WO2020001592A1 - Dihydropyrimidine derivatives and use thereof - Google Patents

Dihydropyrimidine derivatives and use thereof Download PDF

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Publication number
WO2020001592A1
WO2020001592A1 PCT/CN2019/093578 CN2019093578W WO2020001592A1 WO 2020001592 A1 WO2020001592 A1 WO 2020001592A1 CN 2019093578 W CN2019093578 W CN 2019093578W WO 2020001592 A1 WO2020001592 A1 WO 2020001592A1
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Prior art keywords
alkylene
alkyl
haloalkyl
halogen
carbocyclyl
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PCT/CN2019/093578
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French (fr)
Chinese (zh)
Inventor
沙薇
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河南天晟泰丰医药科技有限公司
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Priority to CN201980042061.5A priority Critical patent/CN112469716A/en
Publication of WO2020001592A1 publication Critical patent/WO2020001592A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention belongs to the field of virus control.
  • the present invention relates to a series of dihydropyrimidine derivatives, pharmaceutical compositions containing said derivatives and uses thereof, especially for treating or preventing viral diseases such as hepatitis B.
  • the present invention relates to a dihydropyrimidine derivative capable of inhibiting the function of the hepatitis B virus (HBV) capsid protein, thereby being able to treat or prevent hepatitis B, a pharmaceutical composition containing the derivative, and its use Use for treating or preventing hepatitis B.
  • HBV hepatitis B virus
  • Hepatitis B virus infection is a major public health problem that affects approximately 2 billion people worldwide. About 350 million people develop chronic infections that can cause chronic persistent hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). 500,000 to 1 million people die each year from end-stage liver disease caused by hepatitis B virus infection.
  • HCC hepatocellular carcinoma
  • Hepatitis B virus is a small virus with only four open reading frames in its genome.
  • HBV core protein Cp is a small protein building block (consisting of 183 residues) that self-assembles to form a viral capsid. It can regulate almost every step of the viral life cycle in infected cells, so Cp is antiviral Important targets for drugs.
  • Hepatitis B is currently incurable. There are only two types of drugs, interferon and nucleoside analogs, which have the disadvantages of drug resistance, low efficiency and poor tolerance. Therefore, there is still a need in the art to develop drugs for treating and preventing hepatitis B.
  • the inventors designed a series of dihydropyrimidine derivatives for its structural characteristics, which are used to interfere with the formation of viral capsids by changing the Cp conformation or changing the Cp assembly speed, Produces antiviral effects.
  • the invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
  • R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5
  • R 2 and R 2 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 'can form oxo or thio;
  • R 3 and R 3 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 3 and R 3 'can form oxo or thio;
  • R 4 and R 4 ' are independently selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C ( O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,- (C 0-6 alkylene) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S ( O) p NR e R f
  • R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
  • R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(
  • R 6 and R 7 are independently selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl;
  • R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • the invention provides a compound of formula (I) above, with the proviso that when L is a chemical bond, R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl .
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents.
  • the invention provides a kit comprising a compound of the invention, and optionally other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
  • the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and / or prevention of a viral infection, particularly a hepatitis B virus infection.
  • the invention provides a method of treating and / or preventing a viral infection, particularly a hepatitis B virus infection, in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.
  • the invention provides a compound of the invention or a composition of the invention for use in the treatment and / or prevention of a viral infection, particularly a hepatitis B virus infection.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5, and C 5 -6 alkyl.
  • C 1-6 alkyl refers to a straight or branched chain saturated monovalent alk (hydrocarbon) group containing 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. Typical C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl and the like. An alkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-8 alkenyl means a straight or branched hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2 -Vinylbutyl, 3-hexen-1-yl, etc. In some embodiments, C 2-6 alkenyl is preferred. In some embodiments, C 2-4 alkenyl is particularly preferred.
  • the term "C 2-8 alkenyl” includes cycloalkenyl and heteroalkenyl, wherein 1 to 3 nitrogen atoms selected from O, S, N or substituted nitrogen atoms may be substituted for carbon atoms. An alkenyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-8 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms, which has one or more unsaturated carbon-carbon double bonds and at least one carbon-carbon triple bond.
  • C 2-6 alkynyl is preferred.
  • C 2-4 alkynyl is particularly preferred.
  • Typical alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, and hexynyl.
  • An alkynyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkylene group refers to a divalent alkylene group formed by removing one hydrogen of the C 1-6 alkyl group, and may be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 alkylene is particularly preferred.
  • the unsubstituted alkylene group includes but is not limited to: methylene (-CH 2- ), ethylene (-CH 2 CH 2- ), propylene (-CH 2 CH 2 CH 2- ), butylene (-CH 2 CH 2 CH 2 CH 2- ), pentylene (-CH 2 CH 2 CH 2 CH 2- ), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2- ) ,and many more.
  • Exemplary substituted said alkylene for example, said alkylene substituted with one or more alkyl (methyl), including but not limited to: substituted methylene (-CH (CH 3 )- , -C (CH 3 ) 2- ), substituted ethylene (-CH (CH 3 ) CH 2- , -CH 2 CH (CH 3 )-, -C (CH 3 ) 2 CH 2- , -CH 2 C (CH 3 ) 2- ), substituted propylene (-CH (CH 3 ) CH 2 CH 2- , -CH 2 CH (CH 3 ) CH 2- , -CH 2 CH 2 CH (CH 3 ) -, -C (CH 3 ) 2 CH 2 CH 2- , -CH 2 C (CH 3 ) 2 CH 2- , -CH 2 CH 2 C (CH 3 ) 2- ), and so on.
  • substituted methylene -CH (CH 3 )- , -C (CH 3 ) 2-
  • substituted ethylene -CH (CH 3 ) CH 2-
  • C 0-6 alkylene means a C 1-6 alkylene group and a chemical bond (C 0 alkylene group) as described above.
  • Halogen or halogen means fluorine, chlorine, bromine or iodine.
  • C 1-6 haloalkyl means the above-mentioned "C 1-6 alkyl” which is substituted with one or more halogen groups. Examples include monohalogen substitution, dihalogen substitution, and polyhalogenated alkyl radicals including perhalogenation.
  • a single halogen substituent may have one iodine, bromine, chlorine or fluorine atom in the group; two halogen substituents and multiple halogen substituents may have two or more of the same halogen atom or a combination of different halogens.
  • halogenated alkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl , Dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
  • the haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-7 carbocyclyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, a C 3-6 carbocyclyl is preferred, and a C 5-6 carbocyclyl is more preferred. Carbocyclyl also includes ring systems in which the carbocyclyl ring described above is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in this case, the number of carbons continues to be expressed The number of carbons in a carbocyclyl system.
  • Exemplary 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 ), ring Heptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptadienyl (C 7 ), and the like.
  • Carbocyclyl groups can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3-7 membered heterocyclic group refers to a group of 3 to 7 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus, and silicon.
  • the point of attachment may be a carbon or nitrogen atom.
  • a 3- to 6-membered heterocyclic group is preferred, which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 4- to 6-membered heterocyclic group, which is 4- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably 5- to 6-membered heterocyclic groups, which are 5 to 6 having ring carbon atoms and 1 to 3 ring heteroatoms Element non-aromatic ring system.
  • Heterocyclyl also includes a ring system in which the above heterocyclyl ring is fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl ring, or in which the above heterocyclyl ring and one or more aryl groups or Heteroaryl fused ring systems where the point of attachment is on a heterocyclyl ring; and in this case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system.
  • Exemplary three-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiorenyl.
  • Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietyl.
  • Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfanyl Oxazolidin-2-one.
  • Exemplary five-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexane, and dioxanyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl.
  • Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azacycloheptyl, oxecanyl, and thietyl.
  • Exemplary 5-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to, dihydroindolyl, isodihydroindolyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like.
  • Exemplary 6-membered heterocyclic groups (also referred to herein as 6,6-bicyclic heterocyclic groups) fused with a C 6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.
  • a heterocyclyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-10 aryl refers to a monocyclic or polycyclic (e.g., bicyclic) 4n + 2 aromatic ring system (e.g., having a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms 6 or 10 ⁇ electrons).
  • an aryl group having six ring carbon atoms ( “C 6 aryl”; e.g., phenyl).
  • the aryl group has ten ring carbon atoms ("C 10 aryl”; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems in which the aryl ring described above is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be expressed The number of carbon atoms in the aryl ring system.
  • An aryl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 5-10 membered heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n + 2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having a shared ring arrangement 6 or 10 ⁇ electrons), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • heteroaryl groups containing one or more nitrogen atoms as long as the valence allows, the point of attachment may be a carbon or nitrogen atom.
  • a heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the above heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring.
  • the carbon atom's The number continues to represent the number of carbon atoms in the heteroaryl ring system.
  • a 5-6 membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n + 2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom 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 five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom 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 heteroatom include, but are not limited to, azacycloheptatrienyl, oxecatrienyl, and thiacycloheptatrienyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, Indenazinyl and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, lindenyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolyl ( 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furanyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl Oxazolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl). Heteroaryl groups It may be substituted at any available
  • Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, etc., as defined herein, are optionally substituted groups, regardless of whether the term "optionally substituted” precedes it, which means that it exists
  • At least one hydrogen on a group e.g., a carbon or nitrogen atom
  • an allowable substituent e.g., a substituent that produces a stable compound upon substitution, e.g., does not undergo spontaneous transformation (e.g., by rearrangement, Cyclization, elimination or other reaction).
  • a “substituted” group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position in any given structure, The substituents at the positions are the same or different.
  • substituted includes substitutions with all permissible substituents of the organic compound (any substituent described herein that results in the formation of a stable compound).
  • a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom 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 combined to form a heterocyclyl or Heteroaryl ring in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R dd groups Group replacement
  • Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocyclic ring Or heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;
  • Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon A cyclic group, a heterocyclyl group, an aryl group and a heteroaryl group are independently substituted with 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 combined to form a heterocyclyl Or 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
  • treatment relates to reversing, alleviating, inhibiting or preventing the progress or prevention of a disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition.
  • treatment as used herein relates to the action of the verb therapy, which is as defined just now.
  • pharmaceutically acceptable salts refers to those carboxylic acid salts, amino acid addition salts of the compounds of the present invention, which are suitable for contact with patient tissues within the scope of reliable medical judgment, without causing inappropriate toxicity, Stimuli, allergies, etc., which are commensurate with a reasonable benefit / risk ratio, are effective in terms of their intended use, including, if possible, zwitterionic forms of the compounds of the invention.
  • salt refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or the purified compounds can be separately reacted with the free base form of a suitable organic or inorganic acid and the resulting salts isolated. As long as the compounds of the present invention are basic compounds, they are capable of forming many different salts with various inorganic and organic acids.
  • salts must be pharmaceutically acceptable for administration to animals, it is often necessary in practice to first isolate a pharmaceutically unacceptable salt of a basic compound from the reaction mixture and then simply treat it with the aid of a basic reagent Conversion to a free base compound followed by conversion of the free base to a pharmaceutically acceptable acid addition salt.
  • Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form a salt.
  • the free base can be regenerated by contacting the salt form with a base in a conventional manner and then separating the free base.
  • Free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, salts are also equivalent to their respective free bases.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • the base addition salt of an acidic compound can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt.
  • the free acid can be regenerated by contacting the salt form with the acid in a conventional manner and then separating the free acid.
  • Free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, salts are still equivalent to their respective free acids.
  • the salt may be a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, prepared from an inorganic acid. Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurel Salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Mesylate, glucoheptanoate, lactobionate, laurylsulfonate and isethionate, etc.
  • Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, horse Lamate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Naphthoate, Tosylate, Tosylate, Toluene Acid salt, citrate, lactate, maleate, tartrate, mesylate, etc.
  • Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Also included are salts of amino acids, such as arginine, gluconate, galacturonate, etc. (see, for example, Berger SMetal., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1- 19. This is incorporated by reference).
  • Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include from C 1 -C 6 alkyl esters in which the alkyl group is linear or branched. Acceptable esters also include C 5 -C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl ester. C 1 -C 4 alkyl esters are preferred.
  • the esters of the compounds of the present invention can be prepared according to conventional methods, for example: March's Advanced Organic Chemistry, 5 Edition "MB Smith & J. March, John Wiley & Sons, 2001.
  • Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include amides derived from ammonia, primary C 1 -C 6 alkylamines, and secondary C 1 -C 6 dialkylamines, wherein the alkyl group is linear or branched Chain.
  • the amine may also be in the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom.
  • Amides derived from ammonia, C 1 -C 3 alkyl primary amines and C 1 -C 2 dialkyl secondary amines are preferred.
  • the amides of the compounds of the present invention can be prepared according to conventional methods, for example: March's Advanced Organic Chemistry, 5 Edition ", MB Smith & J. March, John Wiley & Sons, 2001.
  • prodrug means a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • prodrug means a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood.
  • Subjects to be administered include, but are not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and / or non-human animals, such as mammals, for example, primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , Goat, rodent, cat and / or dog.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treatment includes the effect of a subject having a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or development of a condition ("therapeutic treatment"), also includes effects that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest.
  • the effective amount of a compound of the invention may vary depending on factors such as the biological objective, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the subject's Age health and symptoms.
  • An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
  • a "therapeutically effective amount" of a compound used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition. Delayed or minimized.
  • 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” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound used herein 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 a disease , 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 preventative benefit in the prevention of a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prevention, or an amount that enhances the preventive effect of other preventive agents.
  • Combination and related terms refer to simultaneous or sequential administration of a compound of the invention and other therapeutic agent.
  • a compound of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.
  • the "compound of the present invention” refers to the following compounds of formula (I)-formula (IV) (including, for example, (II-1), (II-2), (II-3), (II-4) , (II-5), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), ( III-8), (III-9), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6)), their pharmacy Topically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof.
  • the invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof:
  • X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
  • R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5
  • R 2 and R 2 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 'can form oxo or thio;
  • R 3 and R 3 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 3 and R 3 'can form oxo or thio;
  • R 4 and R 4 ' are independently selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C ( O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,- (C 0-6 alkylene) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S ( O) p NR e R f
  • R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
  • R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(
  • R 6 and R 7 are independently selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl;
  • R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
  • R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5
  • R 2 , R 2 ′, R 3 , R 3 ′, R 4 and R 4 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 ′, R 3 and R 3 ′, R 4 and R 4 ′ may form oxo or thio, respectively;
  • R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
  • R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(
  • R 6 and R 7 are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;
  • R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.
  • R ' is H; in another specific embodiment, R' is halogen; in another specific embodiment, R 'is C1-6 alkyl; in another specific embodiment R ′ is a C 1-6 haloalkyl group; in another specific embodiment, R ′ is a C 3-7 carbocyclyl group; in another specific embodiment, R ′ is a 3-7 membered heterocyclic group.
  • X is a chemical bond; in another embodiment, X is CR b R c ; in another embodiment, X is NR a ; in another embodiment, X is O ; In another specific embodiment, X is S (O) q .
  • R 1 is H; in another embodiment, R 1 is halogen; in another embodiment, R 1 is -CN; in another embodiment, R 1 is -NO 2 ; in another specific embodiment, R 1 is -C (O) R a ; in another specific embodiment, R 1 is -C (O) OR a ; in another specific embodiment, R 1 is -C (O) NR b R c ; in another embodiment, R 1 is C 1-6 alkyl; in another embodiment, R 1 is C 1-6 haloalkyl; In another specific embodiment, R 1 is C 2-8 alkenyl; in another specific embodiment, R 1 is C 2-8 alkynyl; in another specific embodiment, R 1 is C 3-7 Carbocyclyl; in another embodiment, R 1 is a 3-7 membered heterocyclic group; in another embodiment, R 1 is a C 6-10 aryl group; in another embodiment, R 1 is 5-10 membered heteroaryl.
  • R 1 is optionally substituted with 1 R group; in another specific embodiment, R 1 is optionally substituted with 2 R groups; in another specific embodiment, R 1 1 is optionally substituted with 3 R groups.
  • R is independently H; in another embodiment, R is independently halogen; in another embodiment, R is independently -CN; in another embodiment, R is independently -NO 2 ; in another embodiment, R is independently -OR a ; in another embodiment, R is independently -NR b R c ; in another embodiment, R is independently -C (O) OR a ; in another embodiment, R is independently -C (O) NR b R c ; in another embodiment, R is independently C 1-6 Alkyl; in another embodiment, R is independently C 1-6 haloalkyl; in another embodiment, R is independently C 3-7 carbocyclyl; in another embodiment, R is independently a 3-7 membered heterocyclic group; in another embodiment, R is independently a C 6-10 aryl group; in another embodiment, R is independently a 5-10 membered heteroaryl group .
  • R 2 and R 2 ′ are independently H; in another specific embodiment, R 2 and R 2 ′ are independently halogen; in another specific embodiment, R 2 and R 2 'Is independently -CN; in another embodiment, R 2 and R 2 ' are independently -NO 2 ; in another embodiment, R 2 and R 2 'are independently -OR a ; in another specific embodiment, R 2 and R 2 ′ are independently -NR b R c ; in another specific embodiment, R 2 and R 2 ′ are independently -C (O) OR a ; in another In a specific embodiment, R 2 and R 2 ′ are independently —C (O) NR b R c ; in another specific embodiment, R 2 and R 2 ′ are independently C 1-6 alkyl; In a specific embodiment, R 2 and R 2 ′ are independently C 1-6 haloalkyl; in another specific embodiment, R 2 and R 2 ′ are independently C 3-7 carbocyclyl; in another In a specific embodiment, R 2 and
  • R 3 and R 3 ′ are independently H; in another specific embodiment, R 3 and R 3 ′ are independently halogen; in another specific embodiment, R 3 and R 3 'Is independently -CN; in another embodiment, R 3 and R 3 ' are independently -NO 2 ; in another embodiment, R 3 and R 3 'are independently -OR a ; in another specific embodiment, R 3 and R 3 ′ are independently -NR b R c ; in another specific embodiment, R 3 and R 3 ′ are independently -C (O) OR a ; in another In a specific embodiment, R 3 and R 3 ′ are independently —C (O) NR b R c ; in another specific embodiment, R 3 and R 3 ′ are independently C 1-6 alkyl; In a specific embodiment, R 3 and R 3 ′ are independently C 1-6 haloalkyl; in another specific embodiment, R 3 and R 3 ′ are independently C 3-7 carbocyclyl; in another In a specific embodiment, R 3 and
  • R 4 and R 4 ′ are independently H; in another specific embodiment, R 4 and R 4 ′ are independently halogen; in another specific embodiment, R 4 and R 4 'Is independently -CN; in another embodiment, R 4 and R 4 ' are independently -NO 2 ; in another embodiment, R 4 and R 4 'are independently-(C 0- 6 alkylene) -OR a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -NR b R c ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -C (O) R a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 Alkylene) -C (O) OR a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -C (O) NR b R c ; In another specific embodiment, R 4 and R 4 ′ are independently
  • R 2 and R 3 are combined to form a double bond; in another embodiment, R 2 and R 3 are combined to form a C 3-7 carbocyclyl; in another embodiment, R 2 and R 3 combine to form a 3-7 membered heterocyclic group; in another specific embodiment, R 2 and R 3 combine to form a C 6-10 aryl group; in another specific embodiment, R 2 and R 3 combine A 5-10 membered heteroaryl is formed.
  • R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond; in another specific embodiment , R 3 or R 4 may be combined with one of R a , R b and R c to form a C 3-7 carbocyclic group; in another specific embodiment, R 3 or R 4 may be combined with R a , R b and One of R c is combined to form a 3-7 membered heterocyclic group; in another specific embodiment, R 3 or R 4 may be combined with one of R a , R b and R c to form a C 6-10 aryl group; In another specific embodiment, R 3 or R 4 may be combined with one of R a , R b and R c to form a 5-10 membered heteroaryl.
  • R 5 is H; in another specific embodiment, R 5 is halogen; in another specific embodiment, R 5 is -CN; in another specific embodiment, R 5 is -NO 2 ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -OR a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -NR b R c ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -C (O) R a ; in another specific embodiment, R 5 is-(C 0 -6 alkylene) -C (O) OR a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -C (O) NR b R c ; in another specific implementation In the scheme, R 5 is- (C 0-6 alkylene) -OC (O) R a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -N (R b ) -
  • R 6 and R 7 are independently H; in another specific embodiment, R 6 and R 7 are independently halogen; in another specific embodiment, R 6 and R 7 are independently Is -CN; in another specific embodiment, R 6 and R 7 are independently -NO 2 ; in another specific embodiment, R 6 and R 7 are independently -OR a ; in another specific embodiment, R 6 and R 7 are independently -NR b R c ; In another embodiment, R 6 and R 7 are independently C 1-6 alkyl; In another embodiment, R 6 and R 7 R 7 is independently C 1-6 haloalkyl.
  • R a, R b and R c are independently H; In another particular embodiment, R a, R b and R c are independently C 1-6 alkyl; In another specific In an embodiment, R a , R b and R c are independently C 1-6 haloalkyl.
  • any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments.
  • any technical scheme of L or any combination thereof may be combined with any technical scheme of X, R 1 -R 7 , R 2 ′ -R 4 ′, m and n or any combination thereof.
  • the present invention is intended to include a combination of all these technical solutions, which is limited in space and will not be listed one by one.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphic, prodrug or isotope variants, and mixtures thereof, having the general formula (II-1), (II-2), (II-3), (II-4) or (II-5) :
  • R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl , 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 6 ′ and R 6 ′′ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ′′ is Cl or Br;
  • X, R 2 -R 7 , R 3 ′, m and n are as defined above.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (II-3) or (II-4):
  • R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, or C 1-6 haloalkyl;
  • R 2 and R 3 are H;
  • R 5 is- (C 0-6 alkylene) -C (O) OR d ;
  • R 6 ′ and R 6 ′′ are halogen and methyl
  • R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 is selected from H, halogen or C 1-6 haloalkyl
  • R 2 and R 3 are H;
  • R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 6 ′ is F, and R 6 ′′ is Cl or Br;
  • R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 is selected from H, halogen, CF 3 or CHF 2 ; preferably, R 1 is CF 3 ;
  • R 2 and R 3 are H;
  • R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 6 ′ is F, and R 6 ′′ is Cl or Br;
  • R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (II-5):
  • X is a chemical bond or O
  • R 1 is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
  • R 3 is selected from H, halogen or C 1-6 alkyl
  • R 3 ' is selected from H or halogen
  • R 4 is selected from H or C 1-6 alkyl
  • R 5 is selected from H,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O ) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene Group) -OS (O) 2 R d or- (C 0-6 alkylene) -N (R e ) -S (O) 2 R d ; preferably, R 5 is in the (S) configuration; preferably , When R 5 is -COOH, at least one of R 3 , R 3 ′ and R 4 is not H;
  • R 6 ′ and R 6 ′′ are halogen and methyl
  • R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • X is a chemical bond or O
  • R 1 is selected from H, halogen or C 1-6 haloalkyl; preferably, R 1 is C 1-6 haloalkyl;
  • R 3 is selected from H, halogen or C 1-6 alkyl
  • R 3 ' is selected from H or halogen
  • R 4 is selected from H or C 1-6 alkyl
  • R 5 is selected from H,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 Alkylene) -OS (O) 2 R d or- (C 0-6 alkylene) -N (R e ) -S (O) 2 R d ; preferably, R 5 is selected from- (C 0- 6 alkylene) -C (O) OH,-(C 0-6 alkylene) -C (O) NH 2 or- (C 0-6 alkylene) -NH-S (O) 2 R d
  • R 5 is in the (S) configuration; preferably, when R 5 is -COOH, at least one of R 3 , R 3 ′, and R 4 is not H;
  • R 6 ′ and R 6 ′′ are halogen and methyl
  • R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • X is a chemical bond or O
  • R 1 is selected from H, Br, CF 3 or CHF 2 ; preferably, R 1 is CF 3 ;
  • R 3 is H, F or isopropyl
  • R 3 is H or F
  • R 4 is H or methyl
  • R 5 is selected from H, -COOH, -CONH 2 , -CH 2 NHSO 2 Me, -COOMe, or -CH 2 OH; preferably, R 5 is selected from -COOH, -CONH 2 or -CH 2 NHSO 2 Me; preferably Preferably, R 5 is in the (S) configuration; preferably, when R 5 is -COOH, at least one of R 3 , R 3 ′, and R 4 is not H;
  • R 6 ′ is F
  • R 6 ′′ is Cl or Br.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formulae (III-1), (III-2), (III-3), (III-4), (III-5) , (III-6), (III-7), (III-8), or (III-9):
  • R 4 and R 5 are -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 6 ′ and R 6 ′′ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ′′ is Cl or Br;
  • R 1 -R 7 , R ′, R ′′, m and n are as defined above.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphic, prodrug or isotope variants, and mixtures thereof, having the general formula (III-5), (III-6), (III-7) or (III-8):
  • R 1 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, or -C (O) OR a ; preferably R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -C (O) OR a ;
  • R 2 and R 3 are H;
  • R 4 and R 5 are -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R a is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably, R a is independently C 1-6 alkyl or C 1-6 haloalkyl;
  • R d is independently selected from C 1-6 alkyl or C 1-6 haloalkyl
  • R 6 ′ and R 6 ′′ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ′′ is Cl or Br.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (III-9)
  • R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -C (O) OR a ; preferably, R 1 is selected from halogen or -C (O) OR a ;
  • R 4 is H or- (C 0-6 alkylene) -C (O) OR d ; preferably, R 4 is H or- (C 1-6 alkylene) -C (O) OH; preferably , R 4 is (R) configuration;
  • R 5 is H or- (C 0-6 alkylene) -C (O) OR d ; preferably, R 5 is H or -C (O) OR d ; preferably, R 5 is (S) configuration ; Preferably, at least one of R 4 and R 5 is a non-hydrogen group;
  • R 6 ′ and R 6 ′′ are halogen and methyl
  • R a is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R d is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 is selected from Br, Cl or -C (O) Me
  • R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
  • R 5 is H, -C (O) OH, -C (O) OMe or -CH 2 CH 2 C (O) OH; preferably, R 5 is H, -C (O) OH or -C (O) OMe; preferably, R 5 is in the (S) configuration; preferably, at least one of R 4 and R 5 is a non-hydrogen group;
  • R 6 ′ is F
  • R 6 ′′ is Cl or Br.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) Or (IV-6):
  • R 6 ′ and R 6 ′′ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ′′ is Cl or Br;
  • X, R 1 -R 7 , m and n are as defined above.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (IV-3), (IV-4) or (IV-5):
  • R 1 is selected from H, -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; and R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a or -NR b R c ;
  • R 2 and R 3 are H, or R 2 and R 3 combine to form a double bond
  • R 4 is -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 6 ′ and R 6 ′′ are halogen and methyl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1 is selected from H, -C (O) OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, or 3-7 membered heterocyclyl; and R 1 is optionally Substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a or -NR b R c ;
  • R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, or 3-7 membered heterocyclyl; and R 1 is optionally 1, 2, or 3 R group substitutions, where R is independently selected from -OR a or -NR b R c ;
  • R 2 and R 3 are H;
  • R 4 is -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
  • R 6 ′ is F, and R 6 ′′ is Cl or Br;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (IV-6):
  • R 1 is selected from H, C 1-6 alkyl, -C (O) OR a, or C 3-7 carbocyclyl, and wherein C 1-6 alkyl or C 3-7 carbocyclyl is optionally substituted by 1 -OR a group substitution;
  • R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
  • R 5 is H or -C (O) OR a ; preferably, R 5 is (S) configuration;
  • R 6 ′ and R 6 ′′ are halogen and methyl
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1 is selected from H, cyclopropyl, -C (O) OMe or -CH 2 OH;
  • R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
  • R 5 is H, -C (O) OH or -C (O) OMe; preferably, R 5 is H or -C (O) OH; preferably, R 5 is in the (S) configuration; preferably, R At least one of 4 and R 5 is a non-hydrogen group;
  • R 6 ′ is F
  • R 6 ′′ is Cl or Br.
  • the compound of the invention is selected from, but is not limited to, the following compounds:
  • the compounds of the invention may include one or more asymmetric centers, and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and / or diastereomeric forms.
  • the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, This includes racemic mixtures and mixtures rich in one or more stereoisomers.
  • Isomers can be separated from a mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • organic compounds can form complexes with solvents that react in the solvent or precipitate or crystallize from the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called a "hydrate”. The invention encompasses all solvates of the compounds of the invention.
  • solvate refers to the form of a compound or a salt thereof in combination with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • the "solvate” includes a solvate in a solution state and a separable solvate. Representative solvates include hydrates, ethanolates, and methanolates.
