WO2022022448A1 - Neuraminidase inhibitor compound, and pharmaceutical composition and use thereof - Google Patents

Neuraminidase inhibitor compound, and pharmaceutical composition and use thereof Download PDF

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WO2022022448A1
WO2022022448A1 PCT/CN2021/108383 CN2021108383W WO2022022448A1 WO 2022022448 A1 WO2022022448 A1 WO 2022022448A1 CN 2021108383 W CN2021108383 W CN 2021108383W WO 2022022448 A1 WO2022022448 A1 WO 2022022448A1
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alkyl
heterocyclyl
cycloalkyl
aminoalkyl
independently
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French (fr)
Chinese (zh)
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陈晖旋
康宁
刘希红
郭琛
张菊福
何小溪
王坤
李德耀
张礼军
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广州市恒诺康医药科技有限公司
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    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/57—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C233/63—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of medicine, and specifically relates to a new class of neuraminidase (especially influenza neuraminidase) inhibitor compounds, a pharmaceutical composition comprising the compound, and the use of the compound and the pharmaceutical composition in the Use in the preparation of drugs for treating and/or preventing viral diseases or inhibiting neuraminidase activity. More specifically, the compounds of the present invention can well inhibit the activity of influenza neuraminidase, and can be used for preventing and/or treating diseases caused by influenza virus.
  • neuraminidase especially influenza neuraminidase
  • Influenza is a common respiratory infectious disease caused by Influenza virus (Influenza virus for short). According to statistics, influenza virus causes 3 to 5 million severe cases and 250,000 to 500,000 deaths worldwide each year (Thompson MG, et al. (2016) Nat Commun, 9(1): 2407). In 2018, the World Health Organization (WHO) ranked influenza as the top ten threats to global public health (Shao W, et al. (2017) Int J Mol Sci, 18(8): E1650). At present, the main measures for the prevention and treatment of influenza in the world are vaccination and drug treatment. Vaccine research is lagging behind and its use is limited. Anti-influenza drugs are easy to use and have quick effects.
  • antiviral drugs have played an important role in the prevention and treatment of influenza.
  • anti-influenza virus drugs in clinic, namely M2 ion channel blockers and Neuraminidase inhibitors (NAIs); but M2 ion channel blockers are only effective against influenza A virus, and the drugs are not good. The response is large, and most influenza viruses are resistant to it and the drug-resistant strains develop rapidly (Kumar B, et al.
  • Influenza virus is an enveloped virus belonging to the family Orthomyxoviridae (Liu G, et al. (2016) Nat Commun, 9(1): 3199), mainly divided into A (A), B (B) ) and C (C) three types; among them, influenza A virus (Influenza A viruses, IAVs) has frequent antigenic variation, strong infectivity, and often causes outbreaks; influenza B virus (Influenza B viruses, IBVs) and C Influenza C viruses (ICVs) are antigenically very stable (Zhai SL, et al. (2017) Emerg Infect Dis, 23(8): 1392-1396). Humans are mainly infected with influenza A and B viruses.
  • influenza A and B viruses consists of 8 independent single-stranded negative-stranded RNAs, encoding 17 and 11 proteins, respectively (Nturbi E, et al. (2017). ) J Virol, 91(19):e01179-17), in which NA is a tetrameric protein on the viral envelope, and in the process of new viral particles detaching from host cells, viral particles adhere to host cells through sialic acid On the surface, NA can catalyze the hydrolysis of sialic acid, assist the virus to escape from the host cell, and promote the release of progeny virus (Medina RA, Garcia-Sastre A. (2011) Nat Rev Microbiol, 9(8):590-603), in influenza virus It plays a key role in replication and dissemination, and then becomes the target of various NAIs.
  • NAIs are a new class of anti-influenza drugs following M2 ion channel blockers.
  • NAIs play an antiviral role by binding to the specific domain of NA, blocking its active site and reducing the hydrolase activity of NA hydrolyzing cell surface sialic acid, thereby inhibiting virus release and cell-to-cell spread (Kim HO, et al. (2017) Small, 13(32)).
  • M2 ion channel blockers NAIs are more widely used and have become the most important anti-influenza virus drugs in clinical practice.
  • DANA 2,3-dehydro2-deoxyN-acetylneuraminic acid
  • C4-guanidino group which enhanced the binding force of DANA to NA and more effectively inhibited NA. activity, resulting in the development of zanamivir.
  • the drug was approved by the U.S. Food and Drug Administration (FDA) in July 1999 for the treatment of influenza caused by influenza A and B viruses (Kumar B, et al. (2016) Arch Virol, 163(4) :831-844). Zanamivir is rapidly metabolized in the body, and its bioavailability is only 2% to 3% when administered orally, so it is used for inhalation.
  • FDA U.S. Food and Drug Administration
  • Oseltamivir was developed based on zanamivir in which the C4 and glycerol side chains in the DANA structure were replaced by amino and hydrophobic amyl ether side chains, respectively.
  • Oseltamivir tablets are the first orally highly active NAIs that are converted to the active compound oseltamivir carboxylate by hepatic esterase, increasing drug bioavailability to 80%, in the US in October 1999 It is widely used in clinical after approval. Peramivir can only be administered intravenously and may be considered in patients who are resistant to oseltamivir and cannot be administered by inhalation.
  • the influenza neuraminidase inhibitor of the present invention has superior antiviral activity, and has a good curative effect on influenza A and B influenza virus infection, etc. It can be prepared into an inhalation type or injection type long-acting preparation, and then slowly in vivo , sustained and stable release to achieve long-term purpose.
  • the compounds of the present invention also have excellent efficacy, pharmacokinetic properties and toxicological properties, and have better clinical application prospects.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .
  • compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula of the present invention, or specific examples, subclasses, and subclasses of the present invention, as described in the Examples, and encompassed by the present invention. a class of compounds.
  • the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges.
  • C6-22 alkyl specifically refers to the independently disclosed C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl , C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, C18 alkyl, C19 alkyl, C20 alkyl, C21 alkyl, and C22 alkyl base.
  • alkyl or “alkyl group” used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 22 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein.
  • an alkyl group contains 1-22 carbon atoms, ie, a C1-22 alkyl group.
  • the alkyl group contains 6-22 carbon atoms, ie, C6-22 alkyl; in another embodiment, the alkyl group contains 8-22 carbon atoms, ie, C8-22 Alkyl; in another embodiment, the alkyl group contains 10-22 carbon atoms, i.e.
  • the alkyl group contains 1-6 carbon atoms, i.e. C 1-6 alkyl; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, ie, C 1-4 alkyl; in yet another embodiment, the alkyl group contains 1-3 A carbon atom, that is, a C 1-3 alkyl group.
  • the alkyl group may be optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl
  • alkenyl refers to a straight or branched chain monovalent hydrocarbon group containing 2-22 carbon atoms in which there is at least one site of unsaturation, i.e., a carbon-carbon sp double bond, which includes "cis” and “cis”Anti” positioning, or "E” and “Z” positioning.
  • the alkenyl group contains 2-22 carbon atoms, ie, C 2-22 alkenyl; in one embodiment, the alkenyl group contains 4-22 carbon atoms, ie, C 4-22 alkene In one embodiment, an alkenyl group contains 6-22 carbon atoms, ie, C 6-22 alkenyl; in one embodiment, an alkenyl group contains 8-22 carbon atoms, ie, C 8- 22 alkenyl; in one embodiment, an alkenyl group contains 10-22 carbon atoms, i.e. C 10-22 alkenyl; in another embodiment, an alkenyl group contains 2-6 carbon atoms, i.e.
  • an alkenyl group contains 2-4 carbon atoms, ie, a C2-4 alkenyl.
  • the alkenyl group may be optionally substituted with one or more substituents described herein.
  • alkynyl denotes a straight or branched chain monovalent hydrocarbon group containing 2 to 22 carbon atoms having at least one site of unsaturation, ie, a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-22 carbon atoms, ie, C 2-22 alkynyl; in one embodiment, the alkynyl group contains 4-22 carbon atoms, ie, C 4-22 alkynyl In one embodiment, an alkynyl group contains 6-22 carbon atoms, ie, C 6-22 alkynyl; in one embodiment, an alkynyl group contains 8-22 carbon atoms, ie, C 8- 22 alkynyl; in one embodiment, the alkynyl group contains 10-22 carbon atoms, i.e.
  • the alkynyl group contains 2-6 carbon atoms, i.e. C2-6alkynyl ; in yet another embodiment, the alkynyl group contains 2-4 carbon atoms, ie, C2-4alkynyl.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH2C ⁇ CH), 1 -propynyl (-C ⁇ C- CH3 ), C 6 alkynyl, C 8 alkynyl, C 10 alkynyl, C 12 alkynyl, C 14 alkynyl, C 16 alkynyl, C 18 alkynyl, C 20 alkynyl, C 22 alkynyl and the like.
  • the alkynyl group may be optionally substituted with one or more substituents described herein.
  • alkylene refers to a divalent alkyl group, wherein alkyl is as defined herein.
  • heteroalkyl means that one or more heteroatoms may be inserted into the alkyl chain, wherein the alkyl group and the heteroatom are as defined herein. Unless otherwise specified, heteroalkyl groups contain 1-10 carbon atoms. In some embodiments, heteroalkyl groups contain 1-8 carbon atoms. In some embodiments, heteroalkyl groups contain 1-6 carbon atoms. In some embodiments, heteroalkyl groups contain 1-4 carbon atoms. In some embodiments, heteroalkyl groups contain 1-3 carbon atoms.
  • Such examples include, but are not limited to, CH3OCH2- , CH3CH2OCH2- , CH3SCH2- , ( CH3 ) 2NCH2- , ( CH3 ) 2CH2OCH2- , CH3OCH2CH2- , CH3CH2OCH2CH2- , etc. _ _
  • alkoxy means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
  • haloalkyl or “haloalkoxy” refers to an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl ( -CF3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F,-CFHCHF 2 ) and so on.
  • hydroxyalkyl or “hydroxy-substituted alkyl” and “hydroxyalkoxy” or “hydroxy-substituted alkoxy” respectively mean an alkyl or alkoxy group, as the case may be, by one or more substituted with a hydroxy group
  • hydroxyalkyl and “hydroxyalkyl” can be used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl (- -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxypropan-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane group (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OC
  • cyanoalkyl includes C1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
  • cyanoalkyl is a C 1-6 "lower cyanoalkyl” substituted with one or more cyano groups, and in other embodiments, cyanoalkyl is C 1-4 "lower cyanoalkyl" substituted with one or more cyano groups, examples of which include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 - and the like.
  • alkylamino includes “N-alkylamino” and "N,N-dialkylamino” wherein the amino group is independently substituted with one or two alkyl groups, respectively.
  • alkylamino is a lower alkylamino group with one or two C1-6 alkyl groups attached to a nitrogen atom.
  • the alkylamino group is a C 1-3 lower alkylamino group.
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino, etc.
  • aminoalkyl includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups.
  • aminoalkyl is a C 1-6 "lower aminoalkyl” substituted with one or more amino groups, and in other embodiments, aminoalkyl is substituted by one or more amino groups C 1-4 "lower aminoalkyl" substituted with an amino group, such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms.
  • Bicyclic cycloalkyl groups include spirobicycloalkyl groups, fused bicycloalkyl groups and bridged bicycloalkyl groups.
  • the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-10 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms atom; in other embodiments, the cycloalkyl group contains 3-7 carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms; in still other embodiments, the cycloalkyl group is C7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spirobicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl.
  • the cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
  • the term "monocyclic cycloalkyl” or “monocycloalkyl” refers to a cycloalkyl group of a monocyclic ring system, wherein the cycloalkyl group has the previously defined definition, and the monocyclic cycloalkyl group may independently Unsubstituted or substituted with one or more of the substituents described herein.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
  • heterocyclyl and “heterocycle” are used interchangeably herein, unless otherwise specified, to refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system comprising at least one non-aromatic ring; wherein the One or more (in certain embodiments, 1, 2, 3, or 4) of the non-aromatic monocyclic atoms are heteroatoms independently selected from O, S(O) 0-2 , and N, and the The remaining ring atoms are all carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3, or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S(O ) heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
  • the heterocycle contains 1 or 2 heteroatoms, all of which are nitrogen atoms.
  • the heterocyclyl group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two One of the heteroatoms is in an aromatic ring and the other is in a non-aromatic ring.
  • the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
  • the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
  • the heterocyclyl group can be bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic groups.
  • One or more nitrogen and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally replace.
  • Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic.
  • the monocyclic and polycyclic heterocycles can be attached to the main structure at any heteroatom or carbon atom that results in a stable compound.
  • the polycyclic heterocyclyl may be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, whether or not the ring contains a heteroatom.
  • the heterocyclyl group is "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group as described herein containing at least one ring heteroatom , or 2) a saturated or partially unsaturated (but non-aromatic) monovalent bicyclic or tricyclic group wherein at least one ring contains at least one heteroatom as described herein.
  • heterocyclyl and heterocycloalkyl When heterocyclyl and heterocycloalkyl are substituted, they may be substituted on either ring, ie, on any aromatic or non-aromatic ring contained by heterocyclyl and heterocycloalkyl.
  • heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane base, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra
  • oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • the heterocyclyl group is a heterocyclyl group consisting of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
  • heterocyclyl groups of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine base, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl
  • oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl.
  • Said heterocyclyl group consisting of 3-8 atoms can be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclyl group is a heterocyclyl group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
  • the 3-6 atom heterocyclyl group can be optionally substituted by one or more substituents described in the present invention.
  • the heterocyclyl group is a heterocyclyl group consisting of 5-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms.
  • Ring sulfur atoms can optionally be oxidized to S-oxides.
  • the nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds.
  • heterocyclic groups of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine base, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -Thiazolidinyl, sulfolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithianyl, thioxanyl,
  • halogen refers to F, Cl, Br or I.
  • pharmaceutically acceptable salts refer to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate,
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization.
  • Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
  • the invention discloses a class of novel cyclohexene compounds, which can be used as neuraminidase inhibitors, especially influenza neuraminidase inhibitors.
  • the compounds of the present invention can be made into medicines with long-acting properties, such as inhalation or injection, and then slowly, continuously and stably released in the body to achieve long-acting purposes.
  • Such drugs have the characteristics of low water solubility and can release effective drugs slowly, continuously and stably in the body. Therefore, the compounds of the present invention have very good development prospects.
  • the present invention relates to a kind of compound, it has the structure shown in formula (I):
  • X is O, or -N(R a )-;
  • Each R a is independently H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1 -6 cyanoalkyl;
  • R 1 and R 2 are each independently H, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 hydroxyalkyl, C 1-10 aminoalkyl, C 1-10 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-10 alkyl, C 1 -10 haloalkyl, C 1-10 hydroxyalkyl, C 1-10 aminoalkyl, C 1-10 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkane base, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12
  • R 3 is -NH 2 , -N 3 , C 1-6 aminoalkyl, or wherein R3 is optionally substituted with 0, 1, 2, 3, 4 , or 5 R6;
  • R 3a is H, -OH, C 1-6 alkyl, or C 1-6 hydroxyalkyl
  • R 3b is H, -NH 2 , C 1-6 alkyl, C 1-6 alkylamino, or C 1-6 aminoalkyl;
  • R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 cyanoalkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl are independently optionally substituted by 0, 1, 2, 3 or 4 R 5 substitutions.
  • the present invention relates to compounds of formula (II):
  • R 7 is R 4 , or -R b -Y 1 -R 4a .
  • the present invention relates to compounds of formula (III):
  • R 7 is R 4 , or -R b -Y 1 -R 4a .
  • Rb is -CH2- , -CHF-, -CH2CH2- , -CH( CH3 )-, -C( CH3 ) 2- , -CH( CH3 ) CH 2 -, or -CH 2 CH 2 CH 2 -.
  • R 2 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 2-6 heterocyclyl, or C 2-6 heterocyclyl C 1-4 alkyl; wherein each C 1 -4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 ring Alkyl C 1-4 alkyl, C 2-6 heterocyclyl and C 2-6 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 5 .
  • R 2 is methyl, ethyl, propyl, isopropyl, butyl
  • R 3 is -NH 2 , -N 3 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 ,
  • each R5 and R6 are each independently H, D, F, Cl, Br, -N3 , -OH, -SH, -CN, -NO2 , -NH2 , C1 -4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 ring Alkyl, C 3-6 cycloalkyl, C 1-4 alkyl, C 2-6 heterocyclyl, C 2-6 heterocyclyl, C 1-4 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein each C 1-4 alkyl, C 1-4 alkoxy , C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6
  • the present invention relates to compounds having one of the following structures:
  • Compounds of the present disclosure may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms.
  • the present invention is intended to make all stereoisomeric forms of compounds represented by formula (I), (II) or (III), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • stereochemistry of any particular chiral atom when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein .
  • stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are well defined and defined.
  • the compounds represented by formula (I), (II) or (III) may exist in the form of salts.
  • the salt refers to a pharmaceutically acceptable salt.
  • pharmaceutically acceptable means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it.
  • the salt is not necessarily a pharmaceutically acceptable salt, but can be used for the preparation and/or purification of the compound represented by formula (I), (II) or (III) and/or for the isolation of the present Intermediates of enantiomers of compounds of formula (I), (II) or (III).
  • the present invention relates to intermediates for the preparation of compounds of formula (I), (II) or (III).
  • the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I), (II) or (III).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the pharmaceutical composition further comprises an additional therapeutic agent.
  • the pharmaceutical composition is in a long-acting form.
  • the pharmaceutical composition is in the form of an injectable or inhaled formulation.
  • the present invention provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating a viral disease or inhibiting the activity of neuraminidase.
  • the neuraminidase is influenza neuraminidase.
  • the viral disease is a disease caused by an influenza virus.
  • the viral disease is influenza A or influenza B.
  • the compounds of the present invention are usually administered in the form of a pharmaceutical composition, and may be in a long-acting form.
  • Said composition can be prepared in a manner well known in the art of pharmacy and comprises at least one compound of the invention according to formula I, II, or III.
  • the compounds of the present invention are administered in a pharmaceutically effective amount.
  • the amount of the compound of the present invention actually administered will generally be determined by the physician in light of the circumstances, including the condition to be treated, the route of administration chosen, the actual compound of the present invention administered, the age, weight and response of the individual patient, the patient's symptoms severity, etc.
  • the present invention includes pharmaceutical compositions.
  • Such pharmaceutical compositions comprise a compound of the present invention in a pharmaceutically acceptable carrier.
  • Other pharmacologically active substances may also be present.
  • “Pharmaceutically acceptable carrier” as used in this application includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and physiologically compatible similar.
  • Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and may include isotonic agents in the composition, For example sugars, sodium oxide or polyols such as mannitol or sorbitol.
  • Pharmaceutically acceptable substances, such as wetting agents, or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers increase the shelf-life or effectiveness of the antibody or antibody portion.
  • compositions of the present invention may take a variety of forms. These include, for example, liquid, semisolid, and solid dosage forms such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories.
  • liquid solutions eg, injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes, and suppositories.
  • the form will depend on the intended mode of administration and therapeutic application.
  • compositions are in the form of injectable and infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies.
  • One mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular).
  • the antibody system is administered by intravenous infusion or injection.
  • the antibody system is administered by intramuscular or subcutaneous injection.
  • Oral administration of solid dosage forms may, for example, be presented in individual units, such as hard or soft capsules, pills, cachets, chains, or tablets, each containing a predetermined amount of at least one compound of the present invention.
  • oral administration may be in powder or granular form.
  • the oral dosage form is a sublingual form, such as a chain dosage.
  • the compounds of formula I are conventionally combined with one or more adjuvants.
  • Such capsules or tablets may contain controlled release formulations.
  • the dosage form may also contain buffering agents or may be prepared with an enteric coating.
  • compositions for parenteral administration may be emulsions or sterile solutions.
  • propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters can be used as a solvent or carrier, and in some embodiments, ethyl oleate can be used as a solvent or carrier.
  • These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizing agents.
  • Sterilization can be performed in several ways, in certain embodiments, by use of bacteriological filters, by radiation or by heat. They can also be prepared in the form of sterile solid compositions which, at the time of use, can be dissolved in sterile water or any other sterile injectable medium.
  • compositions provided herein are pharmaceutical compositions or single unit dosage forms.
  • the pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (eg, compounds provided herein or other prophylactic or therapeutic agents) and typically one or more prophylactic or therapeutic agents.
  • prophylactic or therapeutic agents eg, compounds provided herein or other prophylactic or therapeutic agents
  • typically one or more prophylactic or therapeutic agents typically one or more prophylactic or therapeutic agents.
  • pharmaceutically acceptable carriers or excipients A variety of pharmaceutically acceptable carriers or excipients.
  • the term "pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government, or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly for use in animals human medicine.
  • carrier includes a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), adjuvant, or vehicle with which the therapeutic agent is administered.
  • adjuvant eg, Freund's adjuvant (complete and incomplete)
  • vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • Typical pharmaceutical compositions and dosage forms contain one or more excipients.
  • suitable excipients are well known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, glycol, water, ethanol, etc.
  • a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is administered to a subject and the particular active ingredient in the dosage form.
  • the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • the total daily dose of a compound of the present invention for the treatment of the indications discussed in this invention is generally from about 0.001 to about 100 mg/kg (ie, milligrams of a compound of the present invention per kilogram of body weight).
  • the total daily dose of a compound of the present invention is about 0.01 to about 30 mg/kg, and in another embodiment about 0.03 to about 10 mg/kg, and in yet another embodiment about 0.1 to about 3 mg/kg. It is not uncommon to repeat the administration of a compound of the present invention many times in a day (usually no more than 4 times). If necessary, multiple daily doses can usually be used to increase the total daily dose.
  • compositions provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
  • the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in medicine.
  • the present invention provides compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for use in the prevention and/or treatment of viral diseases.
  • the viral disease is a disease caused by an influenza virus.
  • the viral disease is influenza A or influenza B.
  • a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention inhibits neuraminidase activity. More specifically, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention inhibits neuraminidase activity in influenza.
  • the present invention provides a class of compounds disclosed herein that are useful as medicaments, particularly as medicaments for the treatment and/or prevention of the diseases and/or disorders described herein.
  • the present invention also provides the use of the disclosed compounds for the preparation of long-acting medicaments for the treatment and/or prevention of the diseases and/or conditions described herein.
  • the medicament is in the form of an injectable or inhaled formulation.
  • Figure 1 shows changes in body weight after administration of the test compound of the present invention, the model group and the reference compound to mice.
  • Figure 2 shows the pulmonary influenza virus titers five days after the mice were infected with the virus after administration of the test compound of the present invention, the model group and the reference compound.
  • Figure 3 shows the survival rate curve after administration of the test compound of the present invention, the model group and the reference compound to mice.
  • the compounds of the present invention can be prepared by the methods described herein, where the substituents are as defined in formula I, II, or III unless otherwise specified.
  • the following reaction schemes and examples serve to further illustrate the content of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
  • reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
  • the chromatographic column is a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Factory.
  • 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).
  • the measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min.
  • Mobile phase 5 %-95% (( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid)) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
  • ESI electrospray ionization
  • Step 2 (3R,4R,5S)-4-acetylamino-5-amino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester
  • Step 2) (3R,4R,5S)-4-acetylamino-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- ene-1-carboxylic acid
  • Step 1) (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- octyl ene-1-carboxylate
  • Step 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester
  • Step 2) (3R,4R,5S)-4-Acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid decyl ester
  • Step 2 (3R,4R,5S)-5-guanidino-4-isopropionamido-3-(pent-3-ylmethyl)cyclohexyl-1-ene-1-carboxylic acid octyl ester
  • Step 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-dodecyl ester
  • Step 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-hexyl ester
  • Step 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-octyl ester
  • Step 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-decyl ester
  • Step 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-octadecyl ester
  • Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid (dodecanoyloxy) methyl ester
  • Step 2 (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid-2-(n-dodecanoyloxy)ethyl ester
  • Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid ethyl ester
  • Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid ethyl ester
  • Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid-(n-hexanoyloxy)methyl ester
  • Example A was synthesized by referring to the method described in CN1013224464A.
  • Molecules with good NA inhibitory activity can be made into long-acting inhaled NA inhibitors by adding long chains.
  • Reference compounds involved in this experiment include Examples A-D. This experiment mainly investigates the long-acting anti-influenza effect of the compounds of the present invention at the same dose.
  • mice Balb/c, female, 6-8 weeks old (18-20 g).
  • Virus A/Puerto Rico/8/1934 (H1N1PR8) rescued the virus.
  • Example A Example A, Example B, Example C, Example D, and the compounds of the present invention (Example 2, Example 3, Example 4, Example 16 and Example 19), and solvent ( Physiological saline + 0.2% Tween80); wherein “Examples” are simply referred to as “Examples” in Figures 1-3.
  • mice were weighed, and the mice were anesthetized on the day of virus infection, and 60 PFU of virus was instilled through the nose;
  • mice 3. Record the body weight of the mice every day, and observe the status, behavior, drinking water, diet, death, etc. of the mice;
  • mice were randomly selected from each group in the model group and the experimental group to be sacrificed for the detection of virus titer in lung tissue;
  • mice The remaining mice were used to observe the survival rate of mice, and the observation and recording were recorded for 14 days. The mice whose body weight decreased by more than 25% were regarded as clinical death.
