl, C 1-6 alkylamino, halogen, -CF 3 , -NH 2 , -CN, -OH, C 1-6 alkoxy, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl and 5-10 membered heterocycloalkyl or one of Multiple substituents are substituted.
  • R 1 , R 2 and R 3 are each independently selected from H, D, fluorine, chlorine and bromine;
  • B is an optionally substituted group: phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto, pyridine-4(1H)-keto, Pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl , Thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl or quinazoline base;
  • Each R 5 is independently selected from H, D, halogen, -CN, -COOH, -OH, -CF 3 , -NH 2 , C 1-6 alkyl and C 1-6 alkoxy;
  • R 6 is selected from H, D and C 1-6 alkyl
  • A is selected from O, S and NH;
  • n 1, 2 or 3;
  • q 0, 1, 2 or 3.
  • B is an optionally substituted phenyl group.
  • Q is optionally substituted -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered heteroalkylene Aryl, where m is any integer from 1-6, when substituted, said Q is selected from C 1-6 alkyl, C 1-6 alkylamino, halogen, -CF 3 , -NH 2 , -CN, -OH, and C 1-6 alkoxy substituted by one or more substituents.
  • Q is -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein m is any integer from 1 to 6, and the cycloalkylene group includes cyclopropylene, cyclobutane, cyclopentylene, cyclohexylene, and cycloheptylene; Heterocycloalkyl is aziridinyl, aziridinyl, oxetanylene, pyrrolidinylene, tetrahydrofuranyl, tetrahydrothienyl, piperidinylene, morpholinylene, Piperazinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl, butyrolactamyl, valerolactam, caprolactamylidene, butyrolactone Group, va
  • the compound of formula (I) has a structure represented by formula (I-1):
  • R 1 , R 2 and R 3 are each independently selected from H, D, fluorine, chlorine and bromine;
  • R 4 is selected from H, D, halogen and -OH;
  • R 5 is selected from H, D, fluorine, chlorine, bromine, -CN, -CF 3 , methyl, ethyl, n-propyl and isopropyl;
  • R 6 is selected from H and D;
  • A is selected from O and S;
  • n 1 or 2;
  • Q is optionally substituted -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein m is any integer from 1-6, when substituted, the Q is selected from C 1-6 alkyl, C 1-6 alkylamino, halogen, -CF 3 , -NH 2 , -CN,- One or more substituents in OH and C 1-6 alkoxy are substituted.
  • Q is optionally substituted -(CH 2 ) m -, C 3-6 cycloalkylene or phenylene, wherein m is any integer from 1 to 6, when substituted, said Q is It is substituted by one or more substituents selected from fluorine, methyl, trifluoromethyl, ethyl, n-propyl and isopropyl.
  • R 1 , R 2 and R 3 are each independently selected from H, D, fluorine, chlorine and bromine;
  • R 4 is selected from fluorine, chlorine and bromine
  • R 5 is selected from H, D, fluorine, chlorine and bromine
  • R 6 is selected from H and D;
  • A is O
  • n 2;
  • Q is optionally substituted -(CH 2 ) m -or C 3-5 cycloalkylene, wherein m is any integer from 1-6, when substituted, said Q is selected from fluorine, methyl , Trifluoromethyl, ethyl, n-propyl and isopropyl substituted by one or more substituents.
  • the compound of formula (I) has a structure represented by formula (I-2):
  • R 1 is selected from H, D, fluorine, chlorine and bromine
  • R 2 is selected from fluorine, chlorine and bromine
  • R 5 is selected from H, D, fluorine, chlorine and bromine
  • Q is optionally substituted -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6- , Cyclopropylidene, cyclobutanyl, cyclopentylene or cyclohexylene, preferably, Q is optionally substituted -CH 2 -or -(CH 2 ) 2 -; when substituted, The Q is substituted with one or more substituents selected from fluorine, methyl, trifluoromethyl and ethyl.
  • the compound of formula (I) is selected from:
  • the present invention also provides a pharmaceutical preparation, which comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope label thereof.
  • a pharmaceutical preparation which comprises a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope label thereof.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope marker, or the pharmaceutical preparation, which is used as Drugs to prevent and/or treat hepatitis B.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope marker, or the pharmaceutical preparation is used in the preparation of prevention and / Or the application of drugs for the treatment of hepatitis B.
  • the present invention also provides a method for preventing and/or treating hepatitis B, which comprises the following steps: a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, ester, or isomer thereof , Solvates, prodrugs or isotope markers, or the pharmaceutical formulations described are administered to patients who need them.
  • the present invention provides a class of pyrazole compounds with a novel structure, which has excellent hepatitis B virus inhibitory activity.
  • the compound of the present invention has low cytotoxicity, high safety, good liver selectivity, high bioavailability, and can be used for prevention. And/or treat hepatitis B.
  • the synthesis method of the present invention has mild conditions, simple and easy operation, and is suitable for industrialized mass production.
  • halogen refers to fluorine, chlorine, bromine or iodine alone or in combination, especially fluorine, chlorine or bromine.
  • C 1-6 alkyl alone or in combination means a saturated linear or branched alkyl group containing 1-6, especially 1-4 carbon atoms, including methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- Butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2 -Pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3 ,-Dimethyl-2-butyl and so on.
  • "C 1-6 alkyl” is any one of methyl, ethyl, propyl
  • C 1-6 alkoxy alone or in combination represents the group C 1-6 alkyl-O-, where "C 1-6 alkyl” is as defined above.
  • C 3-7 cycloalkyl alone or in combination means a cyclic alkyl group having 3-7, especially 3-6 carbon atoms (including monocyclic, fused ring, bridged ring and spiro ring forms) , Including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • Particular "C 3-7 cycloalkyl” is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 3-7 cycloalkylene alone or in combination means from a cyclic alkyl group having 3-7, especially 3-6 carbon atoms (including monocyclic, fused ring, bridged ring and spiro ring).