  • hydrate refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound can be represented, for example, by the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than 0.
  • a given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5 H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5 H 2 O)
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)).
  • the compounds of the invention may be in an amorphous or crystalline form (polymorphic 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.
  • polymorph refers to a crystalline form (or a salt, hydrate, or solvate) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the predominance of a crystalline form.
  • Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds (isotopic variants) which are equivalent to those described in Formulas I-VIII, but where one or more of the atoms have an atomic mass or mass number different from the atomic mass or mass number of atoms commonly found in nature Instead.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 p, 35 S, 18 F, and 36 Cl.
  • Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of the present invention.
  • Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Thallium, i.e. 3 H and carbon-14, i.e. 14 C isotopes, are particularly preferred because they are easy to prepare and detect.
  • Isotopically labeled compounds of formula I-VIII of the present invention and their prodrugs can generally be prepared in such a way that non-isotope-labeled reagents can be replaced with readily available isotopically-labeled reagents when performing the processes disclosed in the following schemes and / or examples and preparations Labeled reagent.
  • prodrugs are also included in the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted into its active form with a medical effect in vivo by, for example, hydrolysis in blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs, 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, or drug, delivery: solubility, limitation, overcome, and use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each article This article is for reference.
  • a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in vivo.
  • Prodrugs are usually prepared by modifying functional groups, and the modification is performed in a manner such that the modification can be performed by routine manipulation or cleavage in vivo to produce the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxy, amino, or thiol group is bonded to an arbitrary group, and when administered to a patient, can be cleaved to form a hydroxy, amino, or thiol group.
  • prodrugs include, but are not limited to, acetate, amide, formate / amide, and benzoate / amide derivatives of hydroxyl, thiol, and amino functional groups of the compound of formula (I).
  • a carboxylic acid -COOH
  • an ester such as methyl ester, ethyl ester, or the like can be used.
  • the esters themselves can be active and / or can be hydrolyzed under conditions in the human body.
  • Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups that readily break down in the human body to release the parent acid or its salt.
  • the invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I-VIII or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.
  • compositions preparations and kits
  • the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
  • a pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compounds 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 (such as human serum albumin Protein), buffer substances (e.g. phosphate), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g.
  • protamine sulfate disodium hydrogen phosphate, potassium hydrogen phosphate , Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols and lanolin.
  • kits eg, pharmaceutical packaging.
  • the kits provided may include compounds of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other Suitable container).
  • the provided kit may 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 and other therapeutic agents are provided in a first container and a second container to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, and sternal administration , Cerebrospinal spinal membrane 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 .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically based on and under the supervision of a physician, at a dosage level as described above.
  • Subjects at risk for developing a particular disorder typically include subjects with a family history of the disorder, or those who are determined by genetic testing or screening to be particularly sensitive to the development of the disorder.
  • the pharmaceutical compositions provided herein can also be administered chronically ("long-term administration").
  • Long-term administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the remainder of a subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
  • a pharmaceutical composition may be administered as a bolus, for example, to increase the concentration of a compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose that slowly releases the active ingredient, while a bolus delivered directly to a vein (e.g., by IV intravenous drip ) Can be delivered more quickly, so that the concentration of the active ingredient in the blood quickly rises to an effective level.
  • the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of a liquid solution or suspension in bulk or a powder in bulk. However, more generally, to facilitate accurate dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined number of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is each useful for forming a desired administration form A carrier or excipient and processing aid.
  • a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg / kg of a compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / kg.
  • transdermal doses are usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • the injection dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour.
  • a preloaded bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be given.
  • the maximum total dose cannot exceed about 2 g / day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint, water Methyl salicylate or orange flavor.
  • binders such as microcrystalline cellulose, tragacanth, or gelatin
  • excipients such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch
  • lubricants such as magnesium stea
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing an active ingredient.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with a paraffin or a water-miscible ointment base.
  • the active ingredient may 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 components for enhancing the 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 achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Remington's Pharmaceuticals, Science, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Section 8, which is incorporated herein by reference.
  • the compounds of the invention may also be administered in a sustained release form or from a sustained release delivery system.
  • sustained-release materials can be found in Remington's Pharmaceuticals Science.
  • the invention also relates to a pharmaceutically acceptable formulation of a compound of the invention.
  • the formulation comprises water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ -, and ⁇ -cyclodextrin consisting of 6, 7, and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or more substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, a sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (eg, 10-50% in water).
  • a compound or composition of the invention may be administered simultaneously with one or more additional agents, or before or after the one or more additional agents, as a combination therapy.
  • the medicament includes a therapeutically active agent.
  • the medicament also includes a prophylactically active agent.
  • Medicaments include small organic molecules, such as pharmaceutical compounds (e.g., human or veterinary compounds approved by the US Federal Regulations (CFR), approved by the US Food and Drug Administration), peptides, proteins, carbohydrates, monosaccharides Oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules of connexins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, Antisense oligonucleotides, lipids, hormones, vitamins and cells.
  • pharmaceutical compounds e.g., human or veterinary compounds approved by the US Federal Regulations (CFR),
  • the additional agent is an agent for treating and / or preventing a disease described herein.
  • Each additional agent may be administered at a dose and / or schedule determined by the agent.
  • the additional agents may also be administered together with each other and / or with a compound or composition described herein in a single dose or separately in different doses.
  • the specific combination employed in this regime will take into account the compatibility of the compounds of this invention with additional agents and / or the desired therapeutic and / or prophylactic effects that will be achieved.
  • the additional agents are used at a level that does not exceed the level at which they are used alone. In some embodiments, the levels used in combination will be lower than when they are used alone.
  • the additional agent is an antiviral agent selected from the group consisting of HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, capsid assembly regulators, reverse transcriptase inhibitors, TLR-agonists, and formulations of different or unknown mechanisms, and combinations thereof.
  • the pegylated interferon is pegylated interferon alpha (IFN- ⁇ ), pegylated interferon lambda (IFN- ⁇ ), or pegylated interferon gamma (IFN - ⁇ ).
  • the reverse transcriptase inhibitor is at least one of: Zidovudine, Didanosine, Zalcitabine, ddA (2 ', 3'-dideoxyadenosine) (ddA (2 ', 3'-dideoxyadenosine)), Stavudine, Lamivudine, Abacavir, Emtricitabine ( Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir Ganciclovir, valganciclovir, tenofovir, adefovir, cidofovir, efavirenz, nevirapine, Delavirdine, or Etravirine.
  • the additional agent is, for example, a T-cell response activator AIC649; interferon-based biological agents such as interferons and pegylated interferons; TLR modulators such as TLR-7 agonists or TLRs -9 agonists such as SM360320 (9-benzyl-8-hydroxy-2- (2-methoxy-ethoxy) adenine), AZD8848 ([3-( ⁇ [3- (6-amino-2 -Butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] [3- (4-morpholinyl) propyl] amino ⁇ methyl) phenyl] acetic acid Methyl ester), GS-9620 and RO6864018; therapeutic vaccines that stimulate HBV-specific immune responses; immune activators such as SB-9200; RNA interference (RNAi) or small RNA interference (siRNA) such as ARC-520, ARC- 521; or a reverse transcriptas
  • the chromatographic conditions were as follows (IntelFlash-1): C18 silica gel column; Mobile phase A: CH 3 CN, mobile phase B: pure water containing 0.05% TFA. The acetonitrile content increased from 10% to 80% in 40 minutes; the UV detector wavelength was 254nm. 24 330 mg (79.82%) of the product was isolated as a yellow solid. MS m / z 621 [M + H].
  • the crude product was purified by preparative HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl); mobile phase B: ACN; flow rate: 60 mL / min; Gradient: Mobile phase B rose from 38% to 56% in 7 minutes. After lyophilization, the product 33 (711.2 mg, yield 35.06%) was obtained as a yellow solid.
  • the crude product was purified by preparative HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl); mobile phase B: ACN; flow rate: 60 mL / min ; Gradient: mobile phase B increased from 30% to 60% in 10 minutes. After lyophilization, the product 37 (92 mg, yield 45%) was obtained as a yellow solid.
  • the crude product 47 (710 mg, 1.1 mmol) was dissolved in dichloromethane (10 ml), 5 mL of trifluoroacetic acid was slowly added, and the reaction solution was stirred at room temperature overnight. The solvent was concentrated and evaporated under reduced pressure. The residue was added with 50 mL of dichloromethane and 20 mL of water, and the aqueous phase was adjusted to pH 6-7 with a saturated sodium bicarbonate solution under stirring. The organic phase was collected in layers, and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phases were washed with saturated sodium chloride, dried, and concentrated. The residue was separated by silica gel column chromatography (P: EA 1: 1) to give the product 48 as a yellow solid (392 mg, 56% in two steps). MS-ESI m / z: 475 [M + H] + .
  • the crude product is prepared by Purification by HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: mobile phase B increased from 20% to 60 in 15 minutes %. After lyophilization, the product 52a (210 mg, yield 31%) was obtained as a yellow solid.
  • HepG2.2.15 cells were used to detect the anti-HBV activity of the test compounds.
  • HepG2.2.15 cells were seeded into 96-well microplates with a density of 3 ⁇ 10 4 cells in 0.1 mL of medium per well, and the multiwell plates were incubated at 37 ° C. overnight.
  • the test compound and the control compound (entecavir, ETV) were three-fold diluted with DMSO solvent to 8 different concentration points, and two duplicate wells were measured in parallel.
  • the initial concentration of the test compound was 10 ⁇ M.
  • 100 ⁇ L of a compound DMSO solution of decreasing concentration was added to the microwells on the plate so that the final concentration of DMSO in each well was 0.5%.
  • the amount of HBV DNA in the supernatant was detected by quantitative PCR, and the cell viability was detected by CellTiter Glo.
  • Compound EC 50 ( ⁇ M) CC 50 ( ⁇ M) Compound EC 50 ( ⁇ M) CC 50 ( ⁇ M) 6 B > 10 34a A > 10 7 B > 10 34b A > 10 8 B > 10 34c B > 10 9 A > 10 34d A > 10 10 B > 10 37 B > 10 11 A > 10 40 B > 10 12 B > 10 48 B > 10 13 A > 10 49 A > 10 14 A > 10 52a A > 10 15 B > 10 52b A > 10 16 A > 10 52c A > 10 25 A > 10 53a A > 10 26 A > 10 53b A > 10 27 A > 10 53c A > 10 32 A > 10 54 B > 10 33 A > 10 ETV 0.002 > 0.02

Abstract

The present invention relates to dihydropyrimidine derivatives as represented by general formula (I), which are applicable to the treatment and prevention of hepatitis B virus infection. The invention further relates to pharmaceutical compositions containing a compound as represented by formula (I), and use thereof for the treatment and prevention of hepatitis B virus infection.

Description

二氢嘧啶衍生物及其用途Dihydropyrimidine derivatives and uses thereof 发明领域Field of invention
本发明属于病毒防治领域。具体地，本发明涉及一系列二氢嘧啶衍生物，含有所述衍生物的药物组合物及其用途，尤其用于治疗或预防病毒性疾病，例如乙型肝炎。更具体地，本发明涉及可以抑制乙型肝炎病毒(HBV)衣壳蛋白的功能、进而能够治疗或预防乙型肝炎的二氢嘧啶衍生物，含有所述衍生物的药物组合物及其用于治疗或预防乙型肝炎的用途。The invention belongs to the field of virus control. In particular, the present invention relates to a series of dihydropyrimidine derivatives, pharmaceutical compositions containing said derivatives and uses thereof, especially for treating or preventing viral diseases such as hepatitis B. More specifically, the present invention relates to a dihydropyrimidine derivative capable of inhibiting the function of the hepatitis B virus (HBV) capsid protein, thereby being able to treat or prevent hepatitis B, a pharmaceutical composition containing the derivative, and its use Use for treating or preventing hepatitis B.
背景技术Background technique
乙型肝炎病毒感染是一个重大的公共健康问题，影响全球约20亿人口。其中约3.5亿人发展为慢性感染，可导致慢性迁延性肝炎、肝硬化和肝细胞癌(HCC)。每年有50万到100万人死于乙型肝炎病毒感染引起的末期肝脏疾病。Hepatitis B virus infection is a major public health problem that affects approximately 2 billion people worldwide. About 350 million people develop chronic infections that can cause chronic persistent hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). 500,000 to 1 million people die each year from end-stage liver disease caused by hepatitis B virus infection.
乙型肝炎病毒是一种小型病毒，其基因组只有四个开放阅读框。HBV核心蛋白(Cp)是一种自我组装形成病毒衣壳的小蛋白砌块(由183个残基构成)，它在感染的细胞中几乎可以调节病毒生命周期的每一步，所以Cp是抗病毒药物的重要靶点。Hepatitis B virus is a small virus with only four open reading frames in its genome. HBV core protein (Cp) is a small protein building block (consisting of 183 residues) that self-assembles to form a viral capsid. It can regulate almost every step of the viral life cycle in infected cells, so Cp is antiviral Important targets for drugs.
目前乙型肝炎还无法治愈，仅有干扰素和核苷类似物两类药物，具有耐药性、低效率和耐受性差等缺点。因此，本领域仍需要研发治疗和预防乙型肝炎的药物。Hepatitis B is currently incurable. There are only two types of drugs, interferon and nucleoside analogs, which have the disadvantages of drug resistance, low efficiency and poor tolerance. Therefore, there is still a need in the art to develop drugs for treating and preventing hepatitis B.
发明内容Summary of the invention
鉴于Cp蛋白在HBV生命周期中的重要性，本发明人针对其结构特点，设计了一系列二氢嘧啶衍生物，用于通过改变Cp构象或者改变Cp组装速度，干扰病毒衣壳的成形，进而产生抗病毒效应。In view of the importance of Cp protein in the life cycle of HBV, the inventors designed a series of dihydropyrimidine derivatives for its structural characteristics, which are used to interfere with the formation of viral capsids by changing the Cp conformation or changing the Cp assembly speed, Produces antiviral effects.
在一方面，本发明提供了通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In one aspect, the invention provides a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and mixtures thereof:
Figure PCTCN2019093578-appb-000001
Figure PCTCN2019093578-appb-000001
其中：among them:
L选自化学键、-CR’＝CR”-或-C≡C-；其中R’和R”独立地选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基； L is selected from a chemical bond, -CR '= CR "-or -C≡C-; wherein R' and R" are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 7 carbocyclyl or 3-7 membered heterocyclyl;
X选自化学键、CR bR c、NR a、O或S(O) q； X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
R 1选自H、卤素、-CN、-NO 2、-C(O)R a、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、 C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
R 2和R 2’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 2和R 2’可以形成氧代或硫代； R 2 and R 2 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 'can form oxo or thio;
R 3和R 3’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 3和R 3’可以形成氧代或硫代； R 3 and R 3 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 3 and R 3 'can form oxo or thio;
R 4和R 4’独立地选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基；或者，R 4和R 4’可以形成氧代或硫代； R 4 and R 4 'are independently selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C ( O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,- (C 0-6 alkylene) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S ( O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 alkyl or C 1-6 haloalkyl; or, R 4 and R 4 ′ may form oxo or thio;
或者，R 2和R 3结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
或者，当X为CR bR c或NR a时，R 3或R 4可以与R a、R b和R c中的一个结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, when X is CR b R c or NR a , R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
R 5选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基； R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 Alkyl or C 1-6 haloalkyl;
R 6和R 7独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基； R 6 and R 7 are independently selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl;
R a、R b、R c、R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基； R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
m＝0、1、2、3、4或5；m = 0, 1, 2, 3, 4 or 5;
n＝0、1或2；n = 0, 1, or 2;
p＝1或2；p = 1 or 2;
q＝0、1或2。q = 0, 1, or 2.
在另一个方面，本发明提供了上述通式(I)的化合物，其中条件是当L为化学键时，R 1选自H、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。 In another aspect, the invention provides a compound of formula (I) above, with the proviso that when L is a chemical bond, R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl .
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
在另一个方面，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。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents.
在另一个方面，本发明提供了包含本发明化合物，和任选地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。In another aspect, the invention provides a kit comprising a compound of the invention, and optionally other therapeutic agents, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防病毒感染尤其是乙型肝炎 病毒感染的药物中的用途。In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and / or prevention of a viral infection, particularly a hepatitis B virus infection.
在另一个方面，本发明提供了在受试者中治疗和/或预防病毒感染尤其是乙型肝炎病毒感染的方法，包括向所述受试者给药本发明化合物或本发明组合物。In another aspect, the invention provides a method of treating and / or preventing a viral infection, particularly a hepatitis B virus infection, in a subject, comprising administering to said subject a compound of the invention or a composition of the invention.
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防病毒感染尤其是乙型肝炎病毒感染。In another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and / or prevention of a viral infection, particularly a hepatitis B virus infection.
由随后的具体实施方案、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。Other objects and advantages of the invention will be apparent to those skilled in the art from the following specific embodiments, examples and claims.
定义definition
化学定义Chemical definition
下面更详细地描述具体官能团和化学术语的定义。Definitions of specific functional groups and chemical terms are described in more detail below.
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 1-6烷基”包括C 1、C 2、C 3、C 4、C 5、C 6、C 1-6、C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-5、C 2-4、C 2-3、C 3-6、C 3-5、C 3-4、C 4-6、C 4-5和C 5-6烷基。 When listing a range of values, it is intended to include each value and subranges within that range. For example, "C 1-6 alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5, and C 5 -6 alkyl.
“C 1-6烷基”是指含有1至6个碳原子的直链或支链的饱和单价烷(烃)基。在一些实施方案中，C 1-4烷基是优选的。典型的C 1-6烷基包括甲基、乙基、丙基、异丙基，正丁基，叔丁基、异丁基、戊基、己基、异己基等。烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "C 1-6 alkyl" refers to a straight or branched chain saturated monovalent alk (hydrocarbon) group containing 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. Typical C 1-6 alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, hexyl, isohexyl and the like. An alkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 2-8烯基”表示具有2至8个碳原子和至少一个碳碳双健的直链或支链的烃基团，包括但不限于乙烯基、3-丁烯-1-基、2-乙烯基丁基、3-己烯-1-基等。在一些实施方案中，C 2-6烯基是优选的。在一些实施方案中，C 2-4烯基是特别优选的。术语“C 2-8烯基”包括环烯基和杂烯基，其中1至3个选自O、S、N或取代的氮原子可以代替碳原子。烯基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "C 2-8 alkenyl" means a straight or branched hydrocarbon group having 2 to 8 carbon atoms and at least one carbon-carbon double bond, including but not limited to vinyl, 3-buten-1-yl, 2 -Vinylbutyl, 3-hexen-1-yl, etc. In some embodiments, C 2-6 alkenyl is preferred. In some embodiments, C 2-4 alkenyl is particularly preferred. The term "C 2-8 alkenyl" includes cycloalkenyl and heteroalkenyl, wherein 1 to 3 nitrogen atoms selected from O, S, N or substituted nitrogen atoms may be substituted for carbon atoms. An alkenyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 2-8炔基”指的是具有2至8个碳原子的直链或支链的烃基团，其中有一个或多个不饱和碳碳双键，其中至少有一个碳碳叁键。在一些实施方案中，C 2-6炔基是优选的。在一些实施方案中，C 2-4炔基是特别优选的。典型的炔基包括乙炔基、丙炔基、异丙炔基、丁炔基、异丁炔基、戊炔基和己炔基。炔基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "C 2-8 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 8 carbon atoms, which has one or more unsaturated carbon-carbon double bonds and at least one carbon-carbon triple bond. In some embodiments, C 2-6 alkynyl is preferred. In some embodiments, C 2-4 alkynyl is particularly preferred. Typical alkynyl groups include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, and hexynyl. An alkynyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 1-6亚烷基”是指除去C 1-6烷基的一个氢而形成二价的亚烷基，并且可以是取代或未取代的亚烷基。在一些实施方案中，C 1-4亚烷基是特别优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚丁基(-CH 2CH 2CH 2CH 2-)、亚戊基(-CH 2CH 2CH 2CH 2CH 2-)、亚己基(-CH 2CH 2CH 2CH 2CH 2CH 2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH 3)-、-C(CH 3) 2-)、取代的亚乙基(-CH(CH 3)CH 2-、-CH 2CH(CH 3)-、-C(CH 3) 2CH 2-、-CH 2C(CH 3) 2-)、取代的亚丙基(-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH 2CH(CH 3)-、-C(CH 3) 2CH 2CH 2-、-CH 2C(CH 3) 2CH 2-、-CH 2CH 2C(CH 3) 2-)，等等。 The "C 1-6 alkylene group" refers to a divalent alkylene group formed by removing one hydrogen of the C 1-6 alkyl group, and may be a substituted or unsubstituted alkylene group. In some embodiments, C 1-4 alkylene is particularly preferred. The unsubstituted alkylene group includes but is not limited to: methylene (-CH 2- ), ethylene (-CH 2 CH 2- ), propylene (-CH 2 CH 2 CH 2- ), butylene (-CH 2 CH 2 CH 2 CH 2- ), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2- ), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2- ) ,and many more. Exemplary substituted said alkylene, for example, said alkylene substituted with one or more alkyl (methyl), including but not limited to: substituted methylene (-CH (CH 3 )- , -C (CH 3 ) 2- ), substituted ethylene (-CH (CH 3 ) CH 2- , -CH 2 CH (CH 3 )-, -C (CH 3 ) 2 CH 2- , -CH 2 C (CH 3 ) 2- ), substituted propylene (-CH (CH 3 ) CH 2 CH 2- , -CH 2 CH (CH 3 ) CH 2- , -CH 2 CH 2 CH (CH 3 ) -, -C (CH 3 ) 2 CH 2 CH 2- , -CH 2 C (CH 3 ) 2 CH 2- , -CH 2 CH 2 C (CH 3 ) 2- ), and so on.
“C 0-6亚烷基”表示上文所述的C 1-6亚烷基以及化学键(C 0亚烷基)。 "C 0-6 alkylene" means a C 1-6 alkylene group and a chemical bond (C 0 alkylene group) as described above.
“卤”或“卤素”是指氟、氯、溴或碘。"Halogen" or "halogen" means fluorine, chlorine, bromine or iodine.
“氧代”表示＝O。"Oxo" means = O.
“硫代”表示＝S。"Thioxo" means = S.
“C 1-6卤代烷基”表示上述“C 1-6烷基”，其被一个或多个卤素基团取代。例子包括单卤素取代、二卤素取代和包括全卤代的多卤素取烷基。一个单卤素取代基在基团中可能有一个碘、溴、氯或氟原子；二个卤素取代基和多个卤素取代基可能有两个或更多相同的卤素原子或不同卤素的联合。优选的卤代烷基例子包括一氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、五氟乙基、七氟丙基、二氟氯甲基、二氯氟甲基、二氟乙基、二氟丙基、二氯乙基和二氯丙基。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "C 1-6 haloalkyl" means the above-mentioned "C 1-6 alkyl" which is substituted with one or more halogen groups. Examples include monohalogen substitution, dihalogen substitution, and polyhalogenated alkyl radicals including perhalogenation. A single halogen substituent may have one iodine, bromine, chlorine or fluorine atom in the group; two halogen substituents and multiple halogen substituents may have two or more of the same halogen atom or a combination of different halogens. Examples of preferred halogenated alkyl groups include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl , Dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 3-7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烃基团。在一些实施方案中，C 3-6碳环基是优选的，更优选C 5-6碳环基。碳环基还包括其中上述碳环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在碳环基环上，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)、环已二烯基(C 6)、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)，等等。碳环基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "C 3-7 carbocyclyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 7 ring carbon atoms and zero heteroatoms. In some embodiments, a C 3-6 carbocyclyl is preferred, and a C 5-6 carbocyclyl is more preferred. Carbocyclyl also includes ring systems in which the carbocyclyl ring described above is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in this case, the number of carbons continues to be expressed The number of carbons in a carbocyclyl system. Exemplary 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 ), ring Heptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptadienyl (C 7 ), and the like. Carbocyclyl groups can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“3-7元杂环基”是指具有环碳原子和1至4个环杂原子的3至7元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。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3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-6元杂环基，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；更优选5-6元杂环基，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。杂环基还包括其中上述杂环基环与一个或多个碳环基稠合的环体系，其中连接点在碳环基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，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(thiorenyl)。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(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)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、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：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(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C 6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C 6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。杂环基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "3-7 membered heterocyclic group" refers to a group of 3 to 7 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus, and silicon. In a heterocyclic group containing one or more nitrogen atoms, as long as the valence allows, the point of attachment may be a carbon or nitrogen atom. In some embodiments, a 3- to 6-membered heterocyclic group is preferred, which is a 3- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; a 4- to 6-membered heterocyclic group, which is 4- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably 5- to 6-membered heterocyclic groups, which are 5 to 6 having ring carbon atoms and 1 to 3 ring heteroatoms Element non-aromatic ring system. Heterocyclyl also includes a ring system in which the above heterocyclyl ring is fused with one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl ring, or in which the above heterocyclyl ring and one or more aryl groups or Heteroaryl fused ring systems where the point of attachment is on a heterocyclyl ring; and in this case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary three-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfanyl Oxazolidin-2-one. Exemplary five-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexane, and dioxanyl. Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azacycloheptyl, oxecanyl, and thietyl. Exemplary 5-membered heterocyclic groups fused to a C 6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are not limited to, dihydroindolyl, isodihydroindolyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups (also referred to herein as 6,6-bicyclic heterocyclic groups) fused with a C 6 aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more. A heterocyclyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)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)。芳基还包括其中上述芳基环与一个或多个碳环基或杂环基稠合的环系统，而且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。芳基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 "C 6-10 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n + 2 aromatic ring system (e.g., having a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms 6 or 10 π electrons). In some embodiments, an aryl group having six ring carbon atoms ( "C 6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C 10 aryl"; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aryl ring described above is fused to one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to be expressed The number of carbon atoms in the aryl ring system. An aryl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“5-10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10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或杂环基稠合的环系统，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。在一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。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。"5-10 membered heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n + 2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (e.g., having a shared ring arrangement 6 or 10 π electrons), wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, as long as the valence allows, the point of attachment may be a carbon or nitrogen atom. A heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused with one or more carbocyclyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring. In this case, the carbon atom's The number continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-6 membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n + 2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom 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 five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom 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 heteroatom include, but are not limited to, azacycloheptatrienyl, oxecatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, Indenazinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, lindenyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
优选的杂芳基的具体例子包括：吡咯基、咪唑基、吡唑基、2-吡啶基、3-吡啶基、4-吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基(4H-1，2，4-三唑基、1H-1，2，3-三唑基、2H-1，2，3-三唑基、吡喃基、2-呋喃基、3-呋喃等、2-噻吩基、3-噻吩基、噁唑基、异噁唑基、噁唑基(1，2，4-噁唑基、1，3，4-噁唑基、1，2，5-噁唑基、噻唑基、噻二唑基(1，2，4-噻二唑基、1，3，4-噻二唑基、1，2，5-噻二唑基)。杂芳基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。Specific examples of preferred heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazolyl ( 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, pyranyl, 2-furanyl, 3-furan, etc., 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1,2,4-oxazolyl, 1,3,4-oxazolyl, 1,2,5-oxazolyl Oxazolyl, thiazolyl, thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl). Heteroaryl groups It may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
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，不论前面是否有术语“任选取代的”，其表示存在于基团(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。Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, etc., as defined herein, are optionally substituted groups, regardless of whether the term "optionally substituted" precedes it, which means that it exists At least one hydrogen on a group (e.g., a carbon or nitrogen atom) is substituted with an allowable substituent, e.g., a substituent that produces a stable compound upon substitution, e.g., does not undergo spontaneous transformation (e.g., by rearrangement, Cyclization, elimination or other reaction). Unless otherwise stated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when substituted at more than one position in any given structure, The substituents at the positions are the same or different. The term "substituted" includes substitutions with all permissible substituents of the organic compound (any substituent described herein that results in the formation of a stable compound). For the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety.
