WO2020001592A1 - Dérivés de dihydropyrimidine et leur utilisation - Google Patents

Dérivés de dihydropyrimidine et leur utilisation 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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English (en)
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/CN112469716B/zh
Publication of WO2020001592A1 publication Critical patent/WO2020001592A1/fr

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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

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Abstract

La présente invention concerne des dérivés de dihydropyrimidine tels que représentés par la formule générale (I), qui sont applicables au traitement et à la prévention d'une infection par le virus de l'hépatite B. L'invention concerne en outre des compositions pharmaceutiques contenant un composé tel que représenté par la formule (I), et leur utilisation pour le traitement et la prévention d'une infection par le virus de l'hépatite B.
PCT/CN2019/093578 2018-06-28 2019-06-28 Dérivés de dihydropyrimidine et leur utilisation WO2020001592A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021031997A1 (fr) * 2019-08-16 2021-02-25 西藏天晟泰丰药业有限公司 Dérivé de dihydropyrimidine et son utilisation
CN114853761A (zh) * 2021-02-05 2022-08-05 刘沛 一种含有二氢嘧啶的双功能衍生物及其用途

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