  • Form such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • the divalent group formed by removing one more hydrogen atom and the two substitution sites can be at the same (if feasible) Or on different carbon atoms.
  • heterocycloalkyl also called “heterocyclyl”, alone or in combination means saturated or partially saturated (containing 1 or 2 double bonds) composed of carbon atoms and heteroatoms (or heteroatom-containing groups) ) Is a non-aromatic cyclic group (monocyclic or bicyclic group), the heteroatom (or heteroatom-containing group) is selected from N, NH, O and S(O) m (m is 0, 1 or 2 ).
  • the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3, or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group may be optionally oxidized.
  • heterocycloalkyl The hydrogen atoms on “heterocycloalkyl” are independently optionally substituted with one or more substituents described in the present invention.
  • the “heterocycloalkyl” can be linked to the parent molecule through any ring atom in the ring.
  • the heterocyclic group includes aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomethanyl Linyl, tetrahydropyranyl, 1,1-dioxythiomorpholinyl, butyrolactamyl, valerolactam, caprolactam, butyrolactone, valerolactone, caprolactone, etc.
  • heterocycloalkylene alone or in combination means from a heterocycloalkyl group having 3-7, especially 3-6 ring atoms (including monocyclic, fused ring, bridged ring and spiro Ring forms, such as aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl, thiomorph A divalent group formed by removing a hydrogen atom from the linyl group, tetrahydropyranyl group, 1,1-dioxythiomorpholinyl group, etc.), and the two substitution sites can be at the same (if feasible) or different
  • the ring atoms include carbon atoms and heteroatoms (or heteroatom-containing groups), and the heteroatoms (or heteroatom-containing groups) are selected from N
  • aryl alone or in combination means any stable 6-10 membered monocyclic or bicyclic aromatic group, including phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydroindenyl, biphenyl Base and so on.
  • heteroaryl alone or in combination means an aromatic cyclic group formed after the carbon atom on the ring is replaced by a heteroatom (or a heteroatom-containing group) (for example, a 5-7 membered monocyclic ring or a 7-10 bicyclic ring).
  • a heteroatom or a heteroatom-containing group
  • the heteroatom (or heteroatom-containing group) is selected from N, NH, O and S(O) m (m is 0, 1 or 2).
  • the number of heteroatoms in the heteroaryl group is preferably 1, 2, 3 or 4, such as thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, thiazolyl , 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazole Group, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, etc.
  • C 6-10 arylene alone or in combination means a divalent group formed by removing one more hydrogen atom from a C 6-10 aryl group, that is, the "-Ar-" structure, where the "aryl” As defined above.
  • heteroarylene alone or in combination means a divalent group formed by removing one more hydrogen atom from a 5-10 membered heteroaryl group, wherein "heteroaryl” is as defined above.
  • amino alone or in combination means a primary amino group (-NH 2 ), a secondary amino group (-NH-) or a tertiary amino group
  • C 1-6 alkylamino also called “C 1-6 alkylamino”, alone or in combination, means “amino” as defined above, wherein the hydrogen atom on the amino group is replaced by at least one C 1-6 alkyl Substituted, where "C 1-6 alkyl” is as defined above.
  • C 1-6 alkylamino includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino , N-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino , 2-Methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4- Methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-di Methyl
  • C 1-6 alkylamino is methylamino, ethylamino, isopropylamino, tert-butylamino and the like.
  • the C 1-6 alkylamino group may be further optionally substituted with a substituent group commonly used in the art.
  • cyano alone or in combination means the group -CN.
  • isomeric forms including enantiomers, diastereomers, and geometric isomers (including cis and trans isomers). Therefore, a single stereochemical isomer of the compound designed in the present invention or a mixture of its enantiomers, diastereomers or geometric isomers (or cis-trans isomers) belongs to the present invention. range.
  • a pharmaceutically acceptable non-toxic acid addition salt means a salt formed by the compound of the present invention and an organic or inorganic acid.
  • the organic or inorganic acid includes, but is not limited to, hydrochloric acid, sulfuric acid, hydrobromic acid, and hydrogen iodide.
  • Acid phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, P-toluenesulfonic acid, malic acid, etc.
  • Non-toxic base addition salts refer to the salts formed by the compounds of the present invention and organic or inorganic bases, including but not limited to alkali metal salts, such as lithium, sodium or potassium salts; alkaline earth metal salts, such as calcium Or magnesium salt; organic base salt, for example, ammonium salt or N + (C 1-6 alkyl) 4 salt formed with N-containing organic base.
  • alkali metal salts such as lithium, sodium or potassium salts
  • alkaline earth metal salts such as calcium Or magnesium salt
  • organic base salt for example, ammonium salt or N + (C 1-6 alkyl) 4 salt formed with N-containing organic base.
  • “Pharmaceutically acceptable salts” can be synthesized by general chemical methods.
  • solvate refers to an association formed by one or more solvent molecules with the compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and the like.
  • esters are used to denote organic esters, including monoesters, diesters, triesters, and more generally polyesters.
  • prodrug means a chemical derivative of the compound of the present invention, which is converted into a compound represented by the general formula (I) by a chemical reaction in the body.