  • mice in the blank control group had no significant changes within two weeks of the experimental period, and the infection model group began to experience continuous weight loss 3 days after infection until clinical death or hard death.
  • the rest of the administration groups started to lose weight after 4 to 5 days of infection, and began to rise and returned to normal body weight after 9 to 10 days of infection (see Figure 1).
  • the body weight of the mice of Compound Examples 3, 16, 19 of the present invention and the positive control drug Example D was consistent with the degree of decrease, and began to decrease on the 5th day after infection, and decreased to about 90% on the 8th day after infection, After that the weight started to come back.
  • the body weight of the mice in Example 4 and Example B decreased to about 85% on the 9th day.
  • Example 2 The body weight of the mice in Example 2 and the original drug Example C decreased to about 80% on the 9th day. In Example A, the body weight of the mice dropped to about 75% on the 10th day. It can be seen from the figure that the weight results of the mice of Examples 3, 16, 19 and the positive drug Example D are similar, with the least decrease, and the weight loss trend from the 3rd to the 10th day is significantly slower than that of the original drug Example C group.
  • Example A Compared with the infection group, except Example A, the pulmonary virus titers of the other administration groups were significantly decreased (see Figure 2). Among them, the pneumovirus titers of Examples 2, 3, 4, 16, 19 and Example B of the compounds of the present invention were relatively low; the pneumovirus titers of the original drug Example C and the positive drug Example D were close, but more 2, 3, 4, 16, 19 and Example B are high.
  • mice in the infection model group died one after another one week after infection, and all died on the ninth day of infection.
  • the positive drug (Example D) and Examples 3 and 16 all survived, and the original drug of La Ninamir (Example B) and Examples 4 and 19 had a survival rate of 88.9% (8/9), Example C and Example 2 had a survival rate of 66.7% (6/9), while Example A had a survival rate of 33.3% (3/9) (see Figure 3). Therefore, the survival rates of mice in Examples 3 and 16 are consistent with the positive drug Example D, and the survival rates of Examples 4 and 19 are also close to 90%, and both are higher than those of the original drug Example C.
  • the compound of the present invention can slowly, continuously and stably release effective drugs in the body to achieve long-term effects, and has a good curative effect on diseases such as virus infection.

Abstract

The present invention belongs to the pharmaceutical field. Specifically, the present invention relates to a neuraminidase inhibitor compound as represented by formula (I), or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition comprising the compound; and the use of the compound and the pharmaceutical composition thereof in the preparation of a drug for treating and/or preventing viral diseases or inhibiting neuraminidase activity. The compound provided can be released slowly, continuously and stably in vivo and a long-acting purpose is achieved.

Description

神经氨酸酶抑制剂类化合物、其药物组合物及其用途Neuraminidase inhibitor compounds, their pharmaceutical compositions and their uses 发明领域Field of Invention
本发明属于药物领域，具体涉及一类新的神经氨酸酶(尤其是流感神经氨酸酶)抑制剂类化合物，包含所述化合物的药物组合物，以及使用所述化合物及其药物组合物在制备治疗和/或预防病毒性疾病或抑制神经氨酸酶活性的药物中的用途。更具体地说，本发明所述化合物可很好地抑制流感神经氨酸酶活性，并用于预防和/或治疗流感病毒引起的疾病。The invention belongs to the field of medicine, and specifically relates to a new class of neuraminidase (especially influenza neuraminidase) inhibitor compounds, a pharmaceutical composition comprising the compound, and the use of the compound and the pharmaceutical composition in the Use in the preparation of drugs for treating and/or preventing viral diseases or inhibiting neuraminidase activity. More specifically, the compounds of the present invention can well inhibit the activity of influenza neuraminidase, and can be used for preventing and/or treating diseases caused by influenza virus.
发明背景Background of the Invention
流行性感冒(Influenza，简称流感)是一种由流行性感冒病毒(Influenza virus，简称流感病毒)引起的常见呼吸道传染病。据统计，流感病毒每年会造成全球300～500万例严重病例和25～50万例死亡病例(Thompson MG,et al.(2018)Nat Commun,9(1):2407)。2018年，世界卫生组织(World health organization，WHO)将流感列为全球公共卫生十大威胁之首(Shao W,et al.(2017)Int J Mol Sci,18(8):E1650)。目前，国际上预防与治疗流感的主要措施有疫苗接种和药物治疗，疫苗研究滞后，使用受限，抗流感药物使用方便、见效快，因此抗病毒药物在防治流感方面发挥了重要作用。临床上主要有两种抗流感病毒药物，即M2离子通道阻滞剂和神经氨酸酶抑制剂(Neuraminidase inhibitors，NAIs)；但M2离子通道阻滞剂只对甲型流感病毒有效，且药物不良反应大，大部分流感病毒对其耐药且耐药株产生迅速(Kumar B,et al.(2018)Arch Virol,163(4):831-844)，故WHO建议M2离子通道阻滞剂耐药性监测不再为各国流感中心监测的主要任务，临床上也建议不再使用该类药物防治流感(Trebbien R,et al.(2017)Euro Surveill,22(3):30445)。相比之下，NAIs对甲型和乙型流感均有效(Mitchell SL,et al.(2018)J Med Microbiol,67(3):358-363,Karthick V,Ramanathan K.(2014)Cell Biochem Biophys,68(2):291-299)，在卫生部颁发的《人禽流感诊疗方案(2005版)》中(杨红茹，等(2008)中国公共卫生，24(9)：1147-1149)，奥司他韦被列为抗流感病毒治疗的首选药物和WHO推荐的人禽流感预防和治疗的储备药物。Influenza (Influenza for short) is a common respiratory infectious disease caused by Influenza virus (Influenza virus for short). According to statistics, influenza virus causes 3 to 5 million severe cases and 250,000 to 500,000 deaths worldwide each year (Thompson MG, et al. (2018) Nat Commun, 9(1): 2407). In 2018, the World Health Organization (WHO) ranked influenza as the top ten threats to global public health (Shao W, et al. (2017) Int J Mol Sci, 18(8): E1650). At present, the main measures for the prevention and treatment of influenza in the world are vaccination and drug treatment. Vaccine research is lagging behind and its use is limited. Anti-influenza drugs are easy to use and have quick effects. Therefore, antiviral drugs have played an important role in the prevention and treatment of influenza. There are mainly two kinds of anti-influenza virus drugs in clinic, namely M2 ion channel blockers and Neuraminidase inhibitors (NAIs); but M2 ion channel blockers are only effective against influenza A virus, and the drugs are not good. The response is large, and most influenza viruses are resistant to it and the drug-resistant strains develop rapidly (Kumar B, et al. (2018) Arch Virol, 163(4):831-844), so WHO recommends that M2 ion channel blockers are resistant to The monitoring of drug properties is no longer the main task of monitoring by national influenza centers, and it is also recommended to no longer use such drugs to prevent and treat influenza (Trebbien R, et al. (2017) Euro Surveill, 22(3): 30445). In contrast, NAIs are effective against both influenza A and B (Mitchell SL, et al. (2018) J Med Microbiol, 67(3):358-363, Karthick V, Ramanathan K. (2014) Cell Biochem Biophys , 68(2):291-299), in the "Human Avian Influenza Diagnosis and Treatment Program (2005 Edition)" issued by the Ministry of Health (Yang Hongru, et al. (2008) Chinese Public Health, 24(9): 1147-1149), Austrian Seltamivir is listed as the drug of choice for anti-influenza virus treatment and a reserve drug for the prevention and treatment of human avian influenza recommended by WHO.
流感病毒是隶属于正黏病毒科(Orthomyxoviridae)的包膜病毒(Liu G,et al.(2018)Nat Commun,9(1):3199)，主要分为甲型(A)、乙型(B)和丙型(C)3种类型；其中，甲型流感病毒(Influenza A viruses，IAVs)抗原变异频繁，传染性强，常引起暴发流行；乙型流感病毒(Influenza B viruses，IBVs)和丙型流感病毒(Influenza C viruses，ICVs)抗原性非常稳定(Zhai SL,et al.(2017)Emerg Infect Dis,23(8):1392-1396)。人类主要感染甲型和乙型流感病毒，甲型和乙型流感病毒的遗传物质由8个独立的单股负链RNA组成，分别编码17种和11种蛋白质(Nturibi E,et al.(2017)J Virol,91(19):e01179-17)，其中NA是病毒包膜上的一种四聚体蛋白，在新病毒颗粒脱离宿主细胞的过程中，病毒颗粒通过唾液酸粘附于宿主细胞表面，NA能够催化唾液酸水解，协助病毒脱离宿主细胞，促进子代病毒释放(Medina RA,Garcia-Sastre A.(2011)Nat Rev Microbiol,9(8):590-603)，在流感病毒的复制和传播中起到了关键作用，继而成为各类NAIs的作用靶点。Influenza virus is an enveloped virus belonging to the family Orthomyxoviridae (Liu G, et al. (2018) Nat Commun, 9(1): 3199), mainly divided into A (A), B (B) ) and C (C) three types; among them, influenza A virus (Influenza A viruses, IAVs) has frequent antigenic variation, strong infectivity, and often causes outbreaks; influenza B virus (Influenza B viruses, IBVs) and C Influenza C viruses (ICVs) are antigenically very stable (Zhai SL, et al. (2017) Emerg Infect Dis, 23(8): 1392-1396). Humans are mainly infected with influenza A and B viruses. The genetic material of influenza A and B viruses consists of 8 independent single-stranded negative-stranded RNAs, encoding 17 and 11 proteins, respectively (Nturbi E, et al. (2017). ) J Virol, 91(19):e01179-17), in which NA is a tetrameric protein on the viral envelope, and in the process of new viral particles detaching from host cells, viral particles adhere to host cells through sialic acid On the surface, NA can catalyze the hydrolysis of sialic acid, assist the virus to escape from the host cell, and promote the release of progeny virus (Medina RA, Garcia-Sastre A. (2011) Nat Rev Microbiol, 9(8):590-603), in influenza virus It plays a key role in replication and dissemination, and then becomes the target of various NAIs.
NAIs是继M2离子通道阻滞剂之后的一类全新作用机制的抗流感药物。NAIs通过与NA的特异性结构域结合，阻断其活性位点并降低NA水解细胞表面唾液酸的水解酶活性，从而抑制病毒释放与细胞间传播，发挥抗病毒作用(Kim HO,et al.(2017)Small,13(32))。相较于M2离子通道阻滞剂，NAIs的应用更为广泛，已成为目前临床上最主要的抗流感病毒药物。NAIs主要有4种：奥司他韦(Oseltamivir，商品名为达菲)、扎那米韦(Zanamivir)、和帕拉米韦(Paramivir)。扎那米韦是首先被研制出的抗流感病毒NAIs。研究者将一种NA抑制物2，3-脱氢2-脱氧N-乙酰神经氨酸(DANA)的C4-羟基用C4-胍基取代，使DANA与NA的结合力增强，更有效抑制NA活性，从而研制出扎那米韦。该药于1999年7月被美国食品药品监督管理局(FDA)批准上市，用于治疗甲型和乙型流感病毒引起的流感(Kumar B,et al.(2018)Arch Virol,163(4):831-844)。扎那米韦在体内代谢迅速，口服给药时生物利用率仅为2％～3％，因此被用于吸入给药。奥司他韦的研制基于扎那米韦，其DANA结构中的C4和甘油侧链分别被氨基和疏水性戊醚侧链代替。奥司他韦片剂是第一个口服的高活性NAIs，可通过肝酯酶转化为活性化合物奥司他韦羧酸盐，将药物生物 利用度提高到80％，于1999年10月在美国批准上市后广泛应用于临床。帕拉米韦只能静脉注射，当患者对奥司他韦耐药且不能吸入给药时可考虑使用此药。NAIs are a new class of anti-influenza drugs following M2 ion channel blockers. NAIs play an antiviral role by binding to the specific domain of NA, blocking its active site and reducing the hydrolase activity of NA hydrolyzing cell surface sialic acid, thereby inhibiting virus release and cell-to-cell spread (Kim HO, et al. (2017) Small, 13(32)). Compared with M2 ion channel blockers, NAIs are more widely used and have become the most important anti-influenza virus drugs in clinical practice. There are four main types of NAIs: Oseltamivir (trade name Tamiflu), Zanamivir, and Paramivir. Zanamivir was the first anti-influenza NAIs to be developed. The researchers replaced the C4-hydroxyl group of 2,3-dehydro2-deoxyN-acetylneuraminic acid (DANA), an NA inhibitor, with C4-guanidino group, which enhanced the binding force of DANA to NA and more effectively inhibited NA. activity, resulting in the development of zanamivir. The drug was approved by the U.S. Food and Drug Administration (FDA) in July 1999 for the treatment of influenza caused by influenza A and B viruses (Kumar B, et al. (2018) Arch Virol, 163(4) :831-844). Zanamivir is rapidly metabolized in the body, and its bioavailability is only 2% to 3% when administered orally, so it is used for inhalation. Oseltamivir was developed based on zanamivir in which the C4 and glycerol side chains in the DANA structure were replaced by amino and hydrophobic amyl ether side chains, respectively. Oseltamivir tablets are the first orally highly active NAIs that are converted to the active compound oseltamivir carboxylate by hepatic esterase, increasing drug bioavailability to 80%, in the US in October 1999 It is widely used in clinical after approval. Peramivir can only be administered intravenously and may be considered in patients who are resistant to oseltamivir and cannot be administered by inhalation.
具有NA抑制活性的分子大多半衰期短、口服利用率低而难以被开发成药。少部分如奥司他韦通过前药技术开发成口服利用度高的抗流感药物，但奥司他韦也依然是一日两次的使用剂量。本发明研究发现，通过利用脂肪侧链来修饰本发明提供的环己烯类化合物，可使本发明化合物在体内缓慢、持续、稳定地释放有效药物从而达到长效目的。本发明研究还发现，本发明化合物可通过调节脂肪侧链的长度来达到不同作用时间长度和给药途径。与接种流感疫苗方式相比，由于NAIs对多种流感病毒株均有抑制效果，作为预防性给药无需预测下一季度流感病毒的类型，且没有流感病毒株预测不准和疫苗接种后免疫不成功的顾虑。Most of the molecules with NA inhibitory activity have short half-lives and low oral availability, making them difficult to develop into drugs. A few, such as oseltamivir, have been developed into anti-influenza drugs with high oral availability through prodrug technology, but oseltamivir is still used twice a day. It is found in the research of the present invention that by modifying the cyclohexene compounds provided by the present invention with aliphatic side chains, the compounds of the present invention can slowly, continuously and stably release effective drugs in the body to achieve long-term effects. The research of the present invention also found that the compounds of the present invention can achieve different action time lengths and administration routes by adjusting the length of the fatty side chain. Compared with influenza vaccination, because NAIs have inhibitory effects on various influenza virus strains, it is not necessary to predict the type of influenza virus in the next quarter as a preventive administration, and there is no inaccurate prediction of influenza virus strains and poor immunity after vaccination. success concerns.
本发明的流感神经氨酸酶抑制剂具有优越的抗病毒活性，对甲型和乙型流感病毒感染等有很好的疗效，其可制成吸入型或注射型长效制剂，进而在体内缓慢、持续、稳定地释放而达到长效目的。本发明化合物还具有优异的药效、药代性质和毒理性质，具备较佳的临床应用前景。The influenza neuraminidase inhibitor of the present invention has superior antiviral activity, and has a good curative effect on influenza A and B influenza virus infection, etc. It can be prepared into an inhalation type or injection type long-acting preparation, and then slowly in vivo , sustained and stable release to achieve long-term purpose. The compounds of the present invention also have excellent efficacy, pharmacokinetic properties and toxicological properties, and have better clinical application prospects.
发明内容SUMMARY OF THE INVENTION
术语定义Definition of Terms
现在详细描述本发明的某些实施方案，其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案，它们均包括在所附权利要求定义的本发明范围内。本领域技术人员应认识到，许多与本发明所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本发明所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术，等等)，以本申请为准。Certain embodiments of the invention will now be described in detail, examples of which are illustrated by the accompanying structural and chemical formulae. The invention is intended to cover all alternatives, modifications and equivalents, which are included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including, but not limited to, terms defined, uses of terms, techniques described, etc.), this Application shall prevail.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"Stereoisomers" refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, etc. .
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如本发明的通式化合物，或者像实施例里面特殊的例子、子类，以及本发明所包含的一类化合物。As described herein, compounds of the present invention may be optionally substituted with one or more substituents, such as compounds of the general formula of the present invention, or specific examples, subclasses, and subclasses of the present invention, as described in the Examples, and encompassed by the present invention. a class of compounds.
应了解“任选取代的”这个术语与“取代或非取代的”这个术语可以交换使用。一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。“任选地”除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。It is to be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure have been replaced with a specified substituent. "Optionally" Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents can be substituted identically or differently at each position.
术语“任选地被……取代”，可以与术语“未取代或被……取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基所取代，本发明所述的取代基包括，但不限于H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-CN、-NO 2、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基等等。 The term "optionally substituted" is used interchangeably with the term "unsubstituted or substituted", ie the structure is unsubstituted or substituted with one or more substituents described herein, The substituents described in the present invention include, but are not limited to, H, D, oxo (=O), F, Cl, Br, -N 3 , -OH, -SH, -CN, -NO 2 , -NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3- 8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6 -12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl, and the like.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 6-22烷基”特别指独立公开的C 6烷基、C 7烷基、C 8烷基、C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基、C 15烷基、C 16烷基、C 17烷基、C 18烷基、C 19烷基、C 20烷基、C 21烷基、和C 22烷基。 In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed in terms of group type or scope. Specifically, the present invention includes each and every independent subcombination of each member of these group species and ranges. For example, the term " C6-22 alkyl" specifically refers to the independently disclosed C6 alkyl, C7 alkyl, C8 alkyl, C9 alkyl, C10 alkyl, C11 alkyl, C12 alkyl , C13 alkyl, C14 alkyl, C15 alkyl, C16 alkyl, C17 alkyl, C18 alkyl, C19 alkyl, C20 alkyl, C21 alkyl, and C22 alkyl base.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至22个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-22个碳原子，即C 1-22烷基。在一实施方案中，烷基基团含有6-22个碳原子，即C 6-22烷基；在另一实施方案中，烷基基团含有8-22个碳原子，即C 8-22烷基；在另一实施方案中，烷基基团含有10-22个碳原子，即C 10-22烷基；在又一实施方案中，烷基基团含有1-6个碳原子，即C 1-6烷基；在又一实施方案中，烷基基团含有1-4个碳原子，即C 1-4烷基；还在一实施方案中，烷基基团含有1-3个碳原子，即C 1-3烷基。所述烷基基团可任选地被一个或多个本发明描述的取代基所取代。 The term "alkyl" or "alkyl group" used in the present invention refers to a saturated linear or branched monovalent hydrocarbon group containing 1 to 22 carbon atoms, wherein the alkyl group may optionally be is substituted with one or more substituents described herein. Unless otherwise specified, an alkyl group contains 1-22 carbon atoms, ie, a C1-22 alkyl group. In one embodiment, the alkyl group contains 6-22 carbon atoms, ie, C6-22 alkyl; in another embodiment, the alkyl group contains 8-22 carbon atoms, ie, C8-22 Alkyl; in another embodiment, the alkyl group contains 10-22 carbon atoms, i.e. C10-22 alkyl; in yet another embodiment, the alkyl group contains 1-6 carbon atoms, i.e. C 1-6 alkyl; in yet another embodiment, the alkyl group contains 1-4 carbon atoms, ie, C 1-4 alkyl; in yet another embodiment, the alkyl group contains 1-3 A carbon atom, that is, a C 1-3 alkyl group. The alkyl group may be optionally substituted with one or more substituents described herein.
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、 -CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，C 9烷基、C 10烷基、C 11烷基、C 12烷基、C 13烷基、C 14烷基、C 15烷基、C 16烷基、C 17烷基、C 18烷基、C 19烷基、C 20烷基、C 21烷基、C 22烷基等等。 Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3 ), ethyl (Et, -CH2CH3), n - propyl (n - Pr, -CH2CH2CH3 ) ), isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH ) (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2CH2CH2CH2CH3), 2 -pentyl (-CH( CH3 ) CH2CH2CH3 ) , 3 - pentyl (-CH( CH2CH3 ) 2 ) , 2 -methyl -2-butyl(-C(CH3)2CH2CH3), 3 -methyl- 2-butyl(-CH(CH3)CH(CH3)2 ) , 3 - methyl -1- Butyl ( -CH2CH2CH ( CH3 ) 2 ), 2 -methyl- 1 -butyl (-CH2CH( CH3 ) CH2CH3 ) , n - hexyl ( -CH2CH2CH2 CH2CH2CH3 ), 2 -hexyl (-CH( CH3 ) CH2CH2CH2CH3 ) , 3 - hexyl (-CH( CH2CH3 ) ( CH2CH2CH3 ) ) , 2-methyl-2-pentyl(-C( CH3 )2CH2CH2CH3), 3 -methyl- 2 -pentyl(-CH( CH3 ) CH ( CH3 ) CH2CH3 ), 4-methyl-2-pentyl (-CH(CH 3 )CH 2 CH(CH 3 ) 2 ), 3-methyl-3-pentyl (-C(CH 3 )(CH 2 CH 3 ) 2 ), 2-methyl-3-pentyl (-CH(CH 2 CH 3 )CH(CH 3 ) 2 ), 2,3-dimethyl-2-butyl (-C(CH 3 ) 2 CH (CH 3 ) 2 ), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH 3 ) 3 ), n-heptyl, n-octyl, C 9 alkyl, C 10 alkane base, C 11 alkyl, C 12 alkyl, C 13 alkyl, C 14 alkyl, C 15 alkyl, C 16 alkyl, C 17 alkyl, C 18 alkyl, C 19 alkyl, C 20 alkyl group, C21 alkyl, C22 alkyl, and the like.
术语“烯基”表示含有2-22个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其包括“顺”和“反”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-22个碳原子，即C 2-22烯基；在一实施方案中，烯基基团包含4-22个碳原子，即C 4-22烯基；在一实施方案中，烯基基团包含6-22个碳原子，即C 6-22烯基；在一实施方案中，烯基基团包含8-22个碳原子，即C 8-22烯基；在一实施方案中，烯基基团包含10-22个碳原子，即C 10-22烯基；在另一实施方案中，烯基基团包含2-6个碳原子，即C 2-6烯基；在又一实施方案中，烯基基团包含2-4个碳原子，即C 2-4烯基。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)、C 6烯基、C 8烯基、C 10烯基、C 12烯基、C 14烯基、C 16烯基、C 18烯基、C 20烯基、C 22烯基等等。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon group containing 2-22 carbon atoms in which there is at least one site of unsaturation, i.e., a carbon-carbon sp double bond, which includes "cis" and "cis"Anti" positioning, or "E" and "Z" positioning. In one embodiment, the alkenyl group contains 2-22 carbon atoms, ie, C 2-22 alkenyl; in one embodiment, the alkenyl group contains 4-22 carbon atoms, ie, C 4-22 alkene In one embodiment, an alkenyl group contains 6-22 carbon atoms, ie, C 6-22 alkenyl; in one embodiment, an alkenyl group contains 8-22 carbon atoms, ie, C 8- 22 alkenyl; in one embodiment, an alkenyl group contains 10-22 carbon atoms, i.e. C 10-22 alkenyl; in another embodiment, an alkenyl group contains 2-6 carbon atoms, i.e. C2-6 alkenyl; in yet another embodiment, an alkenyl group contains 2-4 carbon atoms, ie, a C2-4 alkenyl. Examples of alkenyl groups include, but are not limited to, vinyl (-CH=CH 2 ), allyl (-CH 2 CH=CH 2 ), C 6 alkenyl, C 8 alkenyl, C 10 alkenyl , C 12 alkenyl, C 14 alkenyl, C 16 alkenyl, C 18 alkenyl, C 20 alkenyl, C 22 alkenyl and the like. The alkenyl group may be optionally substituted with one or more substituents described herein.
术语“炔基”表示含有2-22个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键。在一实施方案中，炔基基团包含2-22个碳原子，即C 2-22炔基；在一实施方案中，炔基基团包含4-22个碳原子，即C 4-22炔基；在一实施方案中，炔基基团包含6-22个碳原子，即C 6-22炔基；在一实施方案中，炔基基团包含8-22个碳原子，即C 8-22炔基；在一实施方案中，炔基基团包含10-22个碳原子，即C 10-22炔基；在另一实施方案中，炔基基团包含2-6个碳原子，即C 2-6炔基；在又一实施方案中，炔基基团包含2-4个碳原子，即C 2-4炔基。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)、C 6炔基、C 8炔基、C 10炔基、C 12炔基、C 14炔基、C 16炔基、C 18炔基、C 20炔基、C 22炔基等等。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon group containing 2 to 22 carbon atoms having at least one site of unsaturation, ie, a carbon-carbon sp triple bond. In one embodiment, the alkynyl group contains 2-22 carbon atoms, ie, C 2-22 alkynyl; in one embodiment, the alkynyl group contains 4-22 carbon atoms, ie, C 4-22 alkynyl In one embodiment, an alkynyl group contains 6-22 carbon atoms, ie, C 6-22 alkynyl; in one embodiment, an alkynyl group contains 8-22 carbon atoms, ie, C 8- 22 alkynyl; in one embodiment, the alkynyl group contains 10-22 carbon atoms, i.e. C 10-22 alkynyl; in another embodiment, the alkynyl group contains 2-6 carbon atoms, i.e. C2-6alkynyl ; in yet another embodiment, the alkynyl group contains 2-4 carbon atoms, ie, C2-4alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH2C≡CH), 1 -propynyl (-C≡C- CH3 ), C 6 alkynyl, C 8 alkynyl, C 10 alkynyl, C 12 alkynyl, C 14 alkynyl, C 16 alkynyl, C 18 alkynyl, C 20 alkynyl, C 22 alkynyl and the like. The alkynyl group may be optionally substituted with one or more substituents described herein.