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； Substituent groups include but not limited to the exemplary carbon atoms: halogen, -CN, -NO 2, -N 3 , -SO 2 H, -SO 3 H, -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 2 H, -CHO, -C (OR cc ) 2 , -CO 2 R aa , -OC (= O) R aa , -OCO 2 R aa , -C (= O) N (R bb ) 2 , -OC (= O) N (R bb ) 2 , -NR bb C (= O) R aa , -NR bb CO 2 R aa , -NR bb C (= 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 bb C (= NR bb ) N (R bb ) 2 , -C (= O) NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N (R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R 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) 2 R aa , -OP (= O) 2 R aa , -P (= O) (R aa ) 2 , -OP (= O) (R aa ) 2 , -OP (= O) (OR cc ) 2 , -P (= O) 2 N (R bb ) 2 , -OP (= O) 2 N (R bb ) 2 , -P (= O) (NR bb ) 2 , -OP (= O) (NR bb ) 2 , -NR bb P (= O) (OR cc ) 2 , -NR bb P (= 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 ), alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, Heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
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； Or two hydrazones on a carbon atom are groups = O, = S, = NN (R bb ) 2 , = NNR bb C (= O) R aa , = NNR bb C (= O) OR aa , = NNR bb S (= O) 2 R aa , = NR bb or = NOR cc substitution;
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； Each of R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R aa groups are combined to form a heterocyclyl or Heteroaryl ring in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently 0, 1, 2, 3, 4 or 5 R dd groups Group replacement
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； Each of R bb is independently selected from: hydrogen, -OH, -OR aa , -N (R cc ) 2 , -CN, -C (= O) R aa , -C (= O) N (R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C (= NR cc ) OR aa , -C (= NR cc ) N (R cc ) 2 , -SO 2 N (R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C (= S) N (R cc ) 2 , -C (= O) SR cc , -C (= S) SR cc , -P (= O ) 2 R aa , -P (= O) (R aa ) 2 , -P (= O) 2 N (R cc ) 2 , -P (= O) (NR cc ) 2 , alkyl, haloalkyl, olefin , Alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R bb groups combine to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl Radical, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;
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； Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocyclic ring Or heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R dd group substitution;
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； Each of R dd is independently selected from: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 2 H, -CO 2 R ee , -OC (= O) R ee , -OCO 2 R ee , -C (= O) N (R ff ) 2 , -OC (= O) N (R ff ) 2 ,- NR ff C (= O) R ee , -NR ff CO 2 R ee , -NR ff C (= 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 ff C (= NR ff ) N (R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N (R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R 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) 2 R ee , -P (= O) (R ee ) 2 , -OP (= O) (R ee ) 2 , -OP (= O) (OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclic ring Radical, aryl and hetero Group is independently substituted with 0,1,2,3,4 or 5 groups R gg, or two geminal R dd substituents may combine to form = O or = 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； Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbon A cyclic group, a heterocyclyl group, an aryl group and a heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
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； Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R ff groups are combined to form a heterocyclyl Or 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
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。 Each of R gg is independently: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON (C 1-6 alkyl) 2, -N (C 1-6 alkyl) 2, -N (C 1-6 alkyl) 3 + X -, -NH ( C 1-6 alkyl) 2 + X -, -NH 2 (C 1-6 alkyl) + X -, -NH 3 + X -, -N (OC 1-6 alkyl) (C 1-6 alkyl), - N (OH) ( C 1-6 alkyl ), -NH (OH), -SH, -SC 1-6 alkyl, -SS (C 1-6 alkyl), -C (= O) (C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC (= O) (C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C (= O) NH 2 , -C (= O) N (C 1-6 alkyl) 2 , -OC (= O) NH (C 1-6 alkyl), -NHC (= O) (C 1-6 alkyl), -N (C 1-6 alkyl) C (= O) (C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC (= O) N (C 1-6 alkyl) 2 ,- NHC (= O) NH (C 1-6 alkyl), -NHC (= O) NH 2 , -C (= NH) O (C 1-6 alkyl), -OC (= NH) (C 1- 6 alkyl), -OC (= NH) OC 1-6 alkyl, -C (= NH) N (C 1-6 alkyl) 2 , -C (= NH) NH (C 1-6 alkyl) , -C (= NH) NH 2 , -OC (= NH) N (C 1-6 alkyl) 2 , -OC (NH) NH (C 1-6 alkyl), -OC (NH) NH 2 , -NHC (NH) N (C 1-6 alkyl) 2 , -NHC (= NH) NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N (C 1-6 alkyl) 2, -SO 2 NH (C 1-6 alkyl), - SO 2 NH 2, - SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl -SOC 1-6 alkyl, -Si (C 1-6 alkyl) 3 , -OSi (C 1-6 alkyl) 3 , -C (= S) N (C 1-6 alkyl) 2 , C (= S) NH (C 1-6 alkyl), C (= S) NH 2 , -C (= O) S (C 1-6 alkyl), -C (= S) SC 1-6 alkane Group, -SC (= S) SC 1-6 alkyl, -P (= O) 2 (C 1-6 alkyl), -P (= O) (C 1-6 alkyl) 2 , -OP ( = O) (C 1-6 alkyl) 2 , -OP (= O) (OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl , C 2 -C 6 alkynyl, C 3 -C 7 carbocyclyl, C 6 -C 10 aryl, C 3 -C 7 heterocyclyl, C 5 -C 10 heteroaryl; or two 偕 R gg Substituents can be combined to form = O or = S; where X - is a counter ion.
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。 Exemplary substituents on the nitrogen atom include but are not limited to: hydrogen, -OH, -OR aa , -N (R cc ) 2 , -CN, -C (= O) R aa , -C (= O) N (R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C (= NR bb ) R aa , -C (= NR cc ) OR aa , -C (= NR cc ) N (R cc ) 2 , -SO 2 N (R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C (= S) N (R cc ) 2 , -C (= O) SR cc , -C (= S) SR cc , -P (= O) 2 R aa , -P (= O) (R aa ) 2 , -P (= O) 2 N (R cc ) 2 , -P (= O ) (NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups attached to a nitrogen atom combine to form a heterocyclic ring Or heteroaryl rings in which each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl group is independently replaced by 0, 1, 2, 3, 4, or 5 R The dd group is substituted, and wherein R aa , R bb , R cc, and R dd are as described above.
其它定义Other definitions
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之，或者 这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作，后者是如刚才所定义的。The term "treatment" as used herein relates to reversing, alleviating, inhibiting or preventing the progress or prevention of a disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition. The term "treatment" as used herein relates to the action of the verb therapy, which is as defined just now.
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。The term "pharmaceutically acceptable salts" as used herein refers to those carboxylic acid salts, amino acid addition salts of the compounds of the present invention, which are suitable for contact with patient tissues within the scope of reliable medical judgment, without causing inappropriate toxicity, Stimuli, allergies, etc., which are commensurate with a reasonable benefit / risk ratio, are effective in terms of their intended use, including, if possible, zwitterionic forms of the compounds of the invention.
术语“盐”表示本发明化合物的相对无毒的无机与有机酸加成盐。这些盐可以在化合物的最终分离和纯化期间被原位制备，或者单独使经过纯化的化合物游离碱形式与适合的有机或无机酸反应，再分离所生成的盐。只要本发明化合物是碱性化合物，它们都能够与各种无机和有机酸生成多种不同的盐。尽管这类盐就对动物给药而言必须是药学上可接受的，不过在实践中经常需要首先从反应混合物中分离碱化合物的药学上不可接受的盐，然后借助碱性试剂的处理简单地转化为游离碱化合物，之后将游离碱转化为药学上可接受的酸加成盐。碱性化合物的酸加成盐是这样制备的，按照常规方式使游离碱形式与足量所需的酸接触，生成盐。按照常规方式使盐形式与碱接触，再分离游离碱，可以使游离碱再生。游离碱形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离碱。The term "salt" refers to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds, or the purified compounds can be separately reacted with the free base form of a suitable organic or inorganic acid and the resulting salts isolated. As long as the compounds of the present invention are basic compounds, they are capable of forming many different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often necessary in practice to first isolate a pharmaceutically unacceptable salt of a basic compound from the reaction mixture and then simply treat it with the aid of a basic reagent Conversion to a free base compound followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to form a salt. The free base can be regenerated by contacting the salt form with a base in a conventional manner and then separating the free base. Free base forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, salts are also equivalent to their respective free bases.
药学上可接受的碱加成盐是与金属或胺生成的，例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N，N′-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
酸性化合物的碱加成盐可以这样制备，按照常规方式使游离酸形式与足量所需的碱接触，生成盐。按照常规方式使盐形式与酸接触，再分离游离酸，可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离酸。The base addition salt of an acidic compound can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form a salt. The free acid can be regenerated by contacting the salt form with the acid in a conventional manner and then separating the free acid. Free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, salts are still equivalent to their respective free acids.
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物，酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括：氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的，例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.， ″Pharmaceutical Salts，”J.Pharm.Sci.，1977；66：1-19，引入此作为参考)。The salt may be a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, prepared from an inorganic acid. Salts, chlorides, bromides, iodides, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurel Salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Mesylate, glucoheptanoate, lactobionate, laurylsulfonate and isethionate, etc. Salts can also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, horse Lamate, Mandelate, Benzoate, Chlorobenzoate, Methylbenzoate, Dinitrobenzoate, Naphthoate, Tosylate, Tosylate, Toluene Acid salt, citrate, lactate, maleate, tartrate, mesylate, etc. Pharmaceutically acceptable salts can include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium, and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Also included are salts of amino acids, such as arginine, gluconate, galacturonate, etc. (see, for example, Berger SMetal., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1- 19. This is incorporated by reference).
本发明化合物的药学上可接受的无毒酰胺的实例包括从C 1-C 6烷基酯，其中烷基是直链或支链的。可接受的酯还包括C 5-C 7环烷基酯以及芳基烷基酯，例如但不限于苄基酯。C 1-C 4烷基酯是优选的。本发明化合物的酯可以按照常规方法制备，例如：March′s Advanced Organic Chemistry，5 Edition”M.B.Smith&J.March，John Wiley&Sons，2001。 Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include from C 1 -C 6 alkyl esters in which the alkyl group is linear or branched. Acceptable esters also include C 5 -C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl ester. C 1 -C 4 alkyl esters are preferred. The esters of the compounds of the present invention can be prepared according to conventional methods, for example: March's Advanced Organic Chemistry, 5 Edition "MB Smith & J. March, John Wiley & Sons, 2001.
本发明化合物的药学上可接受的无毒性酰胺的实例包括从氨、伯C 1-C 6烷基胺和仲C 1-C 6二烷基胺衍生的酰胺，其中烷基是直链或支链的。在仲胺的情况下，胺也可以是含有一个氮原子的5或6元杂环的形式。从氨、C 1-C 3烷基伯胺和C 1-C 2二烷基仲胺衍生的酰胺是优选的。本发明化合物的酰胺可以按照常规方法制备，例如：March′s Advanced Organic Chemistry，5 Edition”，M.B.Smith&J.March，John Wiley&Sons，2001。 Examples of pharmaceutically acceptable non-toxic amides of the compounds of the present invention include amides derived from ammonia, primary C 1 -C 6 alkylamines, and secondary C 1 -C 6 dialkylamines, wherein the alkyl group is linear or branched Chain. In the case of a secondary amine, the amine may also be in the form of a 5- or 6-membered heterocyclic ring containing one nitrogen atom. Amides derived from ammonia, C 1 -C 3 alkyl primary amines and C 1 -C 2 dialkyl secondary amines are preferred. The amides of the compounds of the present invention can be prepared according to conventional methods, for example: March's Advanced Organic Chemistry, 5 Edition ", MB Smith & J. March, John Wiley & Sons, 2001.
术语“前药”表示体内迅速转化得到上式母体化合物的化合物，例如借助血液中的水解作用。详尽的讨论参见T.Higuchi and V.Ste11a，，“Pro-drugs as Novel Delivery Systems，”Vol.14 of the A.C.S.Symposium Series和Bioreversible Carriers in Drug Design，ed.Edward B.Roche，American Pharmaceutical Association and Pergamon Press，1987，二者均引入此作为参考。The term "prodrug" means a compound that is rapidly converted in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. For a detailed discussion, see T. Higuchi and V. Ste11a, "Pro-drugs, Novel, Delivery Systems," Vol. 14 of the ACSSymposium Series and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Pergamon Association Press, 1987, both of which are incorporated herein by reference.
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”。"Subjects" to be administered include, but are not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and / or non-human animals, such as mammals, for example, primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep , Goat, rodent, cat and / or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
“疾病”、“障碍”和“病症”在本文中可互换地使用。"Disease", "disorder" and "disorder" are used interchangeably herein.
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”)。As used herein, unless otherwise stated, the term "treatment" includes the effect of a subject having a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or development of a condition ("therapeutic treatment"), also includes effects that occur before a subject begins to suffer from a particular disease, disorder, or condition ("prophylactic treatment").
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。Generally, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be understood by one of ordinary skill in the art, the effective amount of a compound of the invention may vary depending on factors such as the biological objective, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the subject's Age health and symptoms. An effective amount includes a therapeutically effective amount and a prophylactically effective amount.
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。Unless stated otherwise, a "therapeutically effective amount" of a compound used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition. Delayed or minimized. 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" may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
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。Unless otherwise stated, a "prophylactically effective amount" of a compound used herein 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 a disease , 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 preventative benefit in the prevention of a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prevention, or an amount that enhances the preventive effect of other preventive agents.
“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。"Combination" and related terms refer to simultaneous or sequential administration of a compound of the invention and other therapeutic agent. For example, a compound of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.
具体实施方案Specific implementation plan
本文中，“本发明化合物”指的是以下的式(I)-式(IV)化合物(包括例如，(II-1)、(II-2)、(II-3)、(II-4)、(II-5)、(III-1)、(III-2)、(III-3)、(III-4)、(III-5)、(III-6)、(III-7)、(III-8)、(III-9)、(IV-1)、(IV-2)、(IV-3)、(IV-4)、(IV-5)或(IV-6))、其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物。Herein, the "compound of the present invention" refers to the following compounds of formula (I)-formula (IV) (including, for example, (II-1), (II-2), (II-3), (II-4) , (II-5), (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III-7), ( III-8), (III-9), (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6)), their pharmacy Topically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof.
化合物一般在这里描述使用标准的命名法。具有非对称中心的化合物，应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外，除非另有规定，本发明所包括的所有异构体化合物与碳碳双键可能以Z和E的形式出现。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。某些化合物所使用的一般公式，包括描述、变量。除非另有规定，在这样的公式中的每个变量被定义独立于任何其他变量和在每个发生时独立地定义了一个公式中的任何一个变量的多个变量。Compounds are generally described here using standard nomenclature. For compounds with asymmetric centers, it should be understood (unless otherwise stated) that all optical isomers and mixtures thereof are included. In addition, unless otherwise specified, all isomer compounds and carbon-carbon double bonds included in the present invention may appear in the form of Z and E. Compounds that exist in different tautomeric forms, one such compound is not limited to any particular tautomer, but is intended to encompass all tautomeric forms. General formulas used by some compounds, including descriptions, variables. Unless otherwise specified, each variable in such a formula is defined independently of any other variable and multiple variables that independently define any one variable in a formula at each occurrence.
在一个实施方案中，本发明涉及通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In one embodiment, the invention relates to a compound of general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof:
Figure PCTCN2019093578-appb-000002
Figure PCTCN2019093578-appb-000002
其中：among them:
L选自化学键、-CR’＝CR”-或-C≡C-；其中R’和R”独立地选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基； L is selected from a chemical bond, -CR '= CR "-or -C≡C-; wherein R' and R" are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 7 carbocyclyl or 3-7 membered heterocyclyl;
X选自化学键、CR bR c、NR a、O或S(O) q； X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
R 1选自H、卤素、-CN、-NO 2、-C(O)R a、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
R 2和R 2’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 2和R 2’可以形成氧代或硫代； R 2 and R 2 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 'can form oxo or thio;
R 3和R 3’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 3和R 3’可以形成氧代 或硫代； R 3 and R 3 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 3 and R 3 'can form oxo or thio;
R 4和R 4’独立地选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基；或者，R 4和R 4’分别可以形成氧代或硫代； R 4 and R 4 'are independently selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C ( O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,- (C 0-6 alkylene) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S ( O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 alkyl or C 1-6 haloalkyl; or, R 4 and R 4 ′ may form oxo or thio, respectively;
或者，R 2和R 3结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
或者，当X为CR bR c或NR a时，R 3或R 4可以与R a、R b和R c中的一个结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, when X is CR b R c or NR a , R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
R 5选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基； R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 Alkyl or C 1-6 haloalkyl;
R 6和R 7独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基； R 6 and R 7 are independently selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl;
R a、R b、R c、R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基； R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
m＝0、1、2、3、4或5；m = 0, 1, 2, 3, 4 or 5;
n＝0、1或2；n = 0, 1, or 2;
p＝1或2；p = 1 or 2;
q＝0、1或2；q = 0, 1, or 2;
条件是当L为化学键时，R 1选自H、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Provided that when L is a chemical bond, R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
优选地，其中：Preferably, wherein:
L选自化学键、-CR’＝CR”-或-C≡C-；其中R’和R”独立地选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基； L is selected from a chemical bond, -CR '= CR "-or -C≡C-; wherein R' and R" are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 7 carbocyclyl or 3-7 membered heterocyclyl;
X选自化学键、CR bR c、NR a、O或S(O) q； X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
R 1选自H、卤素、-CN、-NO 2、-C(O)R a、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
R 2、R 2’、R 3、R 3’、R 4和R 4’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 2和R 2’、R 3和R 3’、R 4和R 4’分别可以形成氧代或硫代； R 2 , R 2 ′, R 3 , R 3 ′, R 4 and R 4 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 ′, R 3 and R 3 ′, R 4 and R 4 ′ may form oxo or thio, respectively;
或者，R 2和R 3结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
或者，当X为CR bR c或NR a时，R 3或R 4可以与R a、R b和R c中的一个结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, when X is CR b R c or NR a , R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
R 5选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基； R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 Alkyl or C 1-6 haloalkyl;
R 6和R 7独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、C 1-6烷基或C 1-6卤代烷基； R 6 and R 7 are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , C 1-6 alkyl, or C 1-6 haloalkyl;
R a、R b、R c、R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基； R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
m＝0、1、2、3、4或5；m = 0, 1, 2, 3, 4 or 5;
n＝0、1或2；n = 0, 1, or 2;
p＝1或2；p = 1 or 2;
q＝0、1或2；q = 0, 1, or 2;
条件是当L为化学键时，R 1选自H、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。 Provided that when L is a chemical bond, R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.
LL
在一个具体实施方案中，L为化学键；在另一个具体实施方案中，L为-CR’＝CR”-；在另一个具体实施方案中，L为-C≡C-。In one embodiment, L is a chemical bond; in another embodiment, L is -CR '= CR "-; and in another embodiment, L is -C≡C-.
在一个具体实施方案中，R’为H；在另一个具体实施方案中，R’为卤素；在另一个具体实施方案中，R’为C 1-6烷基；在另一个具体实施方案中，R’为C 1-6卤代烷基；在另一个具体实施方案中，R’为C 3-7碳环基；在另一个具体实施方案中，R’为3-7元杂环基。 In a specific embodiment, R 'is H; in another specific embodiment, R' is halogen; in another specific embodiment, R 'is C1-6 alkyl; in another specific embodiment R ′ is a C 1-6 haloalkyl group; in another specific embodiment, R ′ is a C 3-7 carbocyclyl group; in another specific embodiment, R ′ is a 3-7 membered heterocyclic group.
在一个具体实施方案中，R”为H；在另一个具体实施方案中，R”为卤素；在另一个具体实施方案中，R”为C 1-6烷基；在另一个具体实施方案中，R”为C 1-6卤代烷基；在另一个具体实施方案中，R”为C 3-7碳环基；在另一个具体实施方案中，R”为3-7元杂环基。 In a specific embodiment, R "is H; in another specific embodiment, R" is halogen; in another specific embodiment, R "is C1-6 alkyl; in another specific embodiment R "is a C 1-6 haloalkyl group; in another embodiment, R" is a C 3-7 carbocyclyl group; in another embodiment, R "is a 3-7 membered heterocyclic group.
XX
在一个具体实施方案中，X为化学键；在另一个具体实施方案中，X为CR bR c；在另一个具体实施方案中，X为NR a；在另一个具体实施方案中，X为O；在另一个具体实施方案中，X为S(O) q。 In one embodiment, X is a chemical bond; in another embodiment, X is CR b R c ; in another embodiment, X is NR a ; in another embodiment, X is O ; In another specific embodiment, X is S (O) q .
R 1 R 1
在一个具体实施方案中，R 1为H；在另一个具体实施方案中，R 1为卤素；在另一个具体实施方案中，R 1为-CN；在另一个具体实施方案中，R 1为-NO 2；在另一个具体实施方案中，R 1为-C(O)R a；在另一个具体实施方案中，R 1为-C(O)OR a；在另一个具体实施方案中，R 1为-C(O)NR bR c；在另一个具体实施方案中，R 1为C 1-6烷基；在另一个具体实施方案中，R 1为C 1-6卤代烷基；在另一个具体实施方案中，R 1为C 2-8烯基；在另一个具体实施方案中，R 1为C 2-8炔基；在另一个具体实施方案中，R 1为C 3-7碳环基；在另一个具体实施方案中，R 1为3-7元杂环基；在另一个具体实施方案中，R 1为C 6-10芳基；在另一个具体实施方案中，R 1为5-10元杂芳基。 In one embodiment, R 1 is H; in another embodiment, R 1 is halogen; in another embodiment, R 1 is -CN; in another embodiment, R 1 is -NO 2 ; in another specific embodiment, R 1 is -C (O) R a ; in another specific embodiment, R 1 is -C (O) OR a ; in another specific embodiment, R 1 is -C (O) NR b R c ; in another embodiment, R 1 is C 1-6 alkyl; in another embodiment, R 1 is C 1-6 haloalkyl; In another specific embodiment, R 1 is C 2-8 alkenyl; in another specific embodiment, R 1 is C 2-8 alkynyl; in another specific embodiment, R 1 is C 3-7 Carbocyclyl; in another embodiment, R 1 is a 3-7 membered heterocyclic group; in another embodiment, R 1 is a C 6-10 aryl group; in another embodiment, R 1 is 5-10 membered heteroaryl.
在一个具体实施方案中，R 1任选地被1个R基团取代；在另一个具体实施方案中，R 1任选地被 2个R基团取代；在另一个具体实施方案中，R 1任选地被3个R基团取代。 In a specific embodiment, R 1 is optionally substituted with 1 R group; in another specific embodiment, R 1 is optionally substituted with 2 R groups; in another specific embodiment, R 1 1 is optionally substituted with 3 R groups.
在一个具体实施方案中，R独立地为H；在另一个具体实施方案中，R独立地为卤素；在另一个具体实施方案中，R独立地为-CN；在另一个具体实施方案中，R独立地为-NO 2；在另一个具体实施方案中，R独立地为-OR a；在另一个具体实施方案中，R独立地为-NR bR c；在另一个具体实施方案中，R独立地为-C(O)OR a；在另一个具体实施方案中，R独立地为-C(O)NR bR c；在另一个具体实施方案中，R独立地为C 1-6烷基；在另一个具体实施方案中，R独立地为C 1-6卤代烷基；在另一个具体实施方案中，R独立地为C 3-7碳环基；在另一个具体实施方案中，R独立地为3-7元杂环基；在另一个具体实施方案中，R独立地为C 6-10芳基；在另一个具体实施方案中，R独立地为5-10元杂芳基。 In one embodiment, R is independently H; in another embodiment, R is independently halogen; in another embodiment, R is independently -CN; in another embodiment, R is independently -NO 2 ; in another embodiment, R is independently -OR a ; in another embodiment, R is independently -NR b R c ; in another embodiment, R is independently -C (O) OR a ; in another embodiment, R is independently -C (O) NR b R c ; in another embodiment, R is independently C 1-6 Alkyl; in another embodiment, R is independently C 1-6 haloalkyl; in another embodiment, R is independently C 3-7 carbocyclyl; in another embodiment, R is independently a 3-7 membered heterocyclic group; in another embodiment, R is independently a C 6-10 aryl group; in another embodiment, R is independently a 5-10 membered heteroaryl group .
R 2、R 2’、R 3、R 3’、R 4和R 4’ R 2 , R 2 ′, R 3 , R 3 ′, R 4 and R 4 ′
在一个具体实施方案中，R 2和R 2’独立地为H；在另一个具体实施方案中，R 2和R 2’独立地为卤素；在另一个具体实施方案中，R 2和R 2’独立地为-CN；在另一个具体实施方案中，R 2和R 2’独立地为-NO 2；在另一个具体实施方案中，R 2和R 2’独立地为-OR a；在另一个具体实施方案中，R 2和R 2’独立地为-NR bR c；在另一个具体实施方案中，R 2和R 2’独立地为-C(O)OR a；在另一个具体实施方案中，R 2和R 2’独立地为-C(O)NR bR c；在另一个具体实施方案中，R 2和R 2’独立地为C 1-6烷基；在另一个具体实施方案中，R 2和R 2’独立地为C 1-6卤代烷基；在另一个具体实施方案中，R 2和R 2’独立地为C 3-7碳环基；在另一个具体实施方案中，R 2和R 2’独立地为3-7元杂环基；在另一个具体实施方案中，R 2和R 2’独立地为C 6-10芳基；在另一个具体实施方案中，R 2和R 2’独立地为5-10元杂芳基；在另一个具体实施方案中，R 2和R 2’可以形成氧代；在另一个具体实施方案中，R 2和R 2’可以形成硫代。 In a specific embodiment, R 2 and R 2 ′ are independently H; in another specific embodiment, R 2 and R 2 ′ are independently halogen; in another specific embodiment, R 2 and R 2 'Is independently -CN; in another embodiment, R 2 and R 2 ' are independently -NO 2 ; in another embodiment, R 2 and R 2 'are independently -OR a ; in In another specific embodiment, R 2 and R 2 ′ are independently -NR b R c ; in another specific embodiment, R 2 and R 2 ′ are independently -C (O) OR a ; in another In a specific embodiment, R 2 and R 2 ′ are independently —C (O) NR b R c ; in another specific embodiment, R 2 and R 2 ′ are independently C 1-6 alkyl; In a specific embodiment, R 2 and R 2 ′ are independently C 1-6 haloalkyl; in another specific embodiment, R 2 and R 2 ′ are independently C 3-7 carbocyclyl; in another In a specific embodiment, R 2 and R 2 ′ are independently a 3-7 membered heterocyclic group; in another specific embodiment, R 2 and R 2 ′ are independently a C 6-10 aryl group; in another specific embodiment In embodiments, R 2 and R 2 ′ are independently 5-10 membered heteroaryl In another embodiment, R 2 and R 2 ′ may form oxo; in another embodiment, R 2 and R 2 ′ may form thio.
在一个具体实施方案中，R 3和R 3’独立地为H；在另一个具体实施方案中，R 3和R 3’独立地为卤素；在另一个具体实施方案中，R 3和R 3’独立地为-CN；在另一个具体实施方案中，R 3和R 3’独立地为-NO 2；在另一个具体实施方案中，R 3和R 3’独立地为-OR a；在另一个具体实施方案中，R 3和R 3’独立地为-NR bR c；在另一个具体实施方案中，R 3和R 3’独立地为-C(O)OR a；在另一个具体实施方案中，R 3和R 3’独立地为-C(O)NR bR c；在另一个具体实施方案中，R 3和R 3’独立地为C 1-6烷基；在另一个具体实施方案中，R 3和R 3’独立地为C 1-6卤代烷基；在另一个具体实施方案中，R 3和R 3’独立地为C 3-7碳环基；在另一个具体实施方案中，R 3和R 3’独立地为3-7元杂环基；在另一个具体实施方案中，R 3和R 3’独立地为C 6-10芳基；在另一个具体实施方案中，R 3和R 3’独立地为5-10元杂芳基；在另一个具体实施方案中，R 3和R 3’可以形成氧代；在另一个具体实施方案中，R 3和R 3’可以形成硫代。 In a specific embodiment, R 3 and R 3 ′ are independently H; in another specific embodiment, R 3 and R 3 ′ are independently halogen; in another specific embodiment, R 3 and R 3 'Is independently -CN; in another embodiment, R 3 and R 3 ' are independently -NO 2 ; in another embodiment, R 3 and R 3 'are independently -OR a ; in In another specific embodiment, R 3 and R 3 ′ are independently -NR b R c ; in another specific embodiment, R 3 and R 3 ′ are independently -C (O) OR a ; in another In a specific embodiment, R 3 and R 3 ′ are independently —C (O) NR b R c ; in another specific embodiment, R 3 and R 3 ′ are independently C 1-6 alkyl; In a specific embodiment, R 3 and R 3 ′ are independently C 1-6 haloalkyl; in another specific embodiment, R 3 and R 3 ′ are independently C 3-7 carbocyclyl; in another In a specific embodiment, R 3 and R 3 ′ are independently 3 to 7-membered heterocyclic groups; in another specific embodiment, R 3 and R 3 ′ are independently C 6-10 aryl groups; in another specific embodiment In embodiments, R 3 and R 3 ′ are independently 5-10 membered heteroaryl In another embodiment, R 3 and R 3 ′ may form an oxo group; in another embodiment, R 3 and R 3 ′ may form a thio group.