  • isotopic label means that the hydrogen atom in general formula (I) is replaced by 1-6 deuterium atoms (D), and the carbon atom in general formula (I) is replaced by 1-3 carbon 14 Atom ( 14 C) replaced by isotope label.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label thereof, the structure of the compound of formula (I) is:
  • R 1 , R 2 and R 3 are each independently selected from H, D, halogen, -CN, -OH, optionally substituted -NH 2 , optionally substituted C 1-6 alkyl, and optionally substituted C 1 -6 alkoxy;
  • B is selected from optionally substituted aryl and optionally substituted heteroaryl
  • Each R 5 is independently selected from H, D, halogen, -CN, -COOH, -OH, -CF 3 , optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted ⁇ C 1-6 alkoxy;
  • R 6 is selected from H, D, optionally substituted C 1-6 alkyl and optionally substituted C 3-7 cycloalkyl;
  • A is selected from O, S and NH;
  • n 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • Q is an optionally substituted group: -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered Heteroaryl, where m is any integer from 1-10.
  • R 1 , R 2 and R 3 are each independently selected from H, D, halogen, -CN, -OH, optionally substituted -NH 2 , optionally substituted C 1-6 alkyl, and optionally substituted C 1 -6 alkoxy; the optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted C 1-6 alkoxy are unsubstituted or are selected from C 1-6 alkyl, halo, -NH 2, -OH and -CN one or more substituents of -NH 2, C 1-6 alkyl and C 1- 6 alkoxy;
  • B is selected from optionally substituted aryl and optionally substituted heteroaryl, said optionally substituted aryl or optionally substituted heteroaryl is unsubstituted or is selected from deuterium, C 1-6 alkane Aryl or heteroaryl substituted by one or more substituents in the group, halogen, -NH 2 , -CN and -OH, preferably the optionally substituted aryl or optionally substituted heteroaryl is unsubstituted Substituted or aryl and heteroaryl substituted with one or more substituents selected from C 1-6 alkyl, halogen, -NH 2, -CN or -OH;
  • Each R 5 is independently selected from H, D, halogen, -CN, -COOH, -OH, -CF 3 , optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted ⁇ C 1-6 alkoxy; the optionally substituted -NH 2 , optionally substituted C 1-6 alkyl and optionally substituted C 1-6 alkoxy are unsubstituted or are selected from -NH 2 , C 1-6 alkyl and C 1-6 alkoxy substituted by one or more substituents among C 1-6 alkyl, halogen, -NH 2, -CN and -OH;
  • R 6 is selected from H, D, optionally substituted C 1-6 alkyl and optionally substituted C 3-7 cycloalkyl; the optionally substituted C 1-6 alkyl and optionally substituted C 3 -7 cycloalkyl is unsubstituted or is selected from a C 1-6 alkyl, halo, -NH 2, -CN, and -OH or more substituents, and C 1-6 alkyl C 3-7 cycloalkyl;
  • Q is an optionally substituted group: -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered Heteroaryl, where m is any integer from 1 to 10; when substituted, the Q is selected from C 1-6 alkyl, C 1-6 alkylamino, halogen, -CF 3 , -NH 2 , -CN, -OH, C 1-6 alkoxy, C 3-7 cycloalkyl, 5-10 membered heteroaryl, C 6-10 aryl and 5-10 membered heterocycloalkyl or one of Replaced by multiple substituents;
  • A, n and q are as defined above.
  • R 1 , R 2 and R 3 are each independently selected from H, D, fluorine, chlorine and bromine;
  • B is an optionally substituted group: phenyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyridine-2(1H)-keto, pyridine-4(1H)-keto, Pyrrolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, tetrazolyl, isothiazolyl, oxazolyl, isoxazolyl , Thiadiazolyl, oxadiazolyl, naphthyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, quinolinyl, isoquinolinyl or quinazoline base;
  • Each R 5 is independently selected from H, D, halogen, -CN, -COOH, -OH, -NH 2 , -CF 3 , C 1-6 alkyl and C 1-6 alkoxy;
  • R 6 is selected from H, D and C 1-6 alkyl
  • A is selected from O, S and NH;
  • n 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • B is an optionally substituted phenyl group, and the rest are as defined above.
  • Q is optionally substituted -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered heteroarylene, Wherein m is any integer from 1-6; when substituted, the Q is selected from C 1-6 alkyl, C 1-6 alkylamino, halogen, -CF 3 , -NH 2 , -CN, One or more substituents in -OH and C 1-6 alkoxy are substituted, and the rest are as defined above.
  • Q is -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocycloalkylene, C 6-10 arylene or 5-10 membered heteroarylene, where m is 1 Any integer of -6, namely 1, 2, 3, 4, 5 or 6;
  • the cycloalkylene group includes cyclopropene, cyclobutane, cyclopentylene, and cyclohexylene , Cycloheptylene, etc.
  • the heterocycloalkylene group includes aziridinyl, azetidinyl, oxetanylene, pyrrolidinylene, tetrahydrofuranyl, tetrahydrothienyl , Piperidinylene, morpholinylene, piperazinylene, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxide thiomorpholinyl, butyrolactamyl, valerolactam Group,
  • the compound of formula (I) has a structure represented by formula (I-1):
  • R 1 , R 2 and R 3 are each independently selected from H, D, fluorine, chlorine and bromine;
  • R 4 is selected from H, D, halogen and -OH;
  • R 5 is selected from H, D, fluorine, chlorine, bromine, -CN, -CF 3 , methyl, ethyl, n-propyl and isopropyl;
  • R 6 is selected from H and D;
  • A is selected from O and S;
  • n 1 or 2;
  • Q is optionally substituted -(CH 2 ) m -, C 3-7 cycloalkylene, 3-7 membered heterocyclylene, C 6-10 arylene or 5-10 membered heteroarylene, wherein m is any integer from 1-6; when substituted, the Q is selected from C 1-6 alkyl, C 1-6 alkylamino, halogen, -CF 3 , -NH 2 , -CN,- One or more substituents in OH and C 1-6 alkoxy are substituted.
