WO2018214639A1 - 2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compound and preparation method therefor and use thereof - Google Patents

2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compound and preparation method therefor and use thereof Download PDF

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WO2018214639A1
WO2018214639A1 PCT/CN2018/080787 CN2018080787W WO2018214639A1 WO 2018214639 A1 WO2018214639 A1 WO 2018214639A1 CN 2018080787 W CN2018080787 W CN 2018080787W WO 2018214639 A1 WO2018214639 A1 WO 2018214639A1
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substituted
unsubstituted
group
alkyl
compound
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Chinese (zh)
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黄海洪
李鹏
李刚
马辰
张婷婷
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中国医学科学院药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D497/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D497/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having oxygen and sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D497/10—Spiro-condensed systems

Definitions

  • the invention belongs to the field of medical technology.
  • it relates to a 2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compound represented by the formula (I), which is prepared by using the compound as Pharmaceutical compositions of the active ingredients, and their use in the treatment and/or prevention of infectious diseases caused by Mycobacterium tuberculosis.
  • Tuberculosis is a chronic lethal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. Tuberculosis, like AIDS, has become one of the leading causes of death worldwide. According to the World Health Organization (WHO) estimate (Global tuberculosis report 2016), the number of new tuberculosis cases in the world was about 10.4 million in 2015, of which 5.9 million were men (56%) and 3.5 million were women (34%), 100 Ten thousand children (10%). 1.2 million new cases of tuberculosis are HIV-infected (11%), with an estimated 1.4 million deaths from tuberculosis and 400,000 people living with HIV dying from tuberculosis.
  • WHO World Health Organization
  • Chemotherapy is the main means of treatment for tuberculosis.
  • streptomycin in 1944 created a new era of anti-tuberculosis drug treatment.
  • isoniazid, rifampicin and pyrazinamide the treatment of tuberculosis was shortened to 6 months, and it entered the short-course chemotherapy. era”.
  • long-term combined drug treatment has caused adverse reactions in patients, and it is difficult to adhere to regular medication.
  • most of the drugs used were born in the 1950s and 1960s. The long-term, extensive and irregular use of drug-resistant bacteria has become increasingly serious and multi-drugs have emerged.
  • Drug-resistant tuberculosis MDR-TB
  • XDR-TB all drug-resistant tuberculosis
  • TDR-TB drug-resistant tuberculosis
  • the technical problem to be solved by the present invention is to provide a 2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4 which is novel in structure and has strong anti-tuberculosis activity against Mycobacterium tuberculosis. - ketone compounds.
  • the present inventors have found that 2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compounds have strong anti-tuberculosis mycobacteria and can be used by bacteria Infectious diseases, especially treatment or prophylactic treatment of tuberculosis (TB) diseases caused by mycobacteria, can also be used to overcome problems associated with drug resistance.
  • the present invention has been completed based on the above findings.
  • the first aspect of the present invention provides a compound represented by the formula (I), and an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • X is O or S
  • Y is C or N
  • n 0, 1 or 2;
  • R 2 is F, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, a substituted or unsubstituted C 3 -C 6 heterocyclic group, a substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted a C 2 -C 9 heteroaryl group, or together with a carbon atom to which it is attached, denotes a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms or 1 to 3 hetero atoms selected from oxygen and sulfur. a substituted or unsubstituted 4-6 membered heterocyclic group;
  • the C 3 -C 6 -membered heterocyclic group, C 2 -C 9 heteroaryl group contains at least one hetero atom selected from N, O, S;
  • the substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  • Y, R 1 , R 2 , and n are as defined in the first aspect of the invention.
  • Y, R 1 , R 2 , and n are as defined in the first aspect of the invention.