在一个具体实施方案中，R 4和R 4’独立地为H；在另一个具体实施方案中，R 4和R 4’独立地为卤素；在另一个具体实施方案中，R 4和R 4’独立地为-CN；在另一个具体实施方案中，R 4和R 4’独立地为-NO 2；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-OR a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-NR bR c；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-C(O)R a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-C(O)OR a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-C(O)NR bR c；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-O-C(O)R a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-N(R b)-C(O)R a；在另 一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-S(O) pR a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-S(O) pOR a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-S(O) pNR bR c；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-O-S(O) pR a；在另一个具体实施方案中，R 4和R 4’独立地为-(C 0-6亚烷基)-N(R b)-S(O) pR a；在另一个具体实施方案中，R 4和R 4’独立地为-OR a；在另一个具体实施方案中，R 4和R 4’独立地为-NR bR c；在另一个具体实施方案中，R 4和R 4’独立地为-C(O)OR a；在另一个具体实施方案中，R 4和R 4’独立地为-C(O)NR bR c；在另一个具体实施方案中，R 4和R 4’独立地为C 1-6烷基；在另一个具体实施方案中，R 4和R 4’独立地为C 1-6卤代烷基；在另一个具体实施方案中，R 4和R 4’独立地为C 3-7碳环基；在另一个具体实施方案中，R 4和R 4’独立地为3-7元杂环基；在另一个具体实施方案中，R 4和R 4’独立地为C 6-10芳基；在另一个具体实施方案中，R 4和R 4’独立地为5-10元杂芳基；在另一个具体实施方案中，R 4和R 4’可以形成氧代；在另一个具体实施方案中，R 4和R 4’可以形成硫代。 In a specific embodiment, R 4 and R 4 ′ are independently H; in another specific embodiment, R 4 and R 4 ′ are independently halogen; in another specific embodiment, R 4 and R 4 'Is independently -CN; in another embodiment, R 4 and R 4 ' are independently -NO 2 ; in another embodiment, R 4 and R 4 'are independently-(C 0- 6 alkylene) -OR a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -NR b R c ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -C (O) R a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 Alkylene) -C (O) OR a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -C (O) NR b R c ; In another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -OC (O) R a ; in another specific embodiment, R 4 and R 4 ′ are independently Is- (C 0-6 alkylene) -N (R b ) -C (O) R a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene yl) -S (O) p R a ; in another particular Shi embodiment, R 4 and R 4 'is independently - (C 0-6 alkylene) -S (O) p OR a ; In another particular embodiment, R 4 and R 4' is independently - (C 0-6 alkylene) -S (O) p NR b R c ; In another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -OS ( O) p R a ; in another specific embodiment, R 4 and R 4 ′ are independently-(C 0-6 alkylene) -N (R b ) -S (O) p R a ; In a specific embodiment, R 4 and R 4 ′ are independently -OR a ; in another specific embodiment, R 4 and R 4 ′ are independently -NR b R c ; in another specific embodiment, R 4 and R 4 ′ are independently -C (O) OR a ; in another specific embodiment, R 4 and R 4 ′ are independently -C (O) NR b R c ; in another specific embodiment In another embodiment, R 4 and R 4 ′ are independently C 1-6 alkyl; in another specific embodiment, R 4 and R 4 ′ are independently C 1-6 haloalkyl; in another specific embodiment, R 4 and R 4 ′ are independently C 3-7 carbocyclyl groups; in another specific embodiment, R 4 and R 4 ′ are independently 3-7 membered heterocyclic groups; in another specific embodiment, R 4 and R 4 ' Independently is C 6-10 aryl; in another specific embodiment, R 4 and R 4 ′ are independently 5-10 membered heteroaryl; in another specific embodiment, R 4 and R 4 ′ may be Formation of oxo; in another specific embodiment, R 4 and R 4 ′ may form thio.
在另一个具体实施方案中，R 2和R 3结合形成双键；在另一个具体实施方案中，R 2和R 3结合形成C 3-7碳环基；在另一个具体实施方案中，R 2和R 3结合形成3-7元杂环基；在另一个具体实施方案中，R 2和R 3结合形成C 6-10芳基；在另一个具体实施方案中，R 2和R 3结合形成5-10元杂芳基。 In another embodiment, R 2 and R 3 are combined to form a double bond; in another embodiment, R 2 and R 3 are combined to form a C 3-7 carbocyclyl; in another embodiment, R 2 and R 3 combine to form a 3-7 membered heterocyclic group; in another specific embodiment, R 2 and R 3 combine to form a C 6-10 aryl group; in another specific embodiment, R 2 and R 3 combine A 5-10 membered heteroaryl is formed.
当X为CR bR c或NR a时，在另一个具体实施方案中，R 3或R 4可以与R a、R b和R c中的一个结合形成双键；在另一个具体实施方案中，R 3或R 4可以与R a、R b和R c中的一个结合形成C 3-7碳环基；在另一个具体实施方案中，R 3或R 4可以与R a、R b和R c中的一个结合形成3-7元杂环基；在另一个具体实施方案中，R 3或R 4可以与R a、R b和R c中的一个结合形成C 6-10芳基；在另一个具体实施方案中，R 3或R 4可以与R a、R b和R c中的一个结合形成5-10元杂芳基。 When X is CR b R c or NR a , in another specific embodiment, R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond; in another specific embodiment , R 3 or R 4 may be combined with one of R a , R b and R c to form a C 3-7 carbocyclic group; in another specific embodiment, R 3 or R 4 may be combined with R a , R b and One of R c is combined to form a 3-7 membered heterocyclic group; in another specific embodiment, R 3 or R 4 may be combined with one of R a , R b and R c to form a C 6-10 aryl group; In another specific embodiment, R 3 or R 4 may be combined with one of R a , R b and R c to form a 5-10 membered heteroaryl.
R 5 R 5
在一个具体实施方案中，R 5为H；在另一个具体实施方案中，R 5为卤素；在另一个具体实施方案中，R 5为-CN；在另一个具体实施方案中，R 5为-NO 2；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-OR a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-NR bR c；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-C(O)R a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-C(O)OR a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-C(O)NR bR c；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-O-C(O)R a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-N(R b)-C(O)R a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-S(O) pR a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-S(O) pOR a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-S(O) pNR bR c；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-O-S(O) pR a；在另一个具体实施方案中，R 5为-(C 0-6亚烷基)-N(R b)-S(O) pR a；在另一个具体实施方案中，R 5为C 1-6烷基；在另一个具体实施方案中，R 5为C 1-6卤代烷基。 In a specific embodiment, R 5 is H; in another specific embodiment, R 5 is halogen; in another specific embodiment, R 5 is -CN; in another specific embodiment, R 5 is -NO 2 ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -OR a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -NR b R c ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -C (O) R a ; in another specific embodiment, R 5 is-(C 0 -6 alkylene) -C (O) OR a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -C (O) NR b R c ; in another specific implementation In the scheme, R 5 is- (C 0-6 alkylene) -OC (O) R a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -N (R b ) -C (O) R a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -S (O) p R a ; in another specific embodiment, R 5 is -(C 0-6 alkylene) -S (O) p OR a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -S (O) p NR b R c ; In another specific embodiment, R 5 is- (C 0-6 alkylene) -OS (O) p R a ; in another specific embodiment, R 5 is- (C 0-6 alkylene) -N (R b ) -S (O) p R a ; in another specific embodiment, R 5 is C 1-6 alkyl; In another specific embodiment, R 5 is C 1-6 haloalkyl.
R 6和R 7 R 6 and R 7
在一个具体实施方案中，R 6和R 7独立地为H；在另一个具体实施方案中，R 6和R 7独立地为卤素；在另一个具体实施方案中，R 6和R 7独立地为-CN；在另一个具体实施方案中，R 6和R 7独立地为-NO 2； 在另一个具体实施方案中，R 6和R 7独立地为-OR a；在另一个具体实施方案中，R 6和R 7独立地为-NR bR c；在另一个具体实施方案中，R 6和R 7独立地为C 1-6烷基；在另一个具体实施方案中，R 6和R 7独立地为C 1-6卤代烷基。 In a specific embodiment, R 6 and R 7 are independently H; in another specific embodiment, R 6 and R 7 are independently halogen; in another specific embodiment, R 6 and R 7 are independently Is -CN; in another specific embodiment, R 6 and R 7 are independently -NO 2 ; in another specific embodiment, R 6 and R 7 are independently -OR a ; in another specific embodiment In another embodiment, R 6 and R 7 are independently -NR b R c ; In another embodiment, R 6 and R 7 are independently C 1-6 alkyl; In another embodiment, R 6 and R 7 R 7 is independently C 1-6 haloalkyl.
R a、R b和R c R a , R b and R c
在一个具体实施方案中，R a、R b和R c独立地为H；在另一个具体实施方案中，R a、R b和R c独立地为C 1-6烷基；在另一个具体实施方案中，R a、R b和R c独立地为C 1-6卤代烷基。 In one particular embodiment, R a, R b and R c are independently H; In another particular embodiment, R a, R b and R c are independently C 1-6 alkyl; In another specific In an embodiment, R a , R b and R c are independently C 1-6 haloalkyl.
mm
在一个具体实施方案中，m＝0；在另一个具体实施方案中，m＝1；在另一个具体实施方案中，m＝2；在另一个具体实施方案中，m＝3；在另一个具体实施方案中，m＝4；在另一个具体实施方案中，m＝5。In one embodiment, m = 0; in another embodiment, m = 1; in another embodiment, m = 2; in another embodiment, m = 3; in another embodiment In a specific embodiment, m = 4; in another specific embodiment, m = 5.
nn
在一个具体实施方案中，n＝0；在另一个具体实施方案中，n＝1；在另一个具体实施方案中，n＝2。In a specific embodiment, n = 0; in another specific embodiment, n = 1; in another specific embodiment, n = 2.
pp
在一个具体实施方案中，p＝1；在另一个具体实施方案中，p＝2。In one embodiment, p = 1; in another embodiment, p = 2.
qq
在一个具体实施方案中，q＝0；在另一个具体实施方案中，q＝1；在另一个具体实施方案中，q＝2。In a specific embodiment, q = 0; in another specific embodiment, q = 1; in another specific embodiment, q = 2.
Figure PCTCN2019093578-appb-000003
Figure PCTCN2019093578-appb-000003
在一个具体实施方案中，
Figure PCTCN2019093578-appb-000004
选自以下基团： In a specific embodiment,
Figure PCTCN2019093578-appb-000004
Selected from the group:
Figure PCTCN2019093578-appb-000005
Figure PCTCN2019093578-appb-000005
Figure PCTCN2019093578-appb-000006
Figure PCTCN2019093578-appb-000006
在另一个具体实施方案中，
Figure PCTCN2019093578-appb-000007
选自以下基团： In another specific embodiment,
Figure PCTCN2019093578-appb-000007
Selected from the group:
Figure PCTCN2019093578-appb-000008
Figure PCTCN2019093578-appb-000008
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，L的任一技术方案或其任意组合，可以与X、R 1-R 7、R 2’-R 4’、m和n的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。 Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical scheme of L or any combination thereof may be combined with any technical scheme of X, R 1 -R 7 , R 2 ′ -R 4 ′, m and n or any combination thereof. The present invention is intended to include a combination of all these technical solutions, which is limited in space and will not be listed one by one.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(II-1)、(II-2)、(II-3)、(II-4)或(II-5)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphic, prodrug or isotope variants, and mixtures thereof, having the general formula (II-1), (II-2), (II-3), (II-4) or (II-5) :
Figure PCTCN2019093578-appb-000009
Figure PCTCN2019093578-appb-000009
其中，among them,
R 1选自H、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl , 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
X、R 2-R 7、R 3’、m和n如上文所定义。 X, R 2 -R 7 , R 3 ′, m and n are as defined above.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(II-3)或(II-4)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (II-3) or (II-4):
Figure PCTCN2019093578-appb-000010
Figure PCTCN2019093578-appb-000010
其中，among them,
R 1选自H、卤素、-CN、-NO 2、C 1-6烷基或C 1-6卤代烷基； R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, or C 1-6 haloalkyl;
R 2和R 3为H； R 2 and R 3 are H;
R 5为-(C 0-6亚烷基)-C(O)OR d； R 5 is- (C 0-6 alkylene) -C (O) OR d ;
R 6’和R 6”为卤素和甲基； R 6 ′ and R 6 ″ are halogen and methyl;
R d选自H、C 1-6烷基或C 1-6卤代烷基； R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
R 1选自H、卤素或C 1-6卤代烷基； R 1 is selected from H, halogen or C 1-6 haloalkyl;
R 2和R 3为H； R 2 and R 3 are H;
R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
R 6’为F，且R 6”为Cl或Br； R 6 ′ is F, and R 6 ″ is Cl or Br;
R d选自H、C 1-6烷基或C 1-6卤代烷基； R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
R 1选自H、卤素、CF 3或CHF 2；优选地，R 1为CF 3； R 1 is selected from H, halogen, CF 3 or CHF 2 ; preferably, R 1 is CF 3 ;
R 2和R 3为H； R 2 and R 3 are H;
R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
R 6’为F，且R 6”为Cl或Br； R 6 ′ is F, and R 6 ″ is Cl or Br;
R d选自H、C 1-6烷基或C 1-6卤代烷基。 R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、 非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(II-5)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (II-5):
Figure PCTCN2019093578-appb-000011
Figure PCTCN2019093578-appb-000011
其中，among them,
X为化学键或O；X is a chemical bond or O;
R 1选自H、卤素、C 1-6烷基或C 1-6卤代烷基； R 1 is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3选自H、卤素或C 1-6烷基； R 3 is selected from H, halogen or C 1-6 alkyl;
R 3’选自H或卤素； R 3 'is selected from H or halogen;
R 4选自H或C 1-6烷基； R 4 is selected from H or C 1-6 alkyl;
R 5选自H、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-S(O) 2R d或-(C 0-6亚烷基)-N(R e)-S(O) 2R d；优选地，R 5为(S)构型；优选地，当R 5为-COOH时，R 3、R 3’和R 4中至少一个不为H； R 5 is selected from H,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O ) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene Group) -OS (O) 2 R d or- (C 0-6 alkylene) -N (R e ) -S (O) 2 R d ; preferably, R 5 is in the (S) configuration; preferably , When R 5 is -COOH, at least one of R 3 , R 3 ′ and R 4 is not H;
R 6’和R 6”为卤素和甲基； R 6 ′ and R 6 ″ are halogen and methyl;
R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基； R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
X为化学键或O；X is a chemical bond or O;
R 1选自H、卤素或C 1-6卤代烷基；优选地，R 1为C 1-6卤代烷基； R 1 is selected from H, halogen or C 1-6 haloalkyl; preferably, R 1 is C 1-6 haloalkyl;
R 3选自H、卤素或C 1-6烷基； R 3 is selected from H, halogen or C 1-6 alkyl;
R 3’选自H或卤素； R 3 'is selected from H or halogen;
R 4选自H或C 1-6烷基； R 4 is selected from H or C 1-6 alkyl;
R 5选自H、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-S(O) 2R d或-(C 0-6亚烷基)-N(R e)-S(O) 2R d；优选地，R 5选自-(C 0-6亚烷基)-C(O)OH、-(C 0-6亚烷基)-C(O)NH 2或-(C 0-6亚烷基)-NH-S(O) 2R d；优选地，R 5为(S)构型；优选地，当R 5为-COOH时，R 3、R 3’和R 4中至少一个不为H； R 5 is selected from H,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 Alkylene) -OS (O) 2 R d or- (C 0-6 alkylene) -N (R e ) -S (O) 2 R d ; preferably, R 5 is selected from- (C 0- 6 alkylene) -C (O) OH,-(C 0-6 alkylene) -C (O) NH 2 or- (C 0-6 alkylene) -NH-S (O) 2 R d Preferably, R 5 is in the (S) configuration; preferably, when R 5 is -COOH, at least one of R 3 , R 3 ′, and R 4 is not H;
R 6’和R 6”为卤素和甲基； R 6 ′ and R 6 ″ are halogen and methyl;
R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基； R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
X为化学键或O；X is a chemical bond or O;
R 1选自H、Br、CF 3或CHF 2；优选地，R 1为CF 3； R 1 is selected from H, Br, CF 3 or CHF 2 ; preferably, R 1 is CF 3 ;
R 3为H、F或异丙基； R 3 is H, F or isopropyl;
R 3为H或F； R 3 is H or F;
R 4为H或甲基； R 4 is H or methyl;
R 5选自H、-COOH、-CONH 2、-CH 2NHSO 2Me、-COOMe或-CH 2OH；优选地，R 5选自-COOH、-CONH 2或-CH 2NHSO 2Me；优选地，R 5为(S)构型；优选地，当R 5为-COOH时，R 3、R 3’和R 4中至少一个不为H； R 5 is selected from H, -COOH, -CONH 2 , -CH 2 NHSO 2 Me, -COOMe, or -CH 2 OH; preferably, R 5 is selected from -COOH, -CONH 2 or -CH 2 NHSO 2 Me; preferably Preferably, R 5 is in the (S) configuration; preferably, when R 5 is -COOH, at least one of R 3 , R 3 ′, and R 4 is not H;
R 6’为F，且R 6”为Cl或Br。 R 6 ′ is F, and R 6 ″ is Cl or Br.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(III-1)、(III-2)、(III-3)、(III-4)、(III-5)、(III-6)、(III-7)、(III-8)或(III-9)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formulae (III-1), (III-2), (III-3), (III-4), (III-5) , (III-6), (III-7), (III-8), or (III-9):
Figure PCTCN2019093578-appb-000012
Figure PCTCN2019093578-appb-000012
其中，among them,
R 4和R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 and R 5 are -C (O) OH or -CH 2 CH 2 C (O) OH;
R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
X、R 1-R 7、R’、R”、m和n如上文所定义。 X, R 1 -R 7 , R ′, R ″, m and n are as defined above.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、 非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(III-5)、(III-6)、(III-7)或(III-8)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphic, prodrug or isotope variants, and mixtures thereof, having the general formula (III-5), (III-6), (III-7) or (III-8):
Figure PCTCN2019093578-appb-000013
Figure PCTCN2019093578-appb-000013
其中，among them,
R’和R”为H；R 'and R "are H;
R 1选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基或-C(O)OR a；优选地，R 1选自卤素、C 1-6烷基、C 1-6卤代烷基或-C(O)OR a； R 1 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, or -C (O) OR a ; preferably R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -C (O) OR a ;
R 2和R 3为H； R 2 and R 3 are H;
R 4和R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 and R 5 are -C (O) OH or -CH 2 CH 2 C (O) OH;
R a独立地选自H、C 1-6烷基或C 1-6卤代烷基；优选地，R a独立地为C 1-6烷基或C 1-6卤代烷基； R a is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably, R a is independently C 1-6 alkyl or C 1-6 haloalkyl;
R d独立地选自C 1-6烷基或C 1-6卤代烷基； R d is independently selected from C 1-6 alkyl or C 1-6 haloalkyl;
R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br。 R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(III-9)In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (III-9)
Figure PCTCN2019093578-appb-000014
Figure PCTCN2019093578-appb-000014
其中，among them,
R 1选自卤素、C 1-6烷基、C 1-6卤代烷基或-C(O)OR a；优选地，R 1选自卤素或-C(O)OR a； R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -C (O) OR a ; preferably, R 1 is selected from halogen or -C (O) OR a ;
R 4为H或-(C 0-6亚烷基)-C(O)OR d；优选地，R 4为H或-(C 1-6亚烷基)-C(O)OH；优选地，R 4为(R)构型； R 4 is H or- (C 0-6 alkylene) -C (O) OR d ; preferably, R 4 is H or- (C 1-6 alkylene) -C (O) OH; preferably , R 4 is (R) configuration;
R 5为H或-(C 0-6亚烷基)-C(O)OR d；优选地，R 5为H或-C(O)OR d；优选地，R 5为(S)构型；优选地，R 4和R 5中至少有一个为非氢基团； R 5 is H or- (C 0-6 alkylene) -C (O) OR d ; preferably, R 5 is H or -C (O) OR d ; preferably, R 5 is (S) configuration ; Preferably, at least one of R 4 and R 5 is a non-hydrogen group;
R 6’和R 6”为卤素和甲基； R 6 ′ and R 6 ″ are halogen and methyl;
R a独立地选自H、C 1-6烷基或C 1-6卤代烷基； R a is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R d独立地选自H、C 1-6烷基或C 1-6卤代烷基； R d is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
R 1选自Br、Cl或-C(O)Me； R 1 is selected from Br, Cl or -C (O) Me;
R 4为H或-CH 2CH 2C(O)OH；优选地，R 4为(R)构型； R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
R 5为H、-C(O)OH、-C(O)OMe或-CH 2CH 2C(O)OH；优选地，R 5为H、-C(O)OH或-C(O)OMe；优选地，R 5为(S)构型；优选地，R 4和R 5中至少有一个为非氢基团； R 5 is H, -C (O) OH, -C (O) OMe or -CH 2 CH 2 C (O) OH; preferably, R 5 is H, -C (O) OH or -C (O) OMe; preferably, R 5 is in the (S) configuration; preferably, at least one of R 4 and R 5 is a non-hydrogen group;
R 6’为F，且R 6”为Cl或Br。 R 6 ′ is F, and R 6 ″ is Cl or Br.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(IV-1)、(IV-2)、(IV-3)、(IV-4)、(IV-5)或(IV-6)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) Or (IV-6):
Figure PCTCN2019093578-appb-000015
Figure PCTCN2019093578-appb-000015
其中，among them,
R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
X、R 1-R 7、m和n如上文所定义。 X, R 1 -R 7 , m and n are as defined above.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(IV-3)、(IV-4)或(IV-5)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (IV-3), (IV-4) or (IV-5):
Figure PCTCN2019093578-appb-000016
Figure PCTCN2019093578-appb-000016
其中，among them,
R 1选自H、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a或-NR bR c； R 1 is selected from H, -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; and R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a or -NR b R c ;
R 2和R 3为H，或者R 2和R 3结合形成双键； R 2 and R 3 are H, or R 2 and R 3 combine to form a double bond;
R 4为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 is -C (O) OH or -CH 2 CH 2 C (O) OH;
R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
R 6’和R 6”为卤素和甲基； R 6 ′ and R 6 ″ are halogen and methyl;
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基； R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
R 1选自H、-C(O)OR a、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a或-NR bR c； R 1 is selected from H, -C (O) OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, or 3-7 membered heterocyclyl; and R 1 is optionally Substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a or -NR b R c ;
优选地，R 1选自H、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自-OR a或-NR bR c； Preferably, R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, or 3-7 membered heterocyclyl; and R 1 is optionally 1, 2, or 3 R group substitutions, where R is independently selected from -OR a or -NR b R c ;
R 2和R 3为H； R 2 and R 3 are H;
R 4为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 is -C (O) OH or -CH 2 CH 2 C (O) OH;
R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
R 6’为F，且R 6”为Cl或Br； R 6 ′ is F, and R 6 ″ is Cl or Br;
R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基。 R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明涉及如上所述的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(IV-6)：In a more specific embodiment, the invention relates to a compound as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof , Polymorphs, prodrugs or isotopic variants, and mixtures thereof, having the general formula (IV-6):
Figure PCTCN2019093578-appb-000017
Figure PCTCN2019093578-appb-000017
其中，among them,
R 1选自H、C 1-6烷基、-C(O)OR a或C 3-7碳环基，并且其中C 1-6烷基或C 3-7碳环基任选地被1个-OR a基团取代； R 1 is selected from H, C 1-6 alkyl, -C (O) OR a, or C 3-7 carbocyclyl, and wherein C 1-6 alkyl or C 3-7 carbocyclyl is optionally substituted by 1 -OR a group substitution;
R 4为H或-CH 2CH 2C(O)OH；优选地，R 4为(R)构型； R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
R 5为H或-C(O)OR a；优选地，R 5为(S)构型； R 5 is H or -C (O) OR a ; preferably, R 5 is (S) configuration;
R 6’和R 6”为卤素和甲基； R 6 ′ and R 6 ″ are halogen and methyl;
R a选自H、C 1-6烷基或C 1-6卤代烷基； R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
优选地，Preferably,
R 1选自H、环丙基、-C(O)OMe或-CH 2OH； R 1 is selected from H, cyclopropyl, -C (O) OMe or -CH 2 OH;
R 4为H或-CH 2CH 2C(O)OH；优选地，R 4为(R)构型； R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
R 5为H、-C(O)OH或-C(O)OMe；优选地，R 5为H或-C(O)OH；优选地，R 5为(S)构型；优选地，R 4和R 5中至少有一个为非氢基团； R 5 is H, -C (O) OH or -C (O) OMe; preferably, R 5 is H or -C (O) OH; preferably, R 5 is in the (S) configuration; preferably, R At least one of 4 and R 5 is a non-hydrogen group;
R 6’为F，且R 6”为Cl或Br。 R 6 ′ is F, and R 6 ″ is Cl or Br.
在更具体的实施方案中，本发明化合物选自以下化合物，但不局限于此：In a more specific embodiment, the compound of the invention is selected from, but is not limited to, the following compounds:
Figure PCTCN2019093578-appb-000018
Figure PCTCN2019093578-appb-000018
Figure PCTCN2019093578-appb-000019
Figure PCTCN2019093578-appb-000019
Figure PCTCN2019093578-appb-000020
Figure PCTCN2019093578-appb-000020
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，包括外消旋体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。The compounds of the invention may include one or more asymmetric centers, and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and / or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, This includes racemic mixtures and mixtures rich in one or more stereoisomers. Isomers can be separated from a mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be obtained by Prepared by asymmetric synthesis.
本领域技术人员将理解，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。Those skilled in the art will understand that organic compounds can form complexes with solvents that react in the solvent or precipitate or crystallize from the solvent. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate". The invention encompasses all solvates of the compounds of the invention.
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。The term "solvate" refers to the form of a compound or a salt thereof in combination with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to be separated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The "solvate" includes a solvate in a solution state and a separable solvate. Representative solvates include hydrates, ethanolates, and methanolates.
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5 H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2 H 2O)和六水合物(R·6 H 2O))。 The term "hydrate" refers to a compound that is combined with water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound can be represented, for example, by the general formula R · x H 2 O, where R is the compound, and x is a number greater than 0. A given compound can form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R · 0.5 H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R · 2 H 2 O) and hexahydrate (R · 6 H 2 O)).
本发明化合物可以是无定形或结晶形式(多晶型)。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“多晶型物”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。The compounds of the invention may be in an amorphous or crystalline form (polymorphic form). In addition, 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) of a compound in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability, and solubility. Recrystallization solvents, crystallization rates, storage temperatures, and other factors can lead to the predominance of a crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式I-VIII所述的那些，但一个或多 个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32p、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式I-VIII化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。 The present invention also includes isotopically-labeled compounds (isotopic variants) which are equivalent to those described in Formulas I-VIII, but where one or more of the atoms have an atomic mass or mass number different from the atomic mass or mass number of atoms commonly found in nature Instead. Examples of isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 p, 35 S, 18 F, and 36 Cl. Compounds of the present invention containing the above-mentioned isotopes and / or other isotopes of other atoms, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or said prodrugs are all within the scope of the present invention. Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes such as 3 H and 14 C, can be used for drug and / or substrate tissue distribution assays. Thallium, i.e. 3 H and carbon-14, i.e. 14 C isotopes, are particularly preferred because they are easy to prepare and detect. Furthermore, replacement with heavier isotopes, such as deuterium, ie, 2 H, may be preferable in some cases because higher metabolic stability can provide therapeutic benefits, such as extending half-life in the body or reducing dosage requirements. Isotopically labeled compounds of formula I-VIII of the present invention and their prodrugs can generally be prepared in such a way that non-isotope-labeled reagents can be replaced with readily available isotopically-labeled reagents when performing the processes disclosed in the following schemes and / or examples and preparations Labeled reagent.
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。In addition, prodrugs are also included in the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted into its active form with a medical effect in vivo by, for example, hydrolysis in blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs, 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, or drug, delivery: solubility, limitation, overcome, and use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each article This article is for reference.