  • Q in the compound of formula (I) or formula (I-1) is optionally substituted -(CH 2 ) m -, C 3-6 cycloalkylene or phenylene , Where m is any integer from 1-6, and the rest are as defined above; when substituted, the Q is selected from fluorine, methyl, trifluoromethyl, ethyl, n-propyl and isopropyl Is substituted by one or more substituents.
  • R 1 , R 2 and R 3 in the compound of formula (I) or formula (I-1) are each independently selected from H, D, fluorine, chlorine and bromine;
  • R 4 is selected from fluorine, chlorine and bromine
  • R 5 is selected from H, D, fluorine, chlorine and bromine
  • R 6 is selected from H and D;
  • A is O
  • n 2;
  • Q is optionally substituted -(CH 2 ) m -or C 3-5 cycloalkylene, where m is any integer from 1-6, such as 1, 2, 3, 4, 5 or 6; when substituted When, said Q is substituted by one or more substituents selected from fluorine, methyl, trifluoromethyl, ethyl, n-propyl and isopropyl.
  • the compound of formula (I) has a structure represented by formula (I-2):
  • R 1 is selected from H, D, fluorine, chlorine and bromine
  • R 2 is selected from fluorine, chlorine and bromine
  • R 5 is selected from H, D, fluorine, chlorine and bromine
  • Q is optionally substituted -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6- , Cyclopropylidene, cyclobutanyl, cyclopentylene or cyclohexylene, preferably, Q is optionally substituted -CH 2 -or -(CH 2 ) 2 -; when substituted, The Q is substituted with one or more substituents selected from fluorine, methyl, trifluoromethyl and ethyl.
  • the compound of formula (I), formula (I-1) or formula (I-2) is selected from:
  • the present invention also provides a method for preparing the above-mentioned compound of formula (I) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotope label.
  • the following describes the first compound of formula (I)
  • the specific synthesis method is:
  • X in compound e1 is halogen, preferably chlorine, bromine or iodine
  • R 7 is C 1-6 alkyl, preferably methyl or ethyl, and the rest are as defined above.
  • the alkaline reagent in the above step (1) is selected from organic alkaline reagents or inorganic alkaline reagents, preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, ethanol Sodium, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium formate, potassium formate, sodium acetate, potassium acetate, etc.
  • the catalyst in the above step (2) is phosphorous oxychloride.
  • the acid in the above step (3) is preferably a protic acid, more preferably methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc.;
  • the above-described reduction reaction in step (4) is carried out by a conventional reduction of the nitro group reduction reaction in the art, preferably H 2 / Ni reduction, Fe powder, reduction and the like.
  • N-alkylation and N-cycloalkylation reactions can be achieved by conventional N-alkylation and N-cycloalkylation reactions in the art, such as combining the reduction product of compound d with halogenated alkanes or halogenated cycloalkanes. Under the action of a base, the N-alkylation or N-cycloalkylation product e is obtained by the reaction.
  • the base is an organic base or an inorganic base, preferably sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, Sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, sodium formate, potassium formate, sodium acetate, potassium acetate, 2,6-lutidine, pyridine, piperidine, morpholine, tetrahydropyrrole, Diisopropylamine, N,N-diisopropylethylamine, triethylamine, diethylamine, dimethylamine, etc.
  • the deuteration reaction can deuterate one hydrogen atom of the amino group in the reduction product of compound d through a conventional deuteration reaction in the art.
  • the base of the substitution reaction in the above step (5) is an organic base or an inorganic base, preferably 2,6-lutidine, pyridine, piperidine, morpholine, tetrahydropyrrole, diiso Propylamine, N,N-diisopropylethylamine, triethylamine, diethylamine, dimethylamine, etc.
  • the base for the hydrolysis reaction in step (5) is a conventional inorganic base, including sodium hydroxide, lithium hydroxide, Potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, etc.
  • the present invention also provides a typical synthetic route of the second compound of formula (I), and the specific synthetic method is:
  • R 8 in compound g1 is C 1-6 alkyl, preferably methyl or ethyl, and the rest are as defined above.
  • the preferred conditions for preparing compound c in the second preparation method are the same as the preferred conditions for preparing compound c in the first preparation method.
  • the acid in the above step (3) is preferably a protic acid, more preferably methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and the like.
  • the catalyst for the coupling reaction in the above step (4) includes copper powder, cuprous iodide, cuprous chloride, Cu(acac) 2 , copper acetate, Cu(OTf) 2 etc.
  • the base for the hydrolysis reaction in step (4) is a conventional inorganic base, including sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, tert-butyl Potassium alkoxide, lithium tert-butoxide, etc.
  • the present invention also provides a typical synthetic route of the third compound of formula (I), and the specific synthetic method is:
  • Q'in compound h is the following group: when Q is -(CH 2 ) m -, C 3-7 cycloalkylene or 3-7 membered heterocycloalkylene, any one of them is methylene
  • the group is replaced with a carbonyl group, that is, Q';
  • R 9 in compound h is a C 1-6 alkyl group, preferably a methyl group or an ethyl group; the rest are as defined above.
  • compound e is prepared by the method of preparing compound e in the first preparation method.
  • the reagent of the reductive amination reaction in the above step (1) is NaBH 3 CN, NaBH(OAc) 3 or NaBH 4 .
  • the base for the hydrolysis reaction in the above step (2) is a conventional inorganic base, including sodium hydroxide, lithium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, Sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, etc.
  • the present invention also provides a pharmaceutical preparation, which comprises the above-mentioned compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt, ester, isomer, solvate, Prodrugs or isotope markers, the preparations are tablets, capsules, injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, Any of dry suspension, patch, lotion.
  • the present invention also provides the above-mentioned compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, Or the pharmaceutical preparation, which is used as a medicine for preventing and/or treating hepatitis B.