术语“亚烷基”是指二价烷基，其中烷基如本发明所定义。The term "alkylene" refers to a divalent alkyl group, wherein alkyl is as defined herein.
术语“杂烷基”表示烷基链中可以插入一个或多个杂原子，其中烷基基团和杂原子具有如本发明所述的定义。除非另外详细说明，杂烷基基团含有1-10个碳原子。在一些实施方案，杂烷基基团含有1-8个碳原子。在一些实施方案，杂烷基基团含有1-6个碳原子。在一些实施方案，杂烷基基团含有1-4个碳原子。在一些实施方案，杂烷基基团含有1-3个碳原子。这样的实例包括，但并不限于，CH 3OCH 2-，CH 3CH 2OCH 2-，CH 3SCH 2-，(CH 3) 2NCH 2-，(CH 3) 2CH 2OCH 2-，CH 3OCH 2CH 2-，CH 3CH 2OCH 2CH 2-等。 The term "heteroalkyl" means that one or more heteroatoms may be inserted into the alkyl chain, wherein the alkyl group and the heteroatom are as defined herein. Unless otherwise specified, heteroalkyl groups contain 1-10 carbon atoms. In some embodiments, heteroalkyl groups contain 1-8 carbon atoms. In some embodiments, heteroalkyl groups contain 1-6 carbon atoms. In some embodiments, heteroalkyl groups contain 1-4 carbon atoms. In some embodiments, heteroalkyl groups contain 1-3 carbon atoms. Such examples include, but are not limited to, CH3OCH2- , CH3CH2OCH2- , CH3SCH2- , ( CH3 ) 2NCH2- , ( CH3 ) 2CH2OCH2- , CH3OCH2CH2- , CH3CH2OCH2CH2- , etc. _ _
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的定义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "alkoxy" means that an alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the definition as described herein. Unless otherwise specified, the alkoxy groups contain 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The group contains 1-3 carbon atoms. The alkoxy groups may be optionally substituted with one or more substituents described herein.
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基(-CF 3)、三氟甲氧基(-OCF 3)、二氟乙基(-CH 2CHF 2,-CF 2CH 3,-CHFCH 2F)、三氟乙基(-CH 2CF 3,-CF 2CH 2F,-CFHCHF 2)等。 The term "haloalkyl" or "haloalkoxy" refers to an alkyl or alkoxy group substituted with one or more halogen atoms, examples of which include, but are not limited to, trifluoromethyl ( -CF3 ), Trifluoromethoxy (-OCF 3 ), difluoroethyl (-CH 2 CHF 2 , -CF 2 CH 3 , -CHFCH 2 F), trifluoroethyl (-CH 2 CF 3 , -CF 2 CH 2 F,-CFHCHF 2 ) and so on.
术语“羟基烷基”或“羟基取代的烷基”和“羟基烷氧基”或“羟基取代的烷氧基”分别表示烷基或烷氧基基团，视情况而定，被一个或多个羟基基团所取代，其中，“羟基烷基”与“羟烷基”可以交换使用，这样的实例包含，但并不限于，羟甲基(-CH 2OH)、2-羟乙基(-CH 2CH 2OH)、1-羟乙基(-CH(OH)CH 3)、2-羟基丙-2-基(-COH(CH 3) 2)、2-羟基-2-甲基丙基(-CH 2COH(CH 3) 2)、3-羟丙基(-CH 2CH 2CH 2OH)、2-羟丙基(-CH 2CH(OH)CH 3)、2-羟基-2甲基丙基(-CH 2CH(OH)(CH 3)CH 3)、羟基甲氧基(-OCH 2OH)等。 The terms "hydroxyalkyl" or "hydroxy-substituted alkyl" and "hydroxyalkoxy" or "hydroxy-substituted alkoxy" respectively mean an alkyl or alkoxy group, as the case may be, by one or more substituted with a hydroxy group, wherein "hydroxyalkyl" and "hydroxyalkyl" can be used interchangeably, such examples include, but are not limited to, hydroxymethyl (-CH 2 OH), 2-hydroxyethyl (- -CH 2 CH 2 OH), 1-hydroxyethyl (-CH(OH)CH 3 ), 2-hydroxypropan-2-yl (-COH(CH 3 ) 2 ), 2-hydroxy-2-methylpropane group (-CH 2 COH(CH 3 ) 2 ), 3-hydroxypropyl (-CH 2 CH 2 CH 2 OH), 2-hydroxypropyl (-CH 2 CH(OH)CH 3 ), 2-hydroxy- 2methylpropyl (-CH 2 CH(OH)(CH 3 )CH 3 ), hydroxymethoxy (-OCH 2 OH) and the like.
术语“氰基烷基”包括被一个或多个氰基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氰基 烷基是被一个或多个氰基基团所取代的C 1-6“较低级的氰基烷基”，另一些实施例是，氰基烷基是被一个或多个氰基基团所取代的C 1-4“较低级的氰基烷基”，这样的实例包括，但并不限于，CNCH 2-、CNCH 2CH 2-、CNCH 2CH 2CH 2-、CNCH 2CHCNCH 2-等。 The term "cyanoalkyl" includes C1-10 straight or branched chain alkyl groups substituted with one or more cyano groups. In some embodiments, cyanoalkyl is a C 1-6 "lower cyanoalkyl" substituted with one or more cyano groups, and in other embodiments, cyanoalkyl is C 1-4 "lower cyanoalkyl" substituted with one or more cyano groups, examples of which include, but are not limited to, CNCH 2 -, CNCH 2 CH 2 -, CNCH 2 CH 2 CH 2 -, CNCH 2 CHCNCH 2 - and the like.
术语“烷氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。在一些实施方案，烷基氨基是一个或两个C 1-6烷基连接到氮原子上的较低级的烷基氨基基团。在另一些实施方案，烷基氨基是C 1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。 The term "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino" wherein the amino group is independently substituted with one or two alkyl groups, respectively. In some embodiments, alkylamino is a lower alkylamino group with one or two C1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is a C 1-3 lower alkylamino group. Suitable alkylamino groups may be monoalkylamino or dialkylamino, examples of which include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N -Diethylamino, etc.
术语“氨基烷基”包括被一个或多个氨基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-6“较低级的氨基烷基”，另一些实施例是，氨基烷基是被一个或多个氨基基团所取代的C 1-4“较低级的氨基烷基”，这样的实例包括，但并不限于，氨甲基，氨乙基，氨丙基，氨丁基和氨己基。 The term "aminoalkyl" includes a C 1-10 straight or branched chain alkyl group substituted with one or more amino groups. In some embodiments, aminoalkyl is a C 1-6 "lower aminoalkyl" substituted with one or more amino groups, and in other embodiments, aminoalkyl is substituted by one or more amino groups C 1-4 "lower aminoalkyl" substituted with an amino group, such examples include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, aminobutyl and aminohexyl.
术语“环烷基”表示含有3-12个碳原子的，单价或多价的饱和单环，双环或三环体系。双环环烷基包含螺双环烷基、稠合双环烷基和桥双环烷基。在一些实施方案，环烷基包含3-12个碳原子；在另一些实施方案中，环烷基包含3-10个碳原子；在另一些实施方案中，环烷基包含3-8个碳原子；在另一些实施方案中，环烷基包含3-7个碳原子；在另一些实施方案中，环烷基包含3-6个碳原子；还在一些实施方案，环烷基为C 7-C 12环烷基，其包含C 7-C 12单环烷基、C 7-C 12双环烷基(如C 7-C 12螺双环烷基、C 7-C 12稠合双环烷基和C 7-C 12桥双环烷基)或C 7-C 12三环烷基。所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。术语“单环环烷基”或“单环烷基”表示单环体系的环烷基，其中所述环烷基具有如前所述的定义，所述单环环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。环烷基基团的实例包括，但不限于，环丙基、环丁基、环戊基、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-1-烯基、1-环己基-2-烯基、1-环己基-3-烯基、环己二烯基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基，等等。 The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Bicyclic cycloalkyl groups include spirobicycloalkyl groups, fused bicycloalkyl groups and bridged bicycloalkyl groups. In some embodiments, the cycloalkyl group contains 3-12 carbon atoms; in other embodiments, the cycloalkyl group contains 3-10 carbon atoms; in other embodiments, the cycloalkyl group contains 3-8 carbon atoms atom; in other embodiments, the cycloalkyl group contains 3-7 carbon atoms; in other embodiments, the cycloalkyl group contains 3-6 carbon atoms; in still other embodiments, the cycloalkyl group is C7 -C 12 cycloalkyl, which includes C 7 -C 12 monocycloalkyl, C 7 -C 12 bicycloalkyl (such as C 7 -C 12 spirobicycloalkyl, C 7 -C 12 fused bicycloalkyl and C 7 -C 12 bridged bicycloalkyl) or C 7 -C 12 tricycloalkyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein. The term "monocyclic cycloalkyl" or "monocycloalkyl" refers to a cycloalkyl group of a monocyclic ring system, wherein the cycloalkyl group has the previously defined definition, and the monocyclic cycloalkyl group may independently Unsubstituted or substituted with one or more of the substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexadienyl, cycloheptyl , cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
术语“杂环基”和“杂环”在此处可交换使用，除非另有说明，是指包含至少一个非芳香环的一价单环非芳香环体系和/或多环体系；其中所述非芳香单环原子中的一个或多个(在某些实施方案，1、2、3或4个)是独立地选自O、S(O) 0-2和N的杂原子，和所述其余环原子均为碳原子；和其中所述多环体系的环原子中的一个或多个(在某些实施方案，1、2、3或4个)是独立地选自O、S(O) 0-2和N的杂原子，和所述其余环原子均为碳原子。在一些实施方案，所述杂环包含1或2个杂原子，所述杂原子均为氮原子。在一些实施方案，所述杂环基是多环的并且在非芳香环中包含一个杂原子，或者在芳香环中包含一个杂原子，或者在芳香环中包含两个杂原子，或者包含两个杂原子其中一个在芳香环中，而另一个在非芳香环中。在一些实施方案，所述杂环基基团具有3-20、3-15、3-10、3-8、4-7、或5-6个环原子。在一些实施方案，所述杂环基是单环、双环、三环、或四环体系。在一些实施方案，所述杂环基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。一个或多个氮原子和硫原子可任选地被氧化，一个或多个氮原子可任选地被季铵化，一个或多个碳原子可任选地被
Figure PCTCN2021108383-appb-000001
替换。一些环可以是部分或完全饱和的，或者是芳香族的，条件是杂环是非完全芳香性的。所述单环杂环和多环杂环可在任何导致稳定化合物的杂原子或碳原子上与所述主结构连接。所述多环杂环基可通过其任一环，包括任何芳香环或非芳香环，而不管所述环是否含有杂原子，连接至所述主结构上。在一些实施方案，杂环基为“杂环烷基”，其为1)如本发明所述的含有至少一个环杂原子的饱和或部分不饱和(但非芳香族)一价单环基团，或2)饱和或部分不饱和(但非芳香族)一价双环基团或三环基团，其中至少一个环含有至少一个如本发明所述的杂原子。当杂环基和杂环烷基被取代时，其可在任一环上，即在由杂环基和杂环烷基所包含的任何芳香环或非芳香环上被取代。在一些实施方案，此类杂环基包括，但不限于，环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2021108383-appb-000002
基，二氮杂
Figure PCTCN2021108383-appb-000003
基，硫氮杂
Figure PCTCN2021108383-appb-000004
基， 苯并二噁烷基，苯并二氧杂环戊烯基，苯并呋喃酮基，苯并吡喃酮基，苯并吡喃基，二氢苯并呋喃基，苯并四氢噻吩基，苯并噻喃基，苯并噁嗪基，β-咔啉基，苯并二氢吡喃基，色酮基，噌啉基，香豆素基，十氢喹啉基，十氢异喹啉基，二氢苯并异噻嗪基，二氢苯并异噁嗪基，二氢呋喃基，二氢异吲哚基，二氢吡喃基，二氢吡唑基，二氢吡嗪基，二氢吡啶基，二氢嘧啶基，二氢吡咯基，二氧戊环基，1,4-二噻喃基，呋喃酮基，咪唑烷基，2,4-二氧-咪唑烷基，咪唑啉基，吲哚啉基，2-氧-吲哚啉基，异苯并四氢呋喃基，异苯并四氢噻吩基，异苯并二氢吡喃基，异香豆素基，异二氢吲哚基(异吲哚啉基)，1-氧-异二氢吲哚基，1,3-二氧-异二氢吲哚基，异噻唑烷基，异噁唑烷基，3-氧-异噁唑烷基，吗啉基，3,5-二氧-吗啉基，八氢吲哚基，八氢异吲哚基，1-氧-八氢异吲哚基，1,3-二氧-六氢异吲哚基，噁唑烷酮基，噁唑烷基，环氧乙烷基，哌嗪基，2,6-二氧-哌嗪基，哌啶基，2,6-二氧-哌啶基，4-哌啶酮基，2-氧吡咯烷基，2,5-二氧吡咯烷基，奎宁环基，四氢异喹啉基，3,5-二氧-硫代吗啉基，噻唑烷基，2,4-二氧-噻唑烷基，四氢喹啉基，吩噻嗪基，吩噁嗪基，氧杂蒽基和1,3,5-三硫杂环己烷基。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 The terms "heterocyclyl" and "heterocycle" are used interchangeably herein, unless otherwise specified, to refer to a monovalent monocyclic non-aromatic ring system and/or polycyclic ring system comprising at least one non-aromatic ring; wherein the One or more (in certain embodiments, 1, 2, 3, or 4) of the non-aromatic monocyclic atoms are heteroatoms independently selected from O, S(O) 0-2 , and N, and the The remaining ring atoms are all carbon atoms; and wherein one or more (in certain embodiments, 1, 2, 3, or 4) of the ring atoms of the polycyclic ring system are independently selected from O, S(O ) heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms. In some embodiments, the heterocycle contains 1 or 2 heteroatoms, all of which are nitrogen atoms. In some embodiments, the heterocyclyl group is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two One of the heteroatoms is in an aromatic ring and the other is in a non-aromatic ring. In some embodiments, the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system. In some embodiments, the heterocyclyl group can be bridged or unbridged, spirocyclic or non-spirocyclic, and/or fused or non-fused bicyclic groups. One or more nitrogen and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally
Figure PCTCN2021108383-appb-000001
replace. Some rings may be partially or fully saturated, or aromatic, provided that the heterocycle is not fully aromatic. The monocyclic and polycyclic heterocycles can be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. The polycyclic heterocyclyl may be attached to the main structure through any of its rings, including any aromatic or non-aromatic ring, whether or not the ring contains a heteroatom. In some embodiments, the heterocyclyl group is "heterocycloalkyl", which is 1) a saturated or partially unsaturated (but non-aromatic) monovalent monocyclic group as described herein containing at least one ring heteroatom , or 2) a saturated or partially unsaturated (but non-aromatic) monovalent bicyclic or tricyclic group wherein at least one ring contains at least one heteroatom as described herein. When heterocyclyl and heterocycloalkyl are substituted, they may be substituted on either ring, ie, on any aromatic or non-aromatic ring contained by heterocyclyl and heterocycloalkyl. In some embodiments, such heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxolane base, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine
Figure PCTCN2021108383-appb-000002
base, diazepine
Figure PCTCN2021108383-appb-000003
base, thiazepine
Figure PCTCN2021108383-appb-000004
base, benzodioxanyl, benzodioxolyl, benzofuranone, benzopyranone, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothiophene base, benzothiopyranyl, benzoxazinyl, β-carbolinyl, chromanyl, chromone, cinnoline, coumarin, decahydroquinolinyl, decahydroiso Quinolinyl, dihydrobenzoisothiazinyl, dihydrobenzoisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazine base, dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithiopyranyl, furanonyl, imidazolidinyl, 2,4-dioxo-imidazolidinyl , Imidazolinyl, Indolinyl, 2-Oxo-Indolinyl, Isobenzotetrahydrofuranyl, Isobenzotetrahydrothienyl, Isochromanyl, Isocoumarinyl, Isodihydro Indolyl (isoindolinyl), 1-oxo-isoindolinyl, 1,3-dioxo-isoindolinyl, isothiazolidinyl, isoxazolidinyl, 3-oxo -Isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo-octahydroisoindolyl, 1,3- Dioxo-hexahydroisoindolyl, oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazinyl, piperidinyl, 2,6- Dioxy-piperidinyl, 4-piperidinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, quinuclidinyl, tetrahydroisoquinolinyl, 3,5-dioxo- Thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthenyl and 1,3,5-trisulfide Heterocyclohexyl. Examples of heterocyclyl groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinedione. Examples of the oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
在一实施方案中，杂环基为3-8个原子组成的杂环基，是指包含3-8个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，3-8个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。3-8个原子组成的杂环基的实例包括，但不限于：氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2021108383-appb-000005
基，二氮杂
Figure PCTCN2021108383-appb-000006
基，硫氮杂
Figure PCTCN2021108383-appb-000007
基。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的3-8个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In one embodiment, the heterocyclyl group is a heterocyclyl group consisting of 3-8 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl groups of 3-8 atoms may be carbon or nitrogen groups, and -CH2- groups may be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. Examples of heterocyclyl groups of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrroline base, pyrazolinyl, pyrazolidine, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine base, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine
Figure PCTCN2021108383-appb-000005
base, diazepine
Figure PCTCN2021108383-appb-000006
base, thiazepine
Figure PCTCN2021108383-appb-000007
base. Examples of heterocyclyl groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinedione. Examples of the oxidized sulfur atom in the heterocyclyl group include, but are not limited to, sulfolanyl, 1,1-dioxothiomorpholinyl. Said heterocyclyl group consisting of 3-8 atoms can be optionally substituted by one or more substituents described in the present invention.
在一实施方案中，杂环基为3-6个原子组成的杂环基，是指包含3-6个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，3-6个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述的3-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In one embodiment, the heterocyclyl group is a heterocyclyl group consisting of 3-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl groups of 3-6 atoms may be carbon or nitrogen groups, and -CH2- groups may be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. The 3-6 atom heterocyclyl group can be optionally substituted by one or more substituents described in the present invention.
在另一实施方案中，杂环基为5-6个原子组成的杂环基，是指包含5-6个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，5-6个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。5-6个原子组成的杂环基的实例包括，但不限于：吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基、2-氧代吡咯烷基、氧代-1,3-噻唑烷基、环丁砜基、四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基、1,1-二氧代硫代吗啉基。所述的5-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In another embodiment, the heterocyclyl group is a heterocyclyl group consisting of 5-6 atoms, which refers to a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl groups of 5-6 atoms may be carbon or nitrogen groups, and -CH2- groups may be optionally replaced by -C(=O)-. Ring sulfur atoms can optionally be oxidized to S-oxides. The nitrogen atoms of the rings can be optionally oxidized to N-oxygen compounds. Examples of heterocyclic groups of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidine base, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidinyl, oxo-1,3 -Thiazolidinyl, sulfolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholine base, piperazinyl, dioxanyl, dithianyl, thioxanyl, 2-piperidinyl, 3,5-dioxopiperidinyl and pyrimidinedione, 1,1-dioxo Thiomorpholinyl. The 5-6 atom heterocyclyl group can be optionally substituted by one or more substituents described in the present invention.
术语“卤素”是指F，Cl，Br或I。The term "halogen" refers to F, Cl, Br or I.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如 离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。 As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups including hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods such as ion exchange method described in books and literature these salts. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, Gluconate, Hemisulfate, Heptanoate, Caproate, Hydroiodide, 2-Hydroxy-ethanesulfonate, Lacturonate, Lactate, Laurate, Lauryl Sulfate, Malonate, Malonate, Mesylate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Palmitate, Pamoate, Pectate, Persulfate, 3 - Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts. The present invention also contemplates quaternary ammonium salts formed from any compound containing an N-group. Water- or oil-soluble or dispersible products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include appropriate, non-toxic ammonium, quaternary ammonium salts and amine cations that resist the formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 Sulfonates and aromatic sulfonates.
本发明化合物的描述Description of Compounds of the Invention
本发明公开了一类新颖的环己烯类化合物，可作为神经氨酸酶抑制剂，特别是可作为流感神经氨酸酶抑制剂。本发明化合物可制成具有长效属性的药物，如制成吸入剂或注射剂，进而在体内缓慢、持续、稳定地释放而达到长效目的。此类药物具有低水溶性的特点，可在体内缓慢、持续、稳定地释放有效药物。因此，本发明化合物具有非常好的开发前景。The invention discloses a class of novel cyclohexene compounds, which can be used as neuraminidase inhibitors, especially influenza neuraminidase inhibitors. The compounds of the present invention can be made into medicines with long-acting properties, such as inhalation or injection, and then slowly, continuously and stably released in the body to achieve long-acting purposes. Such drugs have the characteristics of low water solubility and can release effective drugs slowly, continuously and stably in the body. Therefore, the compounds of the present invention have very good development prospects.