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。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、氨基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、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。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。A prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in vivo. Prodrugs are usually prepared by modifying functional groups, and the modification is performed in a manner such that the modification can be performed by routine manipulation or cleavage in vivo to produce the parent compound. Prodrugs include, for example, compounds of the invention in which a hydroxy, amino, or thiol group is bonded to an arbitrary group, and when administered to a patient, can be cleaved to form a hydroxy, amino, or thiol group. Accordingly, representative examples of prodrugs include, but are not limited to, acetate, amide, formate / amide, and benzoate / amide derivatives of hydroxyl, thiol, and amino functional groups of the compound of formula (I). In the case of a carboxylic acid (-COOH), an ester such as methyl ester, ethyl ester, or the like can be used. The esters themselves can be active and / or can be hydrolyzed under conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups that readily break down in the human body to release the parent acid or its salt.
本发明还提供药物制剂，包含治疗有效量的式I-VIII化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula I-VIII or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.
药物组合物、制剂和试剂盒Pharmaceutical compositions, preparations and kits
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本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
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。A pharmaceutically acceptable excipient for use in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compounds 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 (such as human serum albumin Protein), buffer substances (e.g. phosphate), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g. protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols and lanolin.
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。The invention also includes kits (eg, pharmaceutical packaging). The kits provided may include compounds of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and / or dispersible packaging or other Suitable container). In some embodiments, the provided kit may 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. In some embodiments, a compound of the invention and other therapeutic agents are provided in a first container and a second container to form a unit dosage form.
给药Dosing
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。The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Medication, implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intra-synovial, and sternal administration , Cerebrospinal spinal membrane administration, intralesional administration, and intracranial injection or infusion techniques.
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。Generally, an effective amount of a compound provided herein is administered. Depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc., the amount of compound actually administered can be determined by the physician .
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。When used to prevent a condition described in the present invention, a compound provided herein is administered to a subject at risk of developing the condition, typically based on and under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder typically include subjects with a family history of the disorder, or those who are determined by genetic testing or screening to be particularly sensitive to the development of the disorder.
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。The pharmaceutical compositions provided herein can also be administered chronically ("long-term administration"). Long-term administration refers to administration of a compound or a pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the remainder of a subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
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。Various methods of administration can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, a pharmaceutical composition may be administered as a bolus, for example, to increase the concentration of a compound in the blood to an effective level. The bolus dose depends on the target systemic level of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose that slowly releases the active ingredient, while a bolus delivered directly to a vein (e.g., by IV intravenous drip ) Can be delivered more quickly, so that the concentration of the active ingredient in the blood quickly rises to an effective level. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV infusion, to provide a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
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。Oral compositions can take the form of a liquid solution or suspension in bulk or a powder in bulk. However, more generally, to facilitate accurate dosing, the composition is provided in unit dosage form. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human patients and other mammals, each unit containing a predetermined number of active substances and suitable pharmaceutical excipients suitable for producing the desired therapeutic effect. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions. In such a composition, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remainder is each useful for forming a desired administration form A carrier or excipient and processing aid.
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。For oral doses, a representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosage modes of administration, each dose provides about 0.01 to about 20 mg / kg of a compound of the invention, and preferred doses each provide about 0.1 to about 10 mg / kg, especially about 1 to about 5 mg / 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。In order to provide a blood level similar to, or lower than, the injected dose, transdermal doses are usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
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。From about 1 to about 120 hours, especially 24 to 96 hours, the injection dose level ranges from about 0.1 mg / kg / hour to at least 10 mg / kg / hour. To obtain a sufficient steady state level, a preloaded bolus of about 0.1 mg / kg to about 10 mg / kg or more can also be given. For human patients from 40 to 80 kg, the maximum total dose cannot exceed about 2 g / day.
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。Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous vehicles and buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, such as microcrystalline cellulose, tragacanth, or gelatin; excipients, such as starch or lactose, disintegrants, For example, alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate; glidants, such as colloidal silicon dioxide; sweeteners, such as sucrose or saccharin; or flavoring agents, such as mint, water Methyl salicylate or orange flavor.
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。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned earlier, in this composition, the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
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。Transdermal compositions are typically formulated as a topical ointment or cream containing an active ingredient. When formulated as an ointment, the active ingredient is typically combined with a paraffin or a water-miscible ointment base. Alternatively, the active ingredient may 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 components for enhancing the stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope of the invention.
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。The compounds of the invention may also be administered via a transdermal device. Therefore, transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
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。The above components of the composition for oral administration, injection or topical administration are merely representative. Other materials and processing techniques are described in Remington's Pharmaceuticals, Science, 17th Edition, 1985, Mack Publishing Company, Easton, Pennsylvania, Section 8, which is incorporated herein by reference.
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。The compounds of the invention may also be administered in a sustained release form or from a sustained release delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceuticals Science.
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％)。The invention also relates to a pharmaceutically acceptable formulation of a compound of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrin consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or more substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, a sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (eg, 10-50% in water).
组合治疗Combination therapy
可将本发明化合物或组合物与一种或多种额外的药剂同时给药、或在所述一种或多种额外的药剂之前或之后给药，用作组合疗法。药剂包括治疗活性剂。药剂还包括预防活性剂。药剂包括小的有机分子，例如药物化合物(例如，由美国食品与药物管理局批准，提供在美国联邦法规汇编(CFR)中的人或兽用化合物)、肽类、蛋白、碳水化合物、单糖、寡糖、多糖、核蛋白、粘蛋白、脂蛋白、合成多肽或蛋白、连接蛋白的小分子、糖蛋白、甾类、核酸、DNA、RNA、核苷酸、核苷、寡核苷酸、反义寡核苷酸、脂质、激素、维生素和细胞。在一些实施方案中，所述额外的药剂是用于治疗和/或预防本文所述疾病的药剂。各额外的药剂可以该药剂确定的剂量和/或时间表进行给药。所述额外的药剂也可彼此一起和/或与本文所述化合物或组合物一起，以单一剂量进行给药或以不同剂量分别进行给药。在该方案中所采用的具体组合将考虑本发明化合物与额外的药剂的相容性和/或将实现的所需的治疗和/或预防效果。通常，所述额外的药剂在组合使用时所采用的水平是以不超过它们单独使用时的水平。在一些实施方案中，组合使用的水平将低于它们单独使用时的水平。A compound or composition of the invention may be administered simultaneously with one or more additional agents, or before or after the one or more additional agents, as a combination therapy. The medicament includes a therapeutically active agent. The medicament also includes a prophylactically active agent. Medicaments include small organic molecules, such as pharmaceutical compounds (e.g., human or veterinary compounds approved by the US Federal Regulations (CFR), approved by the US Food and Drug Administration), peptides, proteins, carbohydrates, monosaccharides Oligosaccharides, polysaccharides, nucleoproteins, mucins, lipoproteins, synthetic polypeptides or proteins, small molecules of connexins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, Antisense oligonucleotides, lipids, hormones, vitamins and cells. In some embodiments, the additional agent is an agent for treating and / or preventing a disease described herein. Each additional agent may be administered at a dose and / or schedule determined by the agent. The additional agents may also be administered together with each other and / or with a compound or composition described herein in a single dose or separately in different doses. The specific combination employed in this regime will take into account the compatibility of the compounds of this invention with additional agents and / or the desired therapeutic and / or prophylactic effects that will be achieved. Generally, the additional agents are used at a level that does not exceed the level at which they are used alone. In some embodiments, the levels used in combination will be lower than when they are used alone.
在具体实施方案中，所述额外的药剂为抗病毒剂，其选自HBV聚合酶抑制剂、干扰素、病毒进入抑制剂、病毒成熟抑制剂、衣壳装配调节剂、逆转录酶抑制剂、TLR-激动剂、和不同或未知机制的制剂、以及它们的组合。In specific embodiments, the additional agent is an antiviral agent selected from the group consisting of HBV polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, capsid assembly regulators, reverse transcriptase inhibitors, TLR-agonists, and formulations of different or unknown mechanisms, and combinations thereof.
在另一个实施方案中，聚乙二醇化干扰素是聚乙二醇化干扰素α(IFN-α)、聚乙二醇化干扰素λ(IFN-λ)、或聚乙二醇化干扰素γ(IFN-γ)。In another embodiment, the pegylated interferon is pegylated interferon alpha (IFN-α), pegylated interferon lambda (IFN-λ), or pegylated interferon gamma (IFN -γ).
在另一个实施方案中，逆转录酶抑制剂是以下项中的至少一种：齐多夫定(Zidovudine)、去羟肌苷(Didanosine)、扎西他滨(Zalcitabine)、ddA(2′，3′-双脱氧腺苷)(ddA(2’，3’-dideoxyadenosine))、司他夫定(Stavudine)、拉米夫定(Lamivudine)、阿巴卡韦(Abacavir)、恩曲他滨(Emtricitabine)、恩替卡韦(Entecavir)、阿立他滨(Apricitabine)、Atevirapine、利巴韦林(ribavirin)、阿昔洛韦(acyclovir)、泛昔洛韦(famciclovir)、伐昔洛韦(valacyclovir)、更昔洛韦(ganciclovir)、缬更昔洛韦(valganciclovir)、替诺福韦(Tenofovir)、阿德福韦(Adefovir)、西多福韦(cidofovir)、依法韦仑(Efavirenz)、奈韦拉平(Nevirapine)、地拉夫定(Delavirdine)、或依曲韦林(Etravirine)。In another embodiment, the reverse transcriptase inhibitor is at least one of: Zidovudine, Didanosine, Zalcitabine, ddA (2 ', 3'-dideoxyadenosine) (ddA (2 ', 3'-dideoxyadenosine)), Stavudine, Lamivudine, Abacavir, Emtricitabine ( Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir Ganciclovir, valganciclovir, tenofovir, adefovir, cidofovir, efavirenz, nevirapine, Delavirdine, or Etravirine.
在另一个实施方案中，所述额外的药剂例如为T细胞应答激活剂AIC649；干扰素类的生物试剂如干扰素和聚乙二醇化的干扰素；TLR调节剂如TLR-7激动剂或TLR-9激动剂如SM360320(9-苄基-8-羟基-2-(2-甲氧基-乙氧基)腺氨酸)、AZD8848([3-({[3-(6-氨基-2-丁氧基-8-氧代-7，8-二氢-9H-嘌呤-9-基)丙基][3-(4-吗啉基)丙基]氨基}甲基)苯基]乙酸甲酯)、GS-9620和RO6864018；刺激HBV特异性免疫应答的治疗性疫苗；免疫激活剂如SB-9200；RNA干扰剂(RNAi)或小RNA干扰剂(siRNA)如ARC-520、ARC-521；或者逆转录酶抑制剂如拉米夫定、替比夫定、恩曲他滨、恩替卡韦、替诺福韦酯、阿德福韦酯。In another embodiment, the additional agent is, for example, a T-cell response activator AIC649; interferon-based biological agents such as interferons and pegylated interferons; TLR modulators such as TLR-7 agonists or TLRs -9 agonists such as SM360320 (9-benzyl-8-hydroxy-2- (2-methoxy-ethoxy) adenine), AZD8848 ([3-({[3- (6-amino-2 -Butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl) propyl] [3- (4-morpholinyl) propyl] amino} methyl) phenyl] acetic acid Methyl ester), GS-9620 and RO6864018; therapeutic vaccines that stimulate HBV-specific immune responses; immune activators such as SB-9200; RNA interference (RNAi) or small RNA interference (siRNA) such as ARC-520, ARC- 521; or a reverse transcriptase inhibitor such as lamivudine, telbivudine, emtricitabine, entecavir, tenofovir disoproxil, adefovir disoproxil.
实施例Examples
提供以下实施例以便为本领域技术人员提供如何实施、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本发明的范围。The following examples are provided to provide those skilled in the art with a complete disclosure and description of how to implement, prepare, and evaluate the methods and compounds claimed herein, and are intended to merely exemplify the invention and not limit the scope of the invention.
在以下实施例中，所有水敏感反应均在干燥条件下进行。苯、四氢呋喃或二氯甲烷在金属钠存在下回流、干燥、蒸馏后保存待用。所有的中间体均通过硅胶色谱纯化。所有的最终化合物均通过制备型HPLC、使用C18反相色谱柱纯化，流动相为(A：含0.1％三氟乙酸的水溶液；B：乙腈)或碱性条件(A：0.1％氨水溶液；B：乙腈)。基于HPLC、LC-MS和1HNMR分析，所有最终化合物的纯度均大于95％。所有报告的产率都没有进行优化。In the following examples, all water sensitive reactions were performed under dry conditions. Benzene, tetrahydrofuran or dichloromethane are refluxed in the presence of sodium metal, dried, and distilled and stored for future use. All intermediates were purified by silica gel chromatography. All final compounds were purified by preparative HPLC using a C18 reversed-phase column with mobile phases (A: 0.1% trifluoroacetic acid in water; B: acetonitrile) or basic conditions (A: 0.1% ammonia in water; B : Acetonitrile). Based on HPLC, LC-MS and 1HNMR analysis, the purity of all final compounds was greater than 95%. All reported yields have not been optimized.
实施例1Example 1
Figure PCTCN2019093578-appb-000021
Figure PCTCN2019093578-appb-000021
化合物 1： Compound 1 :
搅拌下向噻唑-2-甲腈(1.50g，14mmol)的5mL无水甲醇溶液中滴加30％甲醇钠溶液(2.55mL，14mmol)，将反应混合物在室温下搅拌直至原料消失。随后一次性加入氯化铵(1.50g，28mmol)，并将反应混合物搅拌过夜。过滤除去未溶解的物质，滤液真空浓缩得到灰色的噻唑-2-甲脒盐酸盐固体 1，后者无需进一步纯化就可直接用于下一步缩合环化反应。 A 30% sodium methoxide solution (2.55 mL, 14 mmol) was added dropwise to a 5 mL anhydrous methanol solution of thiazole-2-carbonitrile (1.50 g, 14 mmol) with stirring, and the reaction mixture was stirred at room temperature until the starting materials disappeared. Ammonium chloride (1.50 g, 28 mmol) was then added in one portion, and the reaction mixture was stirred overnight. The undissolved material was removed by filtration, and the filtrate was concentrated in vacuo to obtain a gray thiazole-2-formamidine hydrochloride solid 1 , which was used directly in the next condensation cyclization reaction without further purification.
化合物 4： Compound 4 :
将噻唑-2-甲脒盐酸盐( 1，150mg，1.0mmol)、2-氯-4-氟苯甲醛( 2，160mg，1.0mmol)、2-三氟甲基丙酮( 3，126mg，1.0mmol)和乙酸钾(0.20g，2.0mmol)溶于10mL CF 3CH 2OH溶液中，反应混合物在氮气下搅拌回流12小时。冷却至室温后，反应混合物浓缩并将残余物溶于乙酸乙酯，有机层经盐水洗涤后干燥(Na 2SO 4)、浓缩，残余物通过硅胶柱色谱(乙酸乙酯-石油醚：1∶4-1∶2)纯化，得到黄色固体产物 4(195mg，52％)。 1HNMR(DMSO-d 6，400MHz)δ9.98(s，1H)，7.97(d，J＝4.0Hz，1H)，7.90(dd，J＝8.0，4.0Hz，1H)，7.35(dd，J＝8.0，8.0Hz，1H)，7.18 (td，J＝8.0，4.0Hz，1H)，5.98(s，1H)，2.47(s，3H)。 Thiazole-2-carboximidamide hydrochloride (1, 150mg, 1.0mmol), 2- chloro-4-fluorobenzaldehyde (2, 160mg, 1.0mmol), 2- trifluoromethyl-acetone (3, 126mg, 1.0 mmol) and potassium acetate (0.20 g, 2.0 mmol) were dissolved in 10 mL of a solution of CF 3 CH 2 OH, and the reaction mixture was stirred under reflux under nitrogen for 12 hours. After cooling to room temperature, the reaction mixture was concentrated and the residue was dissolved in ethyl acetate. The organic layer was washed with brine, dried (Na 2 SO 4 ), and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate-petroleum ether: 1: 4-1: 2) purification to give product 4 (195 mg, 52%) as a yellow solid. 1 HNMR (DMSO-d 6 , 400 MHz) δ 9.98 (s, 1H), 7.97 (d, J = 4.0 Hz, 1H), 7.90 (dd, J = 8.0, 4.0 Hz, 1H), 7.35 (dd, J = 8.0, 8.0 Hz, 1H), 7.18 (td, J = 8.0, 4.0 Hz, 1H), 5.98 (s, 1H), 2.47 (s, 3H).
化合物 5： Compound 5 :
向化合物 4(375mg，1.0mmol)的CCl 4(5mL)的溶液中加入NBS(200mg，1.1mmol)，反应液在室温下搅拌2小时后，真空除去溶剂并将残余物通过柱色谱法纯化，得到化合物 5(390mg，86％)。MS m/z 445[M+H]。 To a solution of compound 4 (375 mg, 1.0 mmol) in CCl 4 (5 mL) was added NBS (200 mg, 1.1 mmol). After the reaction solution was stirred at room temperature for 2 hours, the solvent was removed in vacuo and the residue was purified by column chromatography. Compound 5 (390 mg, 86%) was obtained. MS m / z 445 [M + H].
化合物 6： Compound 6 :
搅拌下向化合物 5(49mg，0.11mmol)和(3S)-吗啉-3-甲酸盐酸盐(29mg，0.17mmol)的二氯甲烷(5mL)溶液中滴加二异丙基乙基胺(80μL，0.45mmol)，反应混合物在室温下搅拌直到原料5消失。乙酸乙酯(10mL)稀释后，有机相依次用饱和氯化铵溶液和盐水洗涤，干燥(Na 2SO 4)、浓缩、残余物通过制备型HPLC纯化，得到淡黄色固体产物 6(28mg，50％)。MS m/z 506[M+H]； 1HNMR(DMSO-d 6，400MHz)δ12.68(br.s，1H)，9.85(s，1H)，8.03(d，J＝4.0Hz，1H)，7.91(d，J＝4.0Hz，1H)，7.46-7.40(m，2H)，7.11(td，J＝8.76，2.62Hz，1H)，6.01(s，1H)，4.21(d，J＝20Hz，1H)，4.07-3.97(m，2H)，3.89-3.56(m，4H)，3.15-3.05(m，1H)，2.45-2.35(m，1H). To a solution of compound 5 (49 mg, 0.11 mmol) and (3S) -morpholine-3-formate (29 mg, 0.17 mmol) in dichloromethane (5 mL) with stirring, diisopropylethylamine was added dropwise. (80 μL, 0.45 mmol), the reaction mixture was stirred at room temperature until starting material 5 disappeared. After diluting with ethyl acetate (10 mL), the organic phase was washed sequentially with saturated ammonium chloride solution and brine, dried (Na 2 SO 4 ), concentrated, and the residue was purified by preparative HPLC to give the product 6 (28 mg, 50 mg, 50 mg) %). MS m / z 506 [M + H]; 1 HNMR (DMSO-d 6 , 400 MHz) δ 12.68 (br.s, 1H), 9.85 (s, 1H), 8.03 (d, J = 4.0 Hz, 1H) , 7.91 (d, J = 4.0Hz, 1H), 7.46-7.40 (m, 2H), 7.11 (td, J = 8.76, 2.62Hz, 1H), 6.01 (s, 1H), 4.21 (d, J = 20Hz , 1H), 4.07-3.97 (m, 2H), 3.89-3.56 (m, 4H), 3.15-3.05 (m, 1H), 2.45-2.35 (m, 1H).
采用化合物 6相同的合成方法，将溴化物 5与各种吗啉衍生物亲核取代反应，可以得到如下的化合物 7- 16： Using the same synthetic process as Compound 6, bromide morpholine derivative 5 with a variety of nucleophilic substitution reaction, the following compound can give 7 - 16:
Figure PCTCN2019093578-appb-000022
MS m/z 506[M+H]；1HNMR(DMSO-d6，400MHz)δ12.84(br s，1H)，9.85(s，1H)，8.08-7.88(m，2H)，7.44-7.26(m，2H)，7.16(m，1H)，6.01(s，1H)，4.18-4.02(m，2H)，3.90-3.80(m，2H)，3.77-3.58(m，2H)，3.47-3.24(m，1H)，3.14-2.99(m，1H)，1.38-1.12(m，1H).
Figure PCTCN2019093578-appb-000022
MS m / z 506 [M + H]; 1HNMR (DMSO-d6, 400MHz) δ 12.84 (br s, 1H), 9.85 (s, 1H), 8.08-7.88 (m, 2H), 7.44-7.26 (m , 2H), 7.16 (m, 1H), 6.01 (s, 1H), 4.18-4.02 (m, 2H), 3.90-3.80 (m, 2H), 3.77-3.58 (m, 2H), 3.47-3.24 (m , 1H), 3.14-2.99 (m, 1H), 1.38-1.12 (m, 1H).
Figure PCTCN2019093578-appb-000023
MS m/z 506[M+H]；1HNMR(MeOH-d4，400MHz)δ8.01(d，J＝3Hz，0.5H)，8.00(d，J＝3Hz，0.5H)，7.91(dd，J＝3Hz，0.5H)，7.90(d，J＝3Hz，0.5H)，7.54(m，0.5H)，7.53(m，0.5H)，7.30(m，1H)，7.15-7.09(m，1H)，6.21(s，1H)，4.82-4.55(m，3H)，4.31-4.24(m，1H)，4.12-3.91(m，2H)，3.74-3.65(m，1H)，3.55-3.37(m，2H).
Figure PCTCN2019093578-appb-000023
MS m / z 506 [M + H]; 1H NMR (MeOH-d4, 400 MHz) δ 8.01 (d, J = 3 Hz, 0.5 H), 8.00 (d, J = 3 Hz, 0.5 H), 7.91 (dd, J = 3Hz, 0.5H), 7.90 (d, J = 3Hz, 0.5H), 7.54 (m, 0.5H), 7.53 (m, 0.5H), 7.30 (m, 1H), 7.15-7.09 (m, 1H) , 6.21 (s, 1H), 4.82-4.55 (m, 3H), 4.31-4.24 (m, 1H), 4.12-3.91 (m, 2H), 3.74-3.65 (m, 1H), 3.55-3.37 (m, 2H).
Figure PCTCN2019093578-appb-000024
MS m/z 520[M+H]；1HNMR(MeOH-d4，400MHz)：δ8.00(d，J＝3.14Hz，1H)，7.88(d，J＝3.14Hz，1nH)，7.51(m，1H)，7.28(m，1H)，7.11(m，1H)，6.19(s，1H)，4.41(d，J＝16.56Hz，1H)，4.20(d，J＝16.44Hz，1H)，4.00-4.13(m，1H)，3.75-3.98(m，3H)，3.51(d，J＝8.91Hz，1H)，3.06(m，1H)，1.36(d，J＝6.27Hz，3H).
Figure PCTCN2019093578-appb-000024
MS m / z 520 [M + H]; 1HNMR (MeOH-d4, 400MHz): δ8.00 (d, J = 3.14Hz, 1H), 7.88 (d, J = 3.14Hz, 1nH), 7.51 (m, 1H), 7.28 (m, 1H), 7.11 (m, 1H), 6.19 (s, 1H), 4.41 (d, J = 16.56Hz, 1H), 4.20 (d, J = 16.44Hz, 1H), 4.00- 4.13 (m, 1H), 3.75-3.98 (m, 3H), 3.51 (d, J = 8.91 Hz, 1H), 3.06 (m, 1H), 1.36 (d, J = 6.27 Hz, 3H).
Figure PCTCN2019093578-appb-000025
MS m/z 520[M+H]；1H NMR(MeOH-d4，400MHz)δ7.97(d，J＝3.0Hz，1H)，7.74(d，J＝3.3Hz，1H)，7.42(m，1H)，7.23(m，1H)，7.04(m，1H)，6.17(s，1H)，4.40(d，J＝17.8Hz，1H)，3.96-4.15(m，3H)，3.76-3.88(m，4H)，3.13-3.31(m，3H)，2.50(m，1H).
Figure PCTCN2019093578-appb-000025
MS m / z 520 [M + H]; 1H NMR (MeOH-d4, 400MHz) δ 7.97 (d, J = 3.0Hz, 1H), 7.74 (d, J = 3.3Hz, 1H), 7.42 (m, 1H), 7.23 (m, 1H), 7.04 (m, 1H), 6.17 (s, 1H), 4.40 (d, J = 17.8Hz, 1H), 3.96-4.15 (m, 3H), 3.76-3.88 (m , 4H), 3.13-3.31 (m, 3H), 2.50 (m, 1H).
Figure PCTCN2019093578-appb-000026
MS m/z 505[M+H]；1HNMR(MeOH-d4，400MHz)δ7.97(d，J＝3.01Hz，1H)，7.71-7.81(m，1H)，7.42(m，1H)，7.23(m，1H)，7.06(m，1H)，6.08-6.20(m，1H)，4.08-4.27(m，1H)，4.01(dd，J＝3.26，11.29Hz，1H)，3.67-3.92(m，4H)，3.35-3.43(m，1H)，3.00-3.09(m，1H)，2.50-2.68(m，1H).
Figure PCTCN2019093578-appb-000026
MS m / z 505 [M + H]; 1H NMR (MeOH-d4, 400 MHz) δ 7.97 (d, J = 3.01 Hz, 1H), 7.71-7.81 (m, 1H), 7.42 (m, 1H), 7.23 (m, 1H), 7.06 (m, 1H), 6.08-6.20 (m, 1H), 4.08-4.27 (m, 1H), 4.01 (dd, J = 3.26, 11.29Hz, 1H), 3.67-3.92 (m , 4H), 3.35-3.43 (m, 1H), 3.00-3.09 (m, 1H), 2.50-2.68 (m, 1H).
Figure PCTCN2019093578-appb-000027
MS m/z 492[M+H]；1HNMR(MeOH-d4，400MHz)δ7.98-8.02(m，1H)，7.91(dd，J＝3.01，0.75Hz，1H)，7.57(dd，J＝8.66，5.90Hz，1H)，7.30(dd，J＝8.66，2.64Hz，1H)7.12(m，1H)，6.19-6.23(m，1H)，4.85(d，J＝6.53Hz，1H)，4.70(m，1H)，4.05-4.18(m，3H)，3.90-4.01(m，3H)，3.70-3.79(m，2H)，3.43-3.53(m，1H).
Figure PCTCN2019093578-appb-000027
MS m / z 492 [M + H]; 1HNMR (MeOH-d4, 400MHz) δ 7.98-8.02 (m, 1H), 7.91 (dd, J = 3.01, 0.75 Hz, 1H), 7.57 (dd, J = 8.66, 5.90 Hz, 1H), 7.30 (dd, J = 8.66, 2.64 Hz, 1H) 7.12 (m, 1H), 6.19-6.23 (m, 1H), 4.85 (d, J = 6.53 Hz, 1H), 4.70 (m, 1H), 4.05-4.18 (m, 3H), 3.90-4.01 (m, 3H), 3.70-3.79 (m, 2H), 3.43-3.53 (m, 1H).
Figure PCTCN2019093578-appb-000028
MS m/z 569[M+H]；1HNMR(MeOH-d4，400MHz)δ8.19(br s，1H)，7.96(d，J＝3.01Hz，1H)，7.76(d，J＝3.26Hz，1H)，7.48(m，1H)，7.22(m，1H)，7.04(m，1H)，6.18(s，1H)，4.13-4.34(m，2H)，3.93(m，1H)，3.77-3.83(m，2H)，3.72(m，1H)，3.36-3.46(m，2H)，2.98(s，3H)，2.85-2.92(m，1H)，2.80(m，1H)，2.53-2.62(m，1H).
Figure PCTCN2019093578-appb-000028
MS m / z 569 [M + H]; 1HNMR (MeOH-d4, 400MHz) δ 8.19 (br s, 1H), 7.96 (d, J = 3.01 Hz, 1H), 7.76 (d, J = 3.26 Hz, 1H), 7.48 (m, 1H), 7.22 (m, 1H), 7.04 (m, 1H), 6.18 (s, 1H), 4.13-4.34 (m, 2H), 3.93 (m, 1H), 3.77-3.83 (m, 2H), 3.72 (m, 1H), 3.36-3.46 (m, 2H), 2.98 (s, 3H), 2.85-2.92 (m, 1H), 2.80 (m, 1H), 2.53-2.62 (m , 1H).
