WO2019120084A1 - 用于抗病毒的核苷类逆转录酶抑制剂 - Google Patents

用于抗病毒的核苷类逆转录酶抑制剂 Download PDF

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WO2019120084A1
WO2019120084A1 PCT/CN2018/119483 CN2018119483W WO2019120084A1 WO 2019120084 A1 WO2019120084 A1 WO 2019120084A1 CN 2018119483 W CN2018119483 W CN 2018119483W WO 2019120084 A1 WO2019120084 A1 WO 2019120084A1
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optionally substituted
group
compound
alkyl
pharmaceutically acceptable
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PCT/CN2018/119483
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English (en)
French (fr)
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王义汉
赵九洋
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深圳市塔吉瑞生物医药有限公司
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Priority to JP2020534832A priority Critical patent/JP7076158B2/ja
Priority to EP18890107.8A priority patent/EP3730503A4/en
Priority to US16/955,482 priority patent/US11447512B2/en
Publication of WO2019120084A1 publication Critical patent/WO2019120084A1/zh
Priority to US17/836,620 priority patent/US20220389038A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
    • 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
    • A61P31/18—Antivirals for RNA viruses for HIV
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • 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
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of medicine.
  • the present invention relates to a novel class of nucleoside reverse transcriptase inhibitors, pharmaceutical compositions comprising same, and processes for their preparation and use as antiviral drugs, in particular for the treatment and/or prevention of human immunodeficiency virus HIV And/or the use of hepatitis B virus HBV in patients.
  • a virus is a kind of nucleic acid particle. Its structure is extremely simple. Most of it lacks an enzyme system. It can only rely on the host cell to replicate its nucleic acid and protein, and then assemble into a virus particle to proliferate. Viral infections cause a variety of diseases that seriously endanger human health and life. According to incomplete statistics, about 60% of epidemic infectious diseases are caused by viral infections. To date, more than 3,000 viruses have been discovered worldwide, and new viruses are still being discovered. Among them, high-risk, high-risk viral infections such as AIDS, hepatitis B/C, and cytomegalovirus infection.
  • HIV Acquired Immune Deficiency Syndrome
  • HIV human immunodeficiency virus
  • Hepatitis B is a worldwide epidemic disease with high incidence, strong infection and serious harm to human health. At present, about 2 billion people worldwide have been infected with hepatitis B virus (HBV), of which 350 million people are carriers of chronic HBV, and about 1 million people die every year from liver diseases related to HBV infection. China is a high-risk area for hepatitis B. According to the sero-epidemiological survey of HBV-infected people in 2002, the prevalence of HBsAg is 9.09%, and about 120 million people carry HBV. Among them, more than 30 million patients with chronic hepatitis B (CHB).
  • CHB chronic hepatitis B
  • HBV-related liver disease including chronic severe liver disease, cirrhosis and hepatocellular carcinoma.
  • the annual incidence of cirrhosis decompensation is about 3%, and the cumulative incidence rate is 5 years.
  • the 5-year mortality rates for chronic hepatitis B, compensated, and decompensated cirrhosis are 0%-2%, 14%-20%, and 70%-86%, respectively. More than 300,000 people die each year from hepatitis B-related complications in China.
  • HBV-infected children become carriers of chronic HBV, and evolve into chronic hepatitis, cirrhosis, liver failure, and hepatocellular carcinoma with age.
  • Continuous replication of HBV is an important factor in the development of liver inflammation in patients with chronic hepatitis B and leading to cirrhosis and liver cancer.
  • TDF Teenofovir Disoproxil Fumarate
  • FDA US Food and Drug Administration
  • TDF greatly improves cell penetration and oral absorption, and is also recommended by the US Centers for Disease Control for the prevention of AIDS.
  • a disadvantage of TDF is its ease of hydrolysis to TFV (Tenofovir) in plasma; on the other hand, TDF may pose a risk of nephrotoxicity in patients with impaired renal function.
  • TAF Tefofovir Alafenamide Fumarate
  • TAF tephrotoxicity and bone toxicity caused by TDF.
  • TAF is clinically used at very low doses and is highly resistant to HIV and HBV
  • TAF still has a small amount of hydrolysis during its operation and in plasma, and it is still clinically necessary to develop new compounds and specific metabolic methods.
  • Further improve the stability of the drug in plasma increase the drug concentration in the tissue cells, thereby effectively reducing the clinical dose of the drug and further reducing the nephrotoxicity and bone toxicity of the drug, and better playing the clinical effect of treating hepatitis B and AIDS.
  • the present invention provides a novel nucleoside compound and a composition comprising the same and use thereof, which have better anti-HIV and HBV activities and are useful for treating and/or preventing HIV infection or/and HBV infection, and Greatly reduce nephrotoxicity and bone toxicity caused by TDF or TAF.
  • X is selected from O or S
  • Y is selected from a bond, O or S;
  • n is selected from 0 to 5;
  • A is selected from:
  • n is selected from 12 to 21;
  • each R 1 is independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted C 3 -C 7 heterocyclyl, or two
  • the R 1 groups are taken together to form an optionally substituted C 3 -C 7 carbocyclic group or an optionally substituted C 3 -C 7 heterocyclic group;
  • V is selected from O or NH
  • B is H, or is the following structure:
  • R 2 and R 3 are each independently selected from H, an optionally substituted C 1 -C 6 alkyl group or a side chain of a natural or pharmaceutically acceptable amino acid, and if the side chain contains a carboxyl group, the carboxyl group may be optionally alkyl or An aryl esterification, or R 2 , R 3 together with the carbon atom to which they are attached may form an optionally substituted C 3 -C 7 carbocyclic group or an optionally substituted C 3 -C 7 heterocyclic group;
  • each R 4 is independently selected from H, an optionally substituted C 1 -C 6 acyl group, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 7 carbocyclic group, optionally substituted a C 3 -C 7 heterocyclic group, an optionally substituted C 6 -C 11 aryl group or an optionally substituted C 5 -C 11 heteroaryl group, p is selected from 1 or 2;
  • Z is selected from O or S
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 heteroalkyl group, an optionally substituted C 1 -C 6 acyl group, an optionally substituted C 2 -C 6 olefin a optionally substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 7 carbocyclic group, an optionally substituted C 3 -C 7 heterocyclic group, an optionally substituted C 6 -C 11 aryl group a optionally substituted C 5 -C 11 heteroaryl group as long as it is chemically acceptable;
  • the compound does not include a compound of the formula:
  • the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
  • a compound of the invention is provided in the pharmaceutical composition in an effective amount.
  • the compounds of the invention are provided in a therapeutically effective amount.
  • the compounds of the invention are provided in a prophylactically effective amount.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, further comprising other therapeutic agents.
  • the invention provides a compound comprising a compound of the invention, a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form or isotopic variation thereof, and other therapeutic agents, and pharmaceutically acceptable
  • a kit of carriers, adjuvants or vehicles comprising a compound of the invention, a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, crystal form or isotopic variation thereof, and other therapeutic agents, and pharmaceutically acceptable
  • the invention provides a method of treating and/or preventing a condition associated with a viral infection in a subject in need thereof, the method comprising: administering to the subject an effective amount of a compound of the invention.
  • the viral infection is selected from the group consisting of: human immunodeficiency virus HIV infection, hepatitis B virus HBV infection.
  • the compound is administered orally, subcutaneously, intravenously or intramuscularly. In a specific embodiment, the compound is administered chronically.
  • C 1- C 6 alkyl includes C 1, C 2, C 3 , C 4, C 5, C 6, C 1- C 6, C 1- C 5, C 1- C 4, C 1- C 3 , C 1 - C 2 , C 2 - C 6 , C 2 - C 5 , C 2 - C 4 , C 2 - C 3 , C 3 - C 6 , C 3 - C 5 , C 3 - C 4 , C 4- C 6 , C 4- C 5 and C 5- C 6 alkyl.
  • C 1- C 6 alkyl means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms, also referred to herein as "lower alkyl.” In some embodiments, a C 1-4 alkyl group is particularly preferred. Examples of the alkyl group include, but are not limited to, methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), uncle Butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ), n-hexyl (C 6 ), 3-methylhexyl (C 6 ), 2, 2-dimethyl A penty
  • each alkyl group is independently optionally substituted, ie, unsubstituted (“unsubstituted alkyl") or substituted with one or more substituents (“substituted alkyl”) For example, 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • the alkyl group is unsubstituted C 1- C 6 alkyl (e.g., -CH 3).
  • the alkyl group is a substituted C 1- C 6 alkyl.
  • C 1- C 6 heteroalkyl means an alkyl as defined herein, in the parent chain, which further contains one or more (e.g., 2, 3 or 4) heteroatoms (e.g., oxygen, Sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are between adjacent carbon atoms in the parent carbon chain, and/or one or more heteroatoms are in the carbon atom and the parent molecule Between, that is, between the connection points. Unless otherwise stated, each heteroalkyl group is independently substituted, i.e., unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl").
  • heteroatoms e.g., oxygen, Sulfur, nitrogen, boron, silicon, phosphorus
  • the heteroalkyl group is unsubstituted C 1 -C 6 heteroalkyl. In some embodiments, the heteroalkyl group is a substituted C 1 -C 6 heteroalkyl.
  • the C 1 -C 6 heteroalkyl group includes a C 1 -C 6 alkoxy group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkylamino group and the like, which are defined in detail as follows.
  • C 1- C 6 alkoxy refers to the group -OR, wherein, R is a substituted or unsubstituted C 1- C 6 alkyl.
  • a C 1 -C 4 alkoxy group is particularly preferred.
  • the C 1 -C 6 alkoxy group includes, but is not limited to, a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, a n-butoxy group, a t-butoxy group, a sec-butoxy group, N-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.
  • C 1- C 6 alkylthio refers to the group -SR, wherein, R is an optionally substituted C 1- C 6 alkyl.
  • C 1- C 4 alkylthio group is particularly preferable.
  • the C 1 -C 6 alkylthio group includes, but is not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, sec-butylthio, N-pentylthio, n-hexylthio and 1,2-dimethylbutylthio.
  • C 1- C 6 alkylamino refers to the group -NHR or -NR 2, wherein, R is an optionally substituted C 1- C 6 alkyl.
  • C 1- C 4 alkylamino group are particularly preferred.
  • the C 1 -C 6 alkylamino group includes, but is not limited to, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, t-butylamino, dimethylamino, methylethylamino and diethylamino.
  • Halo or halogen refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
  • the halo group is F, Cl or Br.
  • the halogen group is F or Cl.
  • the halogen group is F.
  • C 1- C 6 haloalkyl and “C 1- C 6 haloalkoxy” mean the above-mentioned "C 1- C 6 alkyl group” and "C 1- C 6 alkoxy group" which are one or Multiple halogen groups are substituted.
  • C 1- C 4 haloalkyl groups are particularly preferred, more preferably C 1- C 2 haloalkyl.
  • a C 1-4 haloalkoxy group is particularly preferred, more preferably a C 1 -C 2 haloalkoxy group.
  • Exemplary haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, and the like.
  • Exemplary haloalkoxy groups include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3 , and the like.
  • C 3- C 7 carbon ring group means a non-aromatic hydrocarbon ring group having from 3 to 7 ring carbon atoms and zero heteroatoms.
  • preferably C 4 carbocyclic group which is a ring having 4 carbon atoms, zero heteroatoms and non-aromatic cyclic hydrocarbon radical.
  • Carbocyclyl further includes a ring system wherein the above carbocyclic group is fused, bridged or spirocyclic with one or more carbocyclic, heterocyclic, aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclic ring, and In such cases, the number of carbons continues to indicate the number of carbons in the carbocyclic based system.
  • carbocyclic groups include, but are not limited to, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclopentadienyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and Cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl ( C 8 ), bicyclo [2.2.1] heptyl (C 7 ), bicyclo [2.2.2] octyl (C 8 ), and the
  • each carbocyclic group is independently optionally substituted, ie, unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl” ).
  • the carbocyclic group is unsubstituted C 3 -C 7 carbocyclic group.
  • the carbocyclyl is substituted with C 3 -C 7 carbocyclic group.
  • C 3 -C 7 heterocyclyl refers to a 3 to 7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms, wherein each hetero atom is independently selected from the group consisting of nitrogen, oxygen, sulfur, and boron. , phosphorus and silicon, wherein carbon, nitrogen, sulfur and phosphorus atoms may also exist in their oxidation state, such as C(O), S(O), S(O) 2 , P(O) and the like.
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • a C 4 -C 7 heterocyclyl group is preferred, which is a 4 to 7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • a C 4 -C 6 heterocyclyl group is preferred, which is a 4 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • a C 5 -C 6 heterocyclyl group is preferred, which is a 5 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms.
  • heterocyclic group which 5-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
  • the above heterocyclic group contains 1 to 3 (more preferably 1 or 2) ring heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, preferably nitrogen or oxygen.
  • each heterocyclic group is independently optionally substituted, that is, unsubstituted ("unsubstituted heterocyclic group") or substituted with one or more substituents (“substituted heterocyclic group” ).
  • the heterocyclic group is unsubstituted C 3 -C 7 heterocyclyl group.
  • the heterocyclic group is a substituted C 3 -C 7 heterocyclyl group.
  • Heterocyclyl also includes ring systems wherein the above heterocyclic group is fused, bridged or spirocyclic to one or more carbocyclic, heterocyclic, aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring And in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclic groups containing one hetero atom include, but are not limited to, aziridine, oxacyclopropane, thicyclopropyl.
  • Exemplary 4-membered heterocyclic groups containing one hetero atom include, but are not limited to, azetidinyl, oxetanyl and thietane.
  • Exemplary 5-membered heterocyclic groups containing one hetero atom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolyl, oxathiolanyl, oxathiolanyl (1,2-oxothio) Cyclopentenyl, 1,3-oxathiolanyl, dithiolanyl, dihydropyrazolyl, dihydroimidazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrogen Oxazolyl, dihydroisoxazolyl, dihydrooxadiazolyl and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 6-membered heterocyclic groups containing one hetero atom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, tetrahydropyridyl and thiacyclohexane.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dihydropyrazinyl, piperazinyl, morpholinyl, dithianyl, dioxoalkyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, hexahydrotriazinyl.
  • Exemplary 7-membered heterocyclic groups containing one or two heteroatoms include, but are not limited to, azepanyl, diazepanyl, oxacycloheptyl, and thienyl.
  • Exemplary 5-membered heterocyclic groups (also referred to herein as 5,6-bicyclic heterocyclyl) fused to a 6-membered aryl ring include, but are not limited to, indanyl, isoindoline , dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclic groups fused to a 6-membered aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolinyl, and many more.
  • C 6 -C 10 aryl refers to a monocyclic or polycyclic (eg, bicyclic or tricyclic) 4n+2 having 6-10 ring carbon atoms and zero heteroatoms provided in an aromatic ring system.
  • An aromatic ring system for example, a group having 6 or 10 ⁇ electrons shared in a ring-like arrangement.
  • an aryl group having six ring carbon atoms ( "C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (" C10 aryl”; for example, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • C 6 -C 10 aryl also includes ring systems in which the above aryl ring is fused to one or more carbocyclic, heterocyclic, aryl and heteroaryl groups, wherein The atomic group or point of attachment is on the aryl ring, in which case the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system.
  • Typical aryl groups include, but are not limited to, those derived from acetaminophen, decene, acephenanthrylene, hydrazine, hydrazine, benzene, quinone, acetophenone, fluoranthene, anthracene, hexacene, and hexyl Fen, hexene, asymmetric introduction, symmetric introduction, indole, anthraquinone, naphthalene, octabenzene, octene, octene, egg benzene, penta-2,4-diene, pentacene , pentylene, penfen, hydrazine, phenalene, phenanthrene, anthracene, heptarene, anthracene, quercetin, jade red, benzophenanthrene and quinone.
  • the aryl group includes a phenyl group, a naphthyl group, an anthracenyl group, and a tetrahydronaphthyl group.
  • each aryl group is independently optionally substituted, that is, unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl").
  • the aryl group is an unsubstituted C 6-10 aryl group.
  • the aryl group is a substituted C 6-10 aryl group.
  • C 5 -C 11 heteroaryl means a 5-11 membered monocyclic or bicyclic 4n+2 aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms (for example, having a ring-like arrangement) a group of 6 or 10 ⁇ electrons, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • C 5 heteroaryl groups which is a 5-membered ring having carbon atoms and 1-4 ring heteroatoms 4n + 2 is a monocyclic aromatic ring system (e.g., an annular arrangement having a shared 6 Each ⁇ -electron group, wherein each heteroatom is independently selected from the group consisting of nitrogen, oxygen, and sulfur.
  • C 6 heteroaryl group which is a 6-membered monocyclic 4n + 2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., an annular arrangement having a shared 6
  • the point of attachment may be a carbon or nitrogen atom as long as the valence permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the above heteroaryl ring is fused to one or more carbocyclic, heterocyclyl, aryl or heteroaryl groups, and the point of attachment is on the heteroaryl ring, In this case, the number of carbon atoms continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • each heteroaryl is independently optionally substituted, ie, unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents (“substituted heteroaryl”” ).