一方面，本发明涉及一种化合物，其具有式(I)所示结构：On the one hand, the present invention relates to a kind of compound, it has the structure shown in formula (I):
Figure PCTCN2021108383-appb-000008
Figure PCTCN2021108383-appb-000008
或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof;
其中，in,
X是O、或-N(R a)-； X is O, or -N(R a )-;
Y是-C(＝O)O-R 4、-C(＝O)NH-R 4、-P(＝O)(OR 4c)(OR 4)、-C(＝O)O-R b-Y 1-R 4a、-C(＝O)NH-R b-Y 1-R 4a、-P(＝O)(OH)(O-R b-Y 1-R 4a)、或-P(＝O)(O-R b-Y 1-R 4a)(O-R b-Y 1-R 4b)； Y is -C(=O)OR 4 , -C(=O)NH-R 4 , -P(=O)(OR 4c )(OR 4 ), -C(=O)OR b -Y 1 -R 4a , -C(=O)NH-R b -Y 1 -R 4a , -P(=O)(OH)(OR b -Y 1 -R 4a ), or -P(=O)(OR b - Y 1 -R 4a ) (OR b -Y 1 -R 4b );
Y 1是O、S、-N(R a)-、-C(＝O)-、-C(＝O)O-、-OC(＝O)-、-OC(＝O)O-、-C(＝O)NH-、-NHC(＝O)-、-S(＝O) 1-2O-、-OS(＝O) 1-2-、-NHC(＝O)NH、-NHC(＝S)NH、-OS(＝O) 1-2O-、或-OS(＝O) 1-2O-； Y 1 is O, S, -N(R a )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NH-, -NHC(=O)-, -S(=O) 1-2 O-, -OS(=O) 1-2 -, -NHC(=O)NH, -NHC( =S)NH, -OS(=O) 1-2 O-, or -OS(=O) 1-2 O-;
各R a分别独立地为H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、或C 1-6氰基烷基； Each R a is independently H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1 -6 cyanoalkyl;
R b是C 1-6亚烷基、或C 1-6亚杂烷基；其中所述C 1-6亚烷基和C 1-6亚杂烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代； R b is C 1-6 alkylene, or C 1-6 heteroalkylene; wherein the C 1-6 alkylene and C 1-6 heteroalkylene are independently optionally 0, 1, 2 , 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -N3 , -OH, -SH, -NH2 , -CN, -NO2 , C1- 4 alkyl and C 1-4 alkoxy group substitution;
R 1和R 2分别独立地为H、C 1-10烷基、C 1-10卤代烷基、C 1-10羟基烷基、C 1-10氨基烷基、C 1-10氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-10烷基、C 1-10卤代烷基、C 1-10羟基烷基、C 1-10氨基烷基、C 1-10氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 5取代； R 1 and R 2 are each independently H, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 hydroxyalkyl, C 1-10 aminoalkyl, C 1-10 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-10 alkyl, C 1 -10 haloalkyl, C 1-10 hydroxyalkyl, C 1-10 aminoalkyl, C 1-10 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkane base, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl independently optionally substituted with 0, 1, 2, 3 or 4 R 5 ;
R 3是-NH 2、-N 3、C 1-6氨基烷基、或
Figure PCTCN2021108383-appb-000009
其中R 3任选地被0、1、2、3、4、或5个R 6取代； R 3 is -NH 2 , -N 3 , C 1-6 aminoalkyl, or
Figure PCTCN2021108383-appb-000009
wherein R3 is optionally substituted with 0, 1, 2, 3, 4 , or 5 R6;
R 3a是H、-OH、C 1-6烷基、或C 1-6羟基烷基； R 3a is H, -OH, C 1-6 alkyl, or C 1-6 hydroxyalkyl;
R 3b是H、-NH 2、C 1-6烷基、C 1-6烷基氨基、或C 1-6氨基烷基； R 3b is H, -NH 2 , C 1-6 alkyl, C 1-6 alkylamino, or C 1-6 aminoalkyl;
R 4和R 4c分别独立地为C 6-22烷基、C 6-22烯基、C 6-22炔基、C 3-8环烷基C 6-22烷基、C 2-7杂环基C 6-22烷基、C 6-12芳基C 6-22烷基、或C 1-9杂芳基C 6-22烷基；其中所述各C 6-22烷基、C 6-22烯基、C 6-22炔基、C 3-8环烷基 C 6-22烷基、C 2-7杂环基C 6-22烷基、C 6-12芳基C 6-22烷基和C 1-9杂芳基C 6-22烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基和C 1-6氰基烷基的基团取代； R 4 and R 4c are each independently C 6-22 alkyl, C 6-22 alkenyl, C 6-22 alkynyl, C 3-8 cycloalkyl, C 6-22 alkyl, C 2-7 heterocycle base C 6-22 alkyl, C 6-12 aryl C 6-22 alkyl, or C 1-9 heteroaryl C 6-22 alkyl; wherein each of the C 6-22 alkyl, C 6- 22 alkenyl, C 6-22 alkynyl, C 3-8 cycloalkyl C 6-22 alkyl, C 2-7 heterocyclyl C 6-22 alkyl, C 6-12 aryl C 6-22 alkyl and C 1-9 heteroaryl C 6-22 alkyl independently optionally by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br , -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl group substitution;
R 4a和R 4b分别独立地为C 1-22烷基、C 2-22烯基、C 2-22炔基、C 3-8环烷基C 1-22烷基、C 2-7杂环基C 1-22烷基、C 6-12芳基C 1-22烷基、或C 1-9杂芳基C 1-22烷基；其中所述各C 1-22烷基、C 2-22烯基、C 2-22炔基、C 3-8环烷基C 1-22烷基、C 2-7杂环基C 1-22烷基、C 6-12芳基C 1-22烷基和C 1-9杂芳基C 1-22烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基和C 1-6氰基烷基的基团取代；和 R 4a and R 4b are each independently C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, C 3-8 cycloalkyl, C 1-22 alkyl, C 2-7 heterocycle base C 1-22 alkyl, C 6-12 aryl C 1-22 alkyl, or C 1-9 heteroaryl C 1-22 alkyl; wherein each C 1-22 alkyl, C 2- 22 alkenyl, C 2-22 alkynyl, C 3-8 cycloalkyl C 1-22 alkyl, C 2-7 heterocyclyl C 1-22 alkyl, C 6-12 aryl C 1-22 alkyl and C 1-9 heteroaryl C 1-22 alkyl independently optionally by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br , -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl group substitution; and
各R 5和R 6分别独立地为H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-CN、-NO 2、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 Each R 5 and R 6 is independently H, D, oxo (=O), F, Cl, Br, -N 3 , -OH, -SH, -CN, -NO 2 , -NH 2 , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1 -6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1- 9heteroaryl and C1-9heteroarylC1-6alkyl independently optionally by 0, 1 , 2, 3 or 4 independently selected from H, D, oxo(=O), F, Group substitution of Cl, Br, -N3 , -OH, -SH, -NH2 , -CN, -NO2 , C1-4alkyl and C1-4alkoxy .
在一些实施方案，R 1是H、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、或C 1-6氰基烷基；其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基和C 1-6氰基烷基独立任选地被0、1、2、3或4个R 5取代。 In some embodiments, R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1-6 cyanoalkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl are independently optionally substituted by 0, 1, 2, 3 or 4 R 5 substitutions.
在一些实施方案，本发明涉及式(II)所示化合物：In some embodiments, the present invention relates to compounds of formula (II):
Figure PCTCN2021108383-appb-000010
Figure PCTCN2021108383-appb-000010
或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof;
其中，R 7是R 4、或-R b-Y 1-R 4a。 wherein R 7 is R 4 , or -R b -Y 1 -R 4a .
在一些实施方案，本发明涉及式(III)所示化合物：In some embodiments, the present invention relates to compounds of formula (III):
Figure PCTCN2021108383-appb-000011
Figure PCTCN2021108383-appb-000011
或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof;
其中，R 7是R 4、或-R b-Y 1-R 4a。 wherein R 7 is R 4 , or -R b -Y 1 -R 4a .
在一些实施方案，其中，R b是C 1-4亚烷基；其中所述C 1-4亚烷基任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 In some embodiments, wherein R b is C 1-4 alkylene; wherein said C 1-4 alkylene is optionally selected from 0, 1, 2, 3, or 4 independently selected from H, D, Oxo(=O), F, Cl, Br, -N 3 , -OH, -SH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl and C 1-4 alkoxy groups group replaced.
在一些实施方案，其中，R b是-CH 2-、-CHF-、-CH 2CH 2-、-CH(CH 3)-、-C(CH 3) 2-、-CH(CH 3)CH 2-、或-CH 2CH 2CH 2-。 In some embodiments, wherein Rb is -CH2- , -CHF-, -CH2CH2- , -CH( CH3 )-, -C( CH3 ) 2- , -CH( CH3 ) CH 2 -, or -CH 2 CH 2 CH 2 -.
在一些实施方案，其中，R 2是C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基、或C 2-6杂环基C 1-4烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基和C 2-6杂环基C 1-4烷基独立任选地被0、1、2、3或4个R 5取代。 In some embodiments, wherein R 2 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 2-6 heterocyclyl, or C 2-6 heterocyclyl C 1-4 alkyl; wherein each C 1 -4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 ring Alkyl C 1-4 alkyl, C 2-6 heterocyclyl and C 2-6 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 5 .
在一些实施方案，其中，R 2是甲基、乙基、丙基、异丙基、丁基、
Figure PCTCN2021108383-appb-000012
Figure PCTCN2021108383-appb-000013
In some embodiments, wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl,
Figure PCTCN2021108383-appb-000012
Figure PCTCN2021108383-appb-000013
在一些实施方案，其中，R 3是-NH 2、-N 3、-CH 2NH 2、-CH 2CH 2NH 2、
Figure PCTCN2021108383-appb-000014
Figure PCTCN2021108383-appb-000015
In some embodiments, wherein R 3 is -NH 2 , -N 3 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 ,
Figure PCTCN2021108383-appb-000014
Figure PCTCN2021108383-appb-000015
在一些实施方案，其中，R 4和R 4c分别独立地为C 6-22烷基、C 6-22烯基、或C 6-22炔基；其中所述各C 6-22烷基、C 6-22烯基和C 6-22炔基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基的基团取代。 In some embodiments, wherein R 4 and R 4c are each independently C 6-22 alkyl, C 6-22 alkenyl, or C 6-22 alkynyl; wherein each of said C 6-22 alkyl, C 6-22Alkenyl and C6-22alkynyl are independently optionally selected from 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 Group substitution of aminoalkyl and C 1-4 cyanoalkyl groups.
在一些实施方案，其中，R 4和R 4c分别独立地为C 8-22烷基、C 8-22烯基、或C 8-22炔基；在一些实施方案，其中，R 4和R 4c分别独立地为C 6-22烷基、C 8-22烯基、或C 8-22炔基；其中所述各C 6-22烷基、C 8-22烷基、C 8-22烯基和C 8-22炔基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基的基团取代。 In some embodiments, wherein R 4 and R 4c are each independently C 8-22 alkyl, C 8-22 alkenyl, or C 8-22 alkynyl; in some embodiments, wherein R 4 and R 4c are independently C 6-22 alkyl, C 8-22 alkenyl, or C 8-22 alkynyl; wherein each of said C 6-22 alkyl, C 8-22 alkyl, C 8-22 alkenyl and C 8-22 alkynyl is independently optionally selected by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -N3 , -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl and C 1-4 cyanoalkyl group substitution.
在一些实施方案，其中，R 4a和R 4b分别独立地为C 6-22烷基、C 6-22烯基、或C 6-22炔基；其中所述各C 6-22烷基、C 6-22烯基和C 6-22炔基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基的基团取代。 In some embodiments, wherein R 4a and R 4b are each independently C 6-22 alkyl, C 6-22 alkenyl, or C 6-22 alkynyl; wherein each of said C 6-22 alkyl, C 6-22Alkenyl and C6-22alkynyl are independently optionally selected from 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 Group substitution of aminoalkyl and C 1-4 cyanoalkyl groups.
在一些实施方案，其中，R 4a和R 4b分别独立地为C 8-22烷基、C 8-22烯基、或C 8-22炔基；其中所述各C 8-22烷基、C 8-22烯基和C 8-22炔基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基的基团取代。 In some embodiments, wherein R 4a and R 4b are each independently C 8-22 alkyl, C 8-22 alkenyl, or C 8-22 alkynyl; wherein each C 8-22 alkyl, C 8-22 alkenyl and C 8-22 alkynyl are independently optionally selected by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 Group substitution of aminoalkyl and C 1-4 cyanoalkyl groups.
在一些实施方案，其中，各R 5和R 6分别独立地为H、D、F、Cl、Br、-N 3、-OH、-SH、-CN、-NO 2、-NH 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基、C 2-6杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基、C 2-6杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 In some embodiments, wherein each R5 and R6 are each independently H, D, F, Cl, Br, -N3 , -OH, -SH, -CN, -NO2 , -NH2 , C1 -4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 ring Alkyl, C 3-6 cycloalkyl, C 1-4 alkyl, C 2-6 heterocyclyl, C 2-6 heterocyclyl, C 1-4 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-4 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein each C 1-4 alkyl, C 1-4 alkoxy , C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1 -4 alkyl, C 2-6 heterocyclyl, C 2-6 heterocyclyl, C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-4 alkyl, C 1- 9heteroaryl and C1-9heteroarylC1-4alkyl independently optionally by 0, 1 , 2, 3 or 4 independently selected from H, D, oxo(=O), F, Group substitution of Cl, Br, -N3 , -OH, -SH, -NH2 , -CN, -NO2 , C1-4alkyl and C1-4alkoxy .
在一些实施方案，本发明涉及具有以下结构之一的化合物：In some embodiments, the present invention relates to compounds having one of the following structures:
Figure PCTCN2021108383-appb-000016
Figure PCTCN2021108383-appb-000016
Figure PCTCN2021108383-appb-000017
Figure PCTCN2021108383-appb-000017
Figure PCTCN2021108383-appb-000018
Figure PCTCN2021108383-appb-000018
Figure PCTCN2021108383-appb-000019
Figure PCTCN2021108383-appb-000019
或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐。or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof.
除非另有说明，式(I)、(II)和(III)所示化合物的立体异构体、互变异构体、溶剂化物、代谢产物或药学上可接受的盐均包含在本发明范围内。Unless otherwise specified, the stereoisomers, tautomers, solvates, metabolites or pharmaceutically acceptable salts of the compounds represented by formulae (I), (II) and (III) are included within the scope of the present invention Inside.
本发明公开化合物可含有不对称或手性中心，因此可以不同的立体异构体形式存在。本发明旨在使式(I)、(II)或(III)所示化合物的所有立体异构体形式，包括但不限于非对映异构体、对映异构体、阻转异构体和几何(或构象)异构体，以及它们的混合物如外消旋混合物，成为本发明的组成部分。Compounds of the present disclosure may contain asymmetric or chiral centers and, therefore, may exist in different stereoisomeric forms. The present invention is intended to make all stereoisomeric forms of compounds represented by formula (I), (II) or (III), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
在本发明公开的结构中，当任意特定的手性原子的立体化学未指明时，则该结构的所有立体异构体均考虑在本发明之内，并且作为本发明公开化合物包括在本发明中。当立体化学被表示特定构型的实楔形线(solid wedge)或虚线指明时，则该结构的立体异构体就此明确和定义。In a structure disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated within the present invention and are included in the present invention as compounds disclosed herein . When stereochemistry is indicated by a solid wedge or a dashed line representing a particular configuration, then the stereoisomers of that structure are well defined and defined.
式(I)、(II)或(III)所示化合物可以盐的形式存在。在一实施方案，所述盐是指药学上可接受的盐。术语“药学上可接受的”是指物质或组合物必须与包含制剂的其它成分和/或用其治疗的哺乳动物化学上和/或毒理学上相容。在另一实施方案，所述盐不一定是药学上可接受的盐，可以是用于制备和/或提纯式(I)、(II)或(III)所示化合物和/或用于分离本式(I)、(II)或(III)所示化合物的对映体的中间体。The compounds represented by formula (I), (II) or (III) may exist in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that a substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated with it. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, but can be used for the preparation and/or purification of the compound represented by formula (I), (II) or (III) and/or for the isolation of the present Intermediates of enantiomers of compounds of formula (I), (II) or (III).
另一方面，本发明涉及制备式(I)、(II)或(III)所示化合物的中间体。In another aspect, the present invention relates to intermediates for the preparation of compounds of formula (I), (II) or (III).
另一方面，本发明涉及式(I)、(II)或(III)所示化合物的制备、分离和纯化的方法。In another aspect, the present invention relates to methods for the preparation, isolation and purification of compounds represented by formula (I), (II) or (III).
另一方面，本发明提供一种药物组合物，所述药物组合物包含本发明所述的化合物或其药学上可接受 的盐，以及药学上可接受的辅料、稀释剂或载体。In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
在一些实施方案，所述药物组合物进一步包含附加治疗剂。In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent.
在一些实施方案，所述药物组合物是长效形式。In some embodiments, the pharmaceutical composition is in a long-acting form.
在一些实施方案，所述药物组合物是注射剂或吸入型制剂的形式。In some embodiments, the pharmaceutical composition is in the form of an injectable or inhaled formulation.
另一方面，本发明提供了使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防和/或治疗病毒性疾病或抑制神经氨酸酶活性的药物中的用途。In another aspect, the present invention provides the use of the compound of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing and/or treating a viral disease or inhibiting the activity of neuraminidase.
在一些实施方案，所述神经氨酸酶是流感神经氨酸酶。In some embodiments, the neuraminidase is influenza neuraminidase.
在一些实施方案，所述病毒性疾病是流感病毒引起的疾病。In some embodiments, the viral disease is a disease caused by an influenza virus.
在一些实施方案，所述病毒性疾病是甲型流感或乙型流感。In some embodiments, the viral disease is influenza A or influenza B.
本发明化合物的药物组合物、制剂和用途Pharmaceutical Compositions, Formulations and Uses of the Compounds of the Invention
当用作药物时，本发明化合物通常以药物组合物形式施用，并可以是长效形式。所述组合物可以以制药技术中熟知的方式制备并且包含至少一个根据式I、II、或III的本发明所述化合物。通常，本发明化合物以药物有效量施用。实际施用的本发明化合物的量通常将由医师根据相关情形决定，所述情形包括待治疗病症、所选的施用途径、所施用的本发明的实际化合物、个别患者的年龄、体重和响应、患者症状的严重程度等。When used as a medicament, the compounds of the present invention are usually administered in the form of a pharmaceutical composition, and may be in a long-acting form. Said composition can be prepared in a manner well known in the art of pharmacy and comprises at least one compound of the invention according to formula I, II, or III. Generally, the compounds of the present invention are administered in a pharmaceutically effective amount. The amount of the compound of the present invention actually administered will generally be determined by the physician in light of the circumstances, including the condition to be treated, the route of administration chosen, the actual compound of the present invention administered, the age, weight and response of the individual patient, the patient's symptoms severity, etc.
在一些实施方案，本发明包含药物组合物。此类药物组合物包含以药学上可接受的载体呈示的本发明化合物。亦可有其它的药理活性物质存在。如本申请中所使用的"药学上可接受的载体"包括任何及所有的溶剂、分散介质、包膜、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂及生理上可相容的类似者。药学上可接受的载体的实例包括水、盐水、磷酸盐缓冲盐水、葡萄糖、甘油、乙醇及类似者中的一种或多种，以及它们的组合，且可在组合物中包括等渗剂，例如糖、氧化纳或多元醇，诸如甘露醇或山梨醇。药学上可接受的物质(诸如润湿剂)或少量辅助物质(诸如润湿剂或乳化剂、保存剂或缓冲剂)提高抗体或抗体部分的储存寿命或有效性。In some embodiments, the present invention includes pharmaceutical compositions. Such pharmaceutical compositions comprise a compound of the present invention in a pharmaceutically acceptable carrier. Other pharmacologically active substances may also be present. "Pharmaceutically acceptable carrier" as used in this application includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and physiologically compatible similar. Examples of pharmaceutically acceptable carriers include one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof, and may include isotonic agents in the composition, For example sugars, sodium oxide or polyols such as mannitol or sorbitol. Pharmaceutically acceptable substances, such as wetting agents, or minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, increase the shelf-life or effectiveness of the antibody or antibody portion.
本发明组合物可呈多种形式。这些形式包括例如液体、半固体及固体剂型，诸如液体溶液(例如可注射和可输液溶液)、分散液或悬浮液、片剂、丸剂、粉剂、脂质体和栓剂。该形式系取决于意欲给药方式及治疗应用而定。The compositions of the present invention may take a variety of forms. These include, for example, liquid, semisolid, and solid dosage forms such as liquid solutions (eg, injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form will depend on the intended mode of administration and therapeutic application.
典型的组合物系呈可注射和可输液溶液，诸如类似于那些通常用于以抗体的人类被动免疫的组合物。一种给药方式为肠胃外(例如静脉内、皮下、腹膜内、肌肉内)。在另一实施方案中，抗体系经静脉内输液或注射施用。在又另一实施方案中，抗体系经肌肉内或皮下注射施用。Typical compositions are in the form of injectable and infusible solutions, such as compositions similar to those commonly used for passive immunization of humans with antibodies. One mode of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular). In another embodiment, the antibody system is administered by intravenous infusion or injection. In yet another embodiment, the antibody system is administered by intramuscular or subcutaneous injection.
固体剂型的经口施用可以例如个别单元呈示，诸如硬或软胶囊、丸剂、扁囊剂、链剂或片剂，各含有预定量的至少一种本发明化合物。在另一实施方案中，经口给予可呈粉末或颗粒形式。在另一实施方案中，经口剂型为舌下形式，诸如链剂。在此类固体剂型中，式I的化合物惯常与一种或多种助剂组合。此类胶囊或片剂可含有控制释放型配制物。在胶囊、片剂和丸剂的例子中，剂型亦可包含缓冲剂或可以肠溶衣制备。Oral administration of solid dosage forms may, for example, be presented in individual units, such as hard or soft capsules, pills, cachets, chains, or tablets, each containing a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in powder or granular form. In another embodiment, the oral dosage form is a sublingual form, such as a chain dosage. In such solid dosage forms, the compounds of formula I are conventionally combined with one or more adjuvants. Such capsules or tablets may contain controlled release formulations. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents or may be prepared with an enteric coating.
用于肠胃外给药的组合物可以是乳剂或无菌溶液。在某些实施方案，可使用丙二醇、聚乙二醇、植物油、特别是橄榄油或可注射的有机酯作为溶剂或载体，在一些实施方案，使用油酸乙酯作为溶剂或载体。所述这些组合物还可包含佐剂，特别是润湿剂，等渗剂，乳化剂，分散剂和稳定剂。可以几种方式进行灭菌，在某些实施方案，使用细菌学过滤器，通过辐射或通过加热进行灭菌。它们也可以无菌固体组合物的形式进行制备，其可在使用时溶于无菌水或任何其他可注射的无菌介质中。Compositions for parenteral administration may be emulsions or sterile solutions. In certain embodiments, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, or injectable organic esters can be used as a solvent or carrier, and in some embodiments, ethyl oleate can be used as a solvent or carrier. These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifying agents, dispersing agents and stabilizing agents. Sterilization can be performed in several ways, in certain embodiments, by use of bacteriological filters, by radiation or by heat. They can also be prepared in the form of sterile solid compositions which, at the time of use, can be dissolved in sterile water or any other sterile injectable medium.
在某些实施方案，本发明提供的组合物是药物组合物或单一单位剂型。本发明提供的药物组合物和单一单位剂型包含预防或治疗有效量的一种或多种预防剂或治疗剂(例如，本发明提供的化合物或其他预防剂或治疗剂)以及典型的一种或多种药学上可接受的载体或辅料。在具体实施方案和本发明中，术语“药学上可接受的”是指由联邦或州政府的监管机构批准，或者在美国药典或其他公认的药典中列出的用于动物、特别是用于人类的药物。术语“载体”包括与治疗剂一同施用的稀释剂、佐剂(例如，弗氏佐剂(完全和不完全))、辅料或媒介物。此类药物载体可以是无菌液体，如水和油类，包括石油、动物油、植物油或合成来源的那些，如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时，水可用作载体。盐水溶液和葡萄糖水溶液以及甘油溶液也可用作液体载体，特别是用于注射溶液。合适的药物载体的实例 记载在Remington:The Science and Practice of Pharmacy；医药出版社(Pharmaceutical Press)；22版(2012年9月15日)中。In certain embodiments, the compositions provided herein are pharmaceutical compositions or single unit dosage forms. The pharmaceutical compositions and single unit dosage forms provided herein comprise a prophylactically or therapeutically effective amount of one or more prophylactic or therapeutic agents (eg, compounds provided herein or other prophylactic or therapeutic agents) and typically one or more prophylactic or therapeutic agents. A variety of pharmaceutically acceptable carriers or excipients. In specific embodiments and the present invention, the term "pharmaceutically acceptable" means approved by a regulatory agency of the Federal or a state government, or listed in the US Pharmacopeia or other generally recognized pharmacopeia for use in animals, particularly for use in animals human medicine. The term "carrier" includes a diluent, adjuvant (eg, Freund's adjuvant (complete and incomplete)), adjuvant, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water can be used as a carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
典型的药物组合物和剂型包含一种或多种辅料。合适的辅料对药学领域的技术人员而言是熟知的，在某些实施方案，合适的辅料包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。特定的辅料是否适合掺入药物组合物或剂型，取决于本领域众所周知的各种因素，包括但不限于将所述剂型施用于受试者的方式以及所述剂型中的特定活性成分。若需要，所述组合物或单一单位剂型还可含有少量润湿剂或乳化剂，或pH缓冲剂。Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the art of pharmacy, and in certain embodiments, suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, glycol, water, ethanol, etc. Whether a particular adjuvant is suitable for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including but not limited to the manner in which the dosage form is administered to a subject and the particular active ingredient in the dosage form. If desired, the composition or single unit dosage form may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
本发明化合物和/或含有所述化合物的组合物的剂量方案基于许多因素，包括患者的类型、年龄、体重、性别和医学症状；症状的严重性；给药途径；及所使用的特殊化合物的活性。因此，剂量方案可广泛地改变。在一个实施方案，用于治疗本发明中所讨论的适应症的本发明化合物的总日剂量通常为约0.001至约100毫克/千克(亦即以每千克体重计毫克本发明化合物)。在另一实施方案，本发明化合物的总日剂量为约0.01至约30毫克/千克，且在另一实施方案中为约0.03至约10毫克/千克，且在又一实施方案中为约0.1至约3毫克/千克。以一天内重复施用本发明化合物很多次并不罕见(通常不超过4次)。若需要，通常可使用每天多次剂量以增加总日剂量。Dosage regimens for the compounds of the present invention and/or compositions containing the compounds are based on a number of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the symptoms; the route of administration; active. Thus, the dosage regimen can vary widely. In one embodiment, the total daily dose of a compound of the present invention for the treatment of the indications discussed in this invention is generally from about 0.001 to about 100 mg/kg (ie, milligrams of a compound of the present invention per kilogram of body weight). In another embodiment, the total daily dose of a compound of the present invention is about 0.01 to about 30 mg/kg, and in another embodiment about 0.03 to about 10 mg/kg, and in yet another embodiment about 0.1 to about 3 mg/kg. It is not uncommon to repeat the administration of a compound of the present invention many times in a day (usually no more than 4 times). If necessary, multiple daily doses can usually be used to increase the total daily dose.
本发明提供的药物组合物可以与不会损害预期治疗作用的其它活性成分共同配制，或者与补充预期作用的物质共同配制。The pharmaceutical compositions provided by the present invention can be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
另一方面，本发明提供了本发明化合物或包含本发明化合物的药物组合物，其用于医学用途。在具体实施方案中，本发明提供了本发明化合物或包含本发明化合物的药物组合物，其用于预防和/或治疗病毒性疾病。在一些实施方案，所述病毒性疾病是流感病毒引起的疾病。在一些实施方案，所述病毒性疾病是甲型流感或乙型流感。在一些实施方案，本发明化合物或包含本发明化合物的药物组合物可抑制神经氨酸酶活性。更具体地，本发明化合物或包含本发明化合物的药物组合物可流感抑制神经氨酸酶活性。In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in medicine. In specific embodiments, the present invention provides compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for use in the prevention and/or treatment of viral diseases. In some embodiments, the viral disease is a disease caused by an influenza virus. In some embodiments, the viral disease is influenza A or influenza B. In some embodiments, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention inhibits neuraminidase activity. More specifically, a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention inhibits neuraminidase activity in influenza.