Figure PCTCN2019093578-appb-000029
MS m/z 569[M+H]；1HNMR(MeOH-d4，400MHz)δ8.01(d，J＝3.14Hz，1H)，7.70-7.95(m，1H)，7.50(m，1H)，7.28(m z，1H)，7.10(m，1H)，6.02-6.27(m，1H)，4.35-4.61(m，1H)，4.21-4.35(m，1H)，4.11(m，1H)，3.72-3.97(m，2H)，3.67-3.71(m，1H)，3.35-3.46(m，1H)，2.95-3.17(m，1H)，2.10(m，1H)，1.07(m，6H).
Figure PCTCN2019093578-appb-000029
MS m / z 569 [M + H]; 1H NMR (MeOH-d4, 400 MHz) δ 8.01 (d, J = 3.14 Hz, 1H), 7.70-7.95 (m, 1H), 7.50 (m, 1H), 7.28 (mz, 1H), 7.10 (m, 1H), 6.02-6.27 (m, 1H), 4.35-4.61 (m, 1H), 4.21-4.35 (m, 1H), 4.11 (m, 1H), 3.72-3.97 (m, 2H), 3.67-3.71 (m, 1H), 3.35-3.46 (m, 1H), 2.95-3.17 (m, 1H), 2.10 (m, 1H), 1.07 (m, 6H).
Figure PCTCN2019093578-appb-000030
MS m/z 462[M+H].
Figure PCTCN2019093578-appb-000030
MS m / z 462 [M + H].
Figure PCTCN2019093578-appb-000031
MS m/z 526[M+H]；1HNMR(MeOH-d4，400MHz)δ8.20(s，2H)，7.63-7.60(m，1H)，7.38-7.35(m，1H)，7.22-7.18(m，1H)，6.29(s，1H)，4.57(d，J＝16Hz，1H)，4.13-4.08(m，2H)，3.70-3.67(m，1H)，3.33-3.28(m，1H)，2.92-2.82(m，1H)，2.63-2.56(m，1H).
Figure PCTCN2019093578-appb-000031
MS m / z 526 [M + H]; 1HNMR (MeOH-d4, 400MHz) δ 8.20 (s, 2H), 7.63-7.60 (m, 1H), 7.38-7.35 (m, 1H), 7.22-7.18 ( m, 1H), 6.29 (s, 1H), 4.57 (d, J = 16Hz, 1H), 4.13-4.08 (m, 2H), 3.70-3.67 (m, 1H), 3.33-3.28 (m, 1H), 2.92-2.82 (m, 1H), 2.63-2.56 (m, 1H).
实施例2Example 2
Figure PCTCN2019093578-appb-000032
Figure PCTCN2019093578-appb-000032
化合物 18： Compound 18 :
向500mL圆底烧瓶中加入2-氯-4-氟苯甲醛(9.00g，56.761mmol，1.0当量)，1，3-噻唑-2-甲脒盐酸盐(9.29g，56.778mmol，1.00当量)，化合物 17(8.98g，56.761mmol，1.0当量)，KOAc(16.7g，170.283mmol，3.00当量)和甲醇(300mL)。将所得溶液在80℃下在油浴中搅拌过夜，用水浴将反应混合物冷却至20℃，然后通过加入500mL水/冰淬灭反应。用3×500mL乙酸乙酯萃取所得溶液，有机相用无水硫酸钠干燥。乙酸乙酯液浓缩后将残余物用硅胶柱层析分离，(乙酸乙酯/石油醚0-20％)，得到9.0g化合物 18(33.04％)黄色固体。MS m/z 408[M+H]。 To a 500 mL round bottom flask was added 2-chloro-4-fluorobenzaldehyde (9.00 g, 56.761 mmol, 1.0 equivalent), 1,3-thiazole-2-formamidine hydrochloride (9.29 g, 56.778 mmol, 1.00 equivalent) , Compound 17 (8.98 g, 56.761 mmol, 1.0 equivalent), KOAc (16.7 g, 170.283 mmol, 3.00 equivalent), and methanol (300 mL). The resulting solution was stirred in an oil bath at 80 ° C overnight, the reaction mixture was cooled to 20 ° C with a water bath, and then the reaction was quenched by adding 500 mL of water / ice. The resulting solution was extracted with 3 × 500 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After the ethyl acetate solution was concentrated, the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether 0-20%) to obtain 9.0 g of Compound 18 (33.04%) as a yellow solid. MS m / z 408 [M + H].
化合物 19： Compound 19 :
向500mL圆底烧瓶中加入化合物 18(9.00g，22.065mmol，1.00当量)，HCl的二氧六环溶液(100mL，4N)。将所得溶液在室温下搅拌5小时。浓缩所得混合物用乙醚洗涤，得到5.0g(64.42％)化合物 19黄色固体。MS m/z 352[M+H]。 To a 500 mL round bottom flask was added compound 18 (9.00 g, 22.065 mmol, 1.00 equivalent), a solution of HCl in dioxane (100 mL, 4N). The resulting solution was stirred at room temperature for 5 hours. The resulting mixture was concentrated and washed with diethyl ether to give 5.0 g (64.42%) of Compound 19 as a yellow solid. MS m / z 352 [M + H].
化合物 20： Compound 20 :
向1000mL圆底烧瓶中加入化合物 19(5.00g，14.213mmol，1.00当量)、Na 2CO 3(3.01g，28.426mmol，2.00当量)、NaI(10.66g，71.065mmol，5.0当量)，甲醇、乙腈和水各150.00毫升。然后在室温下搅拌下分批加入Oxone(4.37g，7.106mmol，0.50当量)。将所得溶液在室温下搅拌30分钟，然后加入200mLNaHSO3水溶液淬灭反应。3×200mL乙酸乙酯萃取所得溶液，用无水硫酸钠干燥并浓缩。残余物用硅胶柱纯化，得到3.5g化合物 20(56.78％)黄色油状物。MS m/z 434[M+H]。 To a 1000 mL round bottom flask were added compound 19 (5.00 g, 14.213 mmol, 1.00 equivalent), Na 2 CO 3 (3.01 g, 28.426 mmol, 2.00 equivalent), NaI (10.66 g, 71.065 mmol, 5.0 equivalent), methanol, acetonitrile And 150.00 ml each. Oxone (4.37 g, 7.106 mmol, 0.50 equivalent) was then added in portions with stirring at room temperature. The resulting solution was stirred at room temperature for 30 minutes, and then 200 mL of NaHSO3 aqueous solution was added to quench the reaction. The resulting solution was extracted with 3 × 200 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by a silica gel column to obtain 3.5 g of Compound 20 (56.78%) as a yellow oil. MS m / z 434 [M + H].
化合物 21： Compound 21 :
向500mL圆底烧瓶中加入化合物 20(3.50g，8.071mmol，1.0当量)、DCM(100.00mL)、Et 3N (2450.01g，24.212mmol，3.0当量)、DMAP(98.60g，0.807mmol，0.1当量)，然后在室温搅拌下滴加Boc 2O(1761.39g，8.071mmol，1.0当量)，反应液在室温下搅拌过夜。加入200mL水淬灭反应，3×200mL乙酸乙酯萃取所得溶液，有机相合并后干燥、浓缩。所得残余物用硅胶柱层析分离(乙酸乙酯/石油醚0-50％)，得到4.0g(92.85％)化合物 21黄色固体。MS m/z 534[M+H]。 To a 500 mL round bottom flask was added compound 20 (3.50 g, 8.071 mmol, 1.0 equivalent), DCM (100.00 mL), Et 3 N (2450.01 g, 24.212 mmol, 3.0 equivalent), DMAP (98.60 g, 0.807 mmol, 0.1 equivalent) ), Then Boc 2 O (1761.39 g, 8.071 mmol, 1.0 equivalent) was added dropwise with stirring at room temperature, and the reaction solution was stirred at room temperature overnight. 200 mL of water was added to quench the reaction, and the resulting solution was extracted with 3 × 200 mL of ethyl acetate. The organic phases were combined, dried and concentrated. The obtained residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether 0-50%) to obtain 4.0 g (92.85%) of compound 21 as a yellow solid. MS m / z 534 [M + H].
化合物 22： Compound 22 :
在惰性氮气吹扫过的250mL圆底烧瓶中加入化合物 21(4.00g，7.494mmol，1.0当量)、丙烯酸甲酯(2.26g，26.228mmol，3.5当量)、N-环己基-N-甲基环己胺(1.76g，9.009mmol，1.2当量)、Pd 2(dba) 3(686.45mg，0.749mmol，0.1当量)和PBu t 3.HBF 4(0.44g，1.517mmol，0.2当量)，将所得溶液在95℃下搅拌过夜。加水100mL淬灭反应，再用3×100mL乙酸乙酯萃取，合并的有机相干燥、浓缩，残余物用硅胶柱层析分离(乙酸乙酯/石油醚0-50％)，得到2.6g(70.53％)化合物 22黄色固体。MS m/z 492[M+H]。 In a 250 mL round bottom flask purged with inert nitrogen, add compound 21 (4.00 g, 7.494 mmol, 1.0 equivalent), methyl acrylate (2.26 g, 26.228 mmol, 3.5 equivalent), and N-cyclohexyl-N-methyl ring. Hexylamine (1.76 g, 9.09 mmol, 1.2 equivalents), Pd 2 (dba) 3 (686.45 mg, 0.749 mmol, 0.1 equivalent), and PBu t 3 .HBF 4 (0.44 g, 1.517 mmol, 0.2 equivalent), the resulting solution Stir overnight at 95 ° C. The reaction was quenched by adding 100 mL of water, and then extracted with 3 × 100 mL of ethyl acetate. The combined organic phases were dried and concentrated, and the residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether 0-50%) to obtain 2.6 g (70.53 %) Compound 22 as a yellow solid. MS m / z 492 [M + H].
化合物 23： Compound 23 :
向250mL圆底烧瓶中加入化合物 22(2.10g，4.269mmol，1.00当量)、NBS(911.70mg，5.122mmol，1.20当量)、AIBN(140.19mg，0.854mmol，0.20当量)和氯苯(100.00mL)，溶液在85℃下在油浴中搅拌2小时，然后加入200mL水淬灭反应。用3×200mL乙酸乙酯萃取所得溶液，有机相合并后干燥、浓缩，将残余物用硅胶柱层析分离(乙酸乙酯/石油醚0-30％)，得到380mg(15.59％)溴化物 23黄色固体。MS m/z 570[M+H]。 To a 250 mL round bottom flask were added compound 22 (2.10 g, 4.269 mmol, 1.00 equivalent), NBS (911.70 mg, 5.122 mmol, 1.20 equivalent), AIBN (140.19 mg, 0.854 mmol, 0.20 equivalent), and chlorobenzene (100.00 mL) The solution was stirred in an oil bath at 85 ° C for 2 hours, and then 200 mL of water was added to quench the reaction. The resulting solution was extracted with 3 × 200 mL of ethyl acetate, the organic phases were combined, dried, and concentrated. The residue was separated by silica gel column chromatography (ethyl acetate / petroleum ether 0-30%) to obtain 380 mg (15.59%) of bromide 23 Yellow solid. MS m / z 570 [M + H].
化合物 24： Compound 24 :
向100mL圆底烧瓶中加入(3S)-吗啉-3-羧酸盐酸盐(278.90mg，1.664mmol，2.50当量)、溴化物 23(380.00mg，0.666mmol，1.00当量)、DIPEA(430.16mg，3.328mmol，5.00当量)和乙腈(50mL)，反应液在室温搅拌下过夜。将反应用水(100mL)淬灭后用EtOAc(3×100mL)萃取，有机相合并后干燥、浓缩，然后用Flash-Prep-HPLC纯化粗产物，色谱条件如下(IntelFlash-1)：C18硅胶柱；流动相A：CH 3CN、流动相B：含0.05％TFA的纯水。40分钟内乙腈含量由10％增加至80％；UV探测器波长254nm。分离得到产物 24 330mg(79.82％)，为黄色固体。MS m/z 621[M+H]。 To a 100 mL round bottom flask was added (3S) -morpholine-3-carboxylic acid hydrochloride (278.90 mg, 1.664 mmol, 2.50 equivalent), bromide 23 (380.00 mg, 0.666 mmol, 1.00 equivalent), DIPEA (430.16 mg , 3.328 mmol, 5.00 equiv) and acetonitrile (50 mL), and the reaction was stirred at room temperature overnight. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 × 100 mL). The organic phases were combined, dried, concentrated, and then the crude product was purified by Flash-Prep-HPLC. The chromatographic conditions were as follows (IntelFlash-1): C18 silica gel column; Mobile phase A: CH 3 CN, mobile phase B: pure water containing 0.05% TFA. The acetonitrile content increased from 10% to 80% in 40 minutes; the UV detector wavelength was 254nm. 24 330 mg (79.82%) of the product was isolated as a yellow solid. MS m / z 621 [M + H].
化合物 25： Compound 25 :
将化合物 24(330.00mg，0.531mmol，1.00当量)加入到4NHCl的二氧六环(2.66mL，10.62mmol，20当量)试剂中室温下搅拌过夜。减压旋干溶剂，残余物通过制备级HPLC纯化，色谱条件如下：固定相，C18硅胶柱；流动相A：MeOH，流动相B：含0.05％HCl的水溶液，10分钟内流动相A由10％升至50％梯度；UV检测器波长254nm。得到化合物 25(141.7mg，49.9％产率)，为红色固体。1H NMR(400MHz，DMSO-d6)δ(ppm)：8.12-8.04(m，2H)，7.60-7.70(m，1H)，7.50-7.55(m，2H)，7.18-7.27(m，1H)，5.99(s，1H)，5.55-5.60(m，1H)，4.46-4.58(m，1H)，4.28-4.44(m，2H)，4.10-4.15(m，1H)，4.00-4.10(m，1H)，3.81-3.97(m，2H)，3.62(s，3H)，3.50-3.55(m，1H)，3.20-3.30(m，1H)；MS(ES， m/z)：[M+H]+＝521. Compound 24 (330.00 mg, 0.531 mmol, 1.00 equiv.) Was added to 4N HCl in dioxane (2.66 mL, 10.62 mmol, 20 equiv.) And stirred at room temperature overnight. The solvent was spin-dried under reduced pressure, and the residue was purified by preparative HPLC. The chromatographic conditions were as follows: stationary phase, C18 silica gel column; mobile phase A: MeOH, mobile phase B: aqueous solution containing 0.05% HCl. % To 50% gradient; UV detector wavelength 254nm. Compound 25 (141.7 mg, 49.9% yield) was obtained as a red solid. 1H NMR (400MHz, DMSO-d6) δ (ppm): 8.12-8.04 (m, 2H), 7.60-7.70 (m, 1H), 7.50-7.55 (m, 2H), 7.18-7.27 (m, 1H), 5.99 (s, 1H), 5.55-5.60 (m, 1H), 4.46-4.58 (m, 1H), 4.28-4.44 (m, 2H), 4.10-4.15 (m, 1H), 4.00-4.10 (m, 1H) ), 3.81-3.97 (m, 2H), 3.62 (s, 3H), 3.50-3.55 (m, 1H), 3.20-3.30 (m, 1H); MS (ES, m / z): [M + H] + = 521.
采用类似合成方法，还制备了化合物 26和 27： Using similar synthetic methods, compounds 26 and 27 were also prepared:
Figure PCTCN2019093578-appb-000033
1H NMR(400MHz，MeOH-d4)δ7.97(m，1H)，7.79(m，1H)，7.66-7.45(m，2H)，7.42(m，1H)，7.14-7.10(m，1H)，6.17(s，1H)，5.55-5.60(m，1H)，4.55-4.44(m，1H)，4.38-4.23(m，1H)，4.17-4.01(m，4H)，3.95-3.84(m，2H)，3.70(d，J＝17.6Hz，1H)，3.53-3.36(m，1H)，2.84-2.73(m，1H)，1.15(td，J＝7.1，2.4Hz，3H).；MS(ES，m/z)：[M+H] +565，567。
Figure PCTCN2019093578-appb-000033
1H NMR (400 MHz, MeOH-d4) δ 7.97 (m, 1H), 7.79 (m, 1H), 7.66-7.45 (m, 2H), 7.42 (m, 1H), 7.14-7.10 (m, 1H), 6.17 (s, 1H), 5.55-5.60 (m, 1H), 4.55-4.44 (m, 1H), 4.38-4.23 (m, 1H), 4.17-4.01 (m, 4H), 3.95-3.84 (m, 2H) ), 3.70 (d, J = 17.6 Hz, 1H), 3.53-3.36 (m, 1H), 2.84-2.73 (m, 1H), 1.15 (td, J = 7.1, 2.4Hz, 3H). MS (ES , M / z): [M + H] + 565,567.
Figure PCTCN2019093578-appb-000034
1H NMR(400MHz，DMSO-d6)δ：8.12-8.04(m，2H)，7.60-7.70(m，1H)，7.50-7.55(m，2H)，7.18-7.27(m，1H)，5.99(s，1H)，5.55-5.60(m，1H)，4.83-4.76(m，2H)，2.49(s，3H)，1.32(d，3H)，1.04-1.02(m，6H)；MS(ES，m/z)[M+H] +549.1。
Figure PCTCN2019093578-appb-000034
1H NMR (400MHz, DMSO-d6) δ: 8.12-8.04 (m, 2H), 7.60-7.70 (m, 1H), 7.50-7.55 (m, 2H), 7.18-7.27 (m, 1H), 5.99 (s , 1H), 5.55-5.60 (m, 1H), 4.83-4.76 (m, 2H), 2.49 (s, 3H), 1.32 (d, 3H), 1.04-1.02 (m, 6H); MS (ES, m / z) [M + H] + 549.1.
实施例3Example 3
Figure PCTCN2019093578-appb-000035
Figure PCTCN2019093578-appb-000035
化合物 28： Compound 28 :
室温下，向化合物 21(8.0g，14.987mmol，1.00当量)的CCl 4(125mL)溶液中加入AIBN(0.49g，2.984mmol，0.20当量)和NBS(5.335g，29.974mmol，2.00当量)，反应物在45℃下搅拌过夜。冷至室温后加水(100mL)淬灭反应，并用EtOAc(3×100mL)萃取，有机层合并后用Na 2SO 4干燥、过滤并浓缩，残余物用硅胶柱层析纯化(0％至20％乙酸乙酯/石油醚)，得到产物 28(6.6g，77.85％ 产率)黄色固体。 To a solution of compound 21 (8.0 g, 14.987 mmol, 1.00 equiv.) In CCl 4 (125 mL) at room temperature, AIBN (0.49 g, 2.984 mmol, 0.20 equiv.) And NBS (5.335 g, 29.974 mmol, 2.00 equiv.) Were added and reacted. The contents were stirred at 45 ° C overnight. After cooling to room temperature, water (100 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (3 × 100 mL). The organic layers were combined, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by silica gel column chromatography (0% to 20%). Ethyl acetate / petroleum ether) to give product 28 (6.6 g, 77.85% yield) as a yellow solid.
化合物 29： Compound 29 :
将化合物 28(6.60g，11.667mmol，1.00当量)溶于乙腈(90mL)，室温下慢慢加入(S)-吗啉-3-羧酸甲酯盐酸盐(4.24g，23.335mmol，2.00当量)和DIPEA(10.16mL，78.621mmol，5.00当量)，反应物在45℃下搅拌过夜。冷至室温后加水(50mL)淬灭反应，再用EA(3×80mL)萃取。合并有机层、干燥、过滤并浓缩，粗产物用硅胶柱层析(0％至50％EA/PE)纯化，得到产物 29(5.3g，72.11％产率)黄色固体。 Compound 28 (6.60 g, 11.667 mmol, 1.00 equivalent) was dissolved in acetonitrile (90 mL), and (S) -morpholine-3-carboxylic acid methyl ester hydrochloride (4.24 g, 23.335 mmol, 2.00 equivalent) was slowly added at room temperature. ) And DIPEA (10.16 mL, 78.621 mmol, 5.00 equivalents), the reaction was stirred at 45 ° C. overnight. After cooling to room temperature, water (50 mL) was added to quench the reaction, followed by extraction with EA (3 × 80 mL). The organic layers were combined, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0% to 50% EA / PE) to give the product 29 (5.3 g, 72.11% yield) as a yellow solid.
化合物 30： Compound 30 :
将化合物 29(5.30g，8.414mmol，1.00当量)、丙烯酸叔丁酯(3.24g，25.241mmol，3.00当量)、Pd 2(dba) 3(0.77g，0.841mmol，0.10当量)和P( tBu) 3.HBF 4(0.49g，1.683mmol，0.20当量)的二氧六环(86.00mL)溶液在氮气氛下120℃搅拌过夜。将混合物冷至室温后加水(50mL)淬灭反应，EA(3×80mL)萃取。有机层合并后干燥、过滤并浓缩。残余物用硅胶柱层析纯化(0％至30％EA/PE)，得到产物 30(4.5g，78.98％)黄色固体。 Compound 29 (5.30 g, 8.414 mmol, 1.00 equiv), tert-butyl acrylate (3.24 g, 25.241 mmol, 3.00 equiv), Pd 2 (dba) 3 (0.77 g, 0.841 mmol, 0.10 equiv), and P ( t Bu 3. ) A solution of HBF 4 (0.49 g, 1.683 mmol, 0.20 equivalent) in dioxane (86.00 mL) was stirred at 120 ° C. overnight under a nitrogen atmosphere. After the mixture was cooled to room temperature, water (50 mL) was added to quench the reaction, and EA (3 × 80 mL) was extracted. The organic layers were combined, dried, filtered and concentrated. The residue was purified by silica gel column chromatography (0% to 30% EA / PE) to give the product 30 (4.5 g, 78.98%) as a yellow solid.
化合物 31： Compound 31 :
室温下向化合物30(5.30g，7.826mmol，1.00当量)的二氧六环(50mL)溶液中加入4N HCl的二氧六环溶液(156.53mL，626.120mmol，80.00当量)，搅拌3小时后减压浓缩即得到产物 31(3.3g，80.94％)黄色固体，可直接用于下一步反应。 To a solution of compound 30 (5.30 g, 7.826 mmol, 1.00 equivalent) in dioxane (50 mL) at room temperature was added a 4N HCl solution of dioxane (156.53 mL, 626.120 mmol, 80.00 equivalent), and it was reduced after stirring for 3 hours. The product 31 (3.3 g, 80.94%) was obtained by pressure concentration as a yellow solid, which was used directly in the next reaction.
化合物 32： Compound 3 2:
将化合物31(3.30g，6.334mmol，1.00当量)溶于MeOH(150.00mL)和ACN(150.00mL)的混合溶剂，在室温下慢慢滴加Na2CO3(1.34g，12.669mmol，2.00当量)和NaBr(3.26g，31.672mmol，5.00当量)的水(150.00mL)溶液，然后在20分钟内向上述混合物中滴加Oxone(532.63mg，3.167mmol，0.50当量)的水(20.00mL)溶液，反应物搅拌1小时后，加盐水和亚硫酸钠淬灭，反应物用EA(3×150mL)萃取。有机层合并后干燥、过滤并浓缩，残余物用硅胶柱层析纯化(0％至40％EA/PE)，产物 32(2.0g，56.80％)黄色固体。 Compound 31 (3.30 g, 6.334 mmol, 1.00 equivalent) was dissolved in a mixed solvent of MeOH (150.00 mL) and ACN (150.00 mL), and Na2CO3 (1.34 g, 12.669 mmol, 2.00 equivalent) and NaBr were slowly added dropwise at room temperature. (3.26g, 31.672mmol, 5.00 equivalents) in water (150.00mL), and then a solution of Oxone (532.63mg, 3.167mmol, 0.50 equivalents) in water (20.00mL) was added dropwise to the above mixture over 20 minutes, and the reaction was stirred After 1 hour, brine and sodium sulfite were added to quench, and the reaction was extracted with EA (3 x 150 mL). The organic layers were combined, dried, filtered, and concentrated. The residue was purified by silica gel column chromatography (0% to 40% EA / PE), product 32 (2.0 g, 56.80%) as a yellow solid.
化合物 33： Compound 33 :
将化合物 32(2.00g，3.598mmol，1.00当量)溶于THF(8.00mL)-H 2O(8.00mL)-MeOH(8.00mL)混合溶剂中，室温下分批加入LiOH(258.50mg，10.794mmol，3.00当量)。反应液搅拌过夜后，加入EA(10mL)洗涤所得混合物。然后用1N HCl将水相酸化至pH＝5～6，最后用EA(3×50mL)萃取混合物。有机层后干燥、过滤并浓缩，粗产物用制备型HPLC纯化，色谱条件如下，固定相：C18柱；流动相A：水(含10mM HCl)，流动相B：ACN；流速：60mL/min；梯度：7分钟内流动相B由38％升至56％。冷冻干燥后，得到产物 33(711.2mg，收率35.06％)黄色固体。 1HNMR(400MHz， CD 3OD)δ8.20(s，2H)，7.62-7.70(m，1H)，7.36-7.42(m，1H)，7.18-7.26(m，2H)，6.57(d，J＝13.6Hz，1H)，6.30(d，J＝4.8Hz，1H)，4.12-4.50(m，4H)，3.95-4.05(m，2H)，3.82-3.94(m，1H)，3.56-3.68(m，1H)，3.12-3.26(m，1H)；MS(ES，m/z)：[M+H，M+H+2] +＝540.95，542.9 Compound 32 (2.00 g, 3.598 mmol, 1.00 equivalent) was dissolved in a mixed solvent of THF (8.00 mL) -H 2 O (8.00 mL) -MeOH (8.00 mL), and LiOH (258.50 mg, 10.794 mmol) was added in portions at room temperature. , 3.00 equivalents). After the reaction solution was stirred overnight, EA (10 mL) was added to wash the resulting mixture. The aqueous phase was then acidified with 1N HCl to pH = 5-6, and the mixture was finally extracted with EA (3 × 50 mL). The organic layer was dried, filtered and concentrated. The crude product was purified by preparative HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl); mobile phase B: ACN; flow rate: 60 mL / min; Gradient: Mobile phase B rose from 38% to 56% in 7 minutes. After lyophilization, the product 33 (711.2 mg, yield 35.06%) was obtained as a yellow solid. 1 HNMR (400 MHz, CD 3 OD) δ 8.20 (s, 2H), 7.62-7.70 (m, 1H), 7.36-7.42 (m, 1H), 7.18-7.26 (m, 2H), 6.57 (d, J = 13.6Hz, 1H), 6.30 (d, J = 4.8Hz, 1H), 4.12-4.50 (m, 4H), 3.95-4.05 (m, 2H), 3.82-3.94 (m, 1H), 3.56-3.68 ( m, 1H), 3.12-3.26 (m, 1H); MS (ES, m / z): [M + H, M + H + 2] + = 540.95, 542.9
采用上述合成路线，同样制备了化合物 34a、 34b、 34c和 34d： Using the above synthetic route, compounds 34a , 34b , 34c, and 34d were also prepared:
Figure PCTCN2019093578-appb-000036
1HNMR(400MHz，CD 3OD)δ7.96-7.98(m，1H)，7.78-7.80(m，1H)，7.66-7.45(m，2H)，7.42(m，1H)，7.14-7.10(m，1H)，6.17(s，1H)，4.10-4.49(m，4H)，3.95-4.05(m，2H)，3.82-3.94(m，1H)，3.56-3.68(m，1H)，3.12-3.26(m，1H)。
Figure PCTCN2019093578-appb-000036
1 HNMR (400MHz, CD 3 OD) δ 7.96-7.98 (m, 1H), 7.78-7.80 (m, 1H), 7.66-7.45 (m, 2H), 7.42 (m, 1H), 7.14-7.10 (m , 1H), 6.17 (s, 1H), 4.10-4.49 (m, 4H), 3.95-4.05 (m, 2H), 3.82-3.94 (m, 1H), 3.56-3.68 (m, 1H), 3.12-3.26 (m, 1H).
Figure PCTCN2019093578-appb-000037
1HNMR(400MHz，CD 3OD)δ：8.20(s，1H)，8.16(s，1H)，7.62-7.70(m，1H)，7.18-7.42(m，3H)，6.55(m，1H)，6.30(d，J＝4.8Hz，1H)，4.16-4.03(m，2H)，3.58(m，1H)，3.45-3.53(m，1H)，2.75-2.80(m，2H)，2.35(m，1H)，2.02-2.30(m，3H)，1.57-1.68(m，2H)，1.09(m，3H)；MS(ES，m/z)：[M+H] +569。
Figure PCTCN2019093578-appb-000037
1 HNMR (400 MHz, CD 3 OD) δ: 8.20 (s, 1H), 8.16 (s, 1H), 7.62-7.70 (m, 1H), 7.18-7.42 (m, 3H), 6.55 (m, 1H), 6.30 (d, J = 4.8 Hz, 1H), 4.16-4.03 (m, 2H), 3.58 (m, 1H), 3.45-3.53 (m, 1H), 2.75-2.80 (m, 2H), 2.35 (m, 1H), 2.02-2.30 (m, 3H), 1.57-1.68 (m, 2H), 1.09 (m, 3H); MS (ES, m / z): [M + H] + 569.