  • the heteroaryl is an unsubstituted C 5 -C 11 heteroaryl.
  • the heteroaryl is a substituted C 5 -C 11 heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyrrolyl, furyl and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one hetero atom include, but are not limited to, pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one hetero atom include, but are not limited to, azepandinyl, oxepanethylene, and thiephenylene.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, mercapto, isodecyl, oxazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzooxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Pyridazinyl and fluorenyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, acridinyl, quinolyl, isoquinolinyl, fluorenyl, quinoxalinyl, pyridazinyl and quinazolinyl .
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.
  • substituted whether or not preceded by the term “optionally”, means that at least one hydrogen present on a group (eg, a carbon or nitrogen atom) is substituted with an allowable substituent, for example, when substituted.
  • Substituents that result in stable compounds for example, compounds that do not spontaneously undergo a transition (eg, by rearrangement, cyclization, elimination, or other reaction).
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, The substituents at one position are the same or different.
  • substituted includes substitutions made with all of the permissible substituents of the organic compound that result in the formation of any of the substituents described herein.
  • a hetero atom such as nitrogen can have a hydrogen substituent and/or any suitable substituent described herein that satisfies the valence of the hetero atom and results in the formation of a stable moiety.
  • Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are bonded to form a heterocyclyl or a heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R dd groups Substitute
  • Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc groups are bonded to form a heterocycle a hetero or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R Substituting dd group;
  • Each of R ee is independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon The cyclo, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff groups are bonded to form a heterocyclic group Or a heteroaryl ring wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R gg Group substitution
  • pharmaceutically acceptable salt means that, within the scope of sound medical judgment, it is suitable for contact with tissues of humans and lower animals without excessive toxicity, irritation, allergies, etc., and with reasonable benefits/dangers. Those salts that are proportionate.
  • Pharmaceutically acceptable salts are well known in the art. For example, Berge et al., pharmaceutically acceptable salts as described in detail in J. Pharmaceutical Sciences (1977) 66: 1-19.
  • Pharmaceutically acceptable salts of the compounds of the invention include those derived from suitable inorganic and organic acids and inorganic and organic bases.
  • non-toxic acid addition salts examples include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or salts with organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Also included are salts formed using conventional methods in the art, for example, ion exchange methods.
  • adipic acid salts alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphor Acid salt, camphor sulfonate, citrate, cyclopentanoate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, gluconate, glycerol Phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate , malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate Salt, pectin
  • Pharmaceutically acceptable salts derived from suitable bases include the alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts and amine cations formed with counterions, counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, Nitrate, lower alkyl sulfonate and aryl sulfonate.
  • Subjects for administration include, but are not limited to, humans (ie, males or females of any age group, eg, pediatric subjects (eg, infants, children, adolescents) or adult subjects (eg, young Adults, middle-aged adults or older adults) and/or non-human animals, for example, mammals, for example, primates (eg, cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "person,” “patient,” and “subject” are used interchangeably herein.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition that reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder. Or the development of a condition ("therapeutic treatment"), which also includes the effect that occurs before the subject begins to have a particular disease, disorder or condition (“prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • an effective amount of a compound of the invention can vary depending on, for example, the biological target, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the subject's Age health conditions and symptoms. Effective amounts include therapeutically effective amounts and prophylactically effective amounts.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in the course of treating a disease, disorder or condition, or one or more symptoms associated with a disease, disorder or condition. The amount of delay or minimization.
  • a therapeutically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder or condition.
  • the term "therapeutically effective amount” can include an amount that improves overall treatment, reduces or avoids the symptoms or causes of the disease or condition, or enhances the therapeutic effect of other therapeutic agents.
  • a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or an amount sufficient to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent disease, unless otherwise stated. The amount of recurrence of a disorder or condition.
  • a prophylactically effective amount of a compound refers to the amount of a therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in the prevention of a disease, disorder or condition.
  • the term “prophylactically effective amount” can include an amount that improves the overall prevention, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • Combination and related terms mean the simultaneous or sequential administration of a compound of the invention and other therapeutic agents.
  • the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or together with other therapeutic agents, in a single unit dosage form.
  • the compounds of the invention are useful in the treatment and/or prevention of viral infections. These diseases include, but are not limited to, human immunodeficiency virus HIV infection, hepatitis B virus HBV infection.
  • a compound of the invention refers to a compound of formula (I)-formula (IV), including a subset thereof, such as a compound of formula (Iia), a pharmaceutically acceptable salt thereof, a stereoisomer, Solvate, hydrate, crystalline form or isotope derivative.
  • the invention relates to a compound of formula (I):
  • X is selected from O or S
  • Y is selected from a bond, O or S;
  • n is selected from 0 to 5;
  • A is selected from:
  • n is selected from 12 to 21;
  • each R 1 is independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted C 3 -C 7 heterocyclyl, or two
  • the R 1 groups are taken together to form an optionally substituted C 3 -C 7 carbocyclic group or an optionally substituted C 3 -C 7 heterocyclic group;
  • V is selected from O or NH
  • B is H, or is the following structure:
  • R 2 and R 3 are each independently selected from H, an optionally substituted C 1 -C 6 alkyl group or a side chain of a natural or pharmaceutically acceptable amino acid, and if the side chain contains a carboxyl group, the carboxyl group may be optionally alkyl or An aryl esterification, or R 1 , R 2 together with the carbon atom to which they are attached may form an optionally substituted C 3 -C 7 carbocyclic group or an optionally substituted C 3 -C 7 heterocyclic group;
  • each R 4 is independently selected from H, an optionally substituted C 1 -C 6 acyl group, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 7 carbocyclic group, optionally substituted a C 3 -C 7 heterocyclic group, an optionally substituted C 6 -C 11 aryl group or an optionally substituted C 5 -C 11 heteroaryl group, p is selected from 1 or 2;
  • Z is selected from O or S
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 heteroalkyl group, an optionally substituted C 1 -C 6 acyl group, an optionally substituted C 2 -C 6 olefin a optionally substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 7 carbocyclic group, an optionally substituted C 3 -C 7 heterocyclic group, an optionally substituted C 6 -C 11 aryl group a optionally substituted C 5 -C 11 heteroaryl group as long as it is chemically acceptable;
  • the compound does not include a compound of the formula:
  • A is selected from:
  • phenyl optionally substituted phenyl, pyridyl, pyrimidinyl or naphthyl; preferably phenyl;
  • n is selected from 12, 14, 16 or 18;
  • R 1 is independently selected from optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 6 carbocyclyl, optionally substituted C 3 a -C 6 heterocyclic group; preferably, each R 1 is independently selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 7 carbocyclic group; more preferably, each R 1 is independently Is selected from the group consisting of methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl; most preferably, each R 1 is independently selected from methyl, isopropyl; or, two R 1 groups Forming an optionally substituted
  • each R 4 is independently selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 7 carbocyclyl, optionally substituted C 3 -C 7 Heterocyclic group; preferably, R 4 is independently selected from the group consisting of H, methyl, and cyclopropyl.
  • R 2 is selected from H or an optionally substituted C 1 -C 4 alkyl group, and more preferably, R 2 is selected from H or methyl.
  • R 3 is selected from H or a side chain of a natural or pharmaceutically acceptable amino acid, wherein the amino acid is preferably glycine, alanine, leucine, isoleucine, valine, proline, benzene Alanine, methionine, tryptophan, serine, glutamine, threonine, cysteine, histidine, aspartic acid, tyrosine, aspartic acid, glutamic acid,
  • the naphthylamine or arginine is more preferably glycine, alanine, leucine, phenylalanine, asparagine or arginine, and more preferably glycine, alanine or phenylalanine.
  • R 2 , R 3 may, together with the carbon atom to which they are attached,
  • R 5 is selected from the group consisting of an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 heteroalkyl group, an optionally substituted C 2 -C 6 alkenyl group, An optionally substituted C 2 -C 6 alkynyl group, an optionally substituted C 3 -C 7 carbocyclic group or an optionally substituted C 3 -C 7 heterocyclic group; preferably, R 5 is selected from optionally substituted C 1- C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 7 carbocyclyl or optionally substituted C 3 -C 7 heterocyclyl; preferably, R 5 is selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 3 -C 7 carbocyclic group;
  • R 5 is selected from the group consisting of:
  • R 5 is selected from the group consisting of:
  • n is selected from 0, 2, 3, 4 or 5; more preferably, m is selected from 0, 2 or 3.
  • the invention provides a compound of formula (I):
  • X is selected from O or S
  • n is selected from 0 to 5;
  • Y is selected from a bond, O or S;
  • A is selected from:
  • each R 1 is independently selected from optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 An alkyl group, an optionally substituted C 3 -C 7 carbocyclic group, an optionally substituted C 3 -C 7 heterocyclic group;
  • V is selected from O or NH
  • B is H, or is the following structure:
  • R 2 and R 3 are each independently selected from H or an optionally substituted C 1 -C 6 alkyl group, or R 2 , R 3 may together with the carbon atom to which they are attached form an optionally substituted C 3 -C 7 carbocyclic ring Or optionally substituted C 3 -C 7 heterocyclic group;
  • Z is selected from O or S
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 heteroalkyl group, an optionally substituted C 3 -C 7 carbocyclic group or an optionally substituted C 3 -C 7 heterocyclic group;
  • the compound does not include a compound of the formula:
  • the invention provides a compound of formula (IIa) or formula (IIb):
  • Y is selected from a bond or O
  • the invention provides a compound of formula (IIa) or formula (IIb):
  • n is selected from 0, 2, 3, 4 or 5;
  • Y is selected from a bond or O
  • A is selected from:
  • V is selected from O or NH
  • R 2 and R 3 are each independently selected from H or an optionally substituted C 1 -C 6 alkyl
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 3 -C 7 carbocyclic group;
  • n is selected from 0, 2, 3, 4 or 5; preferably, m is selected from 0, 2 or 3.
  • n is selected from 13 to 17; preferably, n is selected from 13, 15 or 17; more preferably, n is selected from 15.
  • R 2 and R 3 are each independently selected from H or optionally substituted C 1 -C 6 alkyl; preferably, R 2 and R 3 are each independently selected from H or optionally substituted Methyl, ethyl or isopropyl; preferably, R 2 and R 3 are each independently selected from H or methyl; more preferably, R 2 and R 3 are each independently selected from H; more preferably, R 2 It is hydrogen and R 3 is a methyl group.
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 3 -C 7 carbocyclic group; preferably, R 5 is selected from the group consisting of methyl, ethyl, and Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl, cyclopentyl or cyclohexyl; more preferably, R 5 is selected from isopropyl.
  • the invention provides a compound of formula (IIa) or formula (IIb):
  • n 0, 2 or 3;
  • Y is selected from a bond or O
  • A is selected from:
  • V is selected from O or NH
  • R 2 and R 3 are each independently selected from H or methyl
  • R 5 is selected from isopropyl
  • the invention provides a compound of formula (IIIa) or formula (IIIb):
  • the invention provides a compound of formula (IIIa) or formula (IIIb):
  • n is selected from 0, 2, 3, 4 or 5;
  • A is selected from:
  • each R 1 is independently selected from optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 7 carbon Ring base
  • V is selected from O or NH
  • R 2 and R 3 are each independently selected from H or an optionally substituted C 1 -C 6 alkyl
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 3 -C 7 carbocyclic group;
  • n is selected from 0, 2, 3, 4 or 5; preferably, m is selected from 0, 2 or 3.
  • n is selected from 13 to 17; preferably, n is selected from 13, 15 or 17; more preferably, n is selected from 15.
  • R 1 is independently selected from optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 7 carbocyclyl; preferably, R 1 is independently selected from methyl, Ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; more preferably, R 1 is selected from methyl.
  • R 2 and R 3 are each independently selected from H or optionally substituted C 1 -C 6 alkyl; preferably, R 2 and R 3 are each independently selected from H or optionally substituted Methyl, ethyl or isopropyl; preferably, R 2 and R 3 are each independently selected from H or methyl; more preferably, R 2 and R 3 are each independently selected from H; more preferably, R 2 It is hydrogen and R 3 is a methyl group.
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 3 -C 7 carbocyclic group; preferably, R 5 is selected from the group consisting of methyl, ethyl, and Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl, cyclopentyl or cyclohexyl; more preferably, R 5 is selected from isopropyl.
  • the invention provides a compound of formula (IIIa) or (IIIb):
  • n 0, 2 or 3;
  • A is selected from:
  • each R 1 is selected from a methyl group
  • V is selected from O or NH
  • R 2 and R 3 are each independently selected from H or methyl
  • R 5 is selected from isopropyl
  • the invention provides a compound of formula (IV):
  • the compound does not include a compound of the formula:
  • Y is selected from a bond or O; m, A, V, L, R 2 , R 3 and R 5 are as defined above.
  • the invention provides a compound of formula (IV):
  • n is selected from 2, 3, 4 or 5;
  • Y is O
  • A is selected from:
  • each R 1 is independently selected from optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 7 carbon Ring base
  • V is selected from O or NH
  • R 2 and R 3 are each independently selected from H or an optionally substituted C 1 -C 6 alkyl
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 3 -C 7 carbocyclic group;
  • n is selected from 0, 2, 3, 4 or 5; preferably, m is selected from 0, 2 or 3.
  • n is selected from 13 to 17; preferably, n is selected from 13, 15 or 17; more preferably, n is selected from 15.
  • R 1 is independently selected from optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 7 carbocyclyl; preferably, R 1 is independently selected from methyl, Ethyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl; more preferably, R 1 is selected from methyl.
  • R 2 and R 3 are each independently selected from H or optionally substituted C 1 -C 6 alkyl; preferably, R 2 and R 3 are each independently selected from H or optionally substituted Methyl, ethyl or isopropyl; preferably, R 2 and R 3 are each independently selected from H or methyl; more preferably, R 2 and R 3 are each independently selected from H; more preferably, R 2 It is hydrogen and R 3 is a methyl group.
  • R 5 is selected from an optionally substituted C 1 -C 6 alkyl group or an optionally substituted C 3 -C 7 carbocyclic group; preferably, R 5 is selected from the group consisting of methyl, ethyl, and Propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, neopentyl, cyclopentyl or cyclohexyl; more preferably, R 5 is selected from isopropyl.
  • the invention provides a compound of formula (IV):
  • n 0, 2 or 3;
  • Y is O
  • A is selected from:
  • each R 1 is selected from a methyl group
  • V is selected from O or NH
  • R 2 and R 3 are each independently selected from H or methyl
  • R 5 is selected from isopropyl
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the invention may be in the form of individual enantiomers, diastereomers or geometric isomers (e.g., cis and trans isomers), or may be in the form of a mixture of stereoisomers, A racemic mixture and a mixture rich in one or more stereoisomers are included.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of a chiral salt; or preferred isomers can be passed Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • the invention also includes all suitable isotopic derivatives of the compounds of the invention.
  • An isotope derivative of a compound of the invention is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature.
  • isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, for example 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, respectively. 18 F, 31 P, 32 P, 35 S and 36 Cl.
  • isotopic derivatives of the compounds of the invention are useful in drug and/or substrate tissue distribution studies.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with isotopes e.g., hydrazine, i.e., 2 H
  • Isotopic derivatives of the compounds of the invention can generally be prepared by conventional procedures, for example by descriptive methods or by the preparations described in the Examples below, using appropriate isotopic derivatives of the appropriate reagents.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof may be in an amorphous or crystalline form.
  • the compounds of the invention may exist in one or more crystalline forms. Accordingly, the invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • the term "polymorph" refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can result in a crystalline form that predominates. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ACSSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: Solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each This article is incorporated herein by reference.
  • a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo.
  • Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I).
  • an ester such as a methyl ester, an ethyl ester or the like can be used.
  • the ester itself may be active and/or may hydrolyze under conditions in humans.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
  • compositions, formulations and kits are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (also referred to as "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of the active component.
  • the pharmaceutical composition comprises a therapeutically effective amount of the active component.
  • the pharmaceutical composition comprises a prophylactically effective amount of the active component.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle which does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (eg, human serum white) Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene - Block
  • kits e.g., pharmaceutical packs.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents) Suitable container).
  • first and second containers eg, vials, ampoules, bottles, syringes, and/or dispersible packages or other materials containing the compounds of the invention, other therapeutic agents
  • kits can also optionally include a third container containing a pharmaceutically acceptable excipient for diluting or suspending a compound of the invention and/or other therapeutic agent.
  • a compound of the invention provided in a first container and a second container is combined with other therapeutic agents to form a unit dosage form.
  • formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention.
  • the invention is not limited to the following pharmaceutical compositions.
  • Exemplary Formulation 1 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 0.3-30 mg tablets (each tablet contains 0.1-10 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 2 - Tablet The compound of the present invention in dry powder form can be mixed with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 30-90 mg tablet (each tablet contains 10-30 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 3 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 90-150 mg tablet (30-50 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 4-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is formed into a 150-240 mg tablet (each tablet contains 50-80 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 5 - Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 240-270 mg tablets (each tablet contains 80-90 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 6-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into a 270-450 mg tablet (each tablet contains 90-150 mg of active compound) in a tablet press.