  • the compound of formula (I) is selected from the group consisting of compounds of formula (II-a):
  • n 0 or 1
  • R 2 is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with a covalently bonded carbon atom means substituted or unsubstituted cyclopentyl or 1-2 a substituted or unsubstituted 5-membered heterocyclic group selected from hetero atoms of oxygen and sulfur;
  • the substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  • the compound of formula (I) is selected from the group consisting of compounds of formula (II-b):
  • n 0 or 1
  • R 2 is a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrole group. a substituted or unsubstituted furanyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group;
  • the substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino;
  • the compound of formula (I) is selected from the group consisting of compounds of formula (III-a):
  • n 0 or 1
  • R 2 is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with a covalently bonded carbon atom means substituted or unsubstituted cyclopentyl or 1-2 a substituted or unsubstituted 5-membered heterocyclic group selected from hetero atoms of oxygen and sulfur;
  • the substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino;
  • the compound of formula (I) is selected from the group consisting of compounds of formula (III-b):
  • n 0 or 1
  • R 2 is a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrole a substituted or unsubstituted furanyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group;
  • the substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino;
  • n is preferably 0, 1 or 2;
  • R 2 is preferably F
  • R 2 is preferably
  • Rx is F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 - C 3 alkoxy or C 1 -C 3 alkylamino;
  • the pharmaceutically acceptable salt described in the present invention is a salt of the compound of the present invention and an acid selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, and lemon. Acid, acetic acid or trifluoroacetic acid. It is preferably hydrochloric acid, p-toluenesulfonic acid or trifluoroacetic acid.
  • a compound according to any one of the first aspects of the invention which is an object of the invention (expressed by structural formula or by system nomenclature) and an isomer thereof, a pharmaceutically acceptable salt thereof, prepared as an example.
  • a compound according to any one of the first aspects of the invention which is a compound selected from the group consisting of:
  • a second aspect of the invention provides a process for the preparation of a compound of any of the first aspects of the invention, comprising the steps of:
  • the compound of formula C is in an inert solvent (Ar or N 2 ) in a suitable solvent (for example DMF, DMSO, preferably DMF) under basic conditions (for example sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate). Under the protection, the reaction is carried out at 20 to 140 ° C for 0.5 to 12 hours, preferably at 110 ° C for 1-5 hours to obtain a compound of the formula (II).
  • a suitable solvent for example DMF, DMSO, preferably DMF
  • basic conditions for example sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate
  • the compound A in the present invention can be easily produced by referring to a method known in the prior art, for example (J. Med. Chem. 2007, 50, 3369-3379).
  • the compound of formula (III) is dissolved or suspended in a suitable solvent (for example, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, preferably ethanol, isopropanol) at room temperature or under heating, in air or inert Under the protection of gas (Ar or N 2 ), add the corresponding acid solution (such as hydrochloric acid, sulfuric acid, hydrochloric acid ethanol, preferably hydrochloric acid), stir at room temperature or under heating for 1-48 hours, preferably at room temperature for 2 hours, filtered. The corresponding solvent is washed and dried to obtain the corresponding salt of the compound of the formula (III).
  • a suitable solvent for example, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, preferably ethanol, isopropanol
  • a suitable solvent for example, dichloromethane, tetrahydrofuran, methanol, ethanol, iso
  • a third aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the first aspects of the invention, and a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable Accepted accessories.
  • a fourth aspect of the present invention provides the compound according to any one of the first aspects of the present invention, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the third aspects of the present invention for the preparation of a medicament for treating and/or preventing tuberculosis Use in bacilli-induced infectious disease drugs.
  • substituted or unsubstituted means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When the structure given is always more than one position which can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
  • C i -C j represents a moiety having an integer "i" (including i) to an integer "j" (containing j) carbon atoms.
  • C 1 -C 3 alkyl refers to an alkyl group having 1 to 3 (including 1 and 3) carbon atoms.
  • C 2 -C 9 heteroaryl refers to a heteroaryl group having 2 to 9 (including 2 and 9) carbon atoms, and includes a tetrazolyl group, a triazozolyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a quinoline group. base.
  • alkyl refers to an alkyl group having the specified number of carbon atoms, which is a straight or branched alkyl group, and which may include a subgroup thereof, for example, reference to "C 1 - when C 3 alkyl group ", which may also include sub-ranges of the group represented by C 1 -C 2 alkyl group, and specific groups such as methyl, ethyl, n-propyl, isopropyl.