在另一方面，本发明提供了一类可用作药物尤其用作治疗和/或预防本发明所述疾病和/或病症的药物的本发明公开的化合物。本发明也提供了使用本发明公开化合物来制备治疗和/或预防本发明所述疾病和/或病症的长效药物。在一些实施方案，所述药物是注射剂或吸入型制剂形式。In another aspect, the present invention provides a class of compounds disclosed herein that are useful as medicaments, particularly as medicaments for the treatment and/or prevention of the diseases and/or disorders described herein. The present invention also provides the use of the disclosed compounds for the preparation of long-acting medicaments for the treatment and/or prevention of the diseases and/or conditions described herein. In some embodiments, the medicament is in the form of an injectable or inhaled formulation.
附图简要说明Brief Description of Drawings
图1示出了对小鼠施用本发明受试化合物、模型组和参比化合物后的体重变化。Figure 1 shows changes in body weight after administration of the test compound of the present invention, the model group and the reference compound to mice.
图2示出了施用本发明受试化合物、模型组和参比化合物后的小鼠感染病毒五天后肺部流感病毒滴度。Figure 2 shows the pulmonary influenza virus titers five days after the mice were infected with the virus after administration of the test compound of the present invention, the model group and the reference compound.
图3示出了对小鼠施用本发明受试化合物、模型组和参比化合物后的生存率曲线。Figure 3 shows the survival rate curve after administration of the test compound of the present invention, the model group and the reference compound to mice.
具体实施方式detailed description
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。To illustrate the invention, the following examples are set forth. It is to be understood, however, that the invention is not limited to these examples, but merely provides methods of practicing the invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I、II、或III所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。In general, the compounds of the present invention can be prepared by the methods described herein, where the substituents are as defined in formula I, II, or III unless otherwise specified. The following reaction schemes and examples serve to further illustrate the content of the present invention.
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare many other compounds of this invention, and that other methods for preparing compounds of this invention are considered to be within the scope of this invention. Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modifying methods, such as appropriate protection of interfering groups, by using other known reagents in addition to those described herein, or by combining The reaction conditions were modified routinely. In addition, the reactions disclosed herein or known reaction conditions are also acknowledged to be applicable to the preparation of other compounds of the present invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company，Arco Chemical Company，安耐吉化学公司(Energy-chemical Company)，上海绍远(Shanghai Shaoyuan Company)，J&K Chemical Company，阿拉丁化学公司(Aladdin Chemical Company)，Meryer Chemical Company，TCI Chemical Company，Xiya Reagent Company，Bidepharm Company，Macklin Company和Alfa Chemical Company，使用时均没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试 剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。In the examples described below, all temperatures are in degrees Celsius unless otherwise indicated. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, Energy-chemical Company, Shanghai Shaoyuan Company, J&K Chemical Company, Aladdin Chemical Company, Meryer Chemical Company, TCI Chemical Company, Xiya Reagent Company, Bidepharm Company, Macklin Company and Alfa Chemical Company are used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd., and Qingdao Ocean Chemical Factory.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether were obtained by refluxing and drying with metallic sodium. Anhydrous dichloromethane and chloroform were obtained by refluxing with calcium hydride. Ethyl acetate, petroleum ether, n-hexane, N,N-dimethylacetamide and N,N-dimethylformamide were dried over anhydrous sodium sulfate before use.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under positive nitrogen or argon pressure or a drying tube is set over anhydrous solvent (unless otherwise indicated), the reaction flasks are plugged with suitable rubber stoppers, and the substrate is injected through a syringe. Glassware is dry.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 1 H NMR spectra were recorded using a Bruker 400 MHz or 600 MHz nuclear magnetic resonance spectrometer. 1H NMR spectra were performed with CDC13, DMSO - d6, CD3OD or acetone - d6 as solvent (in ppm) and TMS (0 ppm) or chloroform (7.26 ppm) as reference standards. When multiplets are present, the following abbreviations are used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened) peak), dd (doublet of doublets, double doublet), dt (doublet of triplets, double triplet). Coupling constant, expressed in Hertz (Hz).
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％((含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例)，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。 The measurement conditions for low-resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1 x 30 mm, 3.5 microns, 6 min, flow rate 0.6 mL/min. Mobile phase: 5 %-95% (( CH3CN with 0.1% formic acid) in ( H2O with 0.1% formic acid)) using electrospray ionization (ESI) at 210 nm/254 nm with UV detection.
纯的化合物的使用Agilent 1260pre-HPLC或Calesep pump 250 pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm用UV检测。Pure compounds were detected by UV at 210nm/254nm using Agilent 1260 pre-HPLC or Calesep pump 250 pre-HPLC (column type: NOVASEP 50/80mm DAC).
下面简写词的使用贯穿本发明：The following abbreviations are used throughout this disclosure:
CD 3OD 氘代甲醇 CD 3 OD Deuterated methanol
CDC1 3 氘代氯仿 CDC1 3 deuterochloroform
DMSO-d 6 氘代二甲基亚砜 DMSO-d 6 -deuterated dimethyl sulfoxide
g 克g grams
h、hr 小时h, hr hours
mL、ml 毫升mL, ml
RT、rt、r.t. 室温RT, rt, r.t. room temperature
制备本发明化合物的典型合成步骤如以下合成方案1或2所示，其中R 1、R 2、R 3、R 4、R 4a、R b、X和Y 1均具有本发明所述定义；PG是氨基保护基，LG是离去基团，例如卤素等。 Typical synthetic steps for the preparation of compounds of the present invention are shown in the following Synthetic Schemes 1 or 2, wherein R 1 , R 2 , R 3 , R 4 , R 4a , R b , X and Y 1 all have the definitions described in the present invention; PG is an amino protecting group, LG is a leaving group such as halogen, etc.
合成方案1：Synthesis Scheme 1:
Figure PCTCN2021108383-appb-000020
Figure PCTCN2021108383-appb-000020
将化合物1-1与相应的醇溶于适当溶剂中，加入缩合剂和碱，搅拌反应得到化合物1-2，将1-2在酸性条件下脱保护基得到终产物1-3。Compound 1-1 and the corresponding alcohol are dissolved in a suitable solvent, a condensing agent and a base are added, and the reaction is stirred to obtain compound 1-2. The final product 1-3 is obtained by deprotecting the 1-2 under acidic conditions.
合成方案2：Synthesis Scheme 2:
Figure PCTCN2021108383-appb-000021
Figure PCTCN2021108383-appb-000021
将化合物2-1与相应的底物溶于适当溶剂中，在碱性条件下，发生亲核取代反应，得到化合物2-2，将2-2在酸性条件下脱保护基得到终产物1-3。Compound 2-1 and the corresponding substrate are dissolved in a suitable solvent, and under basic conditions, a nucleophilic substitution reaction occurs to obtain compound 2-2, and 2-2 is deprotected under acidic conditions to obtain the final product 1- 3.
实施例Example
实施例1 (3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Example 1 (3R,4R,5S)-4-acetylamino-5-amino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester
Figure PCTCN2021108383-appb-000022
Figure PCTCN2021108383-appb-000022
步骤1)(3R,4R,5S)-4-乙酰氨基-5-((叔丁氧羰基)氨基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Step 1) (3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octanoate ester
向(3R,4R,5S)-4-乙酰氨基-5-((叔丁氧羰基)氨基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(3.0g，7.8mmol)的二氯甲烷(30mL)溶液中加入正辛醇(1.34mL，8.6mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.24g，11.7mmol)、二异丙基乙胺(4.6mL，27.3mmol)和4-二甲胺基吡啶(0.19g，1.56mmol)。混合物在室温下搅拌过夜。反应完全后，减压浓缩除去溶剂。向所得残余物中加入乙酸乙酯(20mL)使其溶解，混合物用饱和氯化钠洗，无水硫酸钠干燥，减压浓缩除去溶剂。所得残余物经柱层析纯化(PE：EA＝2：1)，得到产物(1.98g，51％)。LCMS[M+H] +:497.7。 To (3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid (3.0 g , 7.8 mmol) in dichloromethane (30 mL) was added n-octanol (1.34 mL, 8.6 mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.24 mmol) g, 11.7 mmol), diisopropylethylamine (4.6 mL, 27.3 mmol) and 4-dimethylaminopyridine (0.19 g, 1.56 mmol). The mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Ethyl acetate (20 mL) was added to the obtained residue to dissolve it, and the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (PE:EA=2:1) to give the product (1.98 g, 51%). LCMS[M+H] + : 497.7.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-氨基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Step 2) (3R,4R,5S)-4-acetylamino-5-amino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((叔丁氧羰基)氨基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯(1.98g，3.98mmol)的二氯甲烷(20mL)溶液中加入三氟乙酸(5mL)。混合物在室温下搅拌反应，减压浓缩除去溶剂。所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得到标题化合物(0.2g，12％)。LCMS[M+H] +:397.6。 1H NMR(500MHz,CDCl 3)δ6.79(t,J＝1.8Hz,1H),5.68(d,J＝7.95Hz,1H),4.33(s,1H),4.20–4.05(m,2H),3.57-3.46(m,1H),3.37-3.20(m,2H),2.88(d,J＝15.0Hz,1H),2.36(s,1H),2.21(s,3H),2.03(s,3H),1.66(dd,J＝13.8,6.8Hz,2H),1.50(s,4H),1.36(dd,J＝18.6,10.5Hz,6H),0.97–0.80(m,9H)。 To (3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester ( To a solution of 1.98 g, 3.98 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the title compound (0.2 g, 12%). LCMS[M+H] + : 397.6. 1 H NMR (500MHz, CDCl 3 ) δ 6.79 (t, J=1.8Hz, 1H), 5.68 (d, J=7.95Hz, 1H), 4.33 (s, 1H), 4.20-4.05 (m, 2H) ,3.57-3.46(m,1H),3.37-3.20(m,2H),2.88(d,J＝15.0Hz,1H),2.36(s,1H),2.21(s,3H),2.03(s,3H ), 1.66 (dd, J=13.8, 6.8Hz, 2H), 1.50 (s, 4H), 1.36 (dd, J=18.6, 10.5Hz, 6H), 0.97–0.80 (m, 9H).
实施例2 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸己酯Example 2 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid hexyl ester
Figure PCTCN2021108383-appb-000023
Figure PCTCN2021108383-appb-000023
步骤1)(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸乙酯Step 1) (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- Ethyl ene-1-carboxylate
向磷酸奥司他韦(1.0g，2.44mmol)的四氢呋喃(10mL)溶液中加入三乙胺(1.6mL，12.2mmol)和((叔丁氧基羰基)氨基)(1H-吡唑-1-基)亚甲基)氨基甲酸叔丁酯(0.83g，2.68mmol)，混合物搅拌过夜。反应完全后，减压浓缩除去溶剂。残余物用乙酸乙酯(10mL)萃取，有机相经硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝1：1)，得到产物(1.2g，89％)。LCMS[M+H] +:555.33。 To a solution of oseltamivir phosphate (1.0 g, 2.44 mmol) in tetrahydrofuran (10 mL) was added triethylamine (1.6 mL, 12.2 mmol) and ((tert-butoxycarbonyl)amino)(1H-pyrazole-1- (0.83 g, 2.68 mmol), and the mixture was stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (10 mL), the organic phase was dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=1:1) to give the product (1.2 g, 89%) ). LCMS[M+H] + : 555.33.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸Step 2) (3R,4R,5S)-4-acetylamino-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- ene-1-carboxylic acid
在0℃下，向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸乙酯(0.5g，0.9mmol)的乙二醇二甲醚(5.0mL)溶液中加入氢氧化钾(0.2g，3.6mmol)的水(2.0mL)溶液，混合物在室温下搅拌2小时。反应完全后，将反应混合物冷却至0℃，加入1.0M的盐酸调节PH至中性，减压浓缩除去溶剂。向残余物中加入甲醇溶解，过滤，再次浓缩除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得到产物(0.43g，90％)。LCMS[M+H] +:527.3。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl at 0°C To a solution of ethyl-1-ene-1-carboxylate (0.5 g, 0.9 mmol) in ethylene glycol dimethyl ether (5.0 mL) was added a solution of potassium hydroxide (0.2 g, 3.6 mmol) in water (2.0 mL), and the mixture was Stir at room temperature for 2 hours. After the reaction was completed, the reaction mixture was cooled to 0° C., 1.0 M hydrochloric acid was added to adjust the pH to neutrality, and the solvent was removed by concentration under reduced pressure. Methanol was added to the residue to dissolve, filtered and concentrated again to remove the solvent, and the obtained residue was purified by column chromatography (DCM:MeOH=10:1) to give the product (0.43 g, 90%). LCMS[M+H] + : 527.3.
步骤3)(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸己酯Step 3) (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- Hexyl ene-1-carboxylate
向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(3.0g，5.7mmol)的二氯乙烷(30mL)溶液中加入正己醇(0.76mL，6.3mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(1.65g，8.55mmol)、二异丙基乙胺(3.0mL，21mmol)和4-二甲胺基吡啶(0.135g，1.14mmol)。混合物在室温下搅拌过夜。反应完全后，减压浓缩除去溶剂，向残余物中加入乙酸乙酯使其溶解，混合物用饱和氯化钠洗，无水硫酸钠干燥，减压浓缩除去溶剂。所得残余物经柱层析纯化(PE：EA＝2：1)得到产物(2.0g，57％)。LCMS[M+H] +:611.8。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1-ene- To a solution of 1-carboxylic acid (3.0 g, 5.7 mmol) in dichloroethane (30 mL) was added n-hexanol (0.76 mL, 6.3 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (1.65 g, 8.55 mmol), diisopropylethylamine (3.0 mL, 21 mmol) and 4-dimethylaminopyridine (0.135 g, 1.14 mmol). The mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent, and ethyl acetate was added to the residue to dissolve it. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (PE:EA=2:1) to give the product (2.0 g, 57%). LCMS[M+H] + : 611.8.
步骤4)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸己酯Step 4) (3R,4R,5S)-4-Acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid hexyl ester
向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸己酯(2.0g，3.27mmol)的二氯甲烷(20mL)溶液中加入三氟乙酸(5.0mL)，混合物在室温下搅拌反应。减压浓缩除 去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得到标题化合物(190mg，14％)。LCMS[M+H] +:411.15。 1H NMR(500MHz,CDCl 3)δ8.34(s,1H),7.59(s,1H),6.78(s,1H),4.33(s,1H),4.20–4.05(m,2H),3.85(s,2H),3.37(s,1H),2.88(d,J＝15.0Hz,1H),2.36(s,1H),2.21(s,3H),2.03(s,3H),1.66(dd,J＝13.8,6.8Hz,2H),1.50(s,4H),1.36(dd,J＝18.6,10.5Hz,6H),0.97–0.80(m,9H)。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1-ene- To a solution of hexyl 1-carboxylate (2.0 g, 3.27 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (5.0 mL), and the mixture was stirred at room temperature for reaction. The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the title compound (190 mg, 14%). LCMS[M+H] + : 411.15. 1 H NMR (500MHz, CDCl 3 )δ8.34(s,1H), 7.59(s,1H), 6.78(s,1H), 4.33(s,1H), 4.20-4.05(m,2H), 3.85( s, 2H), 3.37(s, 1H), 2.88(d, J=15.0Hz, 1H), 2.36(s, 1H), 2.21(s, 3H), 2.03(s, 3H), 1.66(dd, J = 13.8, 6.8 Hz, 2H), 1.50 (s, 4H), 1.36 (dd, J = 18.6, 10.5 Hz, 6H), 0.97–0.80 (m, 9H).
实施例3 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Example 3 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester
Figure PCTCN2021108383-appb-000024
Figure PCTCN2021108383-appb-000024
步骤1)(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Step 1) (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- octyl ene-1-carboxylate
向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(4.0g，7.6mmol)的二氯甲烷(40mL)溶液中加入正辛醇(1.44mL，9.12mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.17g，11.4mmol)、二异丙基乙胺(4.0mL，22.8mmol)和4-二甲氨基吡啶(0.18g，1.48mmol)。混合物在室温下搅拌过夜。反应完全后，减压浓缩除去溶剂，向残余物中加入乙酸乙酯使其溶解，混合物用饱和氯化钠洗，无水硫酸钠干燥，减压除去溶剂。所得残余物经柱层析纯化(PE：EA＝2：1)，得到产物(3g，62％)。LCMS[M+H] +:639.8。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1-ene- To a solution of 1-carboxylic acid (4.0 g, 7.6 mmol) in dichloromethane (40 mL) was added n-octanol (1.44 mL, 9.12 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (2.17 g, 11.4 mmol), diisopropylethylamine (4.0 mL, 22.8 mmol) and 4-dimethylaminopyridine (0.18 g, 1.48 mmol). The mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure, ethyl acetate was added to the residue to dissolve, the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography (PE:EA=2:1) to give the product (3 g, 62%). LCMS[M+H] + : 639.8.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Step 2) (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid octyl ester
向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯(3.0g，4.79mmol)的二氯甲烷(30mL)溶液中加入三氟乙酸(8.0mL)，混合物在室温下搅拌反应。除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得到标题化合物(250mg，12％)。LCMS[M+H] +：439.32。 1H NMR(500MHz,CDCl 3)δ8.13(d,J＝7.6Hz,1H),7.50(d,J＝8.2Hz,1H),6.77(s,1H),4.26–4.03(m,3H),3.83(dd,J＝18.7,10.0Hz,2H),3.39–3.26(m,1H),2.87(d,J＝14.2Hz,1H),2.32(s,1H),2.06(d,J＝41.4Hz,6H),1.73–1.58(m,2H),1.56–1.43(m,4H),1.44–1.05(m,14H),0.95–0.79(m,9H)。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1-ene- To a solution of octyl 1-carboxylate (3.0 g, 4.79 mmol) in dichloromethane (30 mL) was added trifluoroacetic acid (8.0 mL), and the mixture was stirred for reaction at room temperature. The solvent was removed and the resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the title compound (250 mg, 12%). LCMS[M+H] + : 439.32. 1 H NMR (500 MHz, CDCl 3 ) δ 8.13 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 6.77 (s, 1H), 4.26-4.03 (m, 3H) ,3.83(dd,J＝18.7,10.0Hz,2H),3.39–3.26(m,1H),2.87(d,J＝14.2Hz,1H),2.32(s,1H),2.06(d,J＝41.4 Hz, 6H), 1.73–1.58 (m, 2H), 1.56–1.43 (m, 4H), 1.44–1.05 (m, 14H), 0.95–0.79 (m, 9H).
实施例4 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸癸酯Example 4 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid decyl ester
Figure PCTCN2021108383-appb-000025
Figure PCTCN2021108383-appb-000025
步骤1)(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸癸酯Step 1) (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1- Decyl ene-1-carboxylate
向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(5.0g，9.12mmol)的二氯甲烷(50mL)溶液中加入正葵醇(1.22mL，10.46mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.74g，13.68mmol)、二异丙基乙胺(5.0mL，33.6mmol)和4-二甲氨基吡啶(0.224g，1.89mmol)，混合物在室温下搅拌过夜。反应完全后，减压浓缩除去溶剂，向残余物中加入乙酸乙酯使其溶解，混合物用饱和氯化钠洗，无水硫酸钠干燥，减压除去溶剂。所得残余物经柱层析纯化(PE：EA＝2：1)，得到产物(4.0g，66％)。LCMS[M+H] +:667.9。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1-ene- To a solution of 1-carboxylic acid (5.0 g, 9.12 mmol) in dichloromethane (50 mL) was added n-decyl alcohol (1.22 mL, 10.46 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide Amine hydrochloride (2.74 g, 13.68 mmol), diisopropylethylamine (5.0 mL, 33.6 mmol) and 4-dimethylaminopyridine (0.224 g, 1.89 mmol), the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure, ethyl acetate was added to the residue to dissolve, the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography (PE:EA=2:1) to give the product (4.0 g, 66%). LCMS[M+H] + : 667.9.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸癸酯Step 2) (3R,4R,5S)-4-Acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid decyl ester
向(3R,4R,5S)-4-乙酰氨基-5-(2,3-二(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸癸酯(4.0g，6.0mmol)的二氯甲烷(40mL)溶液中加入三氟乙酸(10mL)，混合物在室温下搅拌，反应完成后，减压除去溶剂。所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得到标题化合物(200mg，7％)。LCMS[M+H] +:467.15。 1H NMR(500MHz,CDCl 3)δ8.17(d,J＝7.1Hz,1H),7.52(d,J＝7.9Hz,1H),6.76(s,1H),4.14(q,J＝17.4Hz,3H),3.81(dd,J＝24.6,15.0Hz,2H),3.34(s,1H),2.88(d,J＝14.9Hz,1H),2.32(s,1H),2.12(s,2H),2.03(s,3H),1.72–1.62(m,2H),1.56–1.42(m,5H),1.42–1.19(m,16H),0.95–0.81(m,9H)。 To (3R,4R,5S)-4-acetamido-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl-1-ene- To a solution of decyl 1-carboxylate (4.0 g, 6.0 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (10 mL), the mixture was stirred at room temperature, and after completion of the reaction, the solvent was removed under reduced pressure. The resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the title compound (200 mg, 7%). LCMS[M+H] + : 467.15. 1 H NMR (500 MHz, CDCl 3 ) δ 8.17 (d, J=7.1 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 6.76 (s, 1H), 4.14 (q, J=17.4 Hz ,3H),3.81(dd,J＝24.6,15.0Hz,2H),3.34(s,1H),2.88(d,J＝14.9Hz,1H),2.32(s,1H),2.12(s,2H) , 2.03 (s, 3H), 1.72–1.62 (m, 2H), 1.56–1.42 (m, 5H), 1.42–1.19 (m, 16H), 0.95–0.81 (m, 9H).
实施例5 (3R,4R,5S)-5-胍基-4-异丙酰胺基-3-(戊-3-基甲基)环己基-1-烯-1-甲酸辛酯Example 5 (3R,4R,5S)-5-guanidino-4-isopropionamido-3-(pent-3-ylmethyl)cyclohexyl-1-ene-1-carboxylic acid octyl ester
Figure PCTCN2021108383-appb-000026
Figure PCTCN2021108383-appb-000026
步骤1)(3R,4R,5S)-5-(2,3-二(叔丁氧羰基)胍基)-4-异丙酰胺基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯Step 1) (3R,4R,5S)-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-4-isopropionamido-3-(pent-3-yloxy)cyclohexyl- Octyl 1-ene-1-carboxylate
向(3R,4R,5S)-5-(2,3-二(叔丁氧羰基)胍基)-4-异丙酰胺基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(5.0g，9.1mmol，Ref.Antiviral Research,2013,100,698-708；)的二氯甲烷(50mL)溶液中加入辛醇(1.64mL，10.46mmol)、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(2.74g，13.68mmol)、二异丙基乙胺(5.0mL，33.6mmol)和4-二甲氨基吡啶(0.224g，1.89mmol)，混合物在室温下搅拌过夜。反应完全后，减压除去溶剂，向残余物中加入乙酸乙酯使其溶解，混合物用饱和氯化钠洗，无水硫酸钠干燥，减压除去溶剂。所得残余物经柱层析纯化(PE：EA＝2：1)，得到产物(3.8g，57％)。LCMS[M+H] +:667.9。 To (3R,4R,5S)-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-4-isopropionamido-3-(pent-3-yloxy)cyclohexyl-1- To a solution of ene-1-carboxylic acid (5.0 g, 9.1 mmol, Ref. Antiviral Research, 2013, 100, 698-708;) in dichloromethane (50 mL) was added octanol (1.64 mL, 10.46 mmol), 1-ethyl-( 3-Dimethylaminopropyl)carbodiimide hydrochloride (2.74 g, 13.68 mmol), diisopropylethylamine (5.0 mL, 33.6 mmol) and 4-dimethylaminopyridine (0.224 g, 1.89 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, ethyl acetate was added to the residue to dissolve, the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by column chromatography (PE:EA=2:1) to give the product (3.8 g, 57%). LCMS[M+H] + : 667.9.