  • the invention also provides the above-mentioned compound of formula (I), formula (I-1) or formula (I-2) or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug or isotope label, or The application of the pharmaceutical preparation in the preparation of a medicine for preventing and/or treating hepatitis B.
  • the present invention also provides a method for preventing and/or treating hepatitis B, which comprises the following steps: a therapeutically effective amount of the compound of formula (I), formula (I-1) or formula (I-2) or its pharmacologically Acceptable salts, esters, isomers, solvates, prodrugs or isotope markers, or the pharmaceutical formulations are administered to patients in need thereof.
  • terapéuticaally effective amount refers to a dose of a pharmaceutical active ingredient that can induce a biological or medical response in cells, tissues, organs, or organisms (such as patients).
  • administration refers to the application of active pharmaceutical ingredients (such as the compound of the present invention) to the patient or its cells, tissues, organs, biological fluids and other parts, so that the active pharmaceutical ingredients can interact with the patient or its cells, tissues, organs, or organisms.
  • active pharmaceutical ingredients such as the compound of the present invention
  • Common modes of administration include (but are not limited to) oral administration, subcutaneous administration, intramuscular administration, subperitoneal administration, ocular administration, nasal administration, sublingual administration, rectal administration, vaginal administration and the like.
  • the term "has a need for it” refers to the judgment of the doctor or other nursing staff on the needs of the patient or the benefit from the prevention and/or treatment process. This judgment is based on the doctors or other nursing staff’s expertise in their fields of expertise. Kind of factors.
  • patient refers to a human or non-human animal (e.g., a mammal).
  • the intermediate and the final product are separated and purified through a chromatographic column, a preparative chromatography plate and an ICSO rapid preparative chromatography system.
  • the LC-MS liquid chromatography mass spectrometry chromatograph uses the ACQUITY Arc of Waters company equipped with QDa Detector.
  • Mass spectrometry uses the ESI source and only indicates the molecular weight M of the parent molecule, usually reporting [M+H] + .
  • the injection volume is determined by the sample concentration; the flow rate is 1.2 mL/min; the HPLC peak is recorded and read by UV-Vis wavelengths at 220 nm and 254 nm.
  • the mobile phase is an ultrapure aqueous solution of 0.01% formic acid (mobile phase A) and a solution of 0.01% formic acid in acetonitrile (mobile phase B).
  • the gradient elution conditions are shown in Table 1 and Table 2:
  • the NMR spectrum is obtained by using a Varian 400MHz nuclear magnetic resonance spectrometer.
  • CD 3 OD, CDCl 3 or DMSO-d 6 is often used as a solvent, and chemical shifts are reported in ppm.
  • the description of the various peaks is as follows: s (single peak), d (doublet), t (triplet), q (quartet), m (multiple), dd (double doublet).
  • the coupling constant is expressed in Hz.
  • Step 1a Preparation of 4-chloro-3-fluorophenylhydrazine
  • step 1a At -10°C, slowly add dropwise a 2M aqueous sodium nitrite solution (12 mL) to a concentrated hydrochloric acid solution (10 mL) of 4-chloro-3-fluoroaniline (3 g, 20.61 mmol). After the reaction mixture was stirred at room temperature for 1 hour, the temperature of the reaction system was lowered to -10°C, and then 4.55M stannous chloride dihydrate concentrated hydrochloric acid solution (10 mL) was slowly added dropwise to the reaction system. After the addition is complete, add concentrated hydrochloric acid (30 mL) to the system.
  • Step 1b Preparation of 1-(4-chloro-3-fluorophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine
  • step 1b Add 4-chloro-3-fluorophenylhydrazine (2.6g, 17.37mmol) to the ethanol solution (20mL) of 1-(4-fluorophenyl)ethanone (2.4g, 17.37mmol) And potassium acetate (2.05g, 20.85mmol), stirred overnight at 90°C.
  • the reaction solution was concentrated to about 5 mL, filtered to obtain a crude product, and washed with petroleum ether to obtain a yellow solid 1-(4-chloro-3-fluorophenyl)-2-(1-(4-fluorophenyl)ethylene Benzyl)hydrazine (1.8g), the crude product was used directly in the next step without further purification.
  • Step 1c Preparation of 1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde
  • step 1c Add 1-(4-chloro-3-fluorobenzene) to the mixture of phosphorus oxychloride (5mL) and N,N-dimethylformamide (10mL) at room temperature (about 20°C) Yl)-2-(1-(4-fluorophenyl)ethylene)hydrazine (1.8 g, 6.41 mmol) in N,N-dimethylformamide (10 mL).
  • the reaction solution was stirred at room temperature for 1 h, heated to 70° C., and stirred for 5 h.
  • reaction solution was poured into ice water, filtered, and the filter cake was recrystallized from petroleum ether and ethyl acetate to obtain a pale yellow solid 1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H -Pyrazole-4-carbaldehyde (1.8g).
  • Step 1d Preparation of 2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-nitrophenylethyl) Yl)oxazolin-4-one
  • step 1d To a solution of 1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (500mg, 1.57mmol) in toluene (30mL) Add 2-hydroxy-N-(4-nitrophenethyl)acetamide (352mg, 1.57mmol) and p-toluenesulfonic acid monohydrate (165mg, 1.57mmol).
  • Step 1e Preparation of 3-(4-aminophenethyl)-2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl )Oxazolin-4-one
  • Step 1e specific method to 2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-nitro Phenethyl)oxazolin-4-one (610mg, 1.16mmol) in acetic acid (10mL) was added with reduced iron powder (650mg, 11.6mmol), stirred at room temperature for 2h, filtered and concentrated to obtain a yellow oil.