  • alkoxy and alkylamino are used conventionally to refer to an alkyl group attached to the remainder of the molecule through an oxygen or amine group, respectively, wherein the alkyl group is Invention.
  • haloalkyl means that the hydrogen on the alkyl group is replaced by one or more halogen atoms, examples of which include, but are not limited to, monofluoromethyl, monofluoromethoxy, and the like. .
  • cycloalkyl refers to a cyclic alkyl group having the specified number of number of ring carbon atoms, and which may include a sub-group thereof, for example, reference “C 3 -C 6 cycloalkyl” when It may further include a sub-range group represented by a C 3 -C 5 cycloalkyl group, a C 4 -C 6 cycloalkyl group or the like, and a specific group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. .
  • C 3 -C 6 heterocycloalkyl refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 6 ring carbon atoms.
  • a heterocyclic group can be a carbyl or a nitrogen group, and a -CH 2 - group can be optionally substituted with a carbonyl group.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • Heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine , high piperazinyl and the like.
  • C 6 -C 10 aryl denotes a monocyclic and bicyclic carbon ring system containing 6 ring atoms or 6-10 ring atoms, wherein at least one ring is aromatic, wherein Each ring contains a ring of 3-6 atoms and one or more attachment points in the ring system are attached to the remainder of the molecule.
  • the aromatic group may include a phenyl group and a naphthyl group.
  • C 2 -C 9 heteroaryl having 1 to 3 heteroatoms as used herein refers to ring atoms, the remaining ring atoms being carbon of an aromatic group, a hetero atom include oxygen, nitrogen and sulfur, .
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, furyl, thienyl, pyrazinyl Wait.
  • ring refers to a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted. Heteroaryl.
  • the so-called ring includes a fused ring.
  • the number of atoms on the ring is usually defined as the number of elements of the ring. For example, "C 3 -C 6 ring” means that 3-6 atoms are arranged around.
  • heteroatom refers to a form of O, S, N, including any oxidation state of N, S; a form of primary, secondary, tertiary, and quaternary ammonium salts; or a nitrogen atom in a heterocyclic ring.
  • the hydrogen is replaced by the form.
  • halogen means fluorine (F), chlorine (Cl) or bromine (Br).
  • Room temperature in the present invention means that the temperature is from 10 ° C to 40 ° C.
  • room temperature refers to a temperature of from 20 ° C to 30 ° C; in other embodiments, room temperature refers to 25 ° C.
  • the term "effective amount” refers to the amount of drug that can be used to achieve the desired treatment of a disease or condition of the invention in a subject.
  • the term "pharmaceutically acceptable”, for example when describing a “pharmaceutically acceptable salt,” means that the salt is not only physiologically acceptable to the subject, but may also refer to a pharmaceutically useful synthetic. substance.
  • composition which may also refer to a “composition,” which can be used to effect treatment of a disease or condition of the invention in a subject, particularly a mammal.
  • the "treatment” of the disease includes:
  • Therapeutically effective amount refers to an amount of a compound that is sufficient to effect treatment of the disease when administered to a mammal for the treatment of a disease.
  • the therapeutically effective amount will vary depending on the compound, the condition to be treated and its severity, and the age, weight, sex, etc. of the mammal.
  • a therapeutically effective amount can also refer to any amount of a compound sufficient to achieve the desired beneficial effect, including the prevention of a disease, the suppression of a disease, or the alleviation of a disease as described in (1)-(3) above.
  • the amount of the compound may range from 0.1 to 250 mg/kg, or preferably from 0.5 to 100 mg/kg, or more preferably from 1 to 50 mg/kg, or even more preferably from 2 to 20 mg/kg.
  • the amount of the compound is administered to the mammal twice daily. More preferably, the amount of the compound is administered to the mammal once a day.
  • disease and/or condition refers to a physical state of the subject that is associated with the disease and/or condition of the invention.
  • the disease and/or condition of the present invention refers to a Mycobacterium tuberculosis infectious disease.