  • Exemplary Formulation 7-Tablet The compound of the invention in dry powder form can be combined with the dried gel binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate was added as a lubricant. The mixture is shaped into 450-900 mg tablets (each tablet contains 150-300 mg of active compound per tablet) in a tablet press.
  • Exemplary Formulation 8-Capsule The compound of the present invention in dry powder form can be mixed with a starch diluent in a weight ratio of about 1:1. The mixture was filled into 250 mg capsules (each capsule containing 125 mg of active compound).
  • Exemplary Formulation 9-Liquid The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended, passed through a No. 10 mesh U.S. sieve, and then It was mixed with an aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) prepared in advance. Sodium benzoate (10 mg), flavor and color are diluted with water and added with stirring. Then, sufficient water can be added to give a total volume of 5 mL.
  • Exemplary Formulation 10 - Injection The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg/mL.
  • the pharmaceutical composition provided by the present invention can be administered by a variety of routes including, but not limited to, oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intra-articular administration, intra-arterial administration, intrasynovial administration, intrasternal administration. , intracerebroventricular administration, intralesional administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician. .
  • the compound provided herein is administered to a subject at risk of developing the condition, typically based on a physician's recommendation and administered under the supervision of a physician, at the dosage level as described above.
  • Subjects at risk of developing a particular condition typically include subjects with a family history of the condition, or those subjects that are particularly susceptible to developing the condition by genetic testing or screening.
  • long-term administration can also be administered chronically.
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof for a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can be continuously administered indefinitely, For example, the rest of the subject.
  • chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, for example, within a therapeutic window.
  • a pharmaceutical composition of the present invention can be further delivered using various methods of administration.
  • a pharmaceutical composition can be administered by bolus injection, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, for example, an intramuscular or subcutaneous bolus dose that causes a slow release of the active ingredient, while a bolus that is delivered directly to the vein (eg, via IV IV drip) ) can be delivered more quickly, so that the concentration of the active ingredient in the blood is rapidly increased to an effective level.
  • the pharmaceutical composition can be administered in a continuous infusion form, for example, by IV intravenous drip to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition can be administered first, followed by continued infusion.
  • Oral compositions can be in the form of a bulk liquid solution or suspension or bulk powder. More generally, however, the composition is provided in unit dosage form for ease of precise dosing.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active ingredient suitable to produce the desired therapeutic effect with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, pre-measured ampoules or syringes of the liquid compositions, or pills, tablets, capsules and the like in the case of solid compositions.
  • the compound will generally be a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being useful for forming the desired form of administration.
  • a carrier or excipient and a processing aid is provided in unit dosage form for ease of precise dosing.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, each preferably providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably about 0.1. To about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 1 mg/kg/hr to at least 10 mg/kg/hr from about 1 to about 120 hours, especially 24 to 96 hours.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be administered.
  • the maximum total dose cannot exceed about 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous vehicles as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or a compound having similar properties: a binder, for example, microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as mint, water Methyl salicylate or orange flavoring.
  • a binder for example, microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrant, For example, alginic acid, Primogel or corn star
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound will typically be a minor component, often from about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient.
  • the active component When formulated as an ointment, the active component is typically combined with a paraffin or water miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and generally include other ingredients for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
  • transdermal administration can be accomplished using a reservoir or a porous membrane type, or a patch of a plurality of solid matrices.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, part 8 of which is incorporated herein by reference.
  • the compounds of the invention may also be administered in sustained release form or from a sustained release delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention further relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are alpha-, beta- and gamma-cyclodextrins consisting of 6, 7 and 8 alpha-1,4-linked glucose units, respectively, optionally including one on the attached sugar moiety. Or a plurality of substituents including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, eg, sulfobutylether beta-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation comprises hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • the compounds of the invention or compositions thereof may be administered in combination with other therapeutic agents to treat the disease.
  • therapeutic agents include, but are not limited to:
  • Non-nucleoside inhibitors of HIV reverse transcriptase such as capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) Caraline A ((+) calanolide A), etravirine, GW5634, DPC-083, DPC-961, DPC-963, WIV-150, TMC-120, rivivirin ( Rilpivirine), BILR355BS, VPX840773, UK-453061 and RDEA806;
  • nucleoside inhibitors of HIV reverse transcriptase such as zidovudine, emtricitabine, didanosine, stavudine (d4T), zhaxi Zalcitabine (ddC), Lamivudine (3TC), Abacavir, amdoxovir, elvucitabine, alovudine, MIV -210, raxivir, D-d4FC, phosphazide, fozivudine tidoxil, aripipibine (AVX754), GS-7340, KP-1461 and phosphorus Fosalvudine tidoxil;
  • Nucleotide inhibitors of HIV reverse transcriptase such as tenofovir disoproxil and adefovir dipivoxil;
  • HIV integrase inhibitors such as curcumin, curcumin derivatives, cichoric acid, cichoric acid derivatives, 3,5-dicaffeoyl quinic acid, 3,5-dicaffeoyl quinic acid derivatives, gold Refined tricarboxylic acid, aurin tricarboxylic acid derivative, phenethyl caffeate, phenethyl citrate derivative, tyrosine phosphorylation inhibitor, tyrosine phosphorylation inhibitor derivative, dermatan, dermatan Derivatives, S-1360, zintevir, L-870812 and L-870810, raltegravir, entegevir, BMS-538158, GSK364735C, BMS-707035, MK-2048 and BA011 ;
  • gp41 inhibitors such as enfuvirtide, sifuvirtide, FB006M and TRI-1144;
  • a CXCR4 inhibitor such as AMD-070
  • gp120 inhibitor such as BMS-488043 or BlockAide/CR
  • G6PD and NADH-oxidase inhibitors such as immunogen (immunitin);
  • CCR5 inhibitors such as aplaviroc, vicriviroc, maraviroc, PRO-140, INCB15050, PF-233798 and CCR5 mAb004;
  • Interferons such as PEGylated rIFN-a 2b, PEGylated rIFN-a 2a, rIFN-a 2b, rIFN-a 2a, combined IFN a (infergen), enzyme protein (feron) ), reefon, intermax a, r-IFN-, actimmune, IFN-w and DUROS, albumin interferon, locteron, albumin Interferon (Albuferon), Libifu (Rebif), oral interferon alpha, IFN-2bXL, AVI-005, PEG-dry hydrazine and PEGylated IFN-;
  • ribavirin analogs such as rebetol, copegus, viramidine (taribavirin);
  • NS5b polymerase inhibitors such as NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB1941, XTL-2125, MK-0608, NM-107, R7128 (R4048), VCH-759, PF-868554 and GSK625433;
  • NS3 protease inhibitors such as SCH-503034 (SCH-7), VX-950 (telaprevir), BILN-2065, BMS-605339 and ITMN-191;
  • an a-glucosidase 1 inhibitor such as MX-3253 (celgosivir), UT-231B;
  • Hepatoprotective drugs such as IDN-6556, ME3738, LB-84451 and MitoQ;
  • Non-nucleoside inhibitors of HCV for example, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831, GS-9190 and A-689 ;
  • those other active agents can be administered separately from the compositions containing the compounds of the invention as part of a multiple dosing regimen.
  • those active agents may be part of a single dosage form, mixed with the inventive compound in a single composition. If administered as part of a multiple dosing regimen, the two active agents can be provided simultaneously, sequentially, or at intervals from one another (usually within 5 hours of each other).
  • the present invention provides a method for treating and/or preventing a viral infection or a method for treating a disease, which comprises the steps of administering a compound of the present invention, or a pharmaceutically acceptable salt thereof, a stereoisomer thereof to a subject in need of treatment.
  • the compounds of the invention may treat and/or prevent viral infections including, but not limited to, human immunodeficiency virus HIV infection, hepatitis B virus HBV infection.
  • the compounds of the present invention can be prepared according to conventional methods in the art and using suitable reagents, starting materials, and purification methods known to those skilled in the art.
  • each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (e.g., 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C).
  • the reaction time is usually from 0.1 to 60 hours, preferably from 0.5 to 24 hours.
  • Step 1 Synthesis of 3-hexadecyloxy-1-propanol (Compound 1).
  • Step 2 (R)-(1-(6-((Dimethylamino)methylallyl)-9H-indol-9-yl)propan-2-yloxy)methyldichlorophosphonate (Compound 2) Synthesis.
  • Step 3 Synthesis of (R)-9- ⁇ 2-[(hexadecanoxypropyl)phosphate methoxy]propyl ⁇ adenine (Compound 3)
  • Step 1 Synthesis of 3-hexadecanethio-1-propanol (Compound 4).
  • Step 1 Synthesis of (R)-9-[2-(phenoxyphosphorylmethoxy)propyl]adenine (Compound 5).
  • Step 2 9- ⁇ (R)-2-[( ⁇ [(S)-1-(isopropyloxycarbonyl)ethyl]amino ⁇ phenoxyphosphoryl)methoxy]propyl ⁇ adenine (Compound 6 )Synthesis
  • Step 3 9- ⁇ (R)-2-[( ⁇ [(S)-1-(isopropyloxycarbonyl)ethyl)amino ⁇ phenoxythiophosphoryl)methoxy]propyl ⁇ adenine ( Synthesis of Compound T-3)
  • Step 1 Synthesis of (R)-9- ⁇ 2-[(hexadecyloxypropyl)(isopropylcarbamoylmethyl)phosphorylmethoxy]propyl ⁇ adenine (Compound 7).
  • Step 2 Synthesis of (R)-9- ⁇ 2-[(hexadecyloxypropyl)(isopropylcarbamoylmethyl)thiophosphoric acid methoxy]propyl ⁇ adenine (Compound T-4).
  • Step 1 Synthesis of isopropyl chloromethylthiocarbonate (Compound 8).
  • Step 2 Synthesis of (R)-9- ⁇ 2-[(hexadecyloxypropyl)(isopropylthiocarbomethyl)phosphomethoxy]propyl ⁇ adenine (Compound T-5) .
  • Step 1 9- ⁇ (R)-2-[( ⁇ [(S)-1-(isopropyloxycarbonyl)ethyl]amino ⁇ (hexadecaneoxypropyl)phosphoryl)methoxy]propyl ⁇ Synthesis of adenine (Compound 9).
  • Step 2 9- ⁇ (R)-2-[( ⁇ [(S)-1-(isopropyloxycarbonyl)ethyl]amino ⁇ (hexadecyloxypropyl)thiophosphoryl)methoxy] Synthesis of propyl ⁇ adenine (Compound T-6).
  • Step 1 Synthesis of (S)-2-(tert-butoxycarbonylamino)propionic acid isopropyl sulfide (Compound 10).
  • Step 2 Synthesis of (S)-2-aminopropionic acid isopropyl sulfide (Compound 11).
  • Step 3 9- ⁇ (R)-2-[( ⁇ [(S)-1-(isopropylthiocarbonyl)ethyl]amino ⁇ (hexadecaneoxypropyl)phosphoryl)methoxy]propyl ⁇ Synthesis of adenine (Compound T-7).
  • Step 2 Synthesis of (R)-9- ⁇ 2-[(acetylthioethyl)phosphorylmethoxy]propyl ⁇ adenine (Compound 13).
  • Step 3 Synthesis of (R)-9- ⁇ 2-[(acetylthioethyl)(isopropylcarbomethyl)phosphomethoxy]propyl ⁇ adenine (Compound T-8).
  • EC 50 refers to an effective concentration that inhibits 50% of virus production, 50% of viral infectivity, or 50% of virus-induced cellular effects.
  • CC 50 refers to an inhibitory concentration that reduces cell growth or viability of uninfected cells by 50%.
  • test compound and the reference compound will be diluted in DMSO and added to the cell culture plate.
  • the test compound and the reference compound will be tested at 8 concentrations, two duplicate wells.
  • HIV-1 and MT-4 cells were co-cultured for 1 h at 37 ° C in a 5% CO 2 incubator. The infected cells are then seeded in a cell culture plate at a density. The final concentration of DMSO in the cell culture medium was 0.5%. The cells were cultured for 5 days at 37 ° C in a 5% CO 2 incubator. The cells in the cytotoxicity test were uninfected MT-4 cells, and other experimental conditions were consistent with the antiviral activity experiments.
  • Cell viability assay Cell viability was determined by the cell activity assay reagent CellTiter-Glo (Promega). Raw data were used for compound anti-HIV-1 activity and cytotoxicity calculations. The compound dose response curve and its EC 50 and CC 50 values will be obtained after analysis by GraphPad Prism software, where A represents EC 50 ⁇ 5 nM, B represents 5 nM ⁇ EC 50 ⁇ 20 nM, C represents 20 nM ⁇ EC 50 ⁇ 100 nM, and D represents EC.
  • E represents 3000 nM ⁇ CC 50 ⁇ 10000 nM
  • F represents 10000 nM ⁇ CC 50 ⁇ 50000 nM
  • G represents CC 50 > 50000 nM (as shown in Table 1 below).
  • EC 50 refers to an effective concentration that inhibits 50% of virus production, 50% of viral infectivity, or 50% of virus-induced cellular effects.
  • CC 50 refers to an inhibitory concentration that reduces cell growth or viability of uninfected cells by 50%.
  • Anti-Cell Activity Assay The in vitro anti-HBV activity of the Example compounds was tested in HepG2.2.15 cells, with TDF as a positive control compound. On the first day, the cells were seeded into a 96-well plate, the compound was added to the cells for the next day, and the new compound-containing medium was replaced on the fifth day. On the eighth day, the supernatant was collected to extract DNA. The amount of HBV DNA was detected by quantitative PCR. The test compound and TDF were serially diluted 3 times, 8 concentration points, and 2 duplicate wells were determined in parallel. The final concentration of DMSO in the culture broth was 0.5%. The inhibition percentage is calculated as follows:
  • Inhibition rate (1 - copy number of HBV in the sample / copy number of HBV in the DMSO control group) ⁇ 100%
  • the EC 50 was analyzed by Graphpars Prism software (four parameter logistic equations), where I represents EC 50 ⁇ 50 nM, II represents 50 nM ⁇ EC 50 ⁇ 200 nM, III represents 200 nM ⁇ EC 50 ⁇ 500 nM, and IV represents EC 50 > 500 nM (see Table 1 below) Show).
  • Cytotoxicity test The compound plate and compound treatment procedure were consistent with the detection of anti-HIV activity. After six days of treatment of the cells, the cell viability was determined. Add Cell-titer Blue reagent to each well, incubate for 3 hours at 37 °C, read fluorescence values (560Ex/590Em); analyze data and calculate relative cell viability:
  • CC 50 value of the compound was calculated using GraphPad Prism software, where V represents 7000 nM ⁇ CC 50 ⁇ 50000 nM and VI represents CC 50 > 50000 nM (as shown in Table 1 below).
  • the compounds of the present invention have strong anti-HIV activity and HBV activity (both to nanomolar levels). Furthermore, the compounds of the present invention showed no toxicity (optimum CC 50 >50000 nM) in the cell lines tested.
  • Microsomal experiments human liver microsomes: 0.5 mg/mL, Xenotech; rat liver microsomes: 0.5 mg/mL, Xenotech; coenzyme (NADPH/NADH): 1 mM, Sigma Life Science; magnesium chloride: 5 mM, 100 mM phosphate buffer Agent (pH 7.4).
  • Preparation of stock solution A certain amount of the compound example powder was accurately weighed and dissolved to 5 mM with DMSO, respectively.
  • NADPH regeneration system containing 6.5 mM NADP, 16.5 mM G-6-P, 3 U/mL G-6-P D, 3.3 mM magnesium chloride was prepared and placed on wet ice before use.
  • 812.5 ⁇ L of SD rat liver microsomes were added and mixed to obtain a liver microsome dilution with a protein concentration of 0.625 mg/mL.
  • the corresponding compound had a reaction concentration of 1 ⁇ M and a protein concentration of 0.5 mg/mL.
  • 100 ⁇ L of the reaction solution was taken at 10, 30, and 90 min, respectively, and added to the stopper, and the reaction was terminated by vortexing for 3 min.
  • the plate was centrifuged at 5000 x g for 10 min at 4 °C.
  • 100 ⁇ L of the supernatant was taken into a 96-well plate to which 100 ⁇ L of distilled water was previously added, mixed, and sample analysis was performed by LC-MS/MS.
  • the compounds of the present invention were tested in the above microsomal experiments and found to have superior metabolic stability.
  • the results of the human liver microsome experiment and the rat liver microsome experiment of the representative examples are summarized in Table 2 below.
  • the experimental results are shown in Table 2 above.
  • the compound of the present invention has a longer half-life and a smaller clearance rate, and exhibits superior metabolic stability in both human liver microsomes and rat liver microsomes, and is more suitable as an anti-HIV and / or HBV-infected drugs.
  • SD rat grade SPF grade
  • Weight range 180 ⁇ 220g (actual weight range is 187 ⁇ 197g)
  • the pharmacokinetics of the male SD rats were determined by the non-compartmental statistical moment theory to obtain the compound of the example (3 mg/kg) by using Winnonin software. parameter.