  • Step 1f Preparation of 3-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl) ethyl) phenylamino) ethyl propionate
  • Step 1f specific method: to 3-(4-aminophenethyl)-2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4 -Base) oxazolin-4-one (50mg, 0.101mmol) in N-methylpyrrolidone (1mL) solution, add 2,6-lutidine (11mg, 0.101mmol) and ethyl bromopropionate ( 24mg, 0.131mmol).
  • Step 1g Preparation of 3-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)propionic acid
  • step 1g To 3-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl )-4-oxooxazolidin-3-yl)ethyl)phenylamino)propionate (30mg, 0.05mmol) in methanol (5mL) and water (2mL) solution, add lithium hydroxide monohydrate (9mg, 0.02mmol).
  • Step 2a Preparation of 1-(4-bromophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine
  • step 2a The specific method of step 2a: 1-(4-fluorophenyl)ethanone (10g, 72.39mmol), 4-bromophenylhydrazine (16.18g, 72.39mmol) and potassium acetate (7.1g, 72.39mmol) are similar to The yellow solid 1-(4-bromophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine (21g) was prepared by the method of step 1b in Example 1. The crude product was not further purified. Used directly in the next step.
  • Step 2b Preparation of 1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde
  • step 2b add 1-(4-bromophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine (6.1g, 19.86mmol), N,N-dimethylformamide (20mL) and phosphorus oxychloride (5mL) solution was prepared according to the method similar to step 1c in Example 1 to obtain a pale yellow solid 1-(4-bromophenyl)-3-(4-fluorophenyl)-1H- Pyrazole-4-carbaldehyde (5.9 g).
  • Step 2c Preparation of 2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-nitrophenethyl)oxazole Lin-4-one
  • step 2c add 1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (1.6g, 4.64mmol), 2-hydroxy-N-(4 -Nitrophenethyl) acetamide (1.25g, 5.56mmol) and p-toluenesulfonic acid monohydrate (0.44g, 2.32mmol) were prepared according to the method similar to step 1d in Example 1 to obtain a pale yellow solid 2-(1 -(4-Bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-nitrophenethyl)oxazolin-4-one (1.24g ).
  • Step 2d Preparation of 3-(4-aminophenethyl)-2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)oxazoline -4-one
  • Step 2d specific method add 2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-nitrophenethyl) Oxazoline-4-one (600mg, 1.09mmol), iron powder (607mg, 10.88mmol) and acetic acid (30mL) were prepared according to the method similar to step 1e in Example 1 to obtain 3-(4-aminobenzene) as a yellow oil
  • the crude product is not After further purification, it was directly used in the next step.
  • Step 2e Preparation of 3-(4-(2-(2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-oxo Oxazolidine-3-yl) ethyl) phenylamino) ethyl propionate
  • Step 2e specific method 3-(4-aminophenethyl)-2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)oxa Oxazolin-4-one (60mg, 0.115mmol), ethyl bromopropionate (27mg, 0.149mmol) and 2,6-lutidine (12.3mg, 0.115mmol) were similar to those of step 1f in Example 1.
  • Step 2f Preparation of 3-(4-(2-(2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-oxo Oxazolidine-3-yl)ethyl)phenylamino)propionic acid
  • Step 2f specific method 3-(4-(2-(2-(1-(4-bromophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4- (Oxooxazolidine-3-yl) ethyl) phenylamino) ethyl propionate (13 mg, 0.021 mmol) and lithium hydroxide monohydrate (4 mg, 0.08 mmol) according to the method similar to step 1g in Example 1.
  • Step 3a Preparation of 4-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)butyric acid ethyl ester
  • Step 3a specific method 3-(4-aminophenethyl)-2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4 -Base) oxazolin-4-one (30mg, 0.06mmol) and ethyl 4-bromobutyrate (15mg, 0.07mmol) were prepared according to the method similar to step 1f in Example 1 to obtain a yellow solid 4-(4- (2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-oxooxazolidine-3 Ethyl)ethyl)phenylamino)butyrate (10 mg).
  • Step 3b Preparation of 4-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)butyric acid
  • Step 3b specific method: to 4-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl )-4-oxooxazolidin-3-yl)ethyl)phenylamino)ethyl butyrate (10mg, 0.02mmol) in ethanol (5mL) was added sodium hydroxide (3mg, 0.09mmol) and water (1mL). The mixture was stirred at room temperature for 3 hours. After ethyl acetate was added, it was extracted three times with water.
  • aqueous phase was adjusted to pH 5-6 with 1M HCl, and then the aqueous phase was extracted three times with ethyl acetate. After the organic layer was concentrated, a white solid 4 was obtained.
  • Step 4a Preparation of 7-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)heptanoate ethyl
  • step 4a 3-(4-aminophenethyl)-2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4 -Base) oxazolin-4-one (50mg, 0.1mmol) and ethyl 7-bromoheptanoate (28mg, 0.12mmol) were prepared according to the method similar to step 1f in Example 1 to obtain a yellow solid 7-(4- (2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4-oxooxazolidine-3 Ethyl)ethyl)phenylamino)heptanoate (16 mg).
  • Step 4b Preparation of 7-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)heptanoic acid
  • Step 5a Preparation of 3-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)cyclobutane-1-carboxylic acid ethyl ester
  • Step 5a To 3-(4-aminophenethyl)-2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4 -Base) oxazolin-4-one (30mg, 0.06mmol) in methanol (5mL) was added 3-oxocyclobutane-1-carboxylic acid ethyl ester (17mg, 0.12mmol) and sodium cyanoborohydride (5.8mg, 0.09mmol), the mixture was stirred at room temperature for 4h, diluted with dichloromethane (20mL), the organic phase was washed with water (20mL) and saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Step 5b Preparation of 3-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)cyclobutane-1-carboxylic acid
  • Step 6a specific method: 3,4-difluoroaniline (6.5g, 50.34mmol), stannous chloride dihydrate (35.8g, 151mmol), sodium nitrite (3.30g, 48mmol) and concentrated hydrochloric acid (130mL) according to A light yellow solid 3,4-difluorophenylhydrazine (4.6g) was obtained by the method similar to step 1a in Example 1. The crude product was directly used in the next step without further purification.