  • the term "subject" can refer to a patient or other animal, particularly a mammal, such as a human, a dog, that receives a compound of formula I of the invention, or a pharmaceutical composition thereof, for the treatment of a disease or condition according to the invention. Monkeys, cows, horses, etc.
  • Still another aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention as an active ingredient.
  • the pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
  • the compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, Lung and respiratory tract, skin, vagina, rectum, etc.
  • the dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
  • the compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
  • diluents may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • wetting agent may be water, ethanol, or different Propyl alcohol, etc.
  • the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group
  • disintegrant can be dry starch, microcrystalline cellulose, low
  • Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
  • the active ingredient of the present compound may be mixed with a diluent, a co-solvent, and the mixture may be directly placed in a hard capsule or a soft capsule.
  • the active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule.
  • the various diluents, binders, wetting agents, disintegrating agents, and solubilizing agents used in the preparation of the tablets of the present invention are also useful in the preparation of capsules of the compounds of the present invention.
  • water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizer, a solubilizer, a pH adjuster, an osmotic pressure adjusting agent which is commonly used in the art may be added.
  • the solubilizer or cosolvent may be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.;
  • the pH adjuster may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.;
  • osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like.
  • mannitol, glucose or the like may also be added as a proppant.
  • coloring agents may also be added to the pharmaceutical preparations as needed.
  • the pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
  • the compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents.
  • the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
  • the inventors of the present application have conducted extensive research to synthesize a series of compounds, and the minimum inhibitory concentration MIC (Minimum inhibitory concentration) of M. tuberculosis H 37 Rv strain by MABA (Microplate alamar blue assay) method shows that Good anti-tuberculous mycobacterial activity, in which 14 compounds with MIC ⁇ 0.5 ⁇ g/mL were obtained, and the MIC of 13 compounds reached 10 -8 g/mL, which is equivalent to the anti-tuberculosis first-line drug isoniazid, in addition to Vero cytotoxicity Low (IC 50 greater than 64 ⁇ g/mL) showed good safety and showed higher in the HepG2 cytotoxicity test than the benzothiazinone compound PBTZ169 (EMBO Mol.
  • MIC Minimum inhibitory concentration
  • the invention provides a novel compound with novel structure, strong anti-tuberculosis activity in vivo and good pharmacokinetic properties, and the mother core structure is benzopyrone or benzothiopyranone structure, which can be used for infection caused by bacteria. Sexual diseases, especially the treatment or prophylaxis of tuberculosis caused by M. tuberculosis, can also be used to overcome problems related to drug resistance.
  • the structure of the compound was determined by nuclear magnetic resonance spectroscopy ( 1 H NMR).
  • the nuclear magnetic resonance spectrum and the carbon spectral shift ( ⁇ ) are given in units of parts per million (ppm).
  • the coupling constant (J) is in Hertz (Hz).
  • the nuclear magnetic resonance spectrum was measured by a Mercury-400 nuclear magnetic resonance spectrometer, deuterated chloroform (CDCl 3 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ) as a solvent, and tetramethylsilane (TMS) as an internal standard.
  • the electronic balance uses the Japanese Yanaco LY-300 electronic balance.
  • Anhydrous solvents are treated by standard methods. All other reagents were of commercially available analytical grade.
  • the present invention uses the following abbreviations:
  • CDI is carbonyl diimidazole.
  • DCC is dicyclohexylcarbodiimide.
  • DMF is N,N-dimethylformamide.
  • DMSO dimethyl sulfoxide
  • EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HOBT is 1-hydroxybenzotriazole.
  • HATU is 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
  • the first step is 1-(2-chloro-3-nitro-5-trifluoromethylphenyl)-3-(4-(cyclohexylmethyl)piperazin-1-yl)propane-1,3-di Preparation of ketone B-2
  • MABA Microplate Alamar Blue Assay
  • Alamar Blue is added to the medium as a redox indicator, and the color changes from blue to red, reflecting the consumption of oxygen molecules by the microorganisms studied.
  • the color change of Alamar Blue can be measured with a luminometer with an emission wavelength of 590 nm.