  • the compound of the present invention has excellent activity and has excellent pharmacokinetic properties, and thus is more suitable as a compound for inhibiting nucleoside reverse transcriptase, and is therefore suitable for preparing a medicament for treating an antiviral infection.

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Abstract

式(I)所示的抗病毒的核苷类逆转录酶抑制剂化合物和化合物的药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素衍生物。其制备方法和药物组合物，以及其用于制备治疗和/或预防病毒感染性疾病的药物的用途，病毒例如人类免疫缺陷病毒HIV、乙型肝炎病毒HBV。

Description

[根据细则37.2由ISA制定的发明名称]　用于抗病毒的核苷类逆转录酶抑制剂 技术领域
本发明属于医药领域。具体地，本发明涉及一类新型核苷类逆转录酶抑制剂，包含它们的药物组合物，以及它们的制备方法和作为抗病毒药物的用途，特别是治疗和/或预防人类免疫缺陷病毒HIV和/或乙型肝炎病毒HBV的病人的用途。
背景技术
病毒是一种核酸颗粒，结构极其简单，多数缺乏酶系统，只能依赖宿主细胞复制其核酸和蛋白质，然后装配成病毒颗粒而增殖。病毒感染引起多种疾病，严重危害人类的健康和生命。据不完全统计，约60％流行性传染病是由病毒感染引起的。迄今，全世界已发现的病毒超过3000种，而且新的病毒还在不断被发现。其中发病率高、危害大的病毒感染，如艾滋病，乙/丙型肝炎、巨细胞病毒感染等。
艾滋病(Acquired Immune Deficiency Syndrome,AIDS)，即获得性免疫缺陷综合征，是由人体免疫缺陷病毒(Human Immunodeficiency Virus,HIV)感染所引起的一种传染病。它是后天性细胞免疫功能出现缺陷而导致严重随即感染及或激发肿瘤并致命的一种疾病。其特征是HIV特异性攻击辅助性T淋巴细胞，造成免疫系统功能进行性破坏，导致各种机会性感染和相关肿瘤的发生。HIV病毒是一种感染人类免疫系统细胞的慢病毒(Lentivirus)，属反转录病毒的一种。HIV分为两亚型：HIV-1与HIV-2，在致病能力和传染力方面，HIV-1更强，而HIV-2则基本只存在于西部非洲部分地。因此，目前的抗HIV感染药物研究主要针对HIV-1型。根据联合国艾滋病规划署的最新报告：截止2015年底，全球共有3670万HIV感染者，1100万死亡病例；全球范围内有180万儿童HIV感染者。艾滋病不仅是医学问题，而且已是严重的社会问题，威胁者人类的生存、发展和稳定。所以仍然需要开发新型高效低毒的药物以及药物组合物用于治疗和预防艾滋病。
乙型肝炎(hepatitis B)是一种发病率高、感染力强、严重危害人类健康的世界性流行性传染病。目前，全世界约有20亿人感染过乙型肝炎病毒(hepatitis B virus,HBV)，其中3.5亿人成为慢性HBV携带者，全球每年约100万人死于HBV感染相关的肝脏疾病。我国是乙型肝炎的高发区，根根据2002年全国HBV感染者血清流行病学调查，HBsAg的流行率为9.09％，约有1.2亿人携带HBV。 其中慢性乙型肝炎(chronic hepatitis B,CHB)患者3000多万。慢性乙肝患者中有15％-25％的危险死于HBV相关性肝脏疾病，包括慢性重型肝病、肝硬化及肝细胞癌，肝硬化失代偿的年发生率约3％，5年累计发生率约16％，其中6％-15％可发展为肝细胞癌(hepatic cell carcinoma,HCC)。慢性乙肝、代偿期和失代偿期肝硬化的5年病死率分别为0％-2％、14％-20％和70％-86％。我国每年有30万人以上死于乙肝相关性并发症。此外，婴儿时期感染HBV者，90％以上成为慢性HBV携带者，并且随着年龄的增长演变为慢性肝炎、肝硬化、肝衰竭和肝细胞癌。HBV的持续复制是造成慢性乙肝患者肝脏炎症持续发展，并导致肝硬化和肝癌发生的重要因素。
吉利德研发的TDF(Tenofovir Disoproxil Fumarate)分别于2001年和2008年被美国食品药品管理局(FDA)批准用于一线药物治疗HIV和HBV感染。TDF极大的提高了细胞的穿透性和口服吸收利用度，也被美国疾控中心推荐用于预防艾滋病的药物。TDF的缺点是在血浆中容易水解为TFV(Tenofovir)；另一方面，对于肾功能缺陷的病人，TDF可能引起肾毒性的风险。
为了降低TDF在血浆代谢的TFV浓度，吉利德开发了代谢更稳定的药物TAF(Tenofovir Alafenamide Fumarate)，TAF的两个复方被FDA批准用于一线药物治疗HIV。TAF治疗HBV方面也取得成功，于2016年11月被FDA批准用于治疗伴有代偿性肝病的HBV患者。
TAF和TDF相比在两个方面有显著的区别：(1)TAF在血浆中代谢的TFV浓度比TDF低90％。(2)TAF代谢的TFV浓度在免疫细胞中TDF高4倍。所以TAF在临床上可以使用很低的剂量，显著降低了TDF引起的肾毒性和骨毒性。
尽管TAF在临床上使用很低的剂量和很高抗HIV和HBV活性，但是TAF在运转过程中和在血浆中仍有少量的水解，临床上仍然需要开发新的化合物和专一的代谢方式，进一步改善药物在血浆中的稳定性，提高在组织细胞的药物浓度，从而有效降低药物的临床剂量和进一步降低药物的肾毒性和骨毒性，更好的发挥治疗乙肝和艾滋病的临床效果。
发明内容
本发明提供了一种新的核苷类化合物及包含该化合物的组合物及其用途，其具有更好地抗HIV和HBV活性，可用于治疗和/或预防HIV感染或/和HBV感染，并极大的降低TDF或TAF引起的肾毒性和骨毒性。
对此，本发明采用的技术方案如下：
本发明的第一方面中，提供了一种式(I)所示的化合物，
Figure PCTCN2018119483-appb-000001
X选自O或S；
Y选自键、O或S；
m选自0至5；
A选自：
1)任选取代的C 6-C 11芳基或任选取代的C 5-C 11杂芳基；或者
2)-(CH 2) nCH 3，其中n选自12至21；或者
3)-C(＝O)R 1、-C(＝O)OR 1、-C(＝O)N(R 1)(R 1)，其中各R 1独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基，或二个R 1基团一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
V选自O或NH；
B为H，或者为以下结构：
Figure PCTCN2018119483-appb-000002
其中，
R 2和R 3各自独立地选自H、任选取代的C 1-C 6烷基或一种天然或可药用氨基酸的侧链，如果侧链含有羧基，该羧基可以选择被烷基或芳基酯化，或者R 2、R 3可以与其所连接的碳原子一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
L选自-C(＝O)-、-O(C＝O)-、-NR 4(C＝O)-、-S(＝O) p-、-NR 4S(＝O) p-，其中，各R 4独立地选自H、任选取代的C 1-C 6酰基、任选取代的C 1-C 6烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基、任选取代的C 6-C 11芳基或任选取代的C 5-C 11杂芳基，p选自1或2；
Z选自O或S；
R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 1-C 6酰基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基、任选取 代的C 6-C 11芳基、任选取代的C 5-C 11杂芳基，只要化学上允许；
前提是，X、Y、Z中的有且只有一者为S；
附加条件是，所述化合物不包括下式化合物：
Figure PCTCN2018119483-appb-000003
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、或同位素变体。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中，本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中，本发明化合物以治疗有效量提供。在具体实施方案中，本发明化合物以预防有效量提供。
在另一方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。
在另一方面，本发明提供了包含本发明化合物、其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体，和其它治疗剂以及药学上可接受的载剂、佐剂或媒剂的试剂盒。
在另一方面，本发明提供了在需要其的受试者中治疗和/或预防病毒感染相关病症的方法，所述方法包括：给予受试者有效量的本发明化合物。在具体实施方案中，所述病毒感染选自：人类免疫缺陷病毒HIV感染、乙型肝炎病毒HBV感染。在具体实施方案中，口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中，长期给药所述化合物。
由随后的具体实施方式、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-C 6烷基”包括C 1、C 2、C 3、C 4、C 5、C 6、C 1-C 6、C 1-C 5、C 1-C 4、C 1-C 3、C 1-C 2、C 2-C 6、C 2-C 5、C 2-C 4、C 2-C 3、C 3-C 6、C 3-C 5、C 3-C 4、C 4-C 6、C 4-C 5和C 5-C 6烷基。
应该理解，当本文描述时，任何下面所定义的部分可以被许多取代基取代，而且相应的定义在 下面列出的它们的范围内，包括这种取代部分。除非另作说明，否则，术语“取代”如下面所定义。
“C 1-C 6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团，本文也称为“低级烷基”。在一些实施方案中，C 1-4烷基是特别优选的。所述烷基的实例包括但不限于：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)、正己基(C 6)、3-甲基己基(C 6)、2,2-二甲基戊基(C 6)和2,3-二甲基戊基(C 6)。除非另作说明，否则，烷基的每个独立地任选被取代，即，未取代的(“未取代的烷基”)或被一个或多个取代基取代(“取代的烷基”)；例如，1至5个取代基、1至3个取代基或1个取代基。在一些实施方案中，烷基是未取代的C 1-C 6烷基(例如，-CH 3)。在一些实施方案中，烷基是取代的C 1-C 6烷基。
“C 1-C 6杂烷基”是指本文所定义的烷基，在母体链内，它进一步含有一个或多个(例如，1、2、3或4个)杂原子(例如，氧、硫、氮、硼、硅、磷)，其中，一个或多个杂原子在所述母体碳链内的相邻碳原子之间，和/或，一个或多个杂原子在碳原子和母体分子之间，即，在连接点之间。除非另作说明，否则，各杂烷基独立地被取代，即，未取代(“未取代的杂烷基”)或被一个或多个取代基取代(“取代的杂烷基”)。在一些实施方案中，杂烷基是未取代的C 1-C 6杂烷基。在一些实施方案中，杂烷基是取代的C 1-C 6杂烷基。作为具体实例，C 1-C 6杂烷基包括C 1-C 6烷氧基、C 1-C 6烷硫基、C 1-C 6烷氨基等，其详细定义如下。
“C 1-C 6烷氧基”是指基团-OR，其中，R为取代或未取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷氧基是特别优选的。具体的所述C 1-C 6烷氧基包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。
“C 1-C 6烷硫基”是指基团-SR，其中，R为任选取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷硫基是特别优选的。具体的所述C 1-C 6烷硫基包括但不限于：甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、叔丁硫基、仲丁硫基、正戊硫基、正己硫基和1,2-二甲基丁硫基。
“C 1-C 6烷氨基”是指基团-NHR或者-NR 2，其中，R为任选取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4烷氨基是特别优选的。具体的所述C 1-C 6烷氨基包括但不限于：甲氨基、乙氨基、正丙氨基、异丙氨基、正丁氨基、叔丁氨基、二甲氨基、甲乙氨基和二乙氨基。
“C 1-C 6酰基”是指基团-(＝O)R，其中，R为任选取代的C 1-C 6烷基。在一些实施方案中，C 1-C 4酰基是特别优选的。示例性的所述C 1-C 6酰基包括但不限于：-(＝O)CH 3、-(＝O)CH 2CH 3、-(＝O)CH 2CH 2CH 3和-(＝O)CH(CH 3) 2。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中，卤素基团是F、Cl或 Br。在一些实施方案中，卤素基团是F或Cl。在一些实施方案中，卤素基团是F。
因此，“C 1-C 6卤代烷基”和“C 1-C 6卤代烷氧基”是指上述“C 1-C 6烷基”和“C 1-C 6烷氧基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-C 4卤代烷基是特别优选的，更优选C 1-C 2卤代烷基。在一些实施方案中，C 1-4卤代烷氧基是特别优选的，更优选C 1-C 2卤代烷氧基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。示例性的所述卤代烷氧基包括但不限于：-OCH 2F、-OCHF 2、-OCF 3，等等。
“C 3-C 7碳环基”是指具有3至7个环碳原子和零个杂原子的非芳香环环烃基团。在一些实施方案中，优选C 5-C 6碳环基，具有5至6个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，优选C 3碳环基，其为具有3个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，优选C 4碳环基，其为具有4个环碳原子和零个杂原子的非芳香环烃基团。优选C 5碳环基，其为具有5个环碳原子和零个杂原子的非芳香环烃基团。优选C 6碳环基，其为具有6个环碳原子和零个杂原子的非芳香环烃基团。碳环基还包括其中上述碳环基与一个或多个碳环基、杂环基、芳基或杂芳基稠合、桥接或成螺环的环体系，其中连接点在碳环上，且在这样的情况中，碳的数目继续表示碳环基体系中的碳的数目。示例性的所述碳环基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环戊二烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环己二烯基(C 6)，以及环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)、环辛基(C 8)、环辛烯基(C 8)、二环[2.2.1]庚基(C 7)、二环[2.2.2]辛基(C 8)，等等。除非另作说明，否则，各碳环基独立地为任选取代的，即，未取代(“未取代的碳环基”)或被一个或多个取代基取代(“取代的碳环基”)。在一些实施方案中，碳环基是未取代的C 3-C 7碳环基。在一些实施方案中，碳环基是取代的C 3-C 7碳环基。
“C 3-C 7杂环基”是指具有环碳原子和1至3个环杂原子的3至7元非芳香环系，其中每个杂原子独立地选自氮、氧、硫、硼、磷和硅，其中碳、氮、硫和磷原子还可以其氧化态存在，如C(O)、S(O)、S(O) 2、P(O)等。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选C 4-C 7杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系。在一些实施方案中，优选C 4-C 6杂环基，其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系。在一些实施方案中，优选C 5-C 6杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。在一些实施方案中，更优选C 5杂环基，其为具有环碳原子和1至3个环杂原子的5元非芳香环系。在一些实施方案中，上述杂环基含有1至3个(更优选1或2个)选自氮、氧和硫 (优选氮或氧)的环杂原子。除非另作说明，否则，各杂环基独立地为任选取代的，即，未取代(“未取代的杂环基”)或被一个或多个取代基取代(“取代的杂环基”)。在一些实施方案中，杂环基是未取代的C 3-C 7杂环基。在一些实施方案中，杂环基是取代的C 3-C 7杂环基。杂环基还包括其中上述杂环基与一个或多个碳环基、杂环基、芳基或杂芳基稠合、桥接或成螺环的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基、氧硫杂环戊烯基(1,2-氧硫杂环戊烯基、1,3-氧硫杂环戊烯基)、二硫杂环戊烷基、二氢吡唑基、二氢咪唑基、二氢噻唑基、二氢异噻唑基、二氢噁唑基、二氢异噁唑基、二氢噁二唑基和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基、四氢吡啶基和硫杂环己烷基。示例性的包含两个杂原子的6元杂环基包括但不限于：二氢吡嗪基、哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基。示例性的含有一个或两个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、二氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与6元芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与6元芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。
“C 6-C 10芳基”是指具有提供在芳族环系中的6-10个环碳原子和零个杂原子的单环或多环的(例如，双环或三环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。“C 6-C 10芳基”还包括这样的环系统，在这种环系统中，上述芳基环与一个或多个碳环基、杂环基、芳基和杂芳基稠合，其中，原子团或连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。典型的芳基包括但不限于衍生自以下的基团：醋蒽烯、苊烯、醋菲烯(acephenanthrylene)、蒽、薁、苯、屈、晕苯、荧蒽、芴、并六苯、己芬、己搭烯、不对称引达省、对称引达省、茚满、茚、萘、并八苯、辛芬、辛搭烯、卵苯、戊-2,4-二烯、并五苯、戊搭烯、戊芬、苝、非那烯、菲、苉、七曜 烯、芘、皮蒽、玉红省、苯并菲和联三萘。更具体地，芳基包括苯基、萘基、茚基和四氢萘基。除非另作说明，否则，各芳基独立地任选被取代，即，未取代(“未取代的芳基”)或被一个或多个取代基取代(“取代的芳基”)。在一些实施方案中，芳基是未取代的C 6-10芳基。在一些实施方案中，芳基是取代的C 6-10芳基。
“C 5-C 11杂芳基”是指具有环碳原子和1-4个环杂原子的5-11元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在一些实施方案中，优选C 5杂芳基，其为具有环碳原子和1-4个环杂原子的5元单环4n+2芳族环体系(例如，具有以环状排列共享的6个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在一些实施方案中，优选C 6杂芳基，其为具有环碳原子和1-4个环杂原子的6元单环4n+2芳族环体系(例如，具有以环状排列共享的6个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个碳环基、杂环基、芳基或杂芳基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。除非另作说明，否则，各杂芳基独立地任选被取代的，即，未取代(“未取代的杂芳基”)或被一个或多个取代基取代(“取代的杂芳基”)。在一些实施方案中，杂芳基是未取代的C 5-C 11杂芳基。在一些实施方案中，杂芳基是取代的C 5-C 11杂芳基。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
本文定义的烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基等为任选取代的基团。通常，术语“取代的”，不论前面是否有术语“任选”，是指存在于基团(例如，碳或氮原子)上的至少一个氢被 可允许的取代基取代，例如，在取代时产生稳定的化合物的取代基，例如，不自发地进行转变(例如通过重排、环化、消除或其它反应)的化合物。除非另外说明，否则，“取代的”基团在所述基团的一个或多个可取代的位置处具有取代基，且当在任何给定结构中的一个以上的位置被取代时，在每个位置处的取代基是相同或不同的。术语“取代的”包括用有机化合物的所有可允许的取代基(导致形成稳定化合物的本文描述的任何取代基)进行的取代。对于本发明，杂原子例如氮可具有氢取代基和/或本文描述的任何合适的取代基，其满足杂原子的化合价且导致形成稳定的部分。