步骤2)(3R,4R,5S)-5-胍基-4-异丙酰胺基-3-(戊-3-基甲基)环己基-1-烯-1-甲酸辛酯Step 2) (3R,4R,5S)-5-guanidino-4-isopropionamido-3-(pent-3-ylmethyl)cyclohexyl-1-ene-1-carboxylic acid octyl ester
向(3R,4R,5S)-5-(2,3-二(叔丁氧羰基)胍基)-4-异丙酰胺基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸辛酯(3.8g，5.7mmol)的二氯甲烷(40mL)溶液中滴加三氟乙酸(10mL)，混合物在室温下搅拌反应。反应完全后，减压除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得到标题化合物(190mg，7％)LCMS[M+H] +:467.1。 1H NMR(500MHz,CDCl 3)δ8.13(d,J＝7.6Hz,1H),7.50(d,J＝8.2Hz,1H),6.75(s,1H),4.26–4.03(m,3H),3.83(dd,J＝18.7,10.0Hz,2H),3.39–3.26(m,1H),2.87(d,J＝14.2Hz,1H),2.32(s,1H),2.26–2.04(m,1H),2.06(d,J＝41.4Hz,6H),1.73–1.58(m,2H),1.56–1.43(m,4H),1.44–1.05(m,14H),0.95–0.79(m,15H)。 To (3R,4R,5S)-5-(2,3-bis(tert-butoxycarbonyl)guanidino)-4-isopropionamido-3-(pent-3-yloxy)cyclohexyl-1- Trifluoroacetic acid (10 mL) was added dropwise to a solution of octyl ene-1-carboxylate (3.8 g, 5.7 mmol) in dichloromethane (40 mL), and the mixture was stirred at room temperature for reaction. After the reaction was complete, the solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the title compound (190 mg, 7%) LCMS [M+H] + : 467.1. 1 H NMR (500 MHz, CDCl 3 ) δ 8.13 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 6.75 (s, 1H), 4.26-4.03 (m, 3H) ,3.83(dd,J＝18.7,10.0Hz,2H),3.39-3.26(m,1H),2.87(d,J＝14.2Hz,1H),2.32(s,1H),2.26-2.04(m,1H) ), 2.06 (d, J=41.4Hz, 6H), 1.73–1.58 (m, 2H), 1.56–1.43 (m, 4H), 1.44–1.05 (m, 14H), 0.95–0.79 (m, 15H).
实施例6 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十二烷酯Example 6 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-dodecyl ester
Figure PCTCN2021108383-appb-000027
Figure PCTCN2021108383-appb-000027
步骤1)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十二烷酯Step 1) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid n-dodecyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(2.24g，4.26mmol)的N,N’-二甲基甲酰胺(30mL)混合物中加入1-溴十二烷(1.22mL，5.11mmol)和碳酸铯(0.69g，2.13mmol)，混合物搅拌过夜。反应完全后，加入乙酸乙酯(20mL)溶解，用饱和氯化钠洗，有机相经硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝1：1)，得产物(1.2g，41％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid (2.24 g, 4.26 mmol) in N,N'-dimethylformamide (30 mL) was added 1-bromododecane (1.22 mL, 5.11 mmol) and cesium carbonate (0.69 g) , 2.13 mmol), and the mixture was stirred overnight. After the reaction was completed, ethyl acetate (20 mL) was added to dissolve, washed with saturated sodium chloride, the organic phase was dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=1:1) , the product (1.2 g, 41%) was obtained.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十二烷酯Step 2) (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-dodecyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十二烷酯(1.2g，2.28mmol)的二氯甲烷(20mL)混合物中，加入三氟乙酸(10mL)，混合物在室温下搅拌反应，反应完全后，减压浓缩除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝20：1)，得产物(570mg，51％)。LCMS[M+H] +：495.32。 1H NMR(500MHz,CDCl 3)δ8.04(s,1H),6.77(s,1H),4.90(s,4H),4.24(s,1H),4.13(s,2H),3.88(d,J＝30.6Hz,2H),3.34(s,1H),2.85(d,J＝13.9Hz,1H),2.31(s,1H),2.02(s,3H),1.75–1.61(m,2H),1.57–1.42(m,4H),1.30(d,J＝26.4Hz,19H),0.96–0.86(m,6H),0.83(t,J＝7.0Hz,3H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of n-dodecyl 1-ene-1-carboxylate (1.2 g, 2.28 mmol) in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for reaction. After the reaction was completed, the pressure was reduced. The solvent was removed by concentration and the resulting residue was purified by column chromatography (DCM:MeOH=20:1) to give the product (570 mg, 51%). LCMS[M+H] + : 495.32. 1 H NMR (500MHz, CDCl 3 ) δ 8.04(s, 1H), 6.77(s, 1H), 4.90(s, 4H), 4.24(s, 1H), 4.13(s, 2H), 3.88(d, J=30.6Hz, 2H), 3.34(s, 1H), 2.85(d, J=13.9Hz, 1H), 2.31(s, 1H), 2.02(s, 3H), 1.75–1.61(m, 2H), 1.57–1.42 (m, 4H), 1.30 (d, J=26.4Hz, 19H), 0.96–0.86 (m, 6H), 0.83 (t, J=7.0Hz, 3H).
实施例7 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正己酯Example 7 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-hexyl ester
Figure PCTCN2021108383-appb-000028
Figure PCTCN2021108383-appb-000028
步骤1)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正己酯Step 1) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid n-hexyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(3g，5.7mmol)的二氯甲烷(30mL)混合物中，加入正己醇(0.76mL，6.3mmol)，((叔丁氧基羰基)氨基)(1H-吡唑-1-基)亚甲基)氨基甲酸叔丁酯(1.65g，8.55mmol)，DIPEA(3mL，21mmol)和DMAP(0.135g，1.14mmol)，混合物搅拌过夜。反应完全后，减压浓缩除去溶剂。残余物用乙酸乙酯(10mL)萃取，有机相用饱和氯化钠洗，经硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝2：1)，得产物(2g，58％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid (3 g, 5.7 mmol) in dichloromethane (30 mL) was added n-hexanol (0.76 mL, 6.3 mmol), ((tert-butoxycarbonyl)amino)(1H-pyrazole- 1-yl)methylene)carbamate (1.65 g, 8.55 mmol), DIPEA (3 mL, 21 mmol) and DMAP (0.135 g, 1.14 mmol), the mixture was stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (10 mL), the organic phase was washed with saturated sodium chloride, dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=2:1) to obtain Product (2 g, 58%).
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正己酯Step 2) (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-hexyl ester
将(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正己酯(2g，3.28mmol)溶于二氯甲烷(20mL)，向溶液中加入三氟乙酸(10mL)，混合物于室温搅拌反应，反应完全后，减压浓缩除去溶剂。所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得产物(190mg，14％)。LCMS[M+H] +:411.15。 1H NMR(500MHz,CDCl 3)δ8.34(s,1H),7.59(s,1H),6.78(s,1H),4.33(s,1H),4.20–4.05(m,2H),3.85(s,2H),3.37(s,1H),2.88(d,J＝15.0Hz,1H),2.36(s,1H),2.21(s,3H),2.03(s,3H),1.66(dd,J＝13.8,6.8Hz,2H),1.50(s,4H),1.36(dd,J＝18.6,10.5Hz,6H),0.97–0.80(m,10H)。 (3R,4R,5S)-4-acetylamino-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- 1-ene-1-carboxylate n-hexyl ester (2 g, 3.28 mmol) was dissolved in dichloromethane (20 mL), trifluoroacetic acid (10 mL) was added to the solution, the mixture was stirred at room temperature for reaction, after the reaction was completed, the solvent was removed by concentration under reduced pressure . The resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the product (190 mg, 14%). LCMS[M+H] + : 411.15. 1 H NMR (500MHz, CDCl 3 )δ8.34(s,1H), 7.59(s,1H), 6.78(s,1H), 4.33(s,1H), 4.20-4.05(m,2H), 3.85( s, 2H), 3.37(s, 1H), 2.88(d, J=15.0Hz, 1H), 2.36(s, 1H), 2.21(s, 3H), 2.03(s, 3H), 1.66(dd, J = 13.8, 6.8 Hz, 2H), 1.50 (s, 4H), 1.36 (dd, J = 18.6, 10.5 Hz, 6H), 0.97–0.80 (m, 10H).
实施例8 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正辛酯Example 8 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-octyl ester
Figure PCTCN2021108383-appb-000029
Figure PCTCN2021108383-appb-000029
步骤1)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正辛酯Step 1) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid n-octyl ester
将(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(4g，7.6mmol)溶于二氯甲烷(40mL)，向溶液中加入正辛醇(1.44mL，9.12mmol)，((叔丁氧基羰基)氨基)(1H-吡唑-1-基)亚甲基)氨基甲酸叔丁酯(2.17g，11.4mmol)，DIPEA(4mL，22.8mmol)和DMAP(0.18g，1.48mmol)，混合物搅拌过夜。反应完全后，减压浓缩除去溶剂。残余物用乙酸乙酯(10mL)萃取，有机相经硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝2：1)，得产物(3g，62％)。(3R,4R,5S)-4-acetylamino-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- 1-ene-1-carboxylic acid (4 g, 7.6 mmol) was dissolved in dichloromethane (40 mL), to the solution was added n-octanol (1.44 mL, 9.12 mmol), ((tert-butoxycarbonyl)amino)(1H- Pyrazol-1-yl)methylene)carbamate (2.17 g, 11.4 mmol), DIPEA (4 mL, 22.8 mmol) and DMAP (0.18 g, 1.48 mmol), the mixture was stirred overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (10 mL), the organic phase was dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=2:1) to give the product (3 g, 62%) .
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正辛酯Step 2) (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-octyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正辛酯(3g，4.7mmol)的二氯甲烷(30mL)溶液中，加入三氟乙酸(8mL)，混合物于室温搅拌反应，反应完全后，减压浓缩除去溶剂。所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得产物(250mg，12％)。LCMS[M+H] +:439.32。 1H NMR(500MHz,CDCl 3)δ8.13(d,J＝7.6Hz,1H),7.50(d,J＝8.2Hz,1H),6.77(s,1H),4.26–4.03(m,3H),3.83(dd,J＝18.7,10.0Hz,2H),3.39–3.26(m,1H),2.87(d,J＝14.2Hz,1H),2.32(s,1H),2.06(d,J＝41.4Hz,6H),1.73–1.58(m,2H),1.56–1.43(m,4H),1.44–1.05(m,14H),0.95–0.79(m,9H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- Trifluoroacetic acid (8 mL) was added to a solution of n-octyl 1-ene-1-carboxylate (3 g, 4.7 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature to react. After the reaction was completed, the solvent was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the product (250 mg, 12%). LCMS[M+H] + : 439.32. 1 H NMR (500 MHz, CDCl 3 ) δ 8.13 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.2 Hz, 1H), 6.77 (s, 1H), 4.26-4.03 (m, 3H) ,3.83(dd,J＝18.7,10.0Hz,2H),3.39–3.26(m,1H),2.87(d,J＝14.2Hz,1H),2.32(s,1H),2.06(d,J＝41.4 Hz, 6H), 1.73–1.58 (m, 2H), 1.56–1.43 (m, 4H), 1.44–1.05 (m, 14H), 0.95–0.79 (m, 9H).
实施例9 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正癸酯Example 9 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-decyl ester
Figure PCTCN2021108383-appb-000030
Figure PCTCN2021108383-appb-000030
步骤1)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正癸酯Step 1) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylate n-decyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(5g，9.12mmol)的二氯甲烷(50mL)溶液中，加入正葵醇(1.22mL，10.46mmol)，((叔丁氧基羰基)氨基)(1H-吡唑-1-基)亚甲基)氨基甲酸叔丁酯(2.74g，13.68mmol)，DIPEA(5mL，33.6mmol)和DMAP(0.224g，1.89mmol)。混合物于室温搅拌过夜。反应完全后，减压浓缩除去溶剂。残余物用乙酸乙酯(10mL)萃取，有机相经硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝2：1)，得产物(4g， 66％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a solution of 1-ene-1-carboxylic acid (5 g, 9.12 mmol) in dichloromethane (50 mL) was added n-decyl alcohol (1.22 mL, 10.46 mmol), ((tert-butoxycarbonyl)amino)(1H-pyrazole -1-yl)methylene)carbamate tert-butyl ester (2.74 g, 13.68 mmol), DIPEA (5 mL, 33.6 mmol) and DMAP (0.224 g, 1.89 mmol). The mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (10 mL), the organic phase was dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=2:1) to give the product (4 g, 66%) .
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正癸酯Step 2) (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-decyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正癸酯(4g，6mmol)的二氯甲烷(40mL)溶液中，加入三氟乙酸(10mL)，混合物于室温搅拌，反应完全后，减压浓缩除去溶剂。所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得产物(200mg，7％)。LCMS[M+H] +:467.15。 1H NMR(500MHz,CDCl 3)δ8.17(d,J＝7.1Hz,1H),7.52(d,J＝7.9Hz,1H),6.76(s,1H),4.14(q,J＝17.4Hz,3H),3.81(dd,J＝24.6,15.0Hz,2H),3.34(s,1H),2.88(d,J＝14.9Hz,1H),2.32(s,1H),2.12(s,2H),2.03(s,3H),1.72–1.62(m,2H),1.56–1.42(m,5H),1.42–1.19(m,16H),0.95–0.81(m,9H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- Trifluoroacetic acid (10 mL) was added to a solution of n-decyl 1-ene-1-carboxylate (4 g, 6 mmol) in dichloromethane (40 mL), the mixture was stirred at room temperature, and after the reaction was complete, the solvent was removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (DCM:MeOH=10:1) to give the product (200 mg, 7%). LCMS[M+H] + : 467.15. 1 H NMR (500 MHz, CDCl 3 ) δ 8.17 (d, J=7.1 Hz, 1H), 7.52 (d, J=7.9 Hz, 1H), 6.76 (s, 1H), 4.14 (q, J=17.4 Hz ,3H),3.81(dd,J＝24.6,15.0Hz,2H),3.34(s,1H),2.88(d,J＝14.9Hz,1H),2.32(s,1H),2.12(s,2H) , 2.03 (s, 3H), 1.72–1.62 (m, 2H), 1.56–1.42 (m, 5H), 1.42–1.19 (m, 16H), 0.95–0.81 (m, 9H).
实施例10 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十八烷酯Example 10 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-octadecyl ester
Figure PCTCN2021108383-appb-000031
Figure PCTCN2021108383-appb-000031
步骤1)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十八烷酯Step 1) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid n-octadecyl ester
将(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(3g，5.7mmol)溶于N,N’-二甲基甲酰胺(30mL)，向溶液中加入1-溴十八烷(2.28g，6.84mmol)和碳酸铯(1g，3.13mmol)，混合物于室温搅拌过夜。反应完全后，用乙酸乙酯(10mL)萃取，混合物用饱和氯化钠洗，无水硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝1：1)，得产物(1.5g，34％)。(3R,4R,5S)-4-acetylamino-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- 1-ene-1-carboxylic acid (3 g, 5.7 mmol) was dissolved in N,N'-dimethylformamide (30 mL), to the solution was added 1-bromooctadecane (2.28 g, 6.84 mmol) and cesium carbonate ( 1 g, 3.13 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, it was extracted with ethyl acetate (10 mL), the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=1:1) , the product (1.5 g, 34%) was obtained.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十八烷酯Step 2) (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid n-octadecyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸正十八烷酯(1.5g，1.9mmol)的二氯甲烷(20mL)混合物中，加入三氟乙酸(10mL)，混合物于室温搅拌，反应完全后，减压浓缩除去溶剂。所得残余物经柱层析纯化(DCM：MeOH＝20：1)，得产物(570mg，52％)。LCMS[M+H] +:579.48。 1H NMR(500MHz,CDCl 3)δ7.99(d,J＝6.0Hz,1H),7.24(s,1H),6.78(s,1H),6.25(s,3H),4.25(s,1H),4.13(t,J＝10.3Hz,2H),3.88(d,J＝8.5Hz,2H),3.42–3.27(m,1H),2.88(d,J＝14.9Hz,1H),2.32(s,1H),2.05(s,3H),1.71–1.61(m,2H),1.49(d,J＝5.9Hz,4H),1.30(d,J＝28.9Hz,31H),0.90(t,J＝6.9Hz,6H),0.85(t,J＝7.2Hz,3H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of n-octadecyl 1-ene-1-carboxylate (1.5 g, 1.9 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 mL), the mixture was stirred at room temperature, and after the reaction was completed, it was removed by concentration under reduced pressure solvent. The resulting residue was purified by column chromatography (DCM:MeOH=20:1) to give the product (570 mg, 52%). LCMS[M+H] + : 579.48. 1 H NMR (500MHz, CDCl 3 ) δ 7.99(d, J=6.0Hz, 1H), 7.24(s, 1H), 6.78(s, 1H), 6.25(s, 3H), 4.25(s, 1H) ,4.13(t,J＝10.3Hz,2H),3.88(d,J＝8.5Hz,2H),3.42–3.27(m,1H),2.88(d,J＝14.9Hz,1H),2.32(s, 1H), 2.05(s, 3H), 1.71–1.61(m, 2H), 1.49(d, J=5.9Hz, 4H), 1.30(d, J=28.9Hz, 31H), 0.90(t, J=6.9 Hz, 6H), 0.85 (t, J=7.2Hz, 3H).
实施例11 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(十二烷酰氧基)甲酯Example 11 (3R,4R,5S)-4-acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(dodecanoyloxy ) methyl ester
Figure PCTCN2021108383-appb-000032
Figure PCTCN2021108383-appb-000032
步骤1)十二烷酸氯甲酯Step 1) Chloromethyl dodecanoate
向正十二酸(3.0g，15mmol)及四丁基硫酸氢氨(0.51g，1.5mmol)的二氯甲烷(30mL)混合物中加入碳酸钾(8.3g，60mmol)的水(30mL)溶液，混合物搅拌3分钟后，滴加氯磺酸氯甲酯(3.1g，18.75mmol)的二氯甲烷(30mL)溶液。混合物于室温搅拌反应过夜，TLC检测原料基本反应完全，向混合液中加入二氯甲烷(30mL)和饱和食盐水(30mL)，分离有机层，减压浓缩蒸出溶剂，残余物经柱层析纯化(PE：EA＝1：1)，得标题化合物为无色油状物(3.39g，91％)。To a mixture of n-dodecanoic acid (3.0 g, 15 mmol) and tetrabutylammonium hydrogen sulfate (0.51 g, 1.5 mmol) in dichloromethane (30 mL) was added a solution of potassium carbonate (8.3 g, 60 mmol) in water (30 mL), After the mixture was stirred for 3 minutes, a solution of chloromethyl chlorosulfonate (3.1 g, 18.75 mmol) in dichloromethane (30 mL) was added dropwise. The mixture was stirred at room temperature and reacted overnight. TLC detected that the raw materials had basically reacted completely. Dichloromethane (30 mL) and saturated brine (30 mL) were added to the mixture, the organic layer was separated, concentrated under reduced pressure to evaporate the solvent, and the residue was subjected to column chromatography. Purification (PE:EA=1:1) gave the title compound as a colorless oil (3.39 g, 91%).
步骤2)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(十二烷酰氧基)甲酯Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid (dodecanoyloxy) methyl ester
向50mL反应瓶中加入(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(526mg，1.0mmol)，十二烷酸氯甲酯(298mg，1.25mmol)，碳酸铯(480mg，1.5mmol)，和N,N’-二甲基甲酰胺(10mL)，混合物于室温反应过夜。然后将混合物直接浓缩至干，残余物经柱层析纯化(PE：EA＝3：1)，得产物(480mg，65％)。Add (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy) to a 50mL reaction flask yl)cyclohexyl-1-ene-1-carboxylic acid (526 mg, 1.0 mmol), chloromethyl dodecanoate (298 mg, 1.25 mmol), cesium carbonate (480 mg, 1.5 mmol), and N,N'-dimethyl formamide (10 mL), and the mixture was reacted at room temperature overnight. The mixture was then directly concentrated to dryness and the residue was purified by column chromatography (PE:EA=3:1) to give the product (480 mg, 65%).
步骤3)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(十二烷酰氧基)甲酯Step 3) (3R,4R,5S)-4-Acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(dodecanoyloxy ) methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(十二烷酰氧基)甲酯(280mg，0.38mmol)的二氯甲烷(2.8mL)溶液中加入三氟乙酸(0.56mL)，混合物于室温搅拌过夜。TLC检测原料反应完全后，减压浓缩除去溶剂，残余物经柱层析纯化(DCM:MeOH＝15:1)，得标题化合物为白色固体(100mg，49％)。LC-MS[M+H] +:539。 1H NMR(500MHz,CDCl 3)δ7.98(s,1H),6.86(s,1H),5.83(s,2H),4.28(s,1H),3.90(s,2H),3.41(br,5H),2.87(d,J＝15.0Hz,1H),2.37(t,J＝1.5Hz,2H),2.04(s,3H),1.68–1.60(m,2H),1.55–1.44(m,4H),1.27(s,18H),0.90(m,6H),0.85(m,3H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a solution of (dodecanoyloxy)methyl 1-ene-1-carboxylic acid (280 mg, 0.38 mmol) in dichloromethane (2.8 mL) was added trifluoroacetic acid (0.56 mL), and the mixture was stirred at room temperature overnight. After TLC detected the reaction of the raw materials, the solvent was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (DCM:MeOH=15:1) to obtain the title compound as a white solid (100 mg, 49%). LC-MS [M+H] + : 539. 1 H NMR (500MHz, CDCl 3 )δ7.98(s,1H), 6.86(s,1H), 5.83(s,2H), 4.28(s,1H), 3.90(s,2H), 3.41(br, 5H), 2.87(d, J＝15.0Hz, 1H), 2.37(t, J＝1.5Hz, 2H), 2.04(s, 3H), 1.68-1.60(m, 2H), 1.55-1.44(m, 4H) ), 1.27(s, 18H), 0.90(m, 6H), 0.85(m, 3H).
实施例12 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正十二烷酰氧基)乙酯Example 12 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-2-(n-dodecane Acyloxy)ethyl ester
Figure PCTCN2021108383-appb-000033
Figure PCTCN2021108383-appb-000033
步骤1)正十二烷酸氯乙酯Step 1) chloroethyl n-dodecanoate
向十二酸(4g，20mmol)的1,2-二氯乙烷(5mL)溶液中，加入2-氯乙醇(1.4mL，20mmol)和浓硫酸(0.2mL，2mmol)，混合物在60℃搅拌反应4小时。反应完全后，减压浓缩除去溶剂。向残留物中加入乙酸乙酯(10mL)和水(10mL)，分离出有机相，用饱和氯化钠洗，无水硫酸钠干燥，减压浓缩至干，得产物(4g，76％)。To a solution of dodecanoic acid (4 g, 20 mmol) in 1,2-dichloroethane (5 mL), 2-chloroethanol (1.4 mL, 20 mmol) and concentrated sulfuric acid (0.2 mL, 2 mmol) were added, and the mixture was stirred at 60 °C The reaction was carried out for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Ethyl acetate (10 mL) and water (10 mL) were added to the residue, the organic phase was separated, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give the product (4 g, 76%).
步骤2)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正十二烷酰氧基)乙酯Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid-2-(n-dodecanoyloxy)ethyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(0.6g，2.3mmol)和正十二烷酸氯乙酯(1g，2mmol)的N,N’-二甲基甲酰胺(10mL)混合物中，加入碘化钾(0.3g，2mmol)和碳酸铯(1g，3mmol)，混合物在60℃下搅拌反应过夜。反应完全后，加入乙酸乙酯溶解，用饱和氯化钠洗，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，得产物(0.8g，46％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid (0.6 g, 2.3 mmol) and chloroethyl n-dodecanoate (1 g, 2 mmol) in N,N'-dimethylformamide (10 mL) was added potassium iodide (0.3 g, 2 mmol) and cesium carbonate (1 g, 3 mmol), the mixture was stirred at 60 °C overnight. After the reaction was completed, ethyl acetate was added to dissolve, washed with saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent to obtain the product (0.8 g, 46%).
步骤3)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正十二烷酰氧基)乙酯Step 3) (3R,4R,5S)-4-acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-2-(n-dodecane Acyloxy)ethyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正十二烷酰氧基)乙酯(0.8g，0.1mmol)的二氯甲烷(2mL)溶液中加入三氟乙酸(1mL)，混合物于室温搅拌反应过夜，反应完全后，减压浓缩除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝20：1)，得产物(487mg，88％)。LCMS[M+H] +:553.48。 1H NMR(500MHz,CDCl 3)δ6.78(s,1H),4.32(d,J＝15.0Hz,5H),3.89(s,1H),3.34(s,1H),2.83(s,1H),2.30(dd,J＝35.4,28.3Hz,3H),2.02(d,J＝39.3Hz,3H),1.62(s,2H),1.56–1.35(m,4H),1.28(d,J＝12.9Hz,16H),0.97–0.69(m,9H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- Trifluoroacetic acid (1 mL) was added to a solution of 1-ene-1-carboxylic acid-2-(n-dodecanoyloxy)ethyl ester (0.8 g, 0.1 mmol) in dichloromethane (2 mL), and the mixture was stirred at room temperature for reaction Overnight, after the reaction was completed, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by column chromatography (DCM:MeOH=20:1) to obtain the product (487 mg, 88%). LCMS[M+H] + : 553.48. 1 H NMR (500MHz, CDCl 3 ) δ 6.78(s, 1H), 4.32(d, J=15.0Hz, 5H), 3.89(s, 1H), 3.34(s, 1H), 2.83(s, 1H) ,2.30(dd,J＝35.4,28.3Hz,3H),2.02(d,J＝39.3Hz,3H),1.62(s,2H),1.56–1.35(m,4H),1.28(d,J＝12.9 Hz, 16H), 0.97–0.69 (m, 9H).