  • test compound was dissolved in DMSO to prepare a primary solution at a concentration of 5 mg/mL, and the highest concentration well was added to 199 ⁇ L of 7H9 medium, 1 ⁇ L of the initial solution of the compound. After mixing well, the remaining wells were diluted 2-fold sequentially, and the final concentrations of the compounds were: 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, 0.025 ⁇ g/mL.
  • the cultures of Mycobacterium tuberculosis H 37 R v were cultured for 2 to 3 weeks to prepare a bacterial suspension, and inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC, 37
  • the cells were cultured at °C for 1 to 2 weeks and grown to a turbidity of McFarland 1 (corresponding to 10 7 CFU/mL). After dilution at 1:20, 100 ⁇ L of each well was added, and the final concentration of the bacterial solution was 10 6 CFU/mL.
  • Two growth control wells containing no antibacterial agents were placed on each plate, and 96-well plates were incubated at 37 °C.
  • a isoniazid resistant rifampicin, streptomycin, ethambutol, rifapentine, rifabutin and benzoylaminosalicylic acid.
  • the compounds of the present invention have strong activity against anti-tuberculosis-sensitive bacteria and resistant bacteria in vitro.
  • the test drug was dissolved in DMSO, diluted 50 times with the medium to prepare the highest concentration of the test, and then serially diluted with 1:3 in a 96-well plate, and each compound was set to 6 concentrations, the highest.
  • the concentration was 64 ⁇ g/mL, and each concentration was set to 6 parallel wells, 50 ⁇ L/well.
  • the prepared cell suspension was inoculated into a 96-well plate at 50 ⁇ L/well with a cell concentration of 4 ⁇ 10 5 /mL. At the same time, a cell control well containing no drug and a blank control well of the medium were set. After 48 hours of incubation, MTT 10 ⁇ L/well was added and incubation was continued for 4 hours.
  • the compound of the present invention has low cytotoxicity and exhibits higher safety than the positive drug PBTZ169.
  • the target compound was selected for the metabolic stability study of liver microsomes (Bioreclamation).
  • the specific method was as follows: The synthesized target compound was separately prepared into a 1 ⁇ M test solution. The microsomal protein concentration was 1 mg/mL. The reaction was initiated by the addition of NADPH (1 mM) and the samples were incubated in a shaking incubator at 37 °C for up to 60 minutes. The reaction was terminated at 0, 5, 15 and 30 minutes by the addition of an ice-cold acetonitrile/methanol (50:50) containing an internal standard.
  • the compounds of the present invention have high metabolic stability of liver microsomes.
  • the compound 11 of the present invention has a longer half-life than the positive control drug PBTZ169 in five species of hepatocytes, and the metabolic stability is significantly superior to that of PBTZ169.
  • Compound 11 was formulated as a 2.5 mg/mL suspension with 0.5% carboxymethylcellulose and 0.5% Tween 80.
  • Compound 22 was formulated as a 2.5 mg/mL suspension with 0.5% carboxymethylcellulose and 0.5% carboxylate with PBTZ169.
  • Methylcellulose and 4 molar equivalents of 1 N hydrochloric acid were formulated into a 2.5 mg/mL suspension, and all compounds were administered at a dose of 25 mg/kg.
  • Plasma samples were collected at 5, 15, 30 minutes, and 1, 2, 4, 7, 24 hours after oral administration. The collected plasma samples were stored at -80 °C until used for analysis.
  • Plasma samples were extracted with acetonitrile containing the terfenadine internal standard with a ratio of extractant to plasma of 20:1.
  • Analyte quantification was performed by LC/TSQ Quantum Access mass spectrometer (AB Sciex 5500). Chromatographic conditions: column: Kinetex C18 100A (30 mm ⁇ 3.0 mm, 2.6 ⁇ m); column temperature: room temperature, mobile phase: acetonitrile / water (80:20, v / v) (containing 0.1% formic acid); flow rate: 0.8mL /min.
  • Compound detection on the mass spectrometer was performed in electrospray positive ionization mode.