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR aa、-ON(R bb) 2、-N(R bb) 2、-N(R bb) 3 +X -、-N(OR cc)R bb、-SH、-SR aa、-SSR cc、-C(＝O)R aa、-CO 2H、-CHO、-C(OR cc) 2、-CO 2R aa、-OC(＝O)R aa、-OCO 2R aa、-C(＝O)N(R bb) 2、-OC(＝O)N(R bb) 2、-NR bbC(＝O)R aa、-NR bbCO 2R aa、-NR bbC(＝O)N(R bb) 2、-C(＝NR bb)R aa、-C(＝NR bb)OR aa、-OC(＝NR bb)R aa、-OC(＝NR bb)OR aa、-C(＝NR bb)N(R bb) 2、-OC(＝NR bb)N(R bb) 2、-NR bbC(＝NR bb)N(R bb) 2、-C(＝O)NR bbSO 2R aa、-NR bbSO 2R aa、-SO 2N(R bb) 2、-SO 2R aa、-SO 2OR aa、-OSO 2R aa、-S(＝O)R aa、-OS(＝O)R aa、-Si(R aa) 3、-OSi(R aa) 3、-C(＝S)N(R bb) 2、-C(＝O)SR aa、-C(＝S)SR aa、-SC(＝S)SR aa、-SC(＝O)SR aa、-OC(＝O)SR aa、-SC(＝O)OR aa、-SC(＝O)R aa、-P(＝O) 2R aa、-OP(＝O) 2R aa、-P(＝O)(R aa) 2、-OP(＝O)(R aa) 2、-OP(＝O)(OR cc) 2、-P(＝O) 2N(R bb) 2、-OP(＝O) 2N(R bb) 2、-P(＝O)(NR bb) 2、-OP(＝O)(NR bb) 2、-NR bbP(＝O)(OR cc) 2、-NR bbP(＝O)(NR bb) 2、-P(R cc) 2、-P(R cc) 3、-OP(R cc) 2、-OP(R cc) 3、-B(R aa) 2、-B(OR cc) 2、-BR aa(OR cc)、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(R bb) 2、＝NNR bbC(＝O)R aa、＝NNR bbC(＝O)OR aa、＝NNR bbS(＝O) 2R aa、＝NR bb或＝NOR cc取代；
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R aa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R bb的每个独立地选自：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R bb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R cc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代；
R dd的每个独立地选自：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR ee、-ON(R ff) 2、-N(R ff) 2,、-N(R ff) 3 +X -、-N(OR ee)R ff、-SH、-SR ee、-SSR ee、-C(＝O)R ee、-CO 2H、-CO 2R ee、-OC(＝O)R ee、-OCO 2R ee、-C(＝O)N(R ff) 2、-OC(＝O)N(R ff) 2、-NR ffC(＝O)R ee、-NR ffCO 2R ee、-NR ffC(＝O)N(R ff) 2、-C(＝NR ff)OR ee、-OC(＝NR ff)R ee、-OC(＝NR ff)OR ee、-C(＝NR ff)N(R ff) 2、-OC(＝NR ff)N(R ff) 2、-NR ffC(＝NR ff)N(R ff) 2、-NR ffSO 2R ee、-SO 2N(R ff) 2、-SO 2R ee、-SO 2OR ee、-OSO 2R ee、-S(＝O)R ee、-Si(R ee) 3、-OSi(R ee) 3、-C(＝S)N(R ff) 2、-C(＝O)SR ee、-C(＝S)SR ee、-SC(＝S)SR ee、-P(＝O) 2R ee、-P(＝O)(R ee) 2、-OP(＝O)(R ee) 2、-OP(＝O)(OR ee) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代，或者两个偕R dd取代基可结合以形成＝O或＝S；
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、碳环基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代；
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者两个R ff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代；
R gg的每个独立地是：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OC 1-6烷基、-ON(C 1-6烷基) 2、-N(C 1-6烷基) 2、-N(C 1-6烷基) 3 +X -、-NH(C 1-6烷基) 2 +X -、-NH 2(C 1-6烷基) +X -、-NH 3 +X -、-N(OC 1-6烷基)(C 1-6烷基)、-N(OH)(C 1-6烷基)、-NH(OH)、-SH、-SC 1-6烷基、-SS(C 1-6烷基)、-C(＝O)(C 1-6烷基)、-CO 2H、-CO 2(C 1-6烷基)、-OC(＝O)(C 1-6烷基)、-OCO 2(C 1-6烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-OC(＝O)NH(C 1-6烷基)、-NHC(＝O)(C 1-6烷基)、-N(C 1-6烷基)C(＝O)(C 1-6烷基)、-NHCO 2(C 1-6烷基)、-NHC(＝O)N(C 1-6烷基) 2、-NHC(＝O)NH(C 1-6烷基)、-NHC(＝O)NH 2、-C(＝NH)O(C 1-6烷基)、-OC(＝NH)(C 1-6烷基)、-OC(＝NH)OC 1-6烷基、-C(＝NH)N(C 1-6烷基) 2、-C(＝NH)NH(C 1-6烷基)、-C(＝NH)NH 2、-OC(＝NH)N(C 1-6烷基) 2、-OC(NH)NH(C 1-6烷基)、-OC(NH)NH 2、-NHC(NH)N(C 1-6烷基) 2、-NHC(＝NH)NH 2、-NHSO 2(C 1-6烷基)、-SO 2N(C 1-6烷基) 2、-SO 2NH(C 1-6烷基)、-SO 2NH 2、-SO 2C 1-6烷基、-SO 2OC 1-6烷基、-OSO 2C 1-6烷基、-SOC 1-6烷基、-Si(C 1-6烷基) 3、-OSi(C 1-6烷基) 3、-C(＝S)N(C 1-6烷基) 2、C(＝S)NH(C 1-6烷基)、C(＝S)NH 2、-C(＝O)S(C 1-6烷基)、-C(＝S)SC 1-6烷基、-SC(＝S)SC 1-6烷基、 -P(＝O) 2(C 1-6烷基)、-P(＝O)(C 1-6烷基) 2、-OP(＝O)(C 1-6烷基) 2、-OP(＝O)(OC 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7碳环基、C 6-C 10芳基、C 3-C 7杂环基、C 5-C 10杂芳基；或者两个偕R gg取代基可结合形成＝O或＝S；其中，X -为反离子。
示例性的氮原子上取代基包括但不局限于：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR bb)R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基，或者连接至氮原子的两个R cc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、碳环基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代，且其中R aa、R bb、R cc和R dd如上所述。
其他定义
术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如，Berge等人在J.Pharmaceutical Sciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸和无机和有机碱的盐。药学上可接受的无毒的酸加成盐的实例是与无机酸形成的盐，例如盐酸、氢溴酸、磷酸、硫酸和高氯酸，或与有机酸形成的盐，例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸。也包括使用本领域常规方法形成的盐，例如，离子交换方法。其它药学上可接受的盐包括：已二酸盐、海藻酸盐、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、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐，等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N +(C 1-4烷基) 4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐，等等。如果合适的话，其它的药学上可接受的盐包括与反离子形成的无毒的铵盐、季铵盐和胺阳离子，反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低 级烷基磺酸根和芳基磺酸根。
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量，或增强其它预防药剂的预防效果的量。
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。
本发明化合物可用于治疗和/或预防病毒感染的疾病。这些疾病包括但不限于，人免疫缺陷病毒HIV感染、乙型肝炎病毒HBV感染。
具体实施方式
化合物
本文中，“本发明化合物”指的是以下的式(I)-式(IV)化合物(包括其子集，例如式(Iia)化合物)、其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素衍生物。
在一个实施方案中，本发明涉及式(I)化合物：
Figure PCTCN2018119483-appb-000004
其中，
X选自O或S；
Y选自键、O或S；
m选自0至5；
A选自：
1)任选取代的C 6-C 11芳基或任选取代的C 5-C 11杂芳基；或者
2)-(CH 2) nCH 3，其中n选自12至21；或者
3)-C(＝O)R 1、-C(＝O)OR 1、-C(＝O)N(R 1)(R 1)，其中各R 1独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基，或二个R 1基团一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
V选自O或NH；
B为H，或者为以下结构：
Figure PCTCN2018119483-appb-000005
其中，
R 2和R 3各自独立地选自H、任选取代的C 1-C 6烷基或一种天然或可药用氨基酸的侧链，如果侧链含有羧基，该羧基可以选择被烷基或芳基酯化，或者R 1、R 2可以与其所连接的碳原子一起形成任 选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
L选自-C(＝O)-、-O(C＝O)-、-NR 4(C＝O)-、-S(＝O) p-、-NR 4S(＝O) p-，其中，各R 4独立地选自H、任选取代的C 1-C 6酰基、任选取代的C 1-C 6烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基、任选取代的C 6-C 11芳基或任选取代的C 5-C 11杂芳基，p选自1或2；
Z选自O或S；
R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 1-C 6酰基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基、任选取代的C 6-C 11芳基、任选取代的C 5-C 11杂芳基，只要化学上允许；
前提是，X、Y、Z中的有且只有一者为S；
附加条件是，所述化合物不包括下式化合物：
Figure PCTCN2018119483-appb-000006
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、或同位素变体。
在该实施方案中，优选地，A选自：
1)任选取代的苯基、吡啶基、嘧啶基或萘基；优选地，苯基；
2)-(CH 2) nCH 3，其中n选自12，14，16或18；
3)-C(＝O)R 1、-C(＝O)OR 1、-C(＝O)N(R 1)(R 1)；优选地，-C(＝O)R 1；其中各R 1独立地选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 6碳环基、任选取代的C 3-C 6杂环基；优选地，各R 1独立地选自任选取代的C 1-C 6烷基、任选取代的C 3-C 7碳环基；更优选的，各R 1独立地选自甲基、乙基、异丙基、环丙基、环戊基、环己基；最优选地，各R 1独立地选自甲基、异丙基；或者，二个R 1基团一起形成任选取代的C 3-C 6碳环基或任选取代的C 3-C 6杂环基；
在该实施方案中，优选地，L选自-C(＝O)-、-O(C＝O)-、-NR 4(C＝O)-；更优选地，L选自-C(＝O)-、-O(C＝O)-。
在L的上述实施方案中，各R 4独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基；优选地，R 4独立的选自H、甲基、环丙基。
在该实施方案中，优选地，R 2选自H或任选取代的C 1-C 4烷基，更优选地，R 2选自H或甲基。优选地，R 3选自H或一种天然或可药用氨基酸的侧链，其中，氨基酸优选地甘氨酸、丙氨酸、亮氨酸、异亮氨酸、缬氨酸、脯氨酸、苯丙氨酸、甲硫氨酸、色氨酸、丝氨酸、谷氨酰胺、苏氨酸、半胱氨酸、组氨酸、天冬氨酸、络氨酸、天冬氨酸、谷氨酸、萘胺酸或精氨酸，进一步优选甘氨酸、丙氨酸、亮氨酸、苯丙氨酸、天冬酰胺或精氨酸，更优选甘氨酸、丙氨酸或苯丙氨酸。优选地，R 2、R 3可以与其所连接的碳原子一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
在该实施方案中，优选地，R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；优选地，R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；优选地，R 5选自任选取代的C 1-C 6烷基、任选取代的C 3-C 7碳环基；
更优选地，R 5选自以下基团：
甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、叔戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、环丙基、环丁基、环戊基、环己基、环庚基；
最优选地，R 5选自以下基团：
甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、新戊基、环戊基、环己基。
在该实施方案中，优选地，m选自0、2、3、4或5；更优选地，m选自0、2或3。
在另一个实施方案中，本发明提供了式(I)的化合物：
Figure PCTCN2018119483-appb-000007
其中，
X选自O或S；
m选自0至5；
Y选自键、O或S；
A选自：
1)任选取代的苯基；或者
2)-(CH 2) nCH 3，其中n选自13至17；或者
3)-C(＝O)R 1或-C(＝O)OR 1，其中各R 1独立地选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基；
V选自O或NH；
B为H，或者为以下结构：
Figure PCTCN2018119483-appb-000008
其中，
R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基，或者R 2、R 3可以与其所连接的碳原子一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
L选自-C(＝O)-或-O(C＝O)-；
Z选自O或S；
R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
前提是，X、Y、Z中的有且只有一者为S；
附加条件是，所述化合物不包括下式化合物：
Figure PCTCN2018119483-appb-000009
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、或同位素变体。
在另一实施方案中，本发明提供式(IIa)或式(IIb)化合物：
Figure PCTCN2018119483-appb-000010
其中，
Y选自键或O；
m、A、V、L、R 2、R 3和R 5如上文所定义。
在另一个实施方案中，本发明提供了式(IIa)或式(IIb)化合物：
Figure PCTCN2018119483-appb-000011
其中，
m选自0、2、3、4或5；
Y选自键或O；
A选自：
1)任选取代的苯基；或者
2)-(CH 2) nCH 3，其中n选自13至17；
V选自O或NH；
R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；
L选自-C(＝O)-或-O(C＝O)-；
R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
在另一些实施方案中，m选自0、2、3、4或5；优选地，m选自0、2或3。
在另一些实施方案中，n选自13至17；优选地，n选自13、15或17；更优选地，n选自15。
在另一些实施方案中，R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；优选地，R 2和R 3各自独立地选自H或任选取代的甲基、乙基或异丙基；优选地，R 2和R 3各自独立地选自H或甲基；更优选地，R 2和R 3各自独立地选自H；更优选地，R 2为氢和R 3为甲基。
在另一些实施方案中，R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；优选地，R 5选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、新戊基、环戊基或环已基；更优选地，R 5选自异丙基。
在另一些优选地实施方案中，本发明提供了式(IIa)或式(IIb)化合物：
Figure PCTCN2018119483-appb-000012
其中，
m选自0、2或3；
Y选自键或O；
A选自：
1)任选取代的苯基；或者
2)-(CH 2) nCH 3，其中n选自15；
V选自O或NH；
R 2和R 3各自独立地选自H或甲基；
L选自-C(＝O)-或-O(C＝O)-；
R 5选自异丙基；
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
在另一实施方案中，本发明提供了式(IIIa)或式(IIIb)化合物：
Figure PCTCN2018119483-appb-000013
其中，
m、A、V、L、R 2、R 3和R 5如上文所定义。
在另一个实施方案中，本发明提供了式(IIIa)或式(IIIb)化合物：
Figure PCTCN2018119483-appb-000014
其中，
m选自0、2、3、4或5；
A选自：
1)-(CH 2) nCH 3，其中n选自13至17；或者
2)-C(＝O)R 1或-C(＝O)OR 1，其中各R 1独立地选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
V选自O或NH；
R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；
L选自-C(＝O)-或-O(C＝O)-；
R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
在另一些实施方案中，m选自0、2、3、4或5；优选地，m选自0、2或3。
在另一些实施方案中，n选自13至17；优选地，n选自13、15或17；更优选地，n选自15。
在另一些实施方案中，R 1独立地选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；优选地， R 1独立地选自甲基、乙基、异丙基、环丙基、环丁基或环戊基；更优选地，R 1选自甲基。