  • Step 6b Preparation of 1-(3,4-difluorophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine
  • step 6b Combine 1-(4-fluorophenyl)ethanone (2g, 14.48mmol), 3,4-difluorophenylhydrazine (2.09g, 14.48mmol) and potassium acetate (1.71g, 17.37mmol)
  • the yellow solid 1-(3,4-difluorophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine (1.08g) was prepared according to the method similar to step 1b in Example 1. The crude product was used directly in the next step without further purification.
  • Step 6c Preparation of 1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde
  • step 6c add 1-(3,4-difluorophenyl)-2-(1-(4-fluorophenyl)ethylene)hydrazine (1.08g, 4.09mmol), N,N-dimethyl
  • a solution of methyl carboxamide (4mL) and phosphorus oxychloride (1mL) was prepared according to the method similar to step 1c in Example 1 to obtain a pale yellow solid 1-(3,4-difluorophenyl)-3-(4-fluoro Phenyl)-1H-pyrazole-4-carbaldehyde (900 mg).
  • Step 6d Preparation of 2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-nitro Phenylethyl) oxazolin-4-one
  • Step 6d specific method add 1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (100mg, 0.33mmol), 2-hydroxy-N- (2-Fluoro-4-nitrophenethyl)acetamide (82mg, 0.36mmol) and p-toluenesulfonic acid monohydrate (63mg, 0.33mmol) were prepared according to the method similar to step 1d in Example 1 to obtain a pale yellow solid 2-(1-(3,4-Difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-nitrophenethyl ) Oxazolin-4-one (100 mg).
  • Step 6e Preparation of 3-(4-amino-2-fluorophenethyl)-2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole- 4-yl)oxazolin-4-one
  • Step 6e specific method add 2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4 -Nitrophenethyl)oxazolin-4-one (100mg, 0.196mmol), reduced iron powder (110mg, 1.96mmol) and acetic acid (5mL) were prepared according to the method similar to step 1e in Example 1 to obtain a yellow oil 3-(4-Amino-2-fluorophenethyl)-2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl ) Oxazolin-4-one (100mg), the crude product was used directly in the next step without further purification.
  • Step 6f Preparation of 2-(4-(2-(2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4 -Oxooxazolidine-3-yl)ethyl)-3-fluorophenylamino)ethyl acetate
  • Step 6f specific method to 3-(4-amino-2-fluorophenyl)-2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole -4-yl)oxazolin-4-one (40mg, 0.08mmol) in acetonitrile (5mL) was added ethyl bromoacetate (21mg, 0.12mmol) and potassium carbonate (23mg, 0.16mmol), the mixture was at 80 °C Stir for 6h, dilute with dichloromethane (20mL), wash the organic phase with water (20mL) and saturated brine (20mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product.
  • Step 6g Preparation of 2-(4-(2-(2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-4 -Oxooxazolidine-3-yl)ethyl)-3-fluorophenylamino)acetic acid
  • Step 6g specific method: to 2-(4-(2-(2-(1-(3,4-difluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl) -4-oxazolidin-3-yl) ethyl)-3-fluorophenylamino) ethyl acetate (40mg, 0.07mmol) in ethanol (5mL) was added sodium hydroxide (8mg, 0.35mmol) And water (1mL). The mixture was stirred at room temperature for 3 hours, then ethyl acetate was added, and the water was extracted three times.
  • Step 7a Preparation of 2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-iodophenylethyl) )Oxazolin-4-one
  • Step 7a The specific method: add 1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3.88g, 12.17mmol), 2-hydroxy- N-(4-iodophenylethyl)acetamide (3.71g, 12.17mmol) and p-toluenesulfonic acid monohydrate (2.32g, 12.17mmol) were prepared according to the method similar to step 1d in Example 1 to obtain a pale yellow solid 2 -(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-iodophenethyl)oxazoline- 4-ketone (5.9g).
  • Step 7b Preparation of 2-(4-(2-(2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)- 4-oxazolidin-3-yl)ethyl)phenylamino)-2-methylpropionic acid
  • step 7b To 2-(1-(4-chloro-3-fluorophenyl)-3-(4-fluorophenyl)-1H-pyrazol-4-yl)-3-(4-iodobenzene Ethyl) oxazolin-4-one (100mg, 0.165mmol) in anhydrous N, N-dimethylformamide (3mL) was added 2-isobutyrylcyclohexanone (89mg, 0.528mmol), iodide Copper (25mg, 0.132mmol), cesium carbonate (172mg, 0.528mmol) and methyl ⁇ -aminoisobutylcarboxylate hydrochloride (14.5mg, 0.198mmol).
  • HepG2.2.15 cells have inserted the whole genome of HBV and can continuously express HBV (Sells et al., Proc. Natl. Acad. Sci. USA, 1987, 84(4): 1005-1009).
  • the culture conditions were DMEM medium (Thermo), containing 10% serum (Gibco) and 200 ⁇ g/mL G418.
  • the cells were placed in a 5% CO 2 incubator and cultured at 37°C.