实施例13 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(十八烷酰氧基)甲酯Example 13 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(octadecanoyloxy ) methyl ester
Figure PCTCN2021108383-appb-000034
Figure PCTCN2021108383-appb-000034
步骤1)十八烷酰氯甲酯Step 1) Methyl octadecanoyl chloride
向正十八碳酸(3g，10.56mmol)，四丁基硫酸氢胺(350mg，1.026mmol)和碳酸钾(5.8g，42.24mmol)的二氯甲烷和水的混合物(60mL)中滴加氯甲基氯磺酸酯(2.25g，13.2mmol)，混合物于室温搅拌过夜。反应完全后，向混合液中加入二氯甲烷(30mL)和饱和食盐水(30mL)，分离有机层，减压浓缩蒸出溶剂，残余物经柱层析纯化(PE：EA＝1：1)，得产物(3.4g，97％)。To a mixture of n-octadecanoic acid (3 g, 10.56 mmol), tetrabutylamine hydrogen sulfate (350 mg, 1.026 mmol) and potassium carbonate (5.8 g, 42.24 mmol) in dichloromethane and water (60 mL) was added dropwise chloromethane chlorosulfonate (2.25 g, 13.2 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, dichloromethane (30 mL) and saturated brine (30 mL) were added to the mixture, the organic layer was separated, concentrated under reduced pressure to evaporate the solvent, and the residue was purified by column chromatography (PE:EA=1:1) , the product (3.4 g, 97%) was obtained.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸乙酯Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid ethyl ester
向磷酸奥司他韦(10g，24.4mmol)的四氢呋喃(100mL)溶液中，加入三乙胺(16mL，122mmol)和((叔丁氧基羰基)氨基)((1H-吡唑-1-基)亚甲基)氨基甲酸叔丁酯(8.3g，26.8mmol)，混合物于室温搅拌过 夜。反应完全后，减压浓缩除去溶剂。残余物用乙酸乙酯(100mL)萃取，有机相用硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化，得产物(12g，89％)。LCMS[M+H] +:555.33。 To a solution of oseltamivir phosphate (10 g, 24.4 mmol) in tetrahydrofuran (100 mL) was added triethylamine (16 mL, 122 mmol) and ((tert-butoxycarbonyl)amino)((1H-pyrazol-1-yl ) methylene) tert-butyl carbamate (8.3 g, 26.8 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (100 mL), the organic phase was dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography to give the product (12 g, 89%). LCMS[M+H] + : 555.33.
步骤3)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸Step 3) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid
在0℃下，向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸乙酯(5g，9mmol)的乙二醇二甲醚(50mL)混合物中加入氢氧化钾(2g，36mmol)的水(20mL)溶液，混合物于室温搅拌2小时。反应完全后，冷却至0℃，用1M的盐酸调pH值至中性，减压浓缩除去溶剂，残余物用甲醇溶解，过滤，滤液减压浓缩至干，所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得产物(4.3g，91％)。LCMS[M+H] +:527.33。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy) at 0°C To a mixture of ethyl)cyclohexyl-1-ene-1-carboxylate (5 g, 9 mmol) in ethylene glycol dimethyl ether (50 mL) was added a solution of potassium hydroxide (2 g, 36 mmol) in water (20 mL), and the mixture was cooled to room temperature Stir for 2 hours. After the reaction was completed, it was cooled to 0°C, adjusted to neutral pH with 1M hydrochloric acid, concentrated under reduced pressure to remove the solvent, the residue was dissolved in methanol, filtered, the filtrate was concentrated to dryness under reduced pressure, and the obtained residue was purified by column chromatography ( DCM:MeOH=10:1) to give the product (4.3 g, 91%). LCMS[M+H] + : 527.33.
步骤4)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(十八烷酰氧基)甲酯Step 4) (3R,4R,5S)-4-acetylamino-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid-(octadecanoyloxy)methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(2.4g，4.56mmol)的N,N’-二甲基甲酰胺(20mL)混合物中加入十八烷酰氯甲酯(1.8g，5.42mmol)，碳酸铯(2.24g，6.84mmol)和碘化钾(0.75g，4.56mmol)，混合物在50℃下搅拌反应6小时。反应完全后，加入乙酸乙酯溶解，用饱和氯化钠洗，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝1：1)，得产物(1.2g，32％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid (2.4g, 4.56mmol) in N,N'-dimethylformamide (20mL) was added octadecanoyl chloride methyl ester (1.8g, 5.42mmol), cesium carbonate (2.24g) , 6.84 mmol) and potassium iodide (0.75 g, 4.56 mmol), the mixture was stirred at 50 °C for 6 hours. After the reaction was completed, ethyl acetate was added to dissolve, washed with saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=1:1), The product was obtained (1.2 g, 32%).
步骤5)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(十八烷酰氧基)甲酯Step 5) (3R,4R,5S)-4-Acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(octadecanoyloxy ) methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(十八烷酰氧基)甲酯(1.2g，1.46mmol)的二氯甲烷(8mL)混合物中，加入三氟乙酸(4mL)，混合物于室温搅拌反应，反应完全后，减压浓缩除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝20：1)，得产物(318mg，35％)。LCMS[M+H] +:623.32。 1H NMR(500MHz,CDCl 3)δ6.84(s,1H),5.82(s,2H),4.28(s,1H),3.89(s,1H),3.34(s,1H),3.16(s,1H),2.81(s,1H),2.36(s,3H),1.99(s,3H),1.63(s,3H),1.47(s,4H),1.29(d,J＝15.2Hz,29H),0.95–0.63(m,9H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid-(octadecanoyloxy)methyl ester (1.2 g, 1.46 mmol) in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added, and the mixture was stirred at room temperature to react. After completion, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by column chromatography (DCM:MeOH=20:1) to give the product (318 mg, 35%). LCMS[M+H] + : 623.32. 1 H NMR (500MHz, CDCl 3 )δ6.84(s,1H), 5.82(s,2H), 4.28(s,1H), 3.89(s,1H), 3.34(s,1H), 3.16(s, 1H), 2.81(s, 1H), 2.36(s, 3H), 1.99(s, 3H), 1.63(s, 3H), 1.47(s, 4H), 1.29(d, J＝15.2Hz, 29H), 0.95–0.63 (m, 9H).
实施例14 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(二十烷酰氧基)甲酯Example 14 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(eicosanoyloxy) ) methyl ester
Figure PCTCN2021108383-appb-000035
Figure PCTCN2021108383-appb-000035
步骤1)二十烷酸氯甲酯Step 1) Chloromethyl eicosanoate
向二十烷酸(1.6g，5.13mmol)，四丁基硫酸氢胺(170mg，0.513mmol)和碳酸钾(2.8g，20.52mmol)的二氯甲烷和水的混合物(30mL)中，滴加氯甲基氯磺酸酯(0.65mL，6.41mmol)，混合物于室温搅拌过夜。反应完全后，往混合物中加入二氯甲烷(30mL)和饱和食盐水(30mL)，分离有机层，减压浓缩蒸除溶剂，残余物经柱层析纯化(PE：EA＝1：1)，得产物(1.5g，81％)。To a mixture of eicosanoic acid (1.6 g, 5.13 mmol), tetrabutylamine hydrogen sulfate (170 mg, 0.513 mmol) and potassium carbonate (2.8 g, 20.52 mmol) in dichloromethane and water (30 mL) was added dropwise Chloromethyl chlorosulfonate (0.65 mL, 6.41 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, dichloromethane (30 mL) and saturated brine (30 mL) were added to the mixture, the organic layer was separated, concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (PE:EA=1:1), The product was obtained (1.5 g, 81%).
步骤2)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸乙酯Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid ethyl ester
向磷酸奥司他韦(10g，24.4mmol)的四氢呋喃(100mL)溶液中加入三乙胺(16mL，122mmol)和((叔丁氧基羰基)氨基)((1H-吡唑-1-基)亚甲基)氨基甲酸叔丁酯(8.3g，26.8mmol)，混合物于室温搅拌过夜。反应完全后，减压浓缩除去溶剂。残余物用乙酸乙酯(100mL)萃取，有机相用硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化，得产物(12g，89％)。LCMS[M+H] +:555.33。 To a solution of oseltamivir phosphate (10 g, 24.4 mmol) in tetrahydrofuran (100 mL) was added triethylamine (16 mL, 122 mmol) and ((tert-butoxycarbonyl)amino)((1H-pyrazol-1-yl) tert-butyl methylene)carbamate (8.3 g, 26.8 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (100 mL), the organic phase was dried over sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography to give the product (12 g, 89%). LCMS[M+H] + : 555.33.
步骤3)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸Step 3) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid
在0℃下，向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸乙酯(5g，9mmol)的乙二醇二甲醚(50mL)混合物中，加入氢氧化钾(2g，36mmol)的水(20mL)溶液，混合物于室温搅拌2小时。反应完全后，冷却至0℃，混合物用1M的盐酸调pH值至中性，减压浓缩除去溶剂，残余物用甲醇溶解，过滤，滤液减压浓缩至干，所得残余物经柱层析纯化(DCM：MeOH＝10：1)，得产物(4.3g，91％)。LCMS[M+H] +:527.33。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy) at 0°C To a mixture of ethyl)cyclohexyl-1-ene-1-carboxylate (5 g, 9 mmol) in ethylene glycol dimethyl ether (50 mL), potassium hydroxide (2 g, 36 mmol) in water (20 mL) was added, and the mixture was Stir at room temperature for 2 hours. After the reaction was completed, it was cooled to 0°C, the mixture was adjusted to neutral pH with 1M hydrochloric acid, concentrated under reduced pressure to remove the solvent, the residue was dissolved in methanol, filtered, the filtrate was concentrated to dryness under reduced pressure, and the obtained residue was purified by column chromatography (DCM:MeOH=10:1) to give the product (4.3 g, 91%). LCMS[M+H] + : 527.33.
步骤4)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(二十烷酰氧基)甲酯Step 4) (3R,4R,5S)-4-acetylamino-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid-(eicosanoyloxy)methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸 (1.3g，2.47mmol)的N,N’-二甲基甲酰胺(30mL)混合物中加入二十烷酸氯甲酯(1.06g，2.9mmol)，碳酸铯(0.4g，3.7mmol)和碘化钾(0.4g，2.47mmol)。混合物在50℃下搅拌反应6小时。反应完全后，加入乙酸乙酯溶解，用饱和氯化钠洗，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝1：1)，得产物(1.1g，52％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid (1.3 g, 2.47 mmol) in N,N'-dimethylformamide (30 mL) was added chloromethyl eicosanate (1.06 g, 2.9 mmol), cesium carbonate (0.4 g, 3.7 mmol) and potassium iodide (0.4 g, 2.47 mmol). The mixture was stirred at 50°C for 6 hours. After the reaction was completed, ethyl acetate was added to dissolve, washed with saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=1:1), The product was obtained (1.1 g, 52%).
步骤5)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(二十烷酰氧基)甲酯Step 5) (3R,4R,5S)-4-Acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(eicosanoyloxy) ) methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(二十烷酰氧基)甲酯(1.1g，1.29mmol)的二氯甲烷(6mL)溶液中加入三氟乙酸(3mL)，混合物于室温搅拌反应，反应完全后，减压浓缩除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝20：1)，得产物(326.8mg，39％)。LCMS[M+H] +:651.32。 1H NMR(500MHz,CDCl 3)δ6.84(s,1H),5.82(s,2H),4.28(s,1H),3.89(s,1H),3.34(s,1H),3.16(s,1H),2.81(s,1H),2.36(s,3H),1.99(s,3H),1.63(s,3H),1.47(s,4H),1.29(d,J＝15.2Hz,29H),0.95–0.63(m,9H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- Trifluoroacetic acid (3 mL) was added to a solution of 1-ene-1-carboxylic acid-(eicosanoyloxy) methyl ester (1.1 g, 1.29 mmol) in dichloromethane (6 mL), and the mixture was stirred at room temperature to react, and the reaction was complete After that, the solvent was removed by concentration under reduced pressure, and the obtained residue was purified by column chromatography (DCM:MeOH=20:1) to obtain the product (326.8 mg, 39%). LCMS[M+H] + : 651.32. 1 H NMR (500MHz, CDCl 3 )δ6.84(s,1H), 5.82(s,2H), 4.28(s,1H), 3.89(s,1H), 3.34(s,1H), 3.16(s, 1H), 2.81(s, 1H), 2.36(s, 3H), 1.99(s, 3H), 1.63(s, 3H), 1.47(s, 4H), 1.29(d, J＝15.2Hz, 29H), 0.95–0.63 (m, 9H).
实施例15 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(正己酰氧基)甲酯Example 15 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(n-hexanoyloxy)methyl ester
Figure PCTCN2021108383-appb-000036
Figure PCTCN2021108383-appb-000036
步骤1)正己酸氯甲酯Step 1) Chloromethyl n-hexanoate
向己酸(3g，25.86mmol)，四丁基硫酸氢胺(870mg，2.58mmol)和碳酸钾(14g，101.24mmol)的二氯甲烷和水的混合物(60mL)中，滴加氯甲基氯磺酸酯(3.27g，25.86mmol)，混合物于室温搅拌过夜。反应完全后，向反应混合物中加入二氯甲烷(30mL)和饱和食盐水(30mL)，分离有机层，减压浓缩蒸出溶剂，残余物经柱层析纯化(PE：EA＝1：1)，得产物(3.5g，83％)。To a mixture (60 mL) of hexanoic acid (3 g, 25.86 mmol), tetrabutylamine hydrogen sulfate (870 mg, 2.58 mmol) and potassium carbonate (14 g, 101.24 mmol) in dichloromethane and water (60 mL) was added chloromethyl chloride dropwise Sulfonate (3.27 g, 25.86 mmol) and the mixture was stirred at room temperature overnight. After the reaction was completed, dichloromethane (30 mL) and saturated brine (30 mL) were added to the reaction mixture, the organic layer was separated, concentrated under reduced pressure to evaporate the solvent, and the residue was purified by column chromatography (PE:EA=1:1) , the product (3.5 g, 83%) was obtained.
步骤2)(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(正己酰氧基)甲酯Step 2) (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)ring Hexyl-1-ene-1-carboxylic acid-(n-hexanoyloxy)methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸(2g，3.8mmol)的N,N’-二甲基甲酰胺(50mL)混合物中加入正己酸氯甲酯(0.75g，4.56mmol)，碳酸铯(1.85g，5.7mmol)和碘化钾(0.63g，3.8mmol)。混合物在50℃下搅拌反应6小时。反应完全后，加入乙酸乙酯溶解，用饱和氯化钠洗，有机相经无水硫酸钠干燥，减压浓缩除去溶剂，所得残余物经柱层析纯化(PE：EA＝1：1)，得产物(1.5g，60％)。To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- To a mixture of 1-ene-1-carboxylic acid (2 g, 3.8 mmol) in N,N'-dimethylformamide (50 mL) was added chloromethyl n-hexanoate (0.75 g, 4.56 mmol), cesium carbonate (1.85 g, 5.7 mmol) and potassium iodide (0.63 g, 3.8 mmol). The mixture was stirred at 50°C for 6 hours. After the reaction was completed, ethyl acetate was added to dissolve, washed with saturated sodium chloride, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by column chromatography (PE:EA=1:1), The product was obtained (1.5 g, 60%).
步骤3)(3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(正己酰氧基)甲酯Step 3) (3R,4R,5S)-4-acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(n-hexanoyloxy)methyl ester
向(3R,4R,5S)-4-乙酰氨基-5-((E)-2,3-双(叔丁氧羰基)胍基)-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(正己酰氧基)甲酯(1.5g，2.29mmol)的二氯甲烷(6mL)混合物中加入三氟乙酸(3mL)，混合物于室温搅拌反应，反应完全后，减压浓缩除去溶剂，所得残余物经柱层析纯化(DCM：MeOH＝20：1)，得产物(930mg，89％)。LCMS[M+H] +:455.32。 1H NMR(500MHz,MeOD)δ6.91(s,1H),5.86(q,J＝5.7Hz,2H),4.24(d,J＝6.0Hz,1H),3.97–3.85(m,2H),3.49–3.39(m,1H),2.89–2.80(m,1H),2.38(q,J＝7.0Hz,3H),2.00(s,3H),1.68–1.61(m,2H),1.60–1.47(m,4H),1.40–1.29(m,4H),0.93(ddd,J＝14.5,9.7,5.5Hz,9H)。 To (3R,4R,5S)-4-acetamido-5-((E)-2,3-bis(tert-butoxycarbonyl)guanidino)-3-(pent-3-yloxy)cyclohexyl- Trifluoroacetic acid (3 mL) was added to a mixture of 1-ene-1-carboxylic acid-(n-hexanoyloxy) methyl ester (1.5 g, 2.29 mmol) in dichloromethane (6 mL), and the mixture was stirred at room temperature for reaction. After the reaction was completed, The solvent was removed by concentration under reduced pressure, and the resulting residue was purified by column chromatography (DCM:MeOH=20:1) to give the product (930 mg, 89%). LCMS[M+H] + : 455.32. 1 H NMR(500MHz,MeOD)δ6.91(s,1H),5.86(q,J=5.7Hz,2H),4.24(d,J=6.0Hz,1H),3.97-3.85(m,2H), 3.49–3.39(m,1H), 2.89–2.80(m,1H), 2.38(q,J=7.0Hz,3H), 2.00(s,3H), 1.68–1.61(m,2H), 1.60–1.47( m, 4H), 1.40–1.29 (m, 4H), 0.93 (ddd, J=14.5, 9.7, 5.5Hz, 9H).
实施例16 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(正辛酰氧基)甲酯Example 16 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(n-octanoyloxy) methyl ester
Figure PCTCN2021108383-appb-000037
Figure PCTCN2021108383-appb-000037
参照实施例15的方法，合成得到目标产物(820mg，80％)。LCMS[M+H]+:483.32。1H NMR(500MHz,MeOD)δ6.90(s,1H),5.85(q,J＝5.7Hz,2H),4.27(d,J＝6.0Hz,1H),3.97–3.85(m,2H),3.49–3.39(m,1H),2.89–2.80(m,1H),2.38(q,J＝7.0Hz,3H),2.00(s,3H),1.68–1.61(m,2H),1.60–1.47(m, 4H),1.40–1.29(m,8H),0.93(m,9H)。Referring to the method of Example 15, the target product (820 mg, 80%) was synthesized. LCMS[M+H]+: 483.32.1H NMR(500MHz,MeOD)δ6.90(s,1H),5.85(q,J=5.7Hz,2H),4.27(d,J=6.0Hz,1H), 3.97-3.85(m, 2H), 3.49-3.39(m, 1H), 2.89-2.80(m, 1H), 2.38(q, J=7.0Hz, 3H), 2.00(s, 3H), 1.68-1.61( m, 2H), 1.60–1.47 (m, 4H), 1.40–1.29 (m, 8H), 0.93 (m, 9H).
实施例17 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-(正癸酰氧基)甲酯Example 17 (3R,4R,5S)-4-acetylamino-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-(n-decanoyloxy) methyl ester
Figure PCTCN2021108383-appb-000038
Figure PCTCN2021108383-appb-000038
参照实施例15的方法，合成得到目标产物(850mg，72％)。LCMS[M+H]+:511.32。1H NMR(500MHz,MeOD)δ6.89(s,1H),5.84(q,J＝5.6Hz,2H),4.26(d,J＝6.0Hz,1H),3.97–3.85(m,2H),3.49–3.39(m,1H),2.89–2.80(m,1H),2.38(q,J＝7.0Hz,3H),1.99(s,3H),1.68–1.61(m,2H),1.60–1.47(m,4H),1.40–1.29(m,12H),0.93(m,9H)。Referring to the method of Example 15, the target product (850 mg, 72%) was synthesized. LCMS[M+H]+: 511.32.1H NMR(500MHz,MeOD)δ6.89(s,1H),5.84(q,J=5.6Hz,2H),4.26(d,J=6.0Hz,1H), 3.97–3.85 (m, 2H), 3.49–3.39 (m, 1H), 2.89–2.80 (m, 1H), 2.38 (q, J=7.0Hz, 3H), 1.99 (s, 3H), 1.68–1.61 ( m, 2H), 1.60–1.47 (m, 4H), 1.40–1.29 (m, 12H), 0.93 (m, 9H).
实施例18 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正己酰氧基)乙酯Example 18 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-2-(n-hexanoyloxy) ) ethyl ester
Figure PCTCN2021108383-appb-000039
Figure PCTCN2021108383-appb-000039
参照实施例12的方法，合成得到目标产物(600mg，85％)。LCMS[M+H]+:469.30。1H NMR(500MHz,CDCl3)δ6.84(s,1H),4.36(m,5H),3.90(s,1H),3.34(s,1H),2.83(s,1H),2.30(m,3H),2.02(s,3H),1.62(s,2H),1.56–1.35(m,4H),1.28(br,4H),0.97–0.69(m,9H)。Referring to the method of Example 12, the target product (600 mg, 85%) was synthesized. LCMS[M+H]+: 469.30.1H NMR(500MHz,CDCl3)δ6.84(s,1H),4.36(m,5H),3.90(s,1H),3.34(s,1H),2.83(s , 1H), 2.30 (m, 3H), 2.02 (s, 3H), 1.62 (s, 2H), 1.56–1.35 (m, 4H), 1.28 (br, 4H), 0.97–0.69 (m, 9H).
实施例19 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正辛酰氧基)乙酯Example 19 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-2-(n-octanoyloxy) base) ethyl ester
Figure PCTCN2021108383-appb-000040
Figure PCTCN2021108383-appb-000040
参照实施例12的方法，合成得到目标产物(660mg，87％)。LCMS[M+H]+:497.30。1H NMR(500MHz,CDCl3)δ6.83(s,1H),4.35(m,5H),3.90(s,1H),3.34(s,1H),2.83(s,1H),2.30(m,3H),2.02(s,3H),1.62(s,2H),1.56–1.35(m,4H),1.28(br,8H),0.97–0.69(m,9H)。Referring to the method of Example 12, the target product (660 mg, 87%) was synthesized. LCMS[M+H]+: 497.30.1H NMR(500MHz,CDCl3)δ6.83(s,1H),4.35(m,5H),3.90(s,1H),3.34(s,1H),2.83(s , 1H), 2.30 (m, 3H), 2.02 (s, 3H), 1.62 (s, 2H), 1.56–1.35 (m, 4H), 1.28 (br, 8H), 0.97–0.69 (m, 9H).
实施例20 (3R,4R,5S)-4-乙酰氨基-5-胍基-3-(戊-3-基氧基)环己基-1-烯-1-甲酸-2-(正癸酰氧基)乙酯Example 20 (3R,4R,5S)-4-acetamido-5-guanidino-3-(pent-3-yloxy)cyclohexyl-1-ene-1-carboxylic acid-2-(n-decanoyloxy) base) ethyl ester
Figure PCTCN2021108383-appb-000041
Figure PCTCN2021108383-appb-000041
参照实施例12的方法，合成得到目标产物(580mg，87％)。LCMS[M+H]+:524.40。1H NMR(500MHz,CDCl3)δ6.82(s,1H),4.33(m,5H),3.90(s,1H),3.34(s,1H),2.83(s,1H),2.30(m,3H),2.02(s,3H),1.62(s,2H),1.56–1.35(m,4H),1.28(br,12H),0.97–0.69(m,9H)。Referring to the method of Example 12, the target product (580 mg, 87%) was synthesized. LCMS[M+H]+:524.40.1H NMR(500MHz,CDCl3)δ6.82(s,1H),4.33(m,5H),3.90(s,1H),3.34(s,1H),2.83(s , 1H), 2.30 (m, 3H), 2.02 (s, 3H), 1.62 (s, 2H), 1.56–1.35 (m, 4H), 1.28 (br, 12H), 0.97–0.69 (m, 9H).
参比化合物reference compound
实施例A (3R,4R,5S)-4-乙酰氨基-5-胍基-3-((S)-3-(辛酰氧基)哌啶-1-基)环己-1-烯-1-甲酸Example A (3R,4R,5S)-4-acetamido-5-guanidino-3-((S)-3-(octanoyloxy)piperidin-1-yl)cyclohex-1-ene- 1-formic acid
实施例A参见CN1013224464A中记载的方法合成得到。LC-MS(m/z)：466.5[M+1]， 1H NMR(500MHz,DMSO-d 6)δ6.26(s,1H),4.60(s,1H),3.84–3.76(m,1H),3.57(s,1H),2.71(d,J＝7.8Hz,1H),2.65(s,1H),2.41–2.20(m,4H),2.06(s,1H),1.82(s,3H),1.61(s,1H),1.50(p,J＝7.4Hz,2H),1.36(s,1H),1.24(q,J＝6.3,5.8Hz,10H),1.11(s,2H),0.89–0.82(m,3H)。 Example A was synthesized by referring to the method described in CN1013224464A. LC-MS (m/z): 466.5 [M+1], 1 H NMR (500 MHz, DMSO-d 6 ) δ 6.26 (s, 1H), 4.60 (s, 1H), 3.84–3.76 (m, 1H) ), 3.57(s, 1H), 2.71(d, J=7.8Hz, 1H), 2.65(s, 1H), 2.41–2.20(m, 4H), 2.06(s, 1H), 1.82(s, 3H) ,1.61(s,1H),1.50(p,J=7.4Hz,2H),1.36(s,1H),1.24(q,J=6.3,5.8Hz,10H),1.11(s,2H),0.89– 0.82 (m, 3H).