Abstract

Disclosed are a 2-azacyclo-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compound, a preparation method therefor and the use thereof in a drug for treating and/or preventing infectious diseases caused by Mycobacterium tuberculosis. In particular, the present invention relates to a compound as shown in the formula (I) and an isomer thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound of the present invention, wherein X, Y, R1, R2 and n are as described in the description. The present invention is intended to prepare a novel compound having an anti-Mycobacterium tuberculosis activity, which as a potential new drug can be used in the treatment or prophylactic treatment of infectious diseases caused by bacteria, particularly tuberculosis (TB) diseases caused by mycobacteria, and also can be used to overcome problems associated with the drug resistance of Mycobacterium tuberculosis.

Description

2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物及其制备方法和用途2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compound, preparation method and use thereof 技术领域Technical field
本发明属于医药技术领域。特别涉及通式(I)所示的2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物，其制备方法，以该化合物为活性成分的药物组合物，以及它们在治疗和/或预防由结核分枝杆菌引起的感染性疾病中的应用。The invention belongs to the field of medical technology. In particular, it relates to a 2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compound represented by the formula (I), which is prepared by using the compound as Pharmaceutical compositions of the active ingredients, and their use in the treatment and/or prevention of infectious diseases caused by Mycobacterium tuberculosis.
背景技术Background technique
结核病(tuberculosis，TB)是由结核分枝杆菌引起的一种慢性致死性疾病，是危害人类健康和导致人类死亡的重大传染性疾病，结核病与艾滋病一样，成为全世界主要死亡原因之一。据世界卫生组织(WHO)估计(Global tuberculosis report2016)，2015年全世界新发结核病数量约为1040万例，其中590万为男性(占56％)，350万为女性(占34％)，100万为儿童(占10％)。120万新发结核病例为艾滋病毒感染者(占11％)，据估计有140万人死于结核病，还有40万艾滋病毒感染者死于结核病。Tuberculosis (TB) is a chronic lethal disease caused by Mycobacterium tuberculosis. It is a major infectious disease that endangers human health and causes human death. Tuberculosis, like AIDS, has become one of the leading causes of death worldwide. According to the World Health Organization (WHO) estimate (Global tuberculosis report 2016), the number of new tuberculosis cases in the world was about 10.4 million in 2015, of which 5.9 million were men (56%) and 3.5 million were women (34%), 100 Ten thousand children (10%). 1.2 million new cases of tuberculosis are HIV-infected (11%), with an estimated 1.4 million deaths from tuberculosis and 400,000 people living with HIV dying from tuberculosis.
化学治疗是结核病治疗的主要手段。1944年链霉素的使用，开创了抗结核药物治疗的新时代，随着异烟肼、利福平、吡嗪酰胺的相继出现，使得治疗结核病疗程缩短到6个月，进入了“短程化疗时代”。尽管如此，长期药物联合治疗，使患者产生不良反应，难以坚持规律用药，加之所用药物多诞生于上世纪五六十年代，长期、广泛及不规范使用使得耐药菌发展日趋严重，出现多药耐药结核(MDR-TB)、广泛耐药结核(XDR-TB)与全部耐药结核(TDR-TB)。面对耐药结核，需使用价格昂贵且毒性较大的二线甚至三线抗结核药物。因此，研发具有新型骨架、新颖作用机制的抗结核药物以治疗与控制结核病，尤其是耐药结核尤为迫切。抗结核新药需要具有高效力、低毒性以及能够缩短治疗时间等特点。Chemotherapy is the main means of treatment for tuberculosis. The use of streptomycin in 1944 created a new era of anti-tuberculosis drug treatment. With the emergence of isoniazid, rifampicin and pyrazinamide, the treatment of tuberculosis was shortened to 6 months, and it entered the short-course chemotherapy. era". Despite this, long-term combined drug treatment has caused adverse reactions in patients, and it is difficult to adhere to regular medication. In addition, most of the drugs used were born in the 1950s and 1960s. The long-term, extensive and irregular use of drug-resistant bacteria has become increasingly serious and multi-drugs have emerged. Drug-resistant tuberculosis (MDR-TB), XDR-TB and all drug-resistant tuberculosis (TDR-TB). In the face of drug-resistant tuberculosis, it is necessary to use expensive and toxic second- and even third-line anti-tuberculosis drugs. Therefore, it is particularly urgent to develop anti-tuberculosis drugs with novel skeletons and novel mechanisms of action to treat and control tuberculosis, especially drug-resistant tuberculosis. New anti-tuberculosis drugs require high efficiency, low toxicity, and reduced treatment time.