  • HepG2.2.15 cells were seeded into 96-well culture plates at 3 ⁇ 10 4 /well. The next day, the drug dissolved in DMSO was diluted 5-fold with a medium containing 2% serum and added to the cells. 1% DMSO was added alone as a control. After 4 days, aspirate the cell supernatant from each well, add the newly prepared diluted drug of the same concentration after discarding it, and culture for 3 days again, collect the supernatant, and detect the HBV-DNA content.
  • the HBV DNA inhibitory activity of the product of step 2d in Example 2 (control 1) measured by the same method as above was 0.011 ⁇ M, and the CC 50 was 7.8 ⁇ M.
  • Example 1 of the present invention a single intravenous injection (dose 2 mg/kg) and a single oral administration (dose 10 mg/kg) were taken respectively. Blood sampling point: before administration, 5min, 15min, 30min, 1h, 2h, 4h, 8h, 12h, 24h after administration, and 1h, 12h and 24h respectively to take mouse liver tissue to detect compound concentration.
  • the pharmacokinetic parameters of Example 1 in mouse plasma and liver are shown in Table 4 below.
  • Example 1 in plasma and liver is higher than that of Control 1, and the bioavailability of Example 1 is higher, and it has more liver selectivity, which is beneficial for treating hepatitis B infection.
  • the aforementioned compounds represented by the general formula (I), the different implementation modes of the compounds represented by the general formula (I), and all the specific examples of the compounds represented by the general formula (I) are involved.
  • Compounds can be prepared into corresponding isomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts.
  • the compound is prepared as a pharmaceutically acceptable derivative, and the derivative is any one of a prodrug, a salt, an ester, an amide, a salt of an ester, a salt of an amide, and a metabolite.
  • pharmaceutically acceptable salts include the use of inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid), or organic acids (such as acetic acid, propionic acid, succinic acid, benzoic acid, p-aminobenzenesulfonic acid, 2-Acetoxy-benzoic acid, cinnamic acid, mandelic acid, salicylic acid, glycolic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, fumaric acid, tartaric acid, citric acid, p-toluenesulfonate Acid, methanesulfonic acid, ethanesulfonic acid or benzenesulfonic acid) is a conventional non-toxic salt obtained by salting any compound involved in the present invention.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid
  • organic acids such as acetic acid, propionic acid
  • stable isotope derivatives can be introduced into any compound involved in the present invention, and the introduced isotope can be 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P , 32 P, 35 S, 18 F, 36 Cl, specific isotopic derivatives can be prepared by conventional techniques.
  • All the compounds involved in the present invention can be administered into a living body via any administration route.
  • the route of administration can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual injection, nasal inhalation, oral inhalation, eye drops, and local or systemic transdermal administration.
  • All the compounds involved in the present invention can be formulated into a single dose, which contains the active compound of the present invention as well as carriers, excipients, etc.
  • the dosage form can be tablets, capsules, injections, granules, powders, suppositories, and pills. , Creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc.
  • These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostatic agents, and isotonic regulators, Anti-sticking agent, etc.
  • Suitable formulations of the above various dosage forms can be obtained from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, published by Lippincott Williams & Wilkins in 2006 and Rowe, Raymond C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in Published in 2005, so those skilled in the art can easily prepare.
  • the dosage of the compound of the present invention can be 0.01 to 500 mg/kg per day.
  • the daily dose is 1-100 mg/kg, and it can be administered single or multiple times.
  • the new compound can inhibit the production or secretion of hepatitis B DNA, and the new compound can be used to treat and prevent HBV infection.
  • It can be used to treat and prevent HBV infection.

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Abstract

La présente invention concerne un composé pyrazole et son utilisation, la structure du composé étant (I). Le composé présente une excellente activité d'inhibition du virus de l'hépatite B, et le composé de la présente invention présente une faible cytotoxicité, une innocuité élevée, une bonne sélectivité hépatique et une biodisponibilité élevée, et peut être utilisé pour prévenir et/ou traiter l'hépatite B.
PCT/CN2020/118261 2019-09-29 2020-09-28 Composé pyrazole et son utilisation WO2021057994A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135601A1 (fr) * 2020-12-25 2022-06-30 杭州百新生物医药科技有限公司 Dérivé de 5-alkyl-2-pyrazole-oxazolidine-4-cétone et son utilisation

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4269936A (en) * 1971-12-28 1981-05-26 Fuji Photo Film Co., Ltd. Process of forming yellow photographic images
WO2006033995A2 (fr) * 2004-09-16 2006-03-30 Valeant Research And Development Thiazolidine-4-ones possedant une activite antihepatite b
WO2007014023A1 (fr) * 2005-07-21 2007-02-01 Valeant Research & Development Thiazolidinones, oxazolidinones et pyrrolidinones pour le vhb
WO2017173999A1 (fr) * 2016-04-06 2017-10-12 陈焕明 Composé pyrazole-oxazolidinone pour lutter contre le virus de l'hépatite b

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105503730B (zh) * 2015-12-25 2018-06-22 山东大学 吡唑类衍生物及其制备方法与应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4269936A (en) * 1971-12-28 1981-05-26 Fuji Photo Film Co., Ltd. Process of forming yellow photographic images
WO2006033995A2 (fr) * 2004-09-16 2006-03-30 Valeant Research And Development Thiazolidine-4-ones possedant une activite antihepatite b
WO2007014023A1 (fr) * 2005-07-21 2007-02-01 Valeant Research & Development Thiazolidinones, oxazolidinones et pyrrolidinones pour le vhb
WO2017173999A1 (fr) * 2016-04-06 2017-10-12 陈焕明 Composé pyrazole-oxazolidinone pour lutter contre le virus de l'hépatite b

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022135601A1 (fr) * 2020-12-25 2022-06-30 杭州百新生物医药科技有限公司 Dérivé de 5-alkyl-2-pyrazole-oxazolidine-4-cétone et son utilisation

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