其他参比化合物情况如下表所示：Other reference compounds are listed in the table below:
Figure PCTCN2021108383-appb-000042
Figure PCTCN2021108383-appb-000042
生物试验biological test
长效NA抑制剂体内药效筛选实验In vivo efficacy screening experiment of long-acting NA inhibitors
具有良好NA抑制活性的分子可通过添加长链制备成长效吸入NA抑制剂。本次实验涉及参比化合物有实施例A-D。本次实验主要考察在相同剂量下本发明化合物的长效抗流感效果。Molecules with good NA inhibitory activity can be made into long-acting inhaled NA inhibitors by adding long chains. Reference compounds involved in this experiment include Examples A-D. This experiment mainly investigates the long-acting anti-influenza effect of the compounds of the present invention at the same dose.
实验材料Experimental Materials
小鼠：Balb/c，雌性，6-8周龄(18～20g)。Mice: Balb/c, female, 6-8 weeks old (18-20 g).
病毒：A/Puerto Rico/8/1934(H1N1PR8)拯救病毒。Virus: A/Puerto Rico/8/1934 (H1N1PR8) rescued the virus.
受试样品：实施例A、实施例B、实施例C、实施例D、以及本发明化合物(实施例2、实施例3、实施例4、实施例16和实施例19)、和溶剂(生理盐水+0.2％Tween80)；其中“实施例”在图1-3中简称为“实例”。Test samples: Example A, Example B, Example C, Example D, and the compounds of the present invention (Example 2, Example 3, Example 4, Example 16 and Example 19), and solvent ( Physiological saline + 0.2% Tween80); wherein "Examples" are simply referred to as "Examples" in Figures 1-3.
实验分组experimental grouping
组号Group No 分组grouping 药物drug 给药时间点Dosing time point 动物数量number of animals
11 空白对照组Blank control group 溶剂solvent 10～20h10～20h 55
22 感染模型组Infection model group 溶剂solvent 10～20h10～20h 1515
33 拉尼娜米韦前药La ninamivir prodrug 实施例D，1μmol/kgExample D, 1 μmol/kg 10～20h10～20h 1515
44 拉尼娜米韦原药La Nina mivir original drug 实施例B，1μmol/kgExample B, 1 μmol/kg 10～20h10～20h 1515
55 药物组1 drug group 1 实施例A，1μmol/kgExample A, 1 μmol/kg 10～20h10～20h 1515
66 药物组2 Drug group 2 实施例C，1μmol/kgExample C, 1 μmol/kg 10～20h10～20h 1515
77 药物组3 Drug group 3 实施例2，1μmol/kgExample 2, 1 μmol/kg 10～20h10～20h 1515
88 药物组4 Drug group 4 实施例3，1μmol/kgExample 3, 1 μmol/kg 10～20h10～20h 1515
99 药物组5 Drug group 5 实施例4，1μmol/kgExample 4, 1 μmol/kg 10～20h10～20h 1515
1010 药物组6 Drug group 6 实施例16，1μmol/kgExample 16, 1 μmol/kg 10～20h10～20h 1515
1111 药物组7 Drug group 7 实施例19，1μmol/kgExample 19, 1 μmol/kg 10～20h10～20h 1515
实验方法experimental method
1.小鼠称重、感染病毒当天麻醉小鼠后经鼻滴入60PFU病毒；1. The mice were weighed, and the mice were anesthetized on the day of virus infection, and 60 PFU of virus was instilled through the nose;
2.在感染10-20小时后开始滴鼻给药(参比化合物(实施例A至D)，以及本发明化合物(实施例2至4))，空白对照是对未感染小鼠施用溶剂，模型组是对感染小鼠施用溶剂；2. Start intranasal administration 10-20 hours after infection (reference compounds (Examples A to D), and compounds of the present invention (Examples 2 to 4)), and the blank control is to administer solvent to uninfected mice, The model group is to administer solvent to infected mice;
3.每天记录小鼠体重，观察小鼠状态、行为、饮水、饮食、死亡等情况；3. Record the body weight of the mice every day, and observe the status, behavior, drinking water, diet, death, etc. of the mice;
4.感染病毒5天后，在模型组和实验组中每组随机取6只小鼠处死用于肺组织病毒滴度检测；4. After 5 days of virus infection, 6 mice were randomly selected from each group in the model group and the experimental group to be sacrificed for the detection of virus titer in lung tissue;
5.剩余小鼠用于观察小鼠生存率，共观察记录14天，小鼠体重下降25％以上的视为临床死亡。5. The remaining mice were used to observe the survival rate of mice, and the observation and recording were recorded for 14 days. The mice whose body weight decreased by more than 25% were regarded as clinical death.
实验结果Experimental results
1.小鼠体重变化1. Changes in body weight of mice
空白对照组小鼠在实验期两周内没有显著性变化，感染模型组感染3天后开始出现体重持续下降直至临床死亡或硬死亡。其余给药组在感染4至5天后开始体重下降，感染9至10天后开始上升恢复正常体重(参见图1)。本发明化合物实施例3、16、19和阳性对照药实施例D的小鼠体重趋势与下降程度一致，在感染后第5天开始下降，并于感染后第8天体重下降至90％左右，此后体重开始恢复。实施例4与实施例B于第9天小鼠体重下降至85％左右。实施例2和原药实施例C于第9天小鼠体重下降至80％左右。实施例A于第10天小鼠体重下降至75％左右。由图可知，实施例3、16、19和阳性药实施例D的小鼠体重结果接近，下降最少，且在第3至第10天的体重下降趋势比原药实施例C组明显减缓。The mice in the blank control group had no significant changes within two weeks of the experimental period, and the infection model group began to experience continuous weight loss 3 days after infection until clinical death or hard death. The rest of the administration groups started to lose weight after 4 to 5 days of infection, and began to rise and returned to normal body weight after 9 to 10 days of infection (see Figure 1). The body weight of the mice of Compound Examples 3, 16, 19 of the present invention and the positive control drug Example D was consistent with the degree of decrease, and began to decrease on the 5th day after infection, and decreased to about 90% on the 8th day after infection, After that the weight started to come back. The body weight of the mice in Example 4 and Example B decreased to about 85% on the 9th day. The body weight of the mice in Example 2 and the original drug Example C decreased to about 80% on the 9th day. In Example A, the body weight of the mice dropped to about 75% on the 10th day. It can be seen from the figure that the weight results of the mice of Examples 3, 16, 19 and the positive drug Example D are similar, with the least decrease, and the weight loss trend from the 3rd to the 10th day is significantly slower than that of the original drug Example C group.
2.小鼠感染病毒五天后肺部流感病毒滴度2. Influenza virus titers in the lungs of mice five days after virus infection
与感染组相比，除实施例A外，其余给药组的肺病毒滴度均出现显著性降低(参见图2)。其中，本发明化合物实施例2、3、4、16、19和实施例B的肺病毒滴度较低；原药实施例C和阳性药实施例D的肺病毒滴度接近，但比实施例2、3、4、16、19和实施例B组高。Compared with the infection group, except Example A, the pulmonary virus titers of the other administration groups were significantly decreased (see Figure 2). Among them, the pneumovirus titers of Examples 2, 3, 4, 16, 19 and Example B of the compounds of the present invention were relatively low; the pneumovirus titers of the original drug Example C and the positive drug Example D were close, but more 2, 3, 4, 16, 19 and Example B are high.
3.小鼠生存率3. Mouse Survival Rate
感染模型组小鼠在感染一周后陆续出现死亡，感染第9天全部死亡。感染两周后，阳性药(实施例D)和实施例3、16全部存活，拉尼娜米韦原药(实施例B)和实施例4、19存活率为88.9％(8/9)，实施例C和实施例2存活率为66.7％(6/9)，而实施例A存活率为33.3％(3/9)(参见图3)。因此，实施例3和16的小鼠存活率与阳性药实施例D一致，实施例4和19的存活率亦接近90％，且均比原药实施例C高。Mice in the infection model group died one after another one week after infection, and all died on the ninth day of infection. Two weeks after infection, the positive drug (Example D) and Examples 3 and 16 all survived, and the original drug of La Ninamir (Example B) and Examples 4 and 19 had a survival rate of 88.9% (8/9), Example C and Example 2 had a survival rate of 66.7% (6/9), while Example A had a survival rate of 33.3% (3/9) (see Figure 3). Therefore, the survival rates of mice in Examples 3 and 16 are consistent with the positive drug Example D, and the survival rates of Examples 4 and 19 are also close to 90%, and both are higher than those of the original drug Example C.
研究表明，本发明化合物可在体内缓慢、持续、稳定地释放有效药物，达到长效目的，且对病毒感染等疾病有很好的疗效。Studies have shown that the compound of the present invention can slowly, continuously and stably release effective drugs in the body to achieve long-term effects, and has a good curative effect on diseases such as virus infection.
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity, all possible combinations of the technical features in the above-described embodiments are not described. However, as long as there is no contradiction between the combinations of these technical features, All should be regarded as the scope described in this specification.
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明的保护范围应以所附权利要求为准。The above-mentioned embodiments only represent several embodiments of the present invention, and the descriptions thereof are specific and detailed, but should not be construed as limiting the scope of the present invention. It should be pointed out that for those skilled in the art, without departing from the concept of the present invention, several modifications and improvements can be made, which all belong to the protection scope of the present invention. Therefore, the scope of protection of the present invention should be determined by the appended claims.

Claims (18)

  1. 化合物，其具有式(I)所示结构：Compound, it has the structure shown in formula (I):
    Figure PCTCN2021108383-appb-100001
    Figure PCTCN2021108383-appb-100001
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof;
    其中，in,
    X是O、或-N(R a)-； X is O, or -N(R a )-;
    Y是-C(＝O)O-R 4、-C(＝O)NH-R 4、-P(＝O)(OR 4c)(OR 4)、-C(＝O)O-R b-Y 1-R 4a、-C(＝O)NH-R b-Y 1-R 4a、-P(＝O)(OH)(O-R b-Y 1-R 4a)、或-P(＝O)(O-R b-Y 1-R 4a)(O-R b-Y 1-R 4b)； Y is -C(=O)OR 4 , -C(=O)NH-R 4 , -P(=O)(OR 4c )(OR 4 ), -C(=O)OR b -Y 1 -R 4a , -C(=O)NH-R b -Y 1 -R 4a , -P(=O)(OH)(OR b -Y 1 -R 4a ), or -P(=O)(OR b - Y 1 -R 4a ) (OR b -Y 1 -R 4b );
    Y 1是O、S、-N(R a)-、-C(＝O)-、-C(＝O)O-、-OC(＝O)-、-OC(＝O)O-、-C(＝O)NH-、-NHC(＝O)-、-S(＝O) 1-2O-、-OS(＝O) 1-2-、-S(＝O) 1-2NH-、-NHS(＝O) 1-2-、-NHC(＝O)NH、-NHC(＝S)NH、-OS(＝O) 1-2O-、或-OS(＝O) 1-2O-； Y 1 is O, S, -N(R a )-, -C(=O)-, -C(=O)O-, -OC(=O)-, -OC(=O)O-, - C(=O)NH-, -NHC(=O)-, -S(=O) 1-2 O-, -OS(=O) 1-2 -, -S(=O) 1-2 NH- , -NHS(=O) 1-2 -, -NHC(=O)NH, -NHC(=S)NH, -OS(=O) 1-2 O-, or -OS(=O) 1-2 O-;
    各R a分别独立地为H、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、或C 1-6氰基烷基； Each R a is independently H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1 -6 cyanoalkyl;
    R b是C 1-6亚烷基、或C 1-6亚杂烷基；其中所述C 1-6亚烷基和C 1-6亚杂烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代； R b is C 1-6 alkylene, or C 1-6 heteroalkylene; wherein the C 1-6 alkylene and C 1-6 heteroalkylene are independently optionally 0, 1, 2 , 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br, -N3 , -OH, -SH, -NH2 , -CN, -NO2 , C1- 4 alkyl and C 1-4 alkoxy group substitution;
    R 1和R 2分别独立地为H、C 1-10烷基、C 1-10卤代烷基、C 1-10羟基烷基、C 1-10氨基烷基、C 1-10氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-10烷基、C 1-10卤代烷基、C 1-10羟基烷基、C 1-10氨基烷基、C 1-10氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个R 5取代； R 1 and R 2 are each independently H, C 1-10 alkyl, C 1-10 haloalkyl, C 1-10 hydroxyalkyl, C 1-10 aminoalkyl, C 1-10 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl , C 6-12 aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-10 alkyl, C 1 -10 haloalkyl, C 1-10 hydroxyalkyl, C 1-10 aminoalkyl, C 1-10 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-6 alkane base, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1-9 heteroaryl and C 1-9 heteroaryl C 1-6 alkyl independently optionally substituted with 0, 1, 2, 3 or 4 R 5 ;
    R 3是-NH 2、-N 3、C 1-6氨基烷基、或
    Figure PCTCN2021108383-appb-100002
    其中R 3任选地被0、1、2、3、4、或5个R 6取代；     R 3 is -NH 2 , -N 3 , C 1-6 aminoalkyl, or
    Figure PCTCN2021108383-appb-100002
    wherein R3 is optionally substituted with 0, 1, 2, 3, 4 , or 5 R6;
    R 3a是H、-OH、C 1-6烷基、或C 1-6羟基烷基； R 3a is H, -OH, C 1-6 alkyl, or C 1-6 hydroxyalkyl;
    R 3b是H、-NH 2、C 1-6烷基、C 1-6烷基氨基、或C 1-6氨基烷基； R 3b is H, -NH 2 , C 1-6 alkyl, C 1-6 alkylamino, or C 1-6 aminoalkyl;
    R 4和R 4c分别独立地为C 6-22烷基、C 6-22烯基、C 6-22炔基、C 3-8环烷基C 6-22烷基、C 2-7杂环基C 6-22烷基、C 6-12芳基C 6-22烷基、或C 1-9杂芳基C 6-22烷基；其中所述各C 6-22烷基、C 6-22烯基、C 6-22炔基、C 3-8环烷基C 6-22烷基、C 2-7杂环基C 6-22烷基、C 6-12芳基C 6-22烷基和C 1-9杂芳基C 6-22烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基和C 1-6氰基烷基的基团取代； R 4 and R 4c are each independently C 6-22 alkyl, C 6-22 alkenyl, C 6-22 alkynyl, C 3-8 cycloalkyl, C 6-22 alkyl, C 2-7 heterocycle base C 6-22 alkyl, C 6-12 aryl C 6-22 alkyl, or C 1-9 heteroaryl C 6-22 alkyl; wherein each of the C 6-22 alkyl, C 6- 22 alkenyl, C 6-22 alkynyl, C 3-8 cycloalkyl C 6-22 alkyl, C 2-7 heterocyclyl C 6-22 alkyl, C 6-12 aryl C 6-22 alkyl and C 1-9 heteroaryl C 6-22 alkyl independently optionally by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br , -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl group substitution;
    R 4a和R 4b分别独立地为C 1-22烷基、C 2-22烯基、C 2-22炔基、C 3-8环烷基C 1-22烷基、C 2-7杂环基C 1-22烷基、C 6-12芳基C 1-22烷基、或C 1-9杂芳基C 1-22烷基；其中所述各C 1-22烷基、C 2-22烯基、C 2-22炔基、C 3-8环烷基C 1-22烷基、C 2-7杂环基C 1-22烷基、C 6-12芳基C 1-22烷基和C 1-9杂芳基C 1-22烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基和C 1-6氰基烷基的基团取代；和 R 4a and R 4b are each independently C 1-22 alkyl, C 2-22 alkenyl, C 2-22 alkynyl, C 3-8 cycloalkyl, C 1-22 alkyl, C 2-7 heterocycle base C 1-22 alkyl, C 6-12 aryl C 1-22 alkyl, or C 1-9 heteroaryl C 1-22 alkyl; wherein each C 1-22 alkyl, C 2- 22 alkenyl, C 2-22 alkynyl, C 3-8 cycloalkyl C 1-22 alkyl, C 2-7 heterocyclyl C 1-22 alkyl, C 6-12 aryl C 1-22 alkyl and C 1-9 heteroaryl C 1-22 alkyl independently optionally by 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), F, Cl, Br , -N 3 , -OH, -NH 2 , -CN, -NO 2 , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl group substitution; and
    各R 5和R 6分别独立地为H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-CN、-NO 2、-NH 2、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-6烷基；其中所述各C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、C 1-6氰基烷基、C 3-8环烷基、C 3-8环烷基C 1-6烷基、C 2-7杂环基、C 2-7杂环基C 1-6烷基、C 6-12芳基、C 6-12芳基C 1-6烷基、C 1-9杂芳基和C 1-9杂芳基C 1-6烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、 -N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 Each R 5 and R 6 is independently H, D, oxo (=O), F, Cl, Br, -N 3 , -OH, -SH, -CN, -NO 2 , -NH 2 , C 1 -6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 ring Alkyl, C 3-8 cycloalkyl, C 1-6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 Aryl C 1-6 alkyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-6 alkyl; wherein each C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 1-6 cyanoalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1 -6 alkyl, C 2-7 heterocyclyl, C 2-7 heterocyclyl, C 1-6 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-6 alkyl, C 1- 9heteroaryl and C1-9heteroarylC1-6alkyl independently optionally by 0, 1 , 2, 3 or 4 independently selected from H, D, oxo(=O), F, Group substitution of Cl, Br, -N3 , -OH, -SH, -NH2 , -CN, -NO2 , C1-4alkyl and C1-4alkoxy .
  2. 根据权利要求1所述的化合物，其中，R 1是H、C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基、或C 1-6氰基烷基；其中所述C 1-6烷基、C 1-6卤代烷基、C 1-6羟基烷基、C 1-6氨基烷基和C 1-6氰基烷基独立任选地被0、1、2、3或4个R 5取代。 The compound of claim 1, wherein R 1 is H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, or C 1- 6 cyanoalkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl and C 1-6 cyanoalkyl are independently optional ground is substituted with 0, 1, 2, 3 or 4 R 5 .
  3. 根据权利要求1所述的化合物，其具有式(II)所示结构：The compound according to claim 1, which has the structure shown in formula (II):
    Figure PCTCN2021108383-appb-100003
    Figure PCTCN2021108383-appb-100003
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐；or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof;
    其中，R 7是R 4、或-R b-Y 1-R 4a。 wherein R 7 is R 4 , or -R b -Y 1 -R 4a .
  4. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    R b是C 1-4亚烷基；其中所述C 1-4亚烷基任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 R b is C 1-4 alkylene; wherein said C 1-4 alkylene is optionally selected from 0, 1, 2, 3 or 4 independently selected from H, D, oxo (=O), Group substitution of F, Cl, Br, -N 3 , -OH, -SH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl and C 1-4 alkoxy.
  5. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    R 2是C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基、或C 2-6杂环基C 1-4烷基；其中所述各C 1-4烷基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基和C 2-6杂环基C 1-4烷基独立任选地被0、1、2、3或4个R 5取代。 R 2 is C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkyl, C 2-6 heterocyclyl, or C 2-6 heterocyclyl C 1-4 alkyl; wherein each of the C 1-4 alkyl, C 1 -4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl C 1-4 alkane C 2-6 heterocyclyl, C 2-6 heterocyclyl and C 2-6 heterocyclyl C 1-4 alkyl are independently optionally substituted with 0, 1, 2, 3 or 4 R 5 .
  6. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    R 2是甲基、乙基、丙基、异丙基、丁基、
    Figure PCTCN2021108383-appb-100004
    Figure PCTCN2021108383-appb-100005
    R 2 is methyl, ethyl, propyl, isopropyl, butyl,
    Figure PCTCN2021108383-appb-100004
    Figure PCTCN2021108383-appb-100005
  7. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    R 3是-NH 2、-N 3、-CH 2NH 2、-CH 2CH 2NH 2、
    Figure PCTCN2021108383-appb-100006
    R 3 is -NH 2 , -N 3 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 ,
    Figure PCTCN2021108383-appb-100006
  8. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    R 4和R 4c分别独立地为C 6-22烷基、C 8-22烯基、或C 8-22炔基；其中所述各C 6-22烷基、C 8-22烯基和C 8-22炔基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基的基团取代。 R 4 and R 4c are each independently C 6-22 alkyl, C 8-22 alkenyl, or C 8-22 alkynyl; wherein each of said C 6-22 alkyl, C 8-22 alkenyl and C 8-22 Alkynyl is independently optionally selected by 0, 1, 2, 3 or 4 independently selected from H, D, oxo(=O), F, Cl, Br, -N3 , -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl and C 1- 4 cyanoalkyl group substitution.
  9. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    R 4a和R 4b分别独立地为C 6-22烷基、C 6-22烯基、或C 6-22炔基；其中所述各C 6-22烷基、C 6-22烯基和C 6-22炔基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-NH 2、-CN、-NO 2、C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基和C 1-4氰基烷基的基团取代。 R 4a and R 4b are each independently C 6-22 alkyl, C 6-22 alkenyl, or C 6-22 alkynyl; wherein each of said C 6-22 alkyl, C 6-22 alkenyl and C 6-22 Alkynyl is independently optionally selected by 0, 1, 2, 3 or 4 independently selected from H, D, oxo(=O), F, Cl, Br, -N3 , -OH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl and C 1- 4 cyanoalkyl group substitution.
  10. 根据权利要求1-3任一项所述的化合物，其中，The compound of any one of claims 1-3, wherein,
    各R 5和R 6分别独立地为H、D、F、Cl、Br、-N 3、-OH、-SH、-CN、-NO 2、-NH 2、C 1-4烷基、C 1-4 烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基、C 2-6杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中所述各C 1-4烷基、C 1-4烷氧基、C 1-4卤代烷基、C 1-4羟基烷基、C 1-4氨基烷基、C 1-4氰基烷基、C 3-6环烷基、C 3-6环烷基C 1-4烷基、C 2-6杂环基、C 2-6杂环基C 1-4烷基、C 6-12芳基、C 6-12芳基C 1-4烷基、C 1-9杂芳基和C 1-9杂芳基C 1-4烷基独立任选地被0、1、2、3或4个独立地选自H、D、氧代(＝O)、F、Cl、Br、-N 3、-OH、-SH、-NH 2、-CN、-NO 2、C 1-4烷基和C 1-4烷氧基的基团取代。 Each R 5 and R 6 is independently H, D, F, Cl, Br, -N 3 , -OH, -SH, -CN, -NO 2 , -NH 2 , C 1-4 alkyl, C 1 -4 alkoxy, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl C 1-4 alkyl, C 2-6 heterocyclyl, C 2-6 heterocyclyl C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl C 1-4 alkyl group, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein each of said C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl , C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 cyanoalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl, C 1-4 alkyl, C 2 -6 heterocyclyl, C 2-6 heterocyclyl, C 1-4 alkyl, C 6-12 aryl, C 6-12 aryl, C 1-4 alkyl, C 1-9 heteroaryl and C 1 -9heteroarylC1-4alkyl independently optionally by 0, 1 , 2, 3 or 4 independently selected from H, D, oxo(=O), F, Cl, Br, -N3 , -OH, -SH, -NH 2 , -CN, -NO 2 , C 1-4 alkyl and C 1-4 alkoxy groups are substituted.
  11. 具有以下结构之一的化合物：Compounds with one of the following structures:
    Figure PCTCN2021108383-appb-100007
    Figure PCTCN2021108383-appb-100007
    Figure PCTCN2021108383-appb-100008
    Figure PCTCN2021108383-appb-100008
    Figure PCTCN2021108383-appb-100009
    Figure PCTCN2021108383-appb-100009
    或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐。or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof.
  12. 药物组合物，所述药物组合物包含权利要求1-11中任一项所述的化合物或其立体异构体、互变异构体、氮氧化物、溶剂化物、或药学上可接受的盐，以及药学上可接受的辅料、稀释剂或载体、或其组合。A pharmaceutical composition comprising the compound of any one of claims 1-11 or a stereoisomer, tautomer, nitrogen oxide, solvate, or pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable adjuvant, diluent or carrier, or a combination thereof.
  13. 根据权利要求12所述的药物组合物，其进一步包含附加治疗剂。The pharmaceutical composition of claim 12, further comprising an additional therapeutic agent.
  14. 根据权利要求12或13所述的药物组合物，其是长效形式。The pharmaceutical composition of claim 12 or 13, which is in a long-acting form.
  15. 根据权利要求14所述的药物组合物，其是注射剂或吸入型制剂形式。The pharmaceutical composition according to claim 14, which is in the form of an injection or inhalation preparation.
  16. 使用根据权利要求1-11任一项所述的化合物或权利要求12-15任一项所述的药物组合物在制备用于预防和/或治疗病毒性疾病或抑制神经氨酸酶活性的药物中的用途。Using the compound according to any one of claims 1-11 or the pharmaceutical composition according to any one of claims 12-15 in the preparation of a medicament for preventing and/or treating viral diseases or inhibiting neuraminidase activity use in.
  17. 根据权利要求16所述的用途，其中所述神经氨酸酶是流感神经氨酸酶。The use of claim 16, wherein the neuraminidase is influenza neuraminidase.
  18. 根据权利要求16所述的用途，其中所述病毒性疾病是流感病毒引起的疾病。The use according to claim 16, wherein the viral disease is a disease caused by influenza virus.
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