在另一些实施方案中，R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；优选地，R 2和R 3各自独立地选自H或任选取代的甲基、乙基或异丙基；优选地，R 2和R 3各自独立地选自H或甲基；更优选地，R 2和R 3各自独立地选自H；更优选地，R 2为氢和R 3为甲基。
在另一些实施方案中，R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；优选地，R 5选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、新戊基、环戊基或环已基；更优选地，R 5选自异丙基。
在另一些优选地实施方案中，本发明提供了式(IIIa)或式(IIIb)化合物：
Figure PCTCN2018119483-appb-000015
其中，
m选自0、2或3；
A选自：
1)-(CH 2) nCH 3，其中n选自15；
2)-C(＝O)R 1，其中各R 1选自甲基；
V选自O或NH；
R 2和R 3各自独立地选自H或甲基；
L选自-C(＝O)-或-O(C＝O)-；
R 5选自异丙基；
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
在另一实施方案中，本发明提供了式(IV)化合物：
Figure PCTCN2018119483-appb-000016
其中，
附加条件是，所述化合物不包括下式化合物：
Figure PCTCN2018119483-appb-000017
Y选自键或O；m、A、V、L、R 2、R 3和R 5如上文所定义。
在另一个实施方案中，本发明提供式(IV)化合物：
Figure PCTCN2018119483-appb-000018
其中，
m选自2、3、4或5；
Y为O；
A选自：
1)-(CH 2) nCH 3，其中n选自13至17；或者
2)-C(＝O)R 1或-C(＝O)OR 1，其中各R 1独立地选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
V选自O或NH；
R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；
L选自-C(＝O)-或-O(C＝O)-；
R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
在另一些实施方案中，m选自0、2、3、4或5；优选地，m选自0、2或3。
在另一些实施方案中，n选自13至17；优选地，n选自13、15或17；更优选地，n选自15。
在另一些实施方案中，R 1独立地选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；优选地，R 1独立地选自甲基、乙基、异丙基、环丙基、环丁基或环戊基；更优选地，R 1选自甲基。
在另一些实施方案中，R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；优选地，R 2和R 3各自独立地选自H或任选取代的甲基、乙基或异丙基；优选地，R 2和R 3各自独立地选自H或甲基；更优选地，R 2和R 3各自独立地选自H；更优选地，R 2为氢和R 3为甲基。
在另一些实施方案中，R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；优选地，R 5选自甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、新戊基、环戊基或环已基；更优选地，R 5选自异丙基。
在另一些优选地实施方案中，本发明提供了式(IV)化合物：
Figure PCTCN2018119483-appb-000019
其中，
m选自0、2或3；
Y为O；
A选自：
1)-(CH 2) nCH 3，其中n选自15；
2)-C(＝O)R 1，其中各R 1选自甲基；
V选自O或NH；
R 2和R 3各自独立地选自H或甲基；
L选自-C(＝O)-或-O(C＝O)-；
R 5选自异丙基；
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
在最优选的实施方案中，上述式(I)-(IV)化合物为以下化合物：
Figure PCTCN2018119483-appb-000020
Figure PCTCN2018119483-appb-000021
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。
本发明也包括本发明化合物的所有合适的同位素衍生物。本发明化合物的同位素衍生物的定义为其中至少一个原子被具有相同原子数但原子质量与自然界中通常发现的原子质量不同的原子代 替。可以掺入本发明化合物中的同位素的实例包括氢、碳、氮、氧、氟和氯的同位素，例如分别为 2H、 3H、 13C、 14C、 15N、 17O、 18O、 18F、 31P、 32P、 35S和 36Cl。本发明化合物的一些同位素衍生物，例如其中掺入放射性同位素如 3H或 14C的那些，可用于药物和/或底物组织分布研究。氚化(即 3H)和碳-14(即 14C)同位素因其易于制备和可检测性而为特别优选的。此外，用同位素(例如氘，即 2H)取代可以提供由于更大的代谢稳定性而得到的一些治疗优点，例如增加的体内半衰期或减少的剂量需要，并且因此在一些情况下可以是优选的。本发明化合物的同位素衍生物通常可以通过如下制备：常规程序例如通过说明性方法或通过下文实施例中描述的制备，其使用合适试剂的适当同位素衍生物。
本发明化合物或其药学上可接受的盐可以是无定形或结晶形式。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。
本领域技术人员将理解，许多有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。
前药为任何共价键合的载体，当将这种前药给予患者时，其在体内释放式(I)化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、胺或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、胺或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的醇、巯基和胺官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯， 例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
药物组合物、制剂和试剂盒
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的活性组分。在一些实施方案中，所述药物组合物包含治疗有效量的活性组分。在一些实施方案中，所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
下列制剂实施例说明可根据本发明制备的代表性的药物组合物。然而，本发明不限于下列药物组合物。
示例性的制剂1-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为0.3-30mg片剂(每个片剂含有0.1-10mg活性化合物)。
示例性的制剂2-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为30-90mg片剂(每个片剂含有10-30mg活性化合物)。
示例性的制剂3-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为90-150mg片剂(每个片剂 含有30-50mg活性化合物)。
示例性的制剂4-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为150-240mg片剂(每个片剂含有50-80mg活性化合物)。
示例性的制剂5-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为240-270mg片剂(每个片剂含有80-90mg活性化合物)。
示例性的制剂6-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为270-450mg片剂(每个片剂含有90-150mg活性化合物)。
示例性的制剂7-片剂：可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为450-900mg片剂(每个片剂含有150-300mg活性化合物)。
示例性的制剂8-胶囊剂：可以将干粉形式的本发明化合物与淀粉稀释剂以约1:1的重量比混合。将该混合物填充到250mg胶囊中(每个胶囊含有125mg活性化合物)。
示例性的制剂9-液体：可以将本发明化合物(125mg)与蔗糖(1.75g)和黄原胶(4mg)混合，且可将得到的混合物共混，通过No.10筛目美国筛，然后与预先制备的微晶纤维素和羧甲基纤维素钠(11:89，50mg)的水溶液混合。将苯甲酸钠(10mg)、调味剂和着色剂用水稀释，并在搅拌下加入。然后，可以加入充足的水，得到5mL的总体积。
示例性的制剂10-注射剂：可以将本发明化合物溶解或悬浮在缓冲无菌盐水可注射的水性介质中，达到约5mg/mL的浓度。
给药
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途 径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％ 重量，且更优选大约0.5至大约15％重量。
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。
组合治疗
本发明的化合物或其组合物可以与其他治疗剂组合给药，以治疗所述疾病。已知的治疗剂的实例包括但不限于：
1)安普那韦(amprenavir)、阿扎那韦(atazanavir)、夫沙那韦(fosamprenavir)、茚地那韦(indinavir)、咯皮那韦(lopinavir)、力托那韦、奈飞那韦(nelfinavir)、沙喹那韦(saquinavir)、替拉那韦(tipranavir)、贝卡那韦(brecanavir)、地瑞那韦(darunavir)、TMC-126、TMC-114、莫折那韦(mozenavir)、JE-2147(AG1776)、L-756423、R00334649、KNI-272、DPC-681、DPC-684、GW640385X、DG17、GS-8374、PPL-100、DG35和AG1859；
2)HIV逆转录酶的非核苷抑制剂，例如卡普拉林(capravirine)、乙米韦林(emivirine)、地拉夫定(delaviridine)、依法韦伦(efavirenz)、奈维拉平(nevirapine)、(+)卡拉脑力德A((+)calanolide A)、依曲韦林(etravirine)、GW5634、DPC-083、DPC-961、DPC-963、WIV-150、TMC-120、利匹韦林(rilpivirine)、BILR355BS、VPX840773、UK-453061和RDEA806；
3)HIV逆转录酶的核苷抑制剂，例如齐多夫定(zidovudine)、恩曲他滨(Emtricitabine)、去羟肌苷(Didanosine)、司他夫定(Stavudine,d4T)、扎西他滨(Zalcitabine，ddC)、拉米夫定(Lamivudine，3TC)、阿巴卡韦(Abacavir)、安多索韦(amdoxovir)、艾夫他滨(elvucitabine)、阿洛夫定(alovudine)、MIV-210、瑞夕弗(racivir)、D-d4FC、叠氮膦(phosphazide)、福齐夫定替酯(fozivudine tidoxil)、阿里地滨(apricitibine、AVX754)、GS-7340、KP-1461和磷夫定酯(fosalvudine tidoxil)；
4)HIV逆转录酶的核苷酸抑制剂，例如反丁烯二酸替诺福韦酯和阿德福韦酯(adefovir dipivoxil)；
5)HIV整合酶抑制剂，例如姜黄素、姜黄素衍生物、菊苣酸、菊苣酸衍生物、3,5-二咖啡酰奎尼酸、3,5-二咖啡酰奎尼酸衍生物、金精三羧酸、金精三羧酸衍生物、咖啡酸苯乙酯、咖啡酸苯乙酯衍生物、酪氨酸磷酸化抑制剂、酪氨酸磷酸化抑制剂衍生物、皮素、皮素衍生物、S-1360、新特维尔(zintevir)、L-870812和L-870810、雷特格韦(raltegravir)、埃替格韦、BMS-538158、GSK364735C、BMS-707035、MK-2048和BA011；
6)gp41抑制剂，例如恩夫韦地(enfuvirtide)、西夫韦他(sifuvirtide)、FB006M和TRI-1144；
7)CXCR4抑制剂，例如AMD-070；
8)穿入抑制剂，例如SP01A；
9)gp120抑制剂，例如BMS-488043或BlockAide/CR；
10)G6PD和NADH-氧化酶抑制剂，例如免疫素(immunitin)；
11)CCR5抑制剂，例如安普纳维(aplaviroc)、维克利诺(vicriviroc)、马拉维若(maraviroc)、PRO-140、INCB15050、PF-233798和CCR5mAb004；
12)用于治疗HIV的其他药物，例如BAS-100、SPI-452、REP9、SP-01A、TNX-355、DES6、ODN-93、ODN-112、VGX-1、PA-457(贝韦立马(bevirimat))、阿普林津(Ampligen)、HRG214、西妥林(Cytolin)、VGX-410、KD-247、AMZ0026、CYT99007A-221HIV、DEBIO-025、BAY50-4798、MDX010(伊匹单抗(ipilimumab))、PBS119、ALG889和PA-1050040(PA-040)；
13)干扰素，例如聚乙二醇化rIFN-a 2b、聚乙二醇化rIFN-a 2a、rIFN-a 2b、rIFN-a 2a、组合IFN a(干复津(infergen))、酶蛋白(feron)、瑞非隆(reaferon)、intermax a、r-IFN-、干复津阿克姆(actimmune)、IFN-w与DUROS、白蛋白干扰素(albuferon)、洛克特伦(locteron)、白蛋白干扰素(Albuferon)、立比扶(Rebif)、口服干扰素a、IFN-2bXL、AVI-005、PEG-干复津和聚乙二醇化IFN-；
14)病毒唑类似物，例如雷贝妥(rebetol)、柯匹吉(copegus)、韦拉咪定(viramidine，他瑞韦林(taribavirin))；
15)NS5b聚合酶抑制剂，例如NM-283、伐洛比西他滨(valopicitabine)、R1626、PSI-6130(R1656)、HCV-796、BILB1941、XTL-2125、MK-0608、NM-107、R7128(R4048)、VCH-759、PF-868554和GSK625433；
16)NS3蛋白酶抑制剂，例如SCH-503034(SCH-7)、VX-950(特拉普韦(telaprevir))、BILN-2065、BMS-605339和ITMN-191；
17)a-葡糖苷酶1抑制剂，例如MX-3253(赛格西弗(celgosivir))、UT-231B；
18)保肝药，例如IDN-6556、ME3738、LB-84451和MitoQ；
19)HCV的非核苷抑制剂，例如，苯并咪唑衍生物、苯并-1,2,4-噻二嗪衍生物、苯丙氨酸衍生物、A-831、GS-9190和A-689；
20)治疗HCV的其它药物，例如日达仙(zadaxin)、硝唑尼特(nitazoxanide)、BIVN-401(维洛斯塔(virostat))、PYN-17(阿尔替雷(altirex))、KPE02003002、阿迪隆(actilon)、KRN-7000、西瓦塞(civacir)、GI-5005、ANA-975、XTL-6856、ANA971、NOV-205、特瓦新(tarvacin)、EHC-18、NIM811、DEBIO-025、VGX-410C、EMZ-702、AVI4065、巴维昔单抗(Bavituximab)、欧卢酚迪(Oglufanide)和VX-497(美泊地布(merimepodib))。
那些其他活性剂可以与含有本发明化合物的组合物分开给药，作为多次给药方案的一部分。或 者，那些活性剂可以是单一剂型的一部分，与发明化合物一起混合在单一组合物中。如果作为多次给药方案的一部分给药，那么两种活性剂可以同时、依次或彼此间隔一段时间(通常彼此间隔在5小时以内)提供。
治疗
本发明提供一种治疗和/或预防病毒感染的方法或治疗疾病的方法，它包括步骤：给需要治疗的受试者给药本发明化合物，或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素衍生物，或给药本发明所述的药物组合物。
本发明化合物可治疗和/或预防病毒感染包括但不限于人类免疫缺陷病毒HIV感染、乙型肝炎病毒HBV感染。
实施例
提供以下实施例以便为本领域技术人员提供如何进行、制备和评估本文请求保护的方法和化合物的完整公开和说明，旨在仅仅示例本发明而非限制发明人认为的发明范围。
合成方法
本发明化合物可按照本领域常规方法，并使用合适的试剂、原料和本领域技术人员已知的纯化方法制备。
下面更具体地描述本发明式(I)结构化合物的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
通常，在制备中，各反应通常在惰性溶剂中，在室温至回流温度(如0℃～100℃，优选0℃～80℃)进行。反应时间通常为0.1小时-60小时，优选0.5-24小时。
实施例1(R)-9-{2-[(十六烷氧基丙基)硫代磷酸甲氧基]丙基}腺嘌呤(化合物T-1)
Figure PCTCN2018119483-appb-000022
采用以下合成路线进行合成：
Figure PCTCN2018119483-appb-000023
步骤1：3-十六烷氧基-1-丙醇(化合物1)的合成。
在反应瓶中加入溴代十六烷(1.52g，5mmol)和1,3-丙二醇(1.14g，15mmol)，加入5ml二甲基亚砜和5ml四氢呋喃溶解，加入氢氧化钠(800mg，20mmol)室温下反应24小时。加入10ml水稀释，用2M稀盐酸调PH至中性，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得化合物1.0g，收率：66.7％。LC-MS(APCI):m/z＝301.3(M+1) +。
步骤2：(R)-(1-(6-((二甲氨基)甲基烯氨)-9H-嘌呤-9-基)丙烷-2-氧基)甲基二氯氧磷(化合物2)的合成。
向反应瓶中加入(R)-(1-(6-((二甲氨基)甲基烯氨)-9H-嘌呤-9-基)丙烷-2-氧基)甲基磷酸(替诺福韦，500mg，1.74mmol)和无水DMF(153mg，2.1mmol)，加入10ml无水二氯甲烷溶解，氮气保护下室温滴加2M草酰氯(4.35ml，8.7mmol)，加毕，搅拌反应3小时至反应液变澄清，浓缩除去溶剂和过量的草酰氯得到产物658mg，收率：100％，无需纯化，直接投入到下一步。
步骤3：(R)-9-{2-[(十六烷氧丙基)磷酸甲氧]丙基}腺嘌呤(化合物3)的合成
在反应瓶中加入化合物2(658mg，1.74mmol)，加入10ml无水二氯甲烷溶解，氮气保护下降温至0℃，缓慢滴加化合物1(631mg，2.1mmol)和吡啶(826mg，10.44mmol)的无水二氯甲烷溶液。加毕，低温下反应10分钟后升至室温继续反应2小时，MS监测反应完毕，加入1M稀盐酸(10ml)淬灭反应，室温下搅拌过夜，MS监测反应完毕后分出有机相，水相用二氯甲烷萃取2-3遍，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得到815.3mg产物，收率：82.3％。LC-MS(APCI):m/z＝570.3(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.36(s,1H),8.22(s,1H),4.35(d,J＝12.1Hz,1H),4.00(s,1H),3.94–3.82(m,2H),3.71(s,1H),3.33(d,J＝31.5Hz,6H),1.78(s,2H),1.47(s,2H),1.25(d,J＝5.9Hz,27H),1.13(s,3H),0.89(d,J＝6.5Hz,3H).
步骤4：(R)-9-{2-[(十六烷氧基丙基)硫代磷酸甲氧基]丙基}腺嘌呤(化合物T-1)的合成
向反应瓶中加入化合物3(416mg，0.73mmol)和2,4-双(对甲氧苯基)-1,3-二硫一二磷杂环丁烷 -2,4硫化物(劳森试剂，590.5mg，1.46mmol)，加入10ml无水甲苯，加热至100℃反应过夜，TLC检测反应完毕，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到72mg产物，收率：16.9％。LC-MS(APCI):m/z＝586.7(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.37(s,1H),8.24(s,1H),4.35(d,J＝12.1Hz,1H),4.00(s,1H),3.94–3.82(m,2H),3.71(s,1H),3.33(d,J＝31.5Hz,6H),1.77(s,2H),1.47(s,2H),1.24(d,J＝5.9Hz,27H),1.13(s,3H),0.88(d,J＝6.5Hz,3H).