Figure PCTCN2019093578-appb-000038
1HNMR(400MHz，CD 3OD)δ：8.10(s，1H)，8.01(S，1H)，7.60-7.70(m，1H)，7.36-7.42(m，1H)，7.00-7.26(m，2H)，6.54(m，1H)，6.10(d，J＝4.8Hz，1H)，4.33(m，1H)，3.50-3.54(m，1H)，3.00(s，1H)，2.64-2.90(m，3H)，2.46-2.50(m，2H)，2.35-2.42(m，1H)，1.13-1.68(m，4H)；MS(ES，m/z)：[M+H] +569。
Figure PCTCN2019093578-appb-000038
1 HNMR (400 MHz, CD 3 OD) δ: 8.10 (s, 1H), 8.01 (S, 1H), 7.60-7.70 (m, 1H), 7.36-7.42 (m, 1H), 7.00-7.26 (m, 2H ), 6.54 (m, 1H), 6.10 (d, J = 4.8Hz, 1H), 4.33 (m, 1H), 3.50-3.54 (m, 1H), 3.00 (s, 1H), 2.64-2.90 (m, 3H), 2.46-2.50 (m, 2H), 2.35-2.42 (m, 1H), 1.13-1.68 (m, 4H); MS (ES, m / z): [M + H] + 569.
Figure PCTCN2019093578-appb-000039
1HNMR(400MHz，CD 3OD)δ8.21(s，1H)，8.10，7.68-7.78(m，1H)，7.38-7.42(m，1H)，7.18-7.26(m，2H)，6.53(d，1H)，6.34(d，1H)，4.12-4.50(m，4H)，3.95-4.05(m，2H)，3.82-3.94(m，1H)，3.56-3.68(m，1H)，3.12-3.26(m，1H)；MS(ES，m/z)：[M+H] +497。
Figure PCTCN2019093578-appb-000039
1 HNMR (400MHz, CD 3 OD) δ8.21 (s, 1H), 8.10, 7.68-7.78 (m, 1H), 7.38-7.42 (m, 1H), 7.18-7.26 (m, 2H), 6.53 (d , 1H), 6.34 (d, 1H), 4.12-4.50 (m, 4H), 3.95-4.05 (m, 2H), 3.82-3.94 (m, 1H), 3.56-3.68 (m, 1H), 3.12-3.26 (m, 1H); MS (ES, m / z): [M + H] + 497.
实施例4Example 4
Figure PCTCN2019093578-appb-000040
Figure PCTCN2019093578-appb-000040
化合物 35： Compound 35 :
取化合物 19(1.5g，4.27mmol，1eq)加入到二氯甲烷30mL中，升温至回流，分批加入NBS(0.69g，3.84mmol，1eq)，搅拌反应1h后再分批加入NBS(0.77g，4.27mmol，1eq)，TLC检测反应结束后，加水(40mL)淬灭反应，DCM(30mLx3)萃取后干燥、浓缩，粗产物 35直接用于下一步反应。 Compound 19 (1.5g, 4.27mmol, 1eq) was added to 30mL of dichloromethane, heated to reflux, and NBS (0.69g, 3.84mmol, 1eq) was added in portions. After stirring for 1h, NBS (0.77g) was added in portions. (4.27 mmol, 1 eq). After the reaction was detected by TLC, water (40 mL) was added to quench the reaction. After extraction with DCM (30 mL x 3), it was dried and concentrated. The crude product 35 was directly used in the next reaction.
化合物 36： Compound 36 :
将化合物 35(2.0g，4.34mmol，1.00当量)溶于乙腈(50mL)，室温下慢慢加入(S)-吗啉-3-羧酸甲酯盐酸盐(1.58g，8.73mmol，2.00当量)和DIPEA(2.8mL，21.7mmol，5.00当量)，反应物在45℃下搅拌过夜。冷至室温后加水(50mL)淬灭反应，再用乙酸乙酯(3×80mL)萃取。合并有机层、干燥、过滤并浓缩，粗产物用硅胶柱层析(0％至50％EA/PE)纯化，得到产物 36(1.1g，两步总产率48.11％)黄色固体。MS(ES，m/z)：[M+H] +＝529.8，531.8。 Compound 35 (2.0 g, 4.34 mmol, 1.00 equivalent) was dissolved in acetonitrile (50 mL), and (S) -morpholine-3-carboxylic acid methyl ester hydrochloride (1.58 g, 8.73 mmol, 2.00 equivalent) was slowly added at room temperature. ) And DIPEA (2.8 mL, 21.7 mmol, 5.00 equiv), the reaction was stirred at 45 ° C. overnight. After cooling to room temperature, water (50 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (3 × 80 mL). The organic layers were combined, dried, filtered, and concentrated. The crude product was purified by silica gel column chromatography (0% to 50% EA / PE) to give the product 36 (1.1 g, two-step total yield 48.11%) as a yellow solid. MS (ES, m / z): [M + H] + = 529.8, 531.8.
化合物 37： Compound 37 :
将化合物 36(212mg，0.4mmol，1.00当量)溶于THF(3.00mL)-H 2O(3.00mL)-MeOH(3.00mL)混合溶剂中，室温下分批加入LiOH(30mg，0.8mmol，2.00当量)。反应液搅拌过夜后，加入EA(10mL)洗涤所得混合物。然后用1N HCl将水相酸化至pH＝5～6，最后用EA(3×50mL)萃取混合物。有机层合并后干燥、过滤并浓缩，粗产物用制备型HPLC纯化，色谱条件如下，固定相：C18柱；流动相A：水(含10mM HCl)，流动相B：ACN；流速：60mL/min；梯度：10分钟内流动相B由30％升至60％。冷冻干燥后，得到产物 37(92mg，收率45％)黄色固体。 1HNMR(400MHz，DMSO)δ：12.87(s，1H)，8.96(s，1H)，7.99(s，1H)，7.92(s，1H)，7.43-7.52(m，2H)，7.24-7.28(m，1H)，5.86(s，1 H)，3.49-3.87(m，7H)，3.02-3.06(m，1H)，2.48-2.50(m，1H)；MS(ES，m/z)：[M+H] +＝516.98，518.9。 Compound 36 (212 mg, 0.4 mmol, 1.00 equiv) was dissolved in a mixed solvent of THF (3.00 mL) -H 2 O (3.00 mL) -MeOH (3.00 mL), and LiOH (30 mg, 0.8 mmol, 2.00) was added in portions at room temperature. equivalent). After the reaction solution was stirred overnight, EA (10 mL) was added to wash the resulting mixture. The aqueous phase was then acidified with 1N HCl to pH = 5-6, and the mixture was finally extracted with EA (3 × 50 mL). The organic layers were combined, dried, filtered and concentrated. The crude product was purified by preparative HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl); mobile phase B: ACN; flow rate: 60 mL / min ; Gradient: mobile phase B increased from 30% to 60% in 10 minutes. After lyophilization, the product 37 (92 mg, yield 45%) was obtained as a yellow solid. 1 HNMR (400 MHz, DMSO) δ: 12.87 (s, 1H), 8.96 (s, 1H), 7.99 (s, 1H), 7.92 (s, 1H), 7.43-7.52 (m, 2H), 7.24-7.28 ( m, 1H), 5.86 (s, 1 H), 3.49-3.87 (m, 7H), 3.02-3.06 (m, 1H), 2.48-2.50 (m, 1H); MS (ES, m / z): [ M + H] + = 516.98, 518.9.
实施例5Example 5
Figure PCTCN2019093578-appb-000041
Figure PCTCN2019093578-appb-000041
化合物 38 Compound 38
在-78°下，向化合物 20(430mg，1mmol)的20mL四氢呋喃溶液中缓慢滴加0.44mL正丁基锂正己烷溶液(2.5M，1.1mmol)，保持低温搅拌反应2h，加适量饱和氯化铵溶液淬灭反应，再使用乙醚进行萃取，水洗三次后再以无水硫酸钠干燥，过滤浓缩后得黄白色固体300mg，即化合物 38，收率98％。 At -78 °, slowly add 0.44 mL of n-butyllithium-n-hexane solution (2.5M, 1.1 mmol) to a 20 mL tetrahydrofuran solution of compound 20 (430 mg, 1 mmol), keep the reaction stirred at low temperature for 2 h, and add an appropriate amount of saturated chlorination The ammonium solution was used to quench the reaction, and then extracted with ether, washed three times with water, and then dried over anhydrous sodium sulfate. After filtration and concentration, 300 mg of a yellow-white solid was obtained, which is Compound 38 , with a yield of 98%.
化合物 39 Compound 39
化合物 38(306mg，1.0mmol)溶于CCl 4(5mL)中，慢慢加入NBS(200mg，1.1mmol)，反应液在室温下搅拌3小时后，真空除去溶剂并将残余物通过柱色谱法纯化，得到化合物 39(308mg，80％)。MS m/z[M+H]388，390。 Compound 38 (306 mg, 1.0 mmol) was dissolved in CCl 4 (5 mL), and NBS (200 mg, 1.1 mmol) was slowly added. After the reaction solution was stirred at room temperature for 3 hours, the solvent was removed in vacuo and the residue was purified by column chromatography. To give Compound 39 (308 mg, 80%). MS m / z [M + H] 388,390.
化合物 40 Compound 40
搅拌下向化合物 39(40mg，0.11mmol)和(3S)-吗啉-3-甲酸盐酸盐(29mg，0.17mmol)的二氯甲烷(5mL)溶液中滴加二异丙基乙基胺(80μL，0.45mmol)，反应混合物在室温下搅拌直到原料消失。反应物减压蒸除溶剂，残余物通过制备型HPLC纯化，得到淡黄色固体产物 40(20mg，40％)。MS m/z 437[M+H]。 To a solution of compound 39 (40 mg, 0.11 mmol) and (3S) -morpholine-3-formate (29 mg, 0.17 mmol) in dichloromethane (5 mL) with stirring was added diisopropylethylamine dropwise. (80 μL, 0.45 mmol), the reaction mixture was stirred at room temperature until the starting material disappeared. The reaction was distilled off the solvent under reduced pressure, and the residue was purified by prep-HPLC to obtain product 40 (20 mg, 40%) as a pale yellow solid. MS m / z 437 [M + H].
实施例6Example 6
Figure PCTCN2019093578-appb-000042
Figure PCTCN2019093578-appb-000042
Figure PCTCN2019093578-appb-000043
Figure PCTCN2019093578-appb-000043
化合物 42 Compound 42
反应瓶中加入化合物 41(10.0g，22.63mmol，1eq)和二氯甲烷(100mL)，搅拌溶解后分批加入NBS(4.03g，22.63mmol，1eq)，10min加完，加完后室温搅拌反应30min，TLC检测有产物生成，剩余痕量原料。反应液减压蒸去溶剂，粗产物 42直接进行下步反应。 Add compound 41 (10.0 g, 22.63 mmol, 1 eq) and dichloromethane (100 mL) to the reaction flask, stir and dissolve NBS (4.03 g, 22.63 mmol, 1 eq) in portions and add in 10 min. At 30 min, TLC detected product formation, and traces of raw materials remained. The solvent was evaporated under reduced pressure from the reaction solution, and the crude product 42 was directly subjected to the next reaction.
化合物 43 Compound 43
反应瓶中加入溴化物 42粗品(5.9g，11.33mmol，1eq)、(S)-吗啉-3-羧酸甲酯盐酸盐(3.1g，17mmol，1.5eq)、碳酸钾(3.1g，22.7mmol，2eq)和乙醇(50mL)，40℃搅拌反应4h，TLC检测原料反应完全。反应液过滤，滤液浓缩，残余物用硅胶柱层析分离(PE∶EA＝4∶1～2∶1)，得产物 43(4.1g，产率61.8％)黄色固体。MS-ESI m/z：585.2[M]。 To the reaction flask were added crude bromide 42 (5.9 g, 11.33 mmol, 1 eq), (S) -morpholine-3-carboxylic acid methyl ester hydrochloride (3.1 g, 17 mmol, 1.5 eq), and potassium carbonate (3.1 g, 22.7 mmol, 2 eq) and ethanol (50 mL) were stirred at 40 ° C. for 4 h. The reaction of the starting materials was complete by TLC. The reaction solution was filtered, the filtrate was concentrated, and the residue was separated by silica gel column chromatography (PE: EA = 4: 1 to 2: 1) to obtain the product 43 (4.1 g, yield 61.8%) as a yellow solid. MS-ESI m / z: 585.2 [M].
化合物 44 Compound 44
反应瓶中加入中间体 43(2.0g，3.42mmol，1eq)和二氯甲烷(20mL)，搅拌溶解后分批加入三氯化铝(0.9g，6.84mol，2eq)，室温搅拌反应1小时。反应液冰浴下加入10mL冰水淬灭，减压蒸去溶剂，残余物加入100mL 1N HCl搅拌溶解，用50mL乙酸乙酯萃取，弃去有机相，水相用碳酸钠调pH 5-6，乙酸乙酯萃取(50mLx2)，合并后的有机相用饱和氯化钠水洗涤，无水硫酸钠干燥，硅藻土过滤，滤液旋干溶剂得黄色泡沫状固体产物 44(1.6g，产率94％)。该产物不必纯化可以直接用于下步反应。 Intermediate 43 (2.0 g, 3.42 mmol, 1 eq) and dichloromethane (20 mL) were added to the reaction flask. After stirring and dissolving, aluminum trichloride (0.9 g, 6.84 mol, 2 eq) was added in portions, and the reaction was stirred at room temperature for 1 hour. The reaction solution was quenched by adding 10 mL of ice water in an ice bath, and the solvent was evaporated under reduced pressure. The residue was dissolved by adding 100 mL of 1N HCl, extracted with 50 mL of ethyl acetate, and the organic phase was discarded. Ethyl acetate extraction (50 mL x 2), the combined organic phases were washed with saturated sodium chloride water, dried over anhydrous sodium sulfate, filtered through celite, and the filtrate was spin-dried to obtain a yellow foamy solid product 44 (1.6 g, yield 94). %). This product was used directly in the next step without purification.
化合物 45 Compound 45
向反应瓶中加入中间体 44(5.0g，10.1mmol，1eq)和二氯甲烷(50ml)，搅拌溶解后再加入三乙胺(2.0g，20.2mmol，2eq)和N-碘代丁二酰亚胺(3.41g，15.15mmol，1.5eq)，反应液室温搅拌12h。TLC检测反应完全，加50mL饱和亚硫酸钠溶液淬灭、洗涤，再用50mL饱和氯化钠洗涤，有机相浓缩，残余物柱层析分离(PE∶EA 4∶1-2∶1)，得黄色固体产物 45(2.2g，3.81mmol，产率37％)。MS-ESI m/z：577.0[M]。 Add intermediate 44 (5.0g, 10.1mmol, 1eq) and dichloromethane (50ml) to the reaction flask, stir and dissolve, then add triethylamine (2.0g, 20.2mmol, 2eq) and N-iodosuccinyl Imine (3.41 g, 15.15 mmol, 1.5 eq), and the reaction solution was stirred at room temperature for 12 h. The reaction was detected by TLC. The reaction was quenched with 50 mL of saturated sodium sulfite solution, washed with 50 mL of saturated sodium chloride, and the organic phase was concentrated. The residue was separated by column chromatography (PE: EA 4: 1-2: 1) to obtain a yellow solid. Product 45 (2.2 g, 3.81 mmol, 37% yield). MS-ESI m / z: 577.0 [M].
化合物 46 Compound 46
反应瓶中加入碘化物 45(1.3g，2.25mmol，1eq)和二氯甲烷15ml，搅拌溶解后加入Boc 2O(0.74g，3.38mmol，1.5eq)、三乙胺(0.45g，2.51mmol，1.1eq)和DMAP(27mg，225μmol，0.1eq)，加完后室温搅拌4h。加入50mL饱和氯化铵溶液淬灭反应，二氯甲烷萃取(30mLx2)，合并有机相、浓 缩，残余物柱层析(PE∶EA 3∶1)得黄色固体产物 46(1.3g，产率85％)。MS-ESI m/z：676[M]。 Add iodide 45 (1.3g, 2.25mmol, 1eq) and 15ml of dichloromethane to the reaction flask. After stirring and dissolving, add Boc 2 O (0.74g, 3.38mmol, 1.5eq), triethylamine (0.45g, 2.51mmol, 1.1 eq) and DMAP (27 mg, 225 μmol, 0.1 eq). After the addition, the mixture was stirred at room temperature for 4 h. Add 50 mL of saturated ammonium chloride solution to quench the reaction, extract with dichloromethane (30 mL x 2), combine the organic phases, concentrate, and use column chromatography on the residue (PE: EA 3: 1) to obtain the product 46 (1.3 g, yield 85) as a yellow solid. %). MS-ESI m / z: 676 [M].
化合物 48 Compound 48
反应瓶中加入中间体 46(1.0g，1.48mmol，1eq)和DMF(15ml)，搅拌溶解后再加入Pd(PPh 3) 4(170mg，0.1eq)、CuI(28mg，0.1eq)、三乙胺(300mg，2eq)和三甲基硅基乙炔(195mg，2eq)，反应液在氮气保护下60℃反应4h。TLC检测反应完全后，加50mL水淬灭，再用乙酸乙酯萃取(50mL x 2)，合并的有机相用饱和氯化钠洗涤(100mLx3)，无水硫酸钠干燥，过滤浓缩得到的残余物 47直接进行下步反应。 Intermediate 46 (1.0g, 1.48mmol, 1eq) and DMF (15ml) were added to the reaction flask, and Pd (PPh 3 ) 4 (170mg, 0.1eq), CuI (28mg, 0.1eq), triethyl Amine (300 mg, 2 eq) and trimethylsilylacetylene (195 mg, 2 eq) were reacted at 60 ° C. for 4 h under the protection of nitrogen. After the reaction was detected by TLC, it was quenched by adding 50 mL of water, and then extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the residue obtained by filtration. 47 proceeds directly to the next step.
粗产物 47(710mg，1.1mmol)溶于二氯甲烷(10ml)中，慢慢加入三氟乙酸5mL，反应液室温搅拌过夜。减压浓缩蒸去溶剂，残余物加入50mL二氯甲烷和20mL水，搅拌下用饱和碳酸氢钠溶液调水相pH 6-7，分层收集有机相，水相再用20mL二氯甲烷萃取。合并了的有机相用饱和氯化钠洗涤，干燥、浓缩，残余物用硅胶柱层析分离(P∶EA 1∶1)，得到黄色固体产物 48(392mg，两步产率56％)。MS-ESI m/z：475[M+H] +。 The crude product 47 (710 mg, 1.1 mmol) was dissolved in dichloromethane (10 ml), 5 mL of trifluoroacetic acid was slowly added, and the reaction solution was stirred at room temperature overnight. The solvent was concentrated and evaporated under reduced pressure. The residue was added with 50 mL of dichloromethane and 20 mL of water, and the aqueous phase was adjusted to pH 6-7 with a saturated sodium bicarbonate solution under stirring. The organic phase was collected in layers, and the aqueous phase was extracted with 20 mL of dichloromethane. The combined organic phases were washed with saturated sodium chloride, dried, and concentrated. The residue was separated by silica gel column chromatography (P: EA 1: 1) to give the product 48 as a yellow solid (392 mg, 56% in two steps). MS-ESI m / z: 475 [M + H] + .
化合物 49 Compound 49
将中间体48(300mg，0.63mmol，1eq)加到四氢呋喃(5mL)-甲醇(2mL)-水(1mL)的混合溶剂中，搅拌溶解后加入一水合氢氧化锂(54mg，1.26mmol，2eq)，室温搅拌过夜，减压蒸去溶剂，残余物加10mL水，再用1N HCl调pH 5-6，乙酸乙酯萃取(20mL x 2)，有机相合并后干燥、过滤并浓缩，粗产物用制备型HPLC纯化，色谱条件如下，固定相：C18柱；流动相A：水(含10mMHCl)，流动相B：ACN；流速：60mL/min；梯度：15分钟内流动相B由20％升至60％。冷冻干燥后，得到黄色固体产物 49(75mg，收率26％)。 1H NMR(400MHz，CDCl 3)δ7.80(s，1H)，7.50(s，1H)，7.38-7.41(m，1H)，7.11-7.15(m，1H)，6.99-7.03(m，1H)，5.78(s，1H)，4.08-4.12(m，1H)，3.84-3.87(m，1H)，3.65-3.74(m，3H)，3.48-3.58(m，3H)，3.03-3.06(m，1H)，2.63-2.80(m，2H)；MS(ES，m/z)：[M+H] +＝461。 Add intermediate 48 (300mg, 0.63mmol, 1eq) to a mixed solvent of tetrahydrofuran (5mL) -methanol (2mL) -water (1mL), stir and dissolve, and add lithium hydroxide monohydrate (54mg, 1.26mmol, 2eq) Stir overnight at room temperature, evaporate the solvent under reduced pressure, add 10 mL of water to the residue, adjust pH 5-6 with 1N HCl, and extract with ethyl acetate (20 mL x 2). Combine the organic phases, dry, filter, and concentrate. Use the crude product with Purification by preparative HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: mobile phase B increased from 20% to 15 minutes 60%. After freeze-drying, product 49 (75 mg, yield 26%) was obtained as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (s, 1H), 7.50 (s, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H ), 5.78 (s, 1H), 4.08-4.12 (m, 1H), 3.84-3.87 (m, 1H), 3.65-3.74 (m, 3H), 3.48-3.58 (m, 3H), 3.03-3.06 (m , 1H), 2.63-2.80 (m, 2H); MS (ES, m / z): [M + H] + = 461.
实施例7Example 7
Figure PCTCN2019093578-appb-000044
Figure PCTCN2019093578-appb-000044
化合物 51a Compound 51a
反应瓶中加入中间体 46(1.0g，1.48mmol，1eq)和DMF(15ml)，搅拌溶解后再加入Pd(PPh3)2C12(103.7mg，148μmol，0.1eq)、CuI(28mg，148μmol，0.1eq)、三乙胺(300mg，2.95mmol，2eq)和环丙基乙炔(195mg，2.95mmol，2eq)，反应液氮气保护下室温反应12h。TLC检测反应完全后， 加50mL水淬灭，再用乙酸乙酯萃取(50mL x 2)，合并的有机相用饱和氯化钠洗涤(100mLx3)，无水硫酸钠干燥，过滤浓缩得到的残余物 50a直接进行下步反应。 Intermediate 46 (1.0g, 1.48mmol, 1eq) and DMF (15ml) were added to the reaction flask. After stirring and dissolving, Pd (PPh3) 2C12 (103.7mg, 148μmol, 0.1eq), CuI (28mg, 148μmol, 0.1eq) were added. ), Triethylamine (300 mg, 2.95 mmol, 2 eq) and cyclopropylacetylene (195 mg, 2.95 mmol, 2 eq). The reaction solution was reacted at room temperature for 12 h under the protection of nitrogen. After the reaction was detected by TLC, it was quenched by adding 50 mL of water, and then extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain the residue obtained by filtration. 50a directly proceeds to the next step.
化合物 50a(900mg，1.46mmol)溶于二氯甲烷(10ml)中，慢慢加入三氟乙酸5mL，反应液室温搅拌4h。TLC检测反应完全后，减压浓缩蒸去溶剂，残余物加入50mL二氯甲烷和20mL水，搅拌下用饱和碳酸氢钠溶液调水相pH 6-7，分层收集有机相，水相再用20mL二氯甲烷萃取。合并了的有机相用饱和氯化钠洗涤、干燥、浓缩，残余物用硅胶柱层析分离(PE∶EA 1∶1)，得到黄色固体产物 51a(700mg，两步总产率61％)。MS-ESIm/z：515.1[M] +。 Compound 50a (900 mg, 1.46 mmol) was dissolved in dichloromethane (10 ml), 5 mL of trifluoroacetic acid was slowly added, and the reaction solution was stirred at room temperature for 4 h. After the reaction was detected by TLC, the solvent was concentrated under reduced pressure to remove the solvent. The residue was added with 50 mL of dichloromethane and 20 mL of water, and the aqueous phase was adjusted to pH 6-7 with a saturated sodium bicarbonate solution under stirring. The organic phase was collected in layers and the aqueous phase was reused. 20 mL of dichloromethane was extracted. The combined organic phases were washed with saturated sodium chloride, dried, and concentrated. The residue was separated by silica gel column chromatography (PE: EA 1: 1) to give the product 51a (700 mg, total yield 61% in two steps) as a yellow solid. MS-ESIm / z: 515.1 [M] + .
化合物 52a Compound 52a
将中间体 51a(700mg，1.36mmol，1eq)加到四氢呋喃(5mL)-甲醇(2mL)-水(1mL)的混合溶剂中，搅拌溶解后加入一水合氢氧化锂(115mg，2.7mmol，2eq)，室温搅拌过夜，减压蒸去溶剂，残余物加10mL水，再用1N HCl调pH5-6，乙酸乙酯萃取(20mL x 2)，有机相合并后干燥、过滤并浓缩，粗产物用制备型HPLC纯化，色谱条件如下，固定相：C18柱；流动相A：水(含10mMHCl)，流动相B：ACN；流速：60mL/min；梯度：15分钟内流动相B由20％升至60％。冷冻干燥后，得到产物 52a(210mg，收率31％)黄色固体。 1HNMR(400MHz，CDCl 3)δ7.81(d，J＝2.8Hz，1H)，7.50(s，1H)，7.38-7.41(m，1H)，7.11-7.15(m，1H)，6.99-7.03(m，1H)，5.78(s，1H)，4.08-4.12(m，1H)，3.84-3.87(m，1H)，3.65-3.74(m，3H)，3.48-3.58(m，3H)，3.03-3.06(m，1H)，2.67-2.70(m，1H)，1.25-1.29(m，1H)，0.77-0.79(m，2H)，0.60-0.63(m，2H)；MS(ES，m/z)：[M] +＝501。 Intermediate 51a (700mg, 1.36mmol, 1eq) was added to a mixed solvent of tetrahydrofuran (5mL) -methanol (2mL) -water (1mL). After stirring and dissolving, lithium hydroxide monohydrate (115mg, 2.7mmol, 2eq) was added. Stir overnight at room temperature, evaporate the solvent under reduced pressure, add 10 mL of water to the residue, adjust the pH to 5-6 with 1N HCl, and extract with ethyl acetate (20 mL x 2). Combine the organic phases, dry, filter, and concentrate. The crude product is prepared by Purification by HPLC with the following chromatographic conditions: stationary phase: C18 column; mobile phase A: water (containing 10 mM HCl), mobile phase B: ACN; flow rate: 60 mL / min; gradient: mobile phase B increased from 20% to 60 in 15 minutes %. After lyophilization, the product 52a (210 mg, yield 31%) was obtained as a yellow solid. 1 HNMR (400MHz, CDCl 3 ) δ7.81 (d, J = 2.8Hz, 1H), 7.50 (s, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H), 5.78 (s, 1H), 4.08-4.12 (m, 1H), 3.84-3.87 (m, 1H), 3.65-3.74 (m, 3H), 3.48-3.58 (m, 3H), 3.03 -3.06 (m, 1H), 2.67-2.70 (m, 1H), 1.25-1.29 (m, 1H), 0.77-0.79 (m, 2H), 0.60-0.63 (m, 2H); MS (ES, m / z): [M] + = 501.
采用相同的合成路线，还制备了化合物 52b、 52c、 53a、 53b、 53c和 54： Using the same synthetic route, compounds 52b , 52c , 53a , 53b , 53c, and 54 were also prepared:
Figure PCTCN2019093578-appb-000045
MS(ES，m/z)：[M+H] +＝519。
Figure PCTCN2019093578-appb-000045
MS (ES, m / z): [M + H] + = 519.
Figure PCTCN2019093578-appb-000046
1HNMR(400MHz，CDCl 3)δ7.81(d，J＝2.8Hz，1H)，7.48(d，J＝2.8Hz，1H)，7.38-7.41(m，1H)，7.11-7.15(m，1H)，6.99-7.03(m，1H)，5.75(s，1H)，4.08-4.30(m，2H)，3.84-3.87(m，1H)，3.65-3.74(m，3H)，3.48-3.58(m，3H)，3.03-3.06(m，1H)，2.67-2.70(m，1H)；MS(ES，m/z)：[M+H] +＝491.