实施例2(R)-9-{2-[(十六烷硫基丙基)磷酸甲氧基]丙基}腺嘌呤(化合物T-2)
Figure PCTCN2018119483-appb-000024
采用以下合成路线：
Figure PCTCN2018119483-appb-000025
步骤1：3-十六烷硫基-1-丙醇(化合物4)的合成。
在反应瓶中加入溴代十六烷(1.52g，5mmol)和3-巯基-1-丙醇(1.38g，15mmol)，加入5ml二甲基亚砜和5ml四氢呋喃溶解，加入氢氧化钠(800mg，20mmol)室温下反应24小时。加入10ml水稀释，用2M稀盐酸调PH至中性，乙酸乙酯萃取3次，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得化合物1.24g，收率：78.5％。LC-MS(APCI):m/z＝317.5(M+1) +。
步骤2：(R)-9-{2-[(十六烷硫基丙基)磷酸甲氧基]丙基}腺嘌呤(T-2)的合成
在反应瓶中加入化合物2(658mg，1.74mmol)，加入10ml无水二氯甲烷溶解，氮气保护下降温至0℃，缓慢滴加化合物4(664mg，2.1mmol)和吡啶(826mg，10.44mmol)的无水二氯甲烷溶液。加毕，低温下反应10分钟后升至室温继续反应2小时，MS监测反应完毕，加入1M稀盐酸(10ml)淬灭反应，室温下搅拌过夜，MS监测反应完毕后分出有机相，水相用二氯甲烷萃取2-3遍，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得到707.8mg产物，收率：69.5％。LC-MS(APCI):m/z＝586.1(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.37(s,1H),8.24(s,1H),4.35(d,J＝12.1Hz,1H),4.00(s,1H),3.94–3.82(m,2H),3.71(s,1H),3.33(d,J＝31.5Hz,2H),2.33-2.18(m,4H),1.63(s,2H),1.24(d,J＝5.9Hz,29H),1.13(s,3H),0.88(d,J＝6.5Hz,3H).
实施例3 9-{(R)-2-[({[(S)-1-(异丙氧羰基)乙基]氨基}苯氧硫代磷酰基)甲氧基]丙基}腺嘌呤(化合 物T-3)
Figure PCTCN2018119483-appb-000026
采用以下路线合成：
Figure PCTCN2018119483-appb-000027
步骤1：(R)-9-[2-(苯氧基磷酰甲氧基)丙基]腺嘌呤(化合物5)的合成。
在反应瓶中加入替诺福韦(2.4g，8.36mmol)、苯酚(1.62g，16.72mmol)和6.5ml NMP，加热至85℃，加入三乙胺(TEA，1.04g，10.3mmol)，升温至100℃，加入二环己基碳二亚胺(DCC,2.81g，13.63mmol)，再升至120℃搅拌反应16小时。TLC检测原料消失后降温至45℃，加入4.8ml水，降至室温，过滤除去不溶物，用2.5ml水洗涤滤饼，滤液浓缩，加入4ml水，用NaOH调PH至11，氯仿萃取3-4次，水相用浓盐酸调PH至3.1，用氯仿/异丙醇(3：1)萃取4-5遍，合并有机相，蒸干，加入少量甲醇打浆纯化，过滤后干燥得产物1.24g，收率40.4％。LC-MS(APCI):m/z＝364.3(M+1) +。
步骤2：9-{(R)-2-[({[(S)-1-(异丙氧羰基)乙基]氨基}苯氧磷酰基)甲氧基]丙基}腺嘌呤(化合物6)的合成
在反应瓶中加入化合物5(0.325g，0.894mmol)，用3ml乙腈溶解，加入氯化亚砜(240.5mg，2.02mmol)，加热至80℃反应2小时，浓缩除去溶剂，加入4ml无水二氯甲烷，降温至-29℃，滴加丙氨酸异丙酯(258.1mg，1.97mmol)的3ml二氯甲烷溶液，加毕，滴加三乙胺(271.4mg，2.682mmol)，升至室温反应1小时，TLC检测。加入少量水洗涤，饱和食盐水洗涤，浓缩后硅胶柱层析 纯化，得到0.17g产物，收率39.35％。LC-MS(APCI):m/z＝477.5(M+1) +。 1H NMR(300MHz,CDCl 3)δ8.33(d,J＝7.0Hz,1H),7.98(d,J＝1.9Hz,1H),7.34–7.27(m,1H),7.16(dq,J＝11.6,7.5Hz,3H),6.98(d,J＝8.4Hz,1H),5.79(s,2H),4.96(ddt,J＝30.3,12.5,6.2Hz,1H),4.39(ddd,J＝29.8,14.4,2.9Hz,1H),4.21–3.86(m,4H),3.83–3.49(m,2H),1.20(ddd,J＝10.1,6.2,3.4Hz,12H).
步骤3：9-{(R)-2-[({[(S)-1-(异丙氧羰基)乙基]氨基}苯氧硫代磷酰基)甲氧基]丙基}腺嘌呤(化合物T-3)的合成
向反应瓶中加入化合物6(140mg，0.294mmol)和劳森试剂(238.6mg，0.59mmol)，加入8ml无水甲苯，加热至110℃反应过夜，TLC检测反应完毕，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到39mg产物，收率：26.8％。LC-MS(APCI):m/z＝493.6(M+1) +。 1H NMR(300MHz,CDCl 3)δ8.32(d,J＝7.0Hz,1H),7.98(d,J＝1.9Hz,1H),7.34–7.27(m,1H),7.18(dq,J＝11.6,7.5Hz,3H),6.99(d,J＝8.4Hz,1H),5.79(s,2H),4.96(ddt,J＝30.3,12.5,6.2Hz,1H),4.43(ddd,J＝29.8,14.4,2.9Hz,1H),4.21–3.86(m,4H),3.83–3.49(m,2H),1.22(ddd,J＝10.1,6.2,3.4Hz,12H).
实施例4(R)-9-{2-[(十六烷氧基丙基)(异丙基碳酸甲基)硫代磷酸甲氧基]丙基}腺嘌呤(化合物 T-4)
Figure PCTCN2018119483-appb-000028
采用以下路线合成：
Figure PCTCN2018119483-appb-000029
步骤1：(R)-9-{2-[(十六烷氧基丙基)(异丙基碳酸甲基)磷酸甲氧]丙基}腺嘌呤(化合物7)的合成。
向反应瓶中加入化合物3(1.0g，1.756mmol)，氯甲基碳酸异丙酯(1.335g，8.78mmol)，碳 酸钾(1.21g，8.78mmol)和碘化钾(145.7mg，0.878mmol)，加入15ml无水DMF，氮气保护下加热至60℃反应过夜，TLC检测反应完毕后，加入过量水稀释，用乙酸乙酯萃取3-4遍，合并有机相，饱和食盐水洗涤，浓缩，柱层析纯化，真空干燥得产物678.5mg，收率：56.4％。LC-MS(APCI):m/z＝686.5(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.34(s,1H),8.02(s,1H),6.00(s,2H),5.61(m,2H),4.92(m,1H),4.40–4.15(m,4H),3.92(m,4H),3.68(t,J＝10.0Hz,2H),1.79(m,2H),1.47(m,2H),1.33–1.22(m,35H),0.84(t,J＝6.6Hz,3H).
步骤2：(R)-9-{2-[(十六烷氧基丙基)(异丙基碳酸甲基)硫代磷酸甲氧]丙基}腺嘌呤(化合物T-4)的合成。
在反应瓶中加入化合物7(678mg，0.99mmol)和劳森试剂(800.8mg，1.98mmol)，加入15ml无水甲苯。加热至90℃反应过夜，TLC监测反应完毕，浓缩除去溶剂，硅胶柱层析纯化得到58mg产物，收率：8.35％。LC-MS(APCI):m/z＝702.1(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.33(s,1H),8.01(s,1H),6.03(s,2H),5.61(m,2H),4.92(m,1H),4.40–4.12(m,4H),3.92(m,4H),3.68(t,J＝10.0Hz,2H),1.78(m,2H),1.47(m,2H),1.33–1.22(m,35H),0.84(t,J＝6.6Hz,3H).
实施例5(R)-9-{2-[(十六烷氧基丙基)(异丙基硫代碳酸甲基)磷酸甲氧基]丙基}腺嘌呤(化合物 T-5)
Figure PCTCN2018119483-appb-000030
采用以下路线合成：
Figure PCTCN2018119483-appb-000031
步骤1：氯甲基硫代碳酸异丙酯(化合物8)的合成。
向反应瓶中加入氯甲酸氯甲酯(3.0g，23.45mmol)和异丙硫醇(1.78g，23.45mmol)，加入20ml无水乙醚溶解，降温至0℃，缓慢滴加吡啶(1.85g，23.45mmol)，加毕，升至室温搅拌反应过夜，加入水稀释，依次用1％柠檬酸、饱和碳酸氢钠和饱和食盐水洗涤3次，无水硫酸钠干燥，过滤浓缩得到产物2.99g，收率：75.9％。LC-MS(APCI):m/z＝169.7(M+1) +。
步骤2：(R)-9-{2-[(十六烷氧基丙基)(异丙基硫代碳酸甲基)磷酸甲氧基]丙基}腺嘌呤(化合物T-5)的合成。
向反应瓶中加入化合物3(550mg，0.97mmol)、化合物8(811.4mg，4.83mmol)、碳酸钾(667.6mg，4.83mmol)和碘化钾(80.2mg，0.483mmol)，加入10ml DMF，加热至60℃反应过夜，TLC检测反应完毕，降至室温，加入过量水稀释，乙酸乙酯萃取3-4遍，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得到55mg产物，收率：8.1％。LC-MS(APCI):m/z＝702.1(M+1) +。 1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.99(s,1H),6.03(s,2H),5.61(m,2H),4.92(m,1H),4.40–4.12(m,4H),3.92(m,4H),3.68(t,J＝10.0Hz,1H),1.75(m,2H),1.45(m,2H),1.33–1.22(m,35H),0.87(t,J＝6.6Hz,3H).
实施例6 9-{(R)-2-[({[(S)-1-(异丙氧羰基)乙基]氨基}(十六烷氧丙基)硫代磷酰基)甲氧基]丙基} 腺嘌呤(化合物T-6)
Figure PCTCN2018119483-appb-000032
采用以下路线合成：
Figure PCTCN2018119483-appb-000033
步骤1：9-{(R)-2-[({[(S)-1-(异丙氧羰基)乙基]氨基}(十六烷氧丙基)磷酰基)甲氧基]丙基}腺嘌呤(化合物9)的合成。
向反应瓶中加入化合物3(1.0g，1.76mmol)和无水DMF(154mg，2.11mmol)，加入20ml无水二氯甲烷溶解，室温下缓慢滴加草酰氯(4.39ml，8.78mmol)，加毕，搅拌反应2-4小时，浓缩除去溶剂和过量的草酰氯，再加入20ml无水二氯甲烷溶解，降温至0℃，氮气保护下滴加丙氨酸异丙酯(921mg，7.02mmol)和三乙胺(888mg，8.78mmol)的5ml二氯甲烷溶液，加毕，升至室温反应1小时，MS监测反应完毕后加入3ml乙醇胺，室温下搅拌反应过夜，加入少量水，分出有机相，用饱和食盐水洗涤3次，浓缩，硅胶柱层析纯化得到产物516mg，收率：43％。LC-MS(APCI):m/z＝683.7(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.32(d,J＝3.6Hz,1H),8.01(d,J＝11.1Hz,1H),5.97(d,J＝9.4Hz,2H),4.98(ddt,J＝33.9,12.5,6.3Hz,1H),4.36(ddd,J＝24.2,14.4,2.8Hz,1H),4.20–4.08(m,2H),4.07–4.00(m,1H),3.99–3.89(m,2H),3.89–3.81(m,1H),3.71–3.50(m,2H),3.48–3.37(m,3H),1.91–1.77(m,2H),1.53(s,2H),1.30–1.21(m,35H),0.87(t,J＝6.8Hz,3H).
步骤2：9-{(R)-2-[({[(S)-1-(异丙氧羰基)乙基]氨基}(十六烷氧丙基)硫代磷酰基)甲氧基]丙基}腺嘌呤(化合物T-6)的合成。
向反应瓶中加入化合物9(400mg，0.586mmol)和劳森试剂(474mg，1.17mmol)，加入10ml无水甲苯，加热至80℃反应过夜，TLC检测反应完毕，降至室温，浓缩除去溶剂，硅胶柱层析纯化得到105mg产物，收率：25.6％。LC-MS(APCI):m/z＝699.5(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.33(d,J＝3.6Hz,1H),8.02(d,J＝11.1Hz,1H),5.99(d,J＝9.4Hz,2H),4.98(ddt,J＝33.9,12.5,6.3Hz,1H),4.39(ddd,J＝24.2,14.4,2.8Hz,1H),4.20–4.08(m,2H),4.07–4.00(m,1H),3.99–3.89(m,2H),3.89–3.81(m,1H),3.71–3.50(m,2H),3.48–3.37(m,3H),1.91–1.77(m,2H),1.53(s,2H),1.30–1.21(m,35H),0.87(t,J＝6.8Hz,3H).
实施例7 9-{(R)-2-[({[(S)-1-(异丙硫羰基)乙基]氨基}(十六烷氧丙基)磷酰基)甲氧基]丙基}腺嘌 呤(化合物T-7)
Figure PCTCN2018119483-appb-000034
采用以下路线合成：
Figure PCTCN2018119483-appb-000035
步骤1：(S)-2-(叔丁氧羰基氨基)丙酸异丙硫酯(化合物10)的合成。
向反应瓶中加入(S)-2-(叔丁氧羰基氨基)丙氨酸(3.0g，15.9mmol)和N,N'-羰基二咪唑(CDI，3.86g，23.8mmol)，加入20ml无水THF溶解，室温下搅拌反应2小时，加入异丙硫醇(1.33g，17.5mmol)，搅拌反应过夜。TLC监测反应完成后，浓缩除去溶剂，硅胶柱层析纯化得到产物3.47g，收率：88.3％。LC-MS(APCI):m/z＝248.3(M+1) +。
步骤2：(S)-2-氨基丙酸异丙硫酯(化合物11)的合成。
向反应瓶中加入化合物10(3.47g，14.0mmol)，加入15ml二氯甲烷溶解，再加入三氟乙酸(7.98g，70.0mmol)，室温下搅拌反应3小时，TLC监测反应完毕后，浓缩除去溶剂和过量的三氟乙酸，无需纯化直接投入下一步反应。
步骤3：9-{(R)-2-[({[(S)-1-(异丙硫羰基)乙基]氨基}(十六烷氧丙基)磷酰基)甲氧基]丙基}腺嘌呤(化合物T-7)的合成。
向反应瓶中加入化合物3(1.0g，1.76mmol)和无水DMF(154mg，2.11mmol)，加入20ml无水二氯甲烷溶解，室温下缓慢滴加草酰氯(4.39ml，8.78mmol)，加毕，搅拌反应2-4小时，浓缩除去溶剂和过量的草酰氯，再加入20ml无水二氯甲烷溶解，降温至0℃，氮气保护下滴加化合物11(1.83g，7.02mmol)和三乙胺(888mg，8.78mmol)的5ml二氯甲烷溶液，加毕，升至室温反应1小时，MS监测反应完毕后加入3ml乙醇胺，室温下搅拌反应过夜，加入少量水，分出有机相，用饱和食盐水洗涤3次，浓缩，硅胶柱层析纯化得到产物217mg，收率：17.65％。LC-MS(APCI):m/z＝699.5(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.31(d,J＝3.6Hz,1H),8.00(d,J＝11.1Hz,1H),5.95(d,J＝9.4Hz,2H),4.98(ddt,J＝33.9,12.5,6.3Hz,1H),4.39(m,1H),4.20–4.08(m,2H),4.07–4.00 (m,1H),3.99–3.89(m,2H),3.71–3.50(m,2H),3.48–3.37(m,3H),2.34(m,1H),1.91–1.77(m,2H),1.53(s,2H),1.30–1.21(m,35H),0.84(t,J＝6.8Hz,3H).
实施例8(R)-9-{2-[(乙酰硫代乙基)(异丙基碳酸甲基)磷酸甲氧基]丙基}腺嘌呤(化合物T-8)
Figure PCTCN2018119483-appb-000036
采用以下路线合成：
Figure PCTCN2018119483-appb-000037
步骤1：2-(乙酰硫代)乙醇(化合物12)的合成。
向反应瓶中加入硫代乙酸(874mg，11.5mmol)，2-碘乙醇(1.72g，10mmol)，用15ml无水甲苯溶解，0℃下滴加1,8-二氮杂二环十一碳-7-烯(DBU，1.75g，11.5mmol)的5ml甲苯溶液，加毕，升至室温搅拌反应2小时，TLC检测反应完毕后，加入少量水稀释，分出有机相，饱和食盐水洗涤，浓缩，柱层析纯化，真空干燥得产物576mg，收率：48％。
步骤2：(R)-9-{2-[(乙酰硫代乙基)磷酸甲氧]丙基}腺嘌呤(化合物13)的合成。
在反应瓶中加入化合物2(1.21g，3.2mmol)，加入20ml无水二氯甲烷溶解，氮气保护下降温至0℃，缓慢滴加化合物12(461mg，3.84mmol)和吡啶(1.52g，19.2mmol)的无水二氯甲烷溶液。加毕，低温下反应10分钟后升至室温继续反应2小时，MS监测反应完毕，加入1M稀盐酸(10ml)淬灭反应，室温下搅拌过夜，MS监测反应完毕后分出有机相，水相用二氯甲烷萃取2-3遍，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得到846mg产物，收率：68％。LC-MS(APCI):m/z＝390.8(M+1) +。
步骤3：(R)-9-{2-[(乙酰硫代乙基)(异丙基碳酸甲基)磷酸甲氧基]丙基}腺嘌呤(化合物T-8)的合成。
向反应瓶中加入化合物13(952mg，2.45mmol)、氯甲基碳酸异丙酯(1.86g，12.23mmol)、 碳酸钾(1.69g，12.23mmol)和碘化钾(203mg，1.22mmol)，加入15ml DMF，加热至60℃反应过夜，TLC检测反应完毕，降至室温，加入过量水稀释，乙酸乙酯萃取3-4遍，合并有机相，饱和食盐水洗涤，浓缩，硅胶柱层析纯化得到67mg产物，收率：5.4％。LC-MS(APCI):m/z＝506.2(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.34(s,1H),7.98(d,J＝1.6Hz,1H),5.82(s,2H),5.66–5.59(m,2H),5.34(t,J＝4.6Hz,1H),4.92(dq,J＝15.1,6.3Hz,2H),4.36(dd,J＝10.5,7.3Hz,2H),4.16–4.11(m,2H),3.95–3.88(m,2H),3.68–3.61(m,2H),3.10(dd,J＝13.8,6.8Hz,2H),1.31–1.27(m,9H).
实施例9(2’R,1’S)-9-{2-[(乙酰硫代乙基)(异丙氧羰基-1-乙氨基)磷酸甲氧基]丙基}腺嘌呤(化 合物T-9)
Figure PCTCN2018119483-appb-000038
采用以下路线合成：
Figure PCTCN2018119483-appb-000039
向反应瓶中加入化合物13(700mg，1.80mmol)和无水DMF(157.9mg，2.16mmol)，加入15ml无水二氯甲烷溶解，室温下缓慢滴加草酰氯(4.5ml，9.0mmol)，加毕，氮气保护下搅拌反应2-3小时。浓缩除去溶剂和过量的草酰氯，再加入15ml无水二氯甲烷溶解，降温至0℃，氮气保护下缓慢滴加丙氨酸异丙酯(944mg，7.2mmol)和三乙胺(910.7mg，9.0mmol)的二氯甲烷溶液，加毕，升至室温反应1小时，TLC检测反应完毕后，加入2ml乙醇胺搅拌过夜。加入少量水稀释，分出有机相，用饱和食盐水洗涤3次，浓缩，硅胶柱层析纯化得到73mg产物，收率：8.1％。LC-MS(APCI):m/z＝503.3(M+1) +。 1H NMR(400MHz,CDCl 3)δ8.34(d,J＝4.4Hz,1H),7.99(d,J＝12.2Hz,1H),5.76(d,J＝7.0Hz,2H),4.97(ddt,J＝44.7,12.5,6.3Hz,1H),4.38(ddd,J＝19.6,14.4,3.0Hz,1H),4.26–4.07(m,3H),4.02–3.90(m,2H),3.86–3.76(m,1H),3.56(ddd,J＝13.2,10.1,7.6Hz,1H),2.87(ddd,J＝20.3,10.2,5.7Hz,2H),2.72(s,3H),1.35(dd,J＝9.3,7.2Hz,6H),1.21(t,J＝6.8Hz,3H).
生物活性测试
(1)检测化合物体外抗HIV活性
GraphPad Prism软件分析数据，拟合曲线并计算EC 50和CC 50值。EC 50指抑制50％病毒产生、50％病毒传染性或50％病毒诱导的细胞效应的有效浓度。CC 50指降低未感染细胞的细胞生长或生存力50％的抑制浓度。
化合物处理：待测化合物和参考化合物将用DMSO倍比稀释好后加入细胞培养板中。待测化合物和参考化合物将测试8个浓度，两个复孔。
病毒感染和细胞处理：将HIV-1和MT-4细胞于37℃，5％CO 2培养箱中共培养1h。随后将感染细胞以一定密度接种于细胞培养板中。细胞培养基中DMSO终浓度为0.5％。将细胞置于37℃，5％CO 2培养箱中培养5天。细胞毒性测试实验的细胞为未感染的MT-4细胞，其它实验条件和抗病毒活性实验一致。
细胞活性检测：细胞活性由细胞活性检测试剂CellTiter-Glo(Promega)测定。原始数据用于化合物抗HIV-1活性和细胞毒性计算。化合物剂量反应曲线及其EC 50和CC 50值将由GraphPad Prism软件分析后得到，其中，A表示EC 50≤5nM，B表示5nM<EC 50≤20nM，C表示20nM<EC 50≤100nM，D表示EC 50>500nM；E表示3000nM<CC 50≤10000nM，F表示10000nM<CC 50≤50000nM，G表示CC 50>50000nM(如下表1所示)。
(2)检测化合物体外抗HBV活性
实验方法：用Bright-Glo(Promega)检测荧光素酶测定化合物抗乙型肝炎病毒活性。采用GraphPad Prism软件分析数据，拟合曲线并计算EC 50和CC 50值。EC 50指抑制50％病毒产生、50％病毒传染性或50％病毒诱导的细胞效应的有效浓度。CC 50指降低未感染细胞的细胞生长或生存力50％的抑制浓度。
实验步骤：
抗细胞活性实验：在HepG2.2.15细胞中检测实施例化合物的体外抗乙肝病毒活性，TDF作为阳性对照化合物。第一天种细胞到96孔板，第二天加入化合物处理细胞，第五天更换新的含化合物的培养液。第八天收集上清提取DNA。用定量PCR检测HBV DNA的含量。待测化合物和TDF均3倍系列稀释，8个浓度点，平行测定2复孔。培养液中DMSO的终浓度为0.5％。抑制百分比计算公式如下：
抑制率＝(1-样品中HBV的拷贝数/DMSO对照组中HBV的拷贝数)×100％
EC 50由GraphpadPrism软件(four parameter logistic equations)分析，其中I表示EC 50≤50nM， II表示50nM≤EC 50≤200nM，III表示200nM<EC 50≤500nM，IV表示EC 50>500nM(如下表1所示)。
细胞毒性实验：化合物排板、化合物处理流程与与抗HIV活性检测一致。化合物处理细胞六天后，测定细胞活性。每孔加入Cell-titer Blue试剂，37℃孵育3小时，读取荧光值(560Ex/590Em)；分析数据和计算相对细胞活力：
应用如下公式计算细胞活性百分比：％细胞活力＝(样品荧光读数–培养液对照的荧光读数)/(DMSO对照的荧光读数-培养液对照的荧光读数)×100。
最后使用GraphPad Prism软件计算化合物的CC 50值，V表示7000nM<CC 50≤50000nM,VI表示CC 50>50000nM表示(如下表1所示)。
表1实施例化合物HBV活性和HIV活性
Figure PCTCN2018119483-appb-000040
实验结果表明，本发明化合物具有很强的抗HIV活性和HBV活性(均达到纳摩尔水平)此外，在所测的细胞系中，本发明化合物没有显示毒性(最优的CC 50>50000nM)。
(3)肝微粒代谢实验
微粒体实验：人肝微粒体：0.5mg/mL，Xenotech；大鼠肝微粒体：0.5mg/mL，Xenotech；辅酶(NADPH/NADH)：1mM，Sigma Life Science；氯化镁：5mM，100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制：精密称取一定量的化合物实施例粉末，并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM，pH＝7.4)的配制：取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合，再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4，使用前用超纯水稀释5倍，加入氯化镁，得到磷酸盐缓冲液(100mM)，其中含100mM磷酸钾，3.3mM氯化镁， pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP，16.5mM G-6-P，3U/mL G-6-P D，3.3mM氯化镁)，使用前置于湿冰上。
配制终止液：含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH＝7.4)至50mL离心管中，分别加入812.5μL人肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH＝7.4)至50mL离心管中，分别加入812.5μL SD大鼠肝微粒体，混匀，得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育：用含70％乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM，作为工作液，备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N＝2)，分别加入2μL 0.25mM的的工作液中，混匀。
代谢稳定性的测定：在96孔深孔板的每孔中加入300μL预冷的终止液，并置于冰上，作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中，100转/分钟震荡，预孵5min。从孵育板每孔取出80μL孵育液加入终止板，混匀，补充20μL NADPH再生系统溶液，作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液，启动反应，开始计时。相应化合物的反应浓度为1μM，蛋白浓度为0.5mg/mL。分别于反应10、30、90min时，各取100μL反应液，加入终止板中，涡旋3min终止反应。将终止板于5000×g，4℃条件下离心10min。取100μL上清液至预先加入100μL蒸馏水的96孔板中，混匀，采用LC-MS/MS进行样品分析。
数据分析：通过LC-MS/MS系统检测相应化合物及内标的峰面积，计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率，并根据以下公式计算t 1/2和CL int，其中V/M即等于1/蛋白浓度。
Figure PCTCN2018119483-appb-000041
在上述微粒体实验中测试了本发明化合物，发现本发明化合物具有优越的代谢稳定性。代表性的实施例的人肝微粒体实验和大鼠肝微粒体实验的结果归纳于下表2中。
表2实施例化合物的肝微粒代谢评价
Figure PCTCN2018119483-appb-000042
Figure PCTCN2018119483-appb-000043
实验结果如上表2所示，本发明化合物的半衰期较长，清除率较小，在人肝微粒体与大鼠肝微粒体实验中都表现出较优的代谢稳定性，更适合作为抗HIV和/或HBV感染的药物。
(4)大鼠药代动力学实验
实验目的：研究大鼠给予实施例化合物后，考察本发明化合物的药代动力学行为。
实验动物：
种类及品系：SD大鼠等级：SPF级
性别及数量：雄性，6只
体重范围：180～220g(实际体重范围为187～197g)
来源：上海西普尔必凯实验动物有限公司
实验及动物合格证号：SCXK(沪)2013-0016
实验过程：
在血样采集之前，预先在EDTA-K2抗凝管中加入20L的2M氟化钠溶液(酯酶抑制剂)，于80℃烘箱内烘干后，置于4℃冰箱存放。
大鼠，雄性，体重187～197g，随机分为2组，于实验前一天下午开始禁食过夜但可自由饮水，给药后4h给食物。A组给予参考化合物，B组给予实施例化合物3mg/kg，分别于给药后15min、30min、1、2、3、5、8、10h从大鼠眼眶静脉取血100-200L左右，置于经EDTA-K2抗凝的0.5mL的Eppendorf管中，立即混匀，抗凝后，尽快将试管轻轻颠倒混匀5-6次后,血取好后放置在冰盒中，30min内把血样本在4000rpm，10min，4℃条件下离心分离血浆，收集全部血浆后立即于-20℃保存。所有时间点样品采集后测定每个时间点的血浆中的血药浓度。
根据上述所得的给药后平均血药浓度-时间数据，采用Winnonin软件，按非房室统计矩理论求算雄性SD大鼠分别i.g给予实施例化合物(3mg/kg)后的药代动力学相关参数。
实验表明，本发明化合物具有优良的活性，并且具有优异的药代动力学性质，因此更适合作为 抑制核苷类逆转录酶的化合物，进而适合制备治疗抗病毒感染的药物。
应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围，实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比为重量份和重量百分比。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。

Claims (14)

  1. 式(I)化合物，
    Figure PCTCN2018119483-appb-100001
    其中，
    X选自O或S；
    Y选自键、O或S；
    m选自0至5；
    A选自：
    1)任选取代的C 6-C 11芳基或任选取代的C 5-C 11杂芳基；或者
    2)-(CH 2) nCH 3，其中n选自12至21；或者
    3)-C(＝O)R 1、-C(＝O)OR 1、-C(＝O)N(R 1)(R 1)，其中各R 1独立地选自H、任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基，或二个R 1基团一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
    V选自O或NH；
    B为H，或者为以下结构：
    Figure PCTCN2018119483-appb-100002
    其中，
    R 2和R 3各自独立地选自H、任选取代的C 1-C 6烷基或一种天然或可药用氨基酸的侧链，如果侧链含有羧基，该羧基可以选择被烷基或芳基酯化，或者R 2、R 3可以与其所连接的碳原子一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
    L选自-C(＝O)-、-O(C＝O)-、-NR 4(C＝O)-、-S(＝O) p-、-NR 4S(＝O) p-，其中，各R 4独立地选自H、任选取代的C 1-C 6酰基、任选取代的C 1-C 6烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环 基、任选取代的C 6-C 11芳基或任选取代的C 5-C 11杂芳基，p选自1或2；
    Z选自O或S；
    R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 1-C 6酰基、任选取代的C 2-C 6烯基、任选取代的C 2-C 6炔基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基、任选取代的C 6-C 11芳基、任选取代的C 5-C 11杂芳基，只要化学上允许；
    前提是，X、Y、Z中的有且只有一者为S；
    附加条件是，所述化合物不包括下式化合物：
    Figure PCTCN2018119483-appb-100003
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、或同位素变体。
  2. 根据权利要求1所述的化合物，其中
    X选自O或S；
    m选自0至5；
    Y选自键、O或S；
    A选自：
    1)任选取代的苯基；或者
    2)-(CH 2) nCH 3，其中n选自13至17；或者
    3)-C(＝O)R 1或-C(＝O)OR 1，其中各R 1独立地选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基、任选取代的C 3-C 7杂环基；
    V选自O或NH；
    B为H，或者为以下结构：
    Figure PCTCN2018119483-appb-100004
    其中，
    R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基，或者R 2、R 3可以与其所连接的碳原子一起形成任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
    L选自-C(＝O)-或-O(C＝O)-；
    Z选自O或S；
    R 5选自任选取代的C 1-C 6烷基、任选取代的C 1-C 6杂烷基、任选取代的C 3-C 7碳环基或任选取代的C 3-C 7杂环基；
    前提是，X、Y、Z中的有且只有一者为S；
    附加条件是，所述化合物不包括下式化合物：
    Figure PCTCN2018119483-appb-100005
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、或同位素变体。
  3. 根据权利要求2所述的化合物，其为式(IIa)化合物或(IIb)化合物：
    Figure PCTCN2018119483-appb-100006
    其中，
    Y选自键或O；
    m、A、V、L、R 2、R 3和R 5如权利要求2所定义；
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
  4. 根据权利要求3所述的化合物，其中
    m选自0、2、3、4或5；
    Y选自键或O；
    A选自：
    1)任选取代的苯基；或者
    2)-(CH 2) nCH 3，其中n选自13至17；
    V选自O或NH；
    R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；
    L选自-C(＝O)-或-O(C＝O)-；
    R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
  5. 根据权利要求2所述的化合物，其为式(IIIa)化合物或(IIIb)化合物：
    Figure PCTCN2018119483-appb-100007
    其中，
    m、A、V、L、R 2、R 3和R 5如权利要求2所定义，
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
  6. 根据权利要求5所述的化合物，其中，
    m选自0、2、3、4或5；
    A选自：
    1)-(CH 2) nCH 3，其中n选自13至17；或者
    2)-C(＝O)R 1或-C(＝O)OR 1，其中各R 1独立地选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
    V选自O或NH；
    R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；
    L选自-C(＝O)-或-O(C＝O)-；
    R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
  7. 根据权利要求2所述的化合物，其为式(IV)化合物：
    Figure PCTCN2018119483-appb-100008
    其中，
    Y选自键或O；
    m、A、V、L、R 2、R 3和R 5如权利要求2所定义，
    附加条件是，所述化合物不包括下式化合物：
    Figure PCTCN2018119483-appb-100009
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。
  8. 根据权利要求7所述的化合物，其中，
    m选自2、3、4或5；
    Y为O；
    A选自：
    1)-(CH 2) nCH 3，其中n选自13至17；或者
    2)-C(＝O)R 1或-C(＝O)OR 1，其中各R 1独立地选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
    V选自O或NH；
    R 2和R 3各自独立地选自H或任选取代的C 1-C 6烷基；
    L选自-C(＝O)-或-O(C＝O)-；
    R 5选自任选取代的C 1-C 6烷基或任选取代的C 3-C 7碳环基；
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素变体。9.根据权利要求1-8中任一项所述的化合物，其中，
    m选自0、2或3；
    n选自15；
    R 2和R 3各自独立地选自H或甲基；
    R 5选自异丙基。
  9. 根据权利要求1所述化合物，其可选自下式化合物：
    Figure PCTCN2018119483-appb-100010
    Figure PCTCN2018119483-appb-100011
    或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素衍生物。
  10. 药物组合物，其含有权利要求1-9中任一项所述的化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素衍生物，和药学上可接受的赋形剂。
  11. 权利要求10的药物组合物，其还含有其他治疗剂。
  12. 试剂盒，其包括
    第一容器，其中含有权利要求1-9中任一项的化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素衍生物；和
    任选地，第二容器，其中含有其他治疗剂；和
    任选地，第三容器，其中包含有用于稀释或悬浮所述化合物和/或其它治疗剂的药用赋形剂。
  13. 权利要求1-9中任一项化合物或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型或同位素衍生物，或者权利要求10或11的药物组合物在制备用于治疗和/或预防病毒感染的药物中的用途。
  14. 权利要求13的用途，其中所述病毒感染是HIV或HBV。
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