Figure PCTCN2019093578-appb-000046
1 HNMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 2.8 Hz, 1H), 7.48 (d, J = 2.8 Hz, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H ), 6.99-7.03 (m, 1H), 5.75 (s, 1H), 4.08-4.30 (m, 2H), 3.84-3.87 (m, 1H), 3.65-3.74 (m, 3H), 3.48-3.58 (m , 3H), 3.03-3.06 (m, 1H), 2.67-2.70 (m, 1H); MS (ES, m / z): [M + H] + = 491.
Figure PCTCN2019093578-appb-000047
1HNMR(400MHz，CDCl 3)δ7.81(m，1H)，7.50(m，1H)，7.38-7.41(m，1H)，7.11-7.15(m，1H)，6.99-7.03(m，1H)，5.78(s，1H)，4.08-4.12(m，2H)，3.80-3.85(m，1H)，3.28-3.38(m，3H)，2.93-2.96(m，1H)，2.57-2.60(m，1H)，1.05-1.59(m，6H)，0.77-0.79(m，2H)，0.60-0.63(m，2H)。
Figure PCTCN2019093578-appb-000047
1 HNMR (400 MHz, CDCl 3 ) δ 7.81 (m, 1H), 7.50 (m, 1H), 7.38-7.41 (m, 1H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H) , 5.78 (s, 1H), 4.08-4.12 (m, 2H), 3.80-3.85 (m, 1H), 3.28-3.38 (m, 3H), 2.93-2.96 (m, 1H), 2.57-2.60 (m, 1H), 1.05-1.59 (m, 6H), 0.77-0.79 (m, 2H), 0.60-0.63 (m, 2H).
Figure PCTCN2019093578-appb-000048
1HNMR(400MHz，CDCl 3)δ7.60-7.80(m，2H)，7.11-7.15(m，1H)，6.99-7.03(m，1H)，5.80(s，1H)，4.01-4.10(m，2H)，3.87-3.90(m，3H)，3.78-3.84(m，1H)，3.28-3.38(m，3H)，2.93-2.96(m，1H)，2.57-2.60(m，1H)，1.05-1.59(m，5H)。
Figure PCTCN2019093578-appb-000048
1 HNMR (400 MHz, CDCl 3 ) δ 7.60-7.80 (m, 2H), 7.11-7.15 (m, 1H), 6.99-7.03 (m, 1H), 5.80 (s, 1H), 4.01-4.10 (m, 2H), 3.87-3.90 (m, 3H), 3.78-3.84 (m, 1H), 3.28-3.38 (m, 3H), 2.93-2.96 (m, 1H), 2.57-2.60 (m, 1H), 1.05- 1.59 (m, 5H).
Figure PCTCN2019093578-appb-000049
1HNMR(400MHz，CDCl 3)δ7.84(m，1H)，7.61(m，1H)，7.48-7.51(m，1H)，7.15-7.17(m，1H)，6.97-7.00(m，1H)，5.88(s，1H)，4.08-4.12(m，2H)，3.68-3.86(m，4H)，3.48-3.58(m，3H)，3.03-3.06(m，1H)，2.67-2.70(m，1H)，1.05-1.59(m，5H)。
Figure PCTCN2019093578-appb-000049
1 HNMR (400 MHz, CDCl 3 ) δ 7.84 (m, 1H), 7.61 (m, 1H), 7.48-7.51 (m, 1H), 7.15-7.17 (m, 1H), 6.97-7.00 (m, 1H) , 5.88 (s, 1H), 4.08-4.12 (m, 2H), 3.68-3.86 (m, 4H), 3.48-3.58 (m, 3H), 3.03-3.06 (m, 1H), 2.67-2.70 (m, 1H), 1.05-1.59 (m, 5H).
Figure PCTCN2019093578-appb-000050
MS(ES，m/z)：[M+H] +＝489。
Figure PCTCN2019093578-appb-000050
MS (ES, m / z): [M + H] + = 489.
实施例8：体外抗HBV活性测试Example 8: In vitro anti-HBV activity test
实验方法：experimental method:
应用HepG2.2.15细胞检测受试化合物抗HBV活性。HepG2.2.15 cells were used to detect the anti-HBV activity of the test compounds.
HepG2.2.15细胞接种到96孔微孔板上，密度为每孔0.1mL培养基中3×10 4个细胞，多孔板在37℃温育过夜。待测化合物和对照化合物(恩替卡韦，ETV)以DMSO溶剂三倍稀释到8个不同浓度点，平行测定两个复孔，受试化合物的起始浓度为10μM。将100μL浓度递减的化合物DMSO溶液加入板上微孔中，使得每孔中DMSO的终浓度为0.5％。化合物处理细胞六天后，采用定量PCR检测上清HBV DNA的含量，同时用CellTiter Glo检测细胞活力。 HepG2.2.15 cells were seeded into 96-well microplates with a density of 3 × 10 4 cells in 0.1 mL of medium per well, and the multiwell plates were incubated at 37 ° C. overnight. The test compound and the control compound (entecavir, ETV) were three-fold diluted with DMSO solvent to 8 different concentration points, and two duplicate wells were measured in parallel. The initial concentration of the test compound was 10 μM. 100 μL of a compound DMSO solution of decreasing concentration was added to the microwells on the plate so that the final concentration of DMSO in each well was 0.5%. Six days after the compounds were treated with the compound, the amount of HBV DNA in the supernatant was detected by quantitative PCR, and the cell viability was detected by CellTiter Glo.
应用GraphPad Prism软件计算化合物的EC 50和CC 50值。 Application GraphPad Prism software to calculate EC 50 and CC 50 values of the compounds.
实验结果：Experimental results:
按照上述方法，测定本发明的化合物的体外抑制HBV复制的能力，结果见下表：According to the above method, the ability of the compound of the present invention to inhibit HBV replication in vitro was determined, and the results are shown in the following table:
化合物Compound EC 50(μM) EC 50 (μM) CC 50(μM) CC 50 (μM) 化合物Compound EC 50(μM) EC 50 (μM) CC 50(μM) CC 50 (μM)
66 BB ＞10＞ 10 34a34a AA ＞10＞ 10
77 BB ＞10＞ 10 34b34b AA ＞10＞ 10
88 BB ＞10＞ 10 34c34c BB ＞10＞ 10
99 AA ＞10＞ 10 34d34d AA ＞10＞ 10
1010 BB ＞10＞ 10 3737 BB ＞10＞ 10
1111 AA ＞10＞ 10 4040 BB ＞10＞ 10
1212 BB ＞10＞ 10 4848 BB ＞10＞ 10
1313 AA ＞10＞ 10 4949 AA ＞10＞ 10
1414 AA ＞10＞ 10 52a52a AA ＞10＞ 10
1515 BB ＞10＞ 10 52b52b AA ＞10＞ 10
1616 AA ＞10＞ 10 52c52c AA ＞10＞ 10
2525 AA ＞10＞ 10 53a53a AA ＞10＞ 10
2626 AA ＞10＞ 10 53b53b AA ＞10＞ 10
2727 AA ＞10＞ 10 53c53c AA ＞10＞ 10
3232 AA ＞10＞ 10 5454 BB ＞10＞ 10
3333 AA ＞10＞ 10 ETVETV 0.0020.002 ＞0.02＞ 0.02
A：EC 50＜0.1μM；B：0.1μM＜EC 50＜10μM；C：EC 50＞10μM A: EC 50 <0.1 μM; B: 0.1 μM <EC 50 <10 μM; C: EC 50 > 10 μM
实验结论Experimental results
初步体外活性实验证实，本发明涉及的5-烃基取代的二氢吡啶衍生物大多数的EC50小于0.1μM，显示出很强的抗HBV活性，并且所有化合物在10μM没有显示出任何细胞毒性；另外由于避免了5-酯基酶水解而失活的缺点，本发明的化合物作为HBV衣壳蛋白抑制剂具有更佳的代谢稳定性。这类化合物具有出乎预料的抗病毒活性，可以用于治疗HBV感染引起的疾病。Preliminary in vitro activity experiments confirmed that most of the 5-hydrocarbyl-substituted dihydropyridine derivatives involved in the present invention have an EC50 of less than 0.1 μM, showing strong anti-HBV activity, and all compounds did not show any cytotoxicity at 10 μM; Since the disadvantage of inactivation of 5-esterylase is avoided, the compounds of the present invention have better metabolic stability as HBV capsid protein inhibitors. These compounds have unexpected antiviral activity and can be used to treat diseases caused by HBV infection.
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。The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field to which the present invention pertains, without deviating from the concept of the present invention, several simple deductions or replacements can be made, which should all be regarded as belonging to the protection scope of the present invention.

Claims (16)

  1. 通式(I)的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：Compounds of general formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs, or isotopes Variants, and their mixtures:
    Figure PCTCN2019093578-appb-100001
    Figure PCTCN2019093578-appb-100001
    其中：among them:
    L选自化学键、-CR’＝CR”-或-C≡C-；其中R’和R”独立地选自H、卤素、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基； L is selected from a chemical bond, -CR '= CR "-or -C≡C-; wherein R' and R" are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3- 7 carbocyclyl or 3-7 membered heterocyclyl;
    X选自化学键、CR bR c、NR a、O或S(O) q； X is selected from the group consisting of a chemical bond, CR b R c , NR a , O, or S (O) q ;
    R 1选自H、卤素、-CN、-NO 2、-C(O)R a、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； R 1 is selected from H, halogen, -CN, -NO 2 , -C (O) R a , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1 -6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; And R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    R 2和R 2’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 2和R 2’可以形成氧代或硫代； R 2 and R 2 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 2 and R 2 'can form oxo or thio;
    R 3和R 3’独立地选自H、卤素、-CN、-NO 2、-OR a、-NR bR c、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基；或者，R 3和R 3’可以形成氧代或硫代； R 3 and R 3 ′ are independently selected from H, halogen, -CN, -NO 2 , -OR a , -NR b R c , -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; or, R 3 and R 3 'can form oxo or thio;
    R 4和R 4’独立地选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基；或者，R 4和R 4’可以形成氧代或硫代； R 4 and R 4 'are independently selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C ( O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,- (C 0-6 alkylene) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S ( O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 alkyl or C 1-6 haloalkyl; or, R 4 and R 4 ′ may form oxo or thio;
    或者，R 2和R 3结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, R 2 and R 3 combine to form a double bond, a C 3-7 carbocyclyl group, a 3-7 membered heterocyclic group, a C 6-10 aryl group, or a 5-10 membered heteroaryl group;
    或者，当X为CR bR c或NR a时，R 3或R 4可以与R a、R b和R c中的一个结合形成双键、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； Alternatively, when X is CR b R c or NR a , R 3 or R 4 may be combined with one of R a , R b and R c to form a double bond, C 3-7 carbocyclyl, 3-7 membered hetero Cyclic, C 6-10 aryl or 5-10 membered heteroaryl;
    R 5选自H、卤素、-CN、-NO 2、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-C(O)R d、-(C 0-6亚烷基)-N(R e)-C(O)R d、-(C 0-6亚烷基)-S(O) pR d、-(C 0-6亚烷基)-S(O) pOR d、-(C 0-6亚烷基)-S(O) pNR eR f、-(C 0-6 亚烷基)-O-S(O) pR d、-(C 0-6亚烷基)-N(R e)-S(O) pR d、C 1-6烷基或C 1-6卤代烷基； R 5 is selected from H, halogen, -CN, -NO 2 ,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0- 6 alkylene) -C (O) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OC (O) R d ,-(C 0-6 alkylene) -N (R e ) -C (O) R d ,-(C 0-6 alkylene Alkyl) -S (O) p R d ,-(C 0-6 alkylene) -S (O) p OR d ,-(C 0-6 alkylene) -S (O) p NR e R f ,-(C 0-6 alkylene) -OS (O) p R d ,-(C 0-6 alkylene) -N (R e ) -S (O) p R d , C 1-6 Alkyl or C 1-6 haloalkyl;
    R 6和R 7独立地选自H、卤素、-CN、C 1-6烷基或C 1-6卤代烷基； R 6 and R 7 are independently selected from H, halogen, -CN, C 1-6 alkyl, or C 1-6 haloalkyl;
    R a、R b、R c、R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基； R a, R b, R c , R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    m＝0、1、2、3、4或5；m = 0, 1, 2, 3, 4 or 5;
    n＝0、1或2；n = 0, 1, or 2;
    p＝1或2；p = 1 or 2;
    q＝0、1或2；q = 0, 1, or 2;
    条件是当L为化学键时，R 1选自H、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基。 Provided that when L is a chemical bond, R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl , C 3-7 carbocyclyl, 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl.
  2. 根据权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(II-1)、(II-2)、(II-3)、(II-4)或(II-5)：A compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (II-1), (II-2), (II-3), (II-4) or (II-5):
    Figure PCTCN2019093578-appb-100002
    Figure PCTCN2019093578-appb-100002
    其中，among them,
    R 1选自H、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-8烯基、C 2-8炔基、C 3-7碳环基、3-7元杂环基、C 6-10芳基或5-10元杂芳基； R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 carbocyclyl , 3-7 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    X、R 2-R 7、R 3’、m和n如权利要求1所定义。 X, R 2 -R 7 , R 3 ′, m and n are as defined in claim 1.
  3. 根据权利要求2的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(II-3)或(II-4)：A compound according to claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (II-3) or (II-4):
    Figure PCTCN2019093578-appb-100003
    Figure PCTCN2019093578-appb-100003
    其中，among them,
    R 1选自H、卤素、-CN、-NO 2、C 1-6烷基或C 1-6卤代烷基；优选地，R 1选自H、卤素或C 1-6卤代烷基；优选地，R 1选自H、卤素、CF 3或CHF 2；优选地，R 1为CF 3； R 1 is selected from H, halogen, -CN, -NO 2 , C 1-6 alkyl, or C 1-6 haloalkyl; preferably, R 1 is selected from H, halogen, or C 1-6 haloalkyl; preferably, R 1 is selected from H, halogen, CF 3 or CHF 2 ; preferably, R 1 is CF 3 ;
    R 2和R 3为H； R 2 and R 3 are H;
    R 5为-(C 0-6亚烷基)-C(O)OR d；优选地，R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 5 is- (C 0-6 alkylene) -C (O) OR d ; preferably, R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    R d选自H、C 1-6烷基或C 1-6卤代烷基。 R d is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  4. 根据权利要求2的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(II-5)：A compound according to claim 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (II-5):
    Figure PCTCN2019093578-appb-100004
    Figure PCTCN2019093578-appb-100004
    其中，among them,
    X为化学键或O；X is a chemical bond or O;
    R 1选自H、卤素、C 1-6烷基或C 1-6卤代烷基；优选地，R 1选自H、卤素或C 1-6卤代烷基；优选地，R 1为C 1-6卤代烷基；优选地，R 1选自H、Br、CF 3或CHF 2；优选地，R 1为CF 3； R 1 is selected from H, halogen, C 1-6 alkyl, or C 1-6 haloalkyl; preferably, R 1 is selected from H, halogen, or C 1-6 haloalkyl; preferably, R 1 is C 1-6 haloalkyl; preferably, R 1 is selected from H, Br, CF 3 or CHF 2; preferably, R 1 is CF 3;
    R 3选自H、卤素或C 1-6烷基；优选地，R 3为H、F或异丙基； R 3 is selected from H, halogen or C 1-6 alkyl; preferably, R 3 is H, F or isopropyl;
    R 3’选自H或卤素；优选地，R 3为H或F； R 3 ′ is selected from H or halogen; preferably, R 3 is H or F;
    R 4选自H或C 1-6烷基；优选地，R 4为H或甲基； R 4 is selected from H or C 1-6 alkyl; preferably, R 4 is H or methyl;
    R 5选自H、-(C 0-6亚烷基)-OR d、-(C 0-6亚烷基)-NR eR f、-(C 0-6亚烷基)-C(O)R d、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-S(O) 2R d或-(C 0-6亚烷基)-N(R e)-S(O) 2R d；优选地，R 5选自H、-(C 0-6亚烷基)-C(O)OR d、-(C 0-6亚烷基)-C(O)NR eR f、-(C 0-6亚烷基)-O-S(O) 2R d或-(C 0-6亚烷基)-N(R e)-S(O) 2R d；优选地，R 5选自-(C 0-6亚烷基)-C(O)OH、-(C 0-6亚烷基)-C(O)NH 2或-(C 0-6亚烷基)-NH-S(O) 2R d；优选地，R 5选自H、-COOH、-CONH 2、-CH 2NHSO 2Me、-COOMe或-CH 2OH；优选地，R 5选自-COOH、-CONH 2或-CH 2NHSO 2Me； R 5 is selected from H,-(C 0-6 alkylene) -OR d ,-(C 0-6 alkylene) -NR e R f ,-(C 0-6 alkylene) -C (O ) R d ,-(C 0-6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene Group) -OS (O) 2 R d or- (C 0-6 alkylene) -N (R e ) -S (O) 2 R d ; preferably, R 5 is selected from H,-(C 0- 6 alkylene) -C (O) OR d ,-(C 0-6 alkylene) -C (O) NR e R f ,-(C 0-6 alkylene) -OS (O) 2 R d or- (C 0-6 alkylene) -N (R e ) -S (O) 2 R d ; preferably, R 5 is selected from- (C 0-6 alkylene) -C (O) OH -(C 0-6 alkylene) -C (O) NH 2 or- (C 0-6 alkylene) -NH-S (O) 2 R d ; preferably, R 5 is selected from H,- COOH, -CONH 2 , -CH 2 NHSO 2 Me, -COOMe or -CH 2 OH; preferably, R 5 is selected from -COOH, -CONH 2 or -CH 2 NHSO 2 Me;
    优选地，R 5为(S)构型； Preferably, R 5 is in the (S) configuration;
    优选地，当R 5为-COOH时，R 3、R 3’和R 4中至少一个不为H； Preferably, when R 5 is -COOH, at least one of R 3 , R 3 ′ and R 4 is not H;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    R d、R e和R f独立地选自H、C 1-6烷基或C 1-6卤代烷基。 R d, R e and R f are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  5. 根据权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(III-1)、(III-2)、(III-3)、(III-4)、(III-5)、(III-6)、(III-7)、(III-8)或(III-9)：A compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formulae (III-1), (III-2), (III-3), (III-4), (III-5), (III-6), (III- 7), (III-8) or (III-9):
    Figure PCTCN2019093578-appb-100005
    Figure PCTCN2019093578-appb-100005
    其中，among them,
    R 4和R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 and R 5 are -C (O) OH or -CH 2 CH 2 C (O) OH;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    X、R 1-R 7、R’、R”、m和n如权利要求1所定义。 X, R 1 -R 7 , R ′, R ″, m and n are as defined in claim 1.
  6. 根据权利要求5的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(III-5)、(III-6)、(III-7)或(III-8)：A compound according to claim 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (III-5), (III-6), (III-7) or (III-8):
    Figure PCTCN2019093578-appb-100006
    Figure PCTCN2019093578-appb-100006
    其中，among them,
    R’和R”为H；R 'and R "are H;
    R 1选自H、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基或-C(O)OR a；优选地，R 1选自卤素、C 1-6烷基、C 1-6卤代烷基或-C(O)OR a； R 1 is selected from H, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 membered heterocyclyl, or -C (O) OR a ; preferably R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -C (O) OR a ;
    R 2和R 3为H； R 2 and R 3 are H;
    R 4和R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 and R 5 are -C (O) OH or -CH 2 CH 2 C (O) OH;
    R a独立地选自H、C 1-6烷基或C 1-6卤代烷基；优选地，R a独立地为C 1-6烷基或C 1-6卤代烷基； R a is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably, R a is independently C 1-6 alkyl or C 1-6 haloalkyl;
    R d独立地选自C 1-6烷基或C 1-6卤代烷基； R d is independently selected from C 1-6 alkyl or C 1-6 haloalkyl;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br。 R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br.
  7. 根据权利要求5的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(III-9)A compound according to claim 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (III-9)
    Figure PCTCN2019093578-appb-100007
    Figure PCTCN2019093578-appb-100007
    其中，among them,
    R 1选自卤素、C 1-6烷基、C 1-6卤代烷基或-C(O)OR a；优选地，R 1选自卤素或-C(O)OR a；优选地，R 1选自Br、Cl或-C(O)Me； R 1 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, or -C (O) OR a ; preferably, R 1 is selected from halogen or -C (O) OR a ; preferably, R 1 Selected from Br, Cl or -C (O) Me;
    R 4为H或-(C 0-6亚烷基)-C(O)OR d；优选地，R 4为H或-(C 1-6亚烷基)-C(O)OH；优选地，R 4为H或-CH 2CH 2C(O)OH；优选地，R 4为(R)构型； R 4 is H or- (C 0-6 alkylene) -C (O) OR d ; preferably, R 4 is H or- (C 1-6 alkylene) -C (O) OH; preferably , R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is (R) configuration;
    R 5为H或-(C 0-6亚烷基)-C(O)OR d；优选地，R 5为H或-C(O)OR d；优选地，R 5为H、-C(O)OH、-C(O)OMe或-CH 2CH 2C(O)OH；优选地，R 5为H、-C(O)OH或-C(O)OMe；优选地，R 5为(S)构型； R 5 is H or- (C 0-6 alkylene) -C (O) OR d ; preferably, R 5 is H or -C (O) OR d ; preferably, R 5 is H, -C ( O) OH, -C (O) OMe or -CH 2 CH 2 C (O) OH; preferably, R 5 is H, -C (O) OH or -C (O) OMe; preferably, R 5 is (S) configuration;
    优选地，R 4和R 5中至少有一个为非氢基团； Preferably, at least one of R 4 and R 5 is a non-hydrogen group;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    R a独立地选自H、C 1-6烷基或C 1-6卤代烷基；优选地，R a独立地为C 1-6烷基或C 1-6卤代烷基； R a is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably, R a is independently C 1-6 alkyl or C 1-6 haloalkyl;
    R d独立地选自H、C 1-6烷基或C 1-6卤代烷基。 R d is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  8. 根据权利要求1的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(IV-1)、(IV-2)、(IV-3)、(IV-4)、(IV-5)或(IV-6)：A compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (IV-1), (IV-2), (IV-3), (IV-4), (IV-5) or (IV-6):
    Figure PCTCN2019093578-appb-100008
    Figure PCTCN2019093578-appb-100008
    其中，among them,
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    X、R 1-R 7、m和n如权利要求1所定义。 X, R 1 -R 7 , m and n are as defined in claim 1.
  9. 根据权利要求8的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(IV-3)、(IV-4)或(IV-5)：A compound according to claim 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change And their mixtures, which have the general formula (IV-3), (IV-4) or (IV-5):
    Figure PCTCN2019093578-appb-100009
    Figure PCTCN2019093578-appb-100009
    其中，among them,
    R 1选自H、-C(O)OR a、-C(O)NR bR c、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基、3-7元杂环基、C 6-10 芳基或5-10元杂芳基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a或-NR bR c； R 1 is selected from H, -C (O) OR a , -C (O) NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, 3-7 member Heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; and R 1 is optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a or -NR b R c ;
    优选地，R 1选自H、-C(O)OR a、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自H、卤素、-CN、-NO 2、-OR a或-NR bR c； Preferably, R 1 is selected from H, -C (O) OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, or 3-7 membered heterocyclyl; and R 1 Optionally substituted with 1, 2 or 3 R groups, wherein R is independently selected from H, halogen, -CN, -NO 2 , -OR a or -NR b R c ;
    优选地，R 1选自H、C 1-6烷基、C 1-6卤代烷基、C 3-7碳环基或3-7元杂环基；并且R 1任选地被1、2或3个R基团取代，其中R独立地选自-OR a或-NR bR c； Preferably, R 1 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 carbocyclyl, or 3-7 membered heterocyclyl; and R 1 is optionally 1, 2, or 3 R group substitutions, where R is independently selected from -OR a or -NR b R c ;
    R 2和R 3为H，或者R 2和R 3结合形成双键；优选地，R 2和R 3为H； R 2 and R 3 are H, or R 2 and R 3 are combined to form a double bond; preferably, R 2 and R 3 are H;
    R 4为-C(O)OH或者-CH 2CH 2C(O)OH； R 4 is -C (O) OH or -CH 2 CH 2 C (O) OH;
    R 5为-C(O)OH或者-CH 2CH 2C(O)OH； R 5 is -C (O) OH or -CH 2 CH 2 C (O) OH;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    R a、R b和R c独立地选自H、C 1-6烷基或C 1-6卤代烷基。 R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  10. 根据权利要求8的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有通式(IV-6)：A compound according to claim 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope change thereof And their mixtures, which have the general formula (IV-6):
    Figure PCTCN2019093578-appb-100010
    Figure PCTCN2019093578-appb-100010
    其中，among them,
    R 1选自H、C 1-6烷基、-C(O)OR a或C 3-7碳环基，并且其中C 1-6烷基或C 3-7碳环基任选地被1个-OR a基团取代；优选地，R 1选自H、环丙基、-C(O)OMe或-CH 2OH； R 1 is selected from H, C 1-6 alkyl, -C (O) OR a, or C 3-7 carbocyclyl, and wherein C 1-6 alkyl or C 3-7 carbocyclyl is optionally substituted by 1 -OR a group substitution; preferably, R 1 is selected from H, cyclopropyl, -C (O) OMe or -CH 2 OH;
    R 4为H或-CH 2CH 2C(O)OH；优选地，R 4为(R)构型； R 4 is H or -CH 2 CH 2 C (O) OH; preferably, R 4 is in the (R) configuration;
    R 5为H或-C(O)OR a；优选地，R 5为H、-C(O)OH或-C(O)OMe；优选地，R 5为H或-C(O)OH；优选地，R 5为(S)构型； R 5 is H or -C (O) OR a ; preferably, R 5 is H, -C (O) OH or -C (O) OMe; preferably, R 5 is H or -C (O) OH; Preferably, R 5 is in the (S) configuration;
    优选地，R 4和R 5中至少有一个为非氢基团； Preferably, at least one of R 4 and R 5 is a non-hydrogen group;
    R 6’和R 6”为卤素和甲基；优选地，R 6’为F，且R 6”为Cl或Br； R 6 ′ and R 6 ″ are halogen and methyl; preferably, R 6 ′ is F, and R 6 ″ is Cl or Br;
    R a选自H、C 1-6烷基或C 1-6卤代烷基。 R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  11. 化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，其中所述化合物选自以下：A compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope variant thereof, wherein The compound is selected from the following:
    Figure PCTCN2019093578-appb-100011
    Figure PCTCN2019093578-appb-100011
    Figure PCTCN2019093578-appb-100012
    Figure PCTCN2019093578-appb-100012
  12. 药物组合物，其含有权利要求1-11中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，和药学上可接受的赋形剂；优选地，所述药物组合物还含有其它治疗剂。Pharmaceutical composition containing a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and pharmaceutically acceptable excipients; preferably, the pharmaceutical composition also contains other therapeutic agents.
  13. 试剂盒，其包括Kit comprising
    第一容器，其中含有权利要求1-11中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体；和任选地，第二容器，其中含有其它治疗剂；和任选地，第三容器，其中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。A first container containing the compound of any one of claims 1-11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants; and optionally, a second container containing other therapeutic agents; and optionally a third container containing a compound for dilution or suspension and / or Pharmaceutical excipients for other therapeutic agents.
  14. 权利要求1-11中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体在制备用于治疗和/或预防病毒感染尤其是乙型肝炎病毒感染的药物中的用途。The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, Use of a drug or an isotope variant in the manufacture of a medicament for the treatment and / or prevention of viral infections, especially hepatitis B virus infections.
  15. 权利要求1-11中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体或权利要求12的药物组合物，其用于治疗和/或预防病毒感染尤其是乙型肝炎病毒感染。The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, A drug or an isotope variant or a pharmaceutical composition according to claim 12 for use in the treatment and / or prevention of a viral infection, especially a hepatitis B virus infection.
  16. 一种在受试者中治疗和/或预防病毒感染尤其是乙型肝炎病毒感染的方法，所述方法包括向所述受试者给药权利要求1-11中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、 外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体或权利要求12的药物组合物。A method of treating and / or preventing a viral infection, especially a hepatitis B virus infection in a subject, the method comprising administering to the subject a compound according to any one of claims 1-11 or a pharmacy thereof The above-acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, or the pharmaceutical composition of claim 12.
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