发明内容Summary of the invention
本发明要解决的技术问题是提供一种结构新颖并具有强抗结核分枝杆菌活性的2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物。本发明发现，2-氮杂环-5-三氟甲基-8-硝基苯并(硫代)吡喃-4-酮类化合物具有强的抗结核分枝杆 菌作用，可用于由细菌引起的感染性疾病，特别是由分枝杆菌引起的肺结核(TB)疾病的治疗或预防性治疗，同时可用于克服与耐药性有关的问题。本发明基于以上发现而得以完成。The technical problem to be solved by the present invention is to provide a 2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4 which is novel in structure and has strong anti-tuberculosis activity against Mycobacterium tuberculosis. - ketone compounds. The present inventors have found that 2-nitrohetero-5-trifluoromethyl-8-nitrobenzo(thio)pyran-4-one compounds have strong anti-tuberculosis mycobacteria and can be used by bacteria Infectious diseases, especially treatment or prophylactic treatment of tuberculosis (TB) diseases caused by mycobacteria, can also be used to overcome problems associated with drug resistance. The present invention has been completed based on the above findings.
发明概述Summary of invention
为此，本发明第一方面提供通式(I)所示的化合物及其异构体、或其药学上可接受的盐，To this end, the first aspect of the present invention provides a compound represented by the formula (I), and an isomer thereof, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2018080787-appb-000001
Figure PCTCN2018080787-appb-000001
其中，among them,
X为O或S；X is O or S;
Y为C或N；Y is C or N;
R 1为H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)、(＝S)； R 1 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN , OH, (= O), (= S);
n为0、1或2；n is 0, 1 or 2;
R 2为F、取代或未取代的C 3-C 6环烷基、取代或未取代的C 3-C 6杂环基、取代或未取代的C 6-C 10芳基、取代或未取代的C 2-C 9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基； R 2 is F, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, a substituted or unsubstituted C 3 -C 6 heterocyclic group, a substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted a C 2 -C 9 heteroaryl group, or together with a carbon atom to which it is attached, denotes a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms or 1 to 3 hetero atoms selected from oxygen and sulfur. a substituted or unsubstituted 4-6 membered heterocyclic group;
所述C 3-C 6元杂环基、C 2-C 9杂芳基至少含有一个选自N、O、S中的杂原子； The C 3 -C 6 -membered heterocyclic group, C 2 -C 9 heteroaryl group contains at least one hetero atom selected from N, O, S;
所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
在一优选例中，所述化合物结构式如(II)所示：In a preferred embodiment, the structural formula of the compound is as shown in (II):
Figure PCTCN2018080787-appb-000002
Figure PCTCN2018080787-appb-000002
其中，Y、R 1、R 2、n定义同本发明第一方面所述。 Wherein Y, R 1 , R 2 , and n are as defined in the first aspect of the invention.
在另一优选例中，所述化合物结构式如(III)所示：In another preferred embodiment, the structural formula of the compound is as shown in (III):
Figure PCTCN2018080787-appb-000003
Figure PCTCN2018080787-appb-000003
其中，Y、R 1、R 2、n定义同本发明第一方面所述。 Wherein Y, R 1 , R 2 , and n are as defined in the first aspect of the invention.
在一些方面，式(I)化合物选自式(II-a)化合物：In some aspects, the compound of formula (I) is selected from the group consisting of compounds of formula (II-a):
Figure PCTCN2018080787-appb-000004
Figure PCTCN2018080787-appb-000004
其中，among them,
R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
n为0或1；n is 0 or 1;
R 2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基； R 2 is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with a covalently bonded carbon atom means substituted or unsubstituted cyclopentyl or 1-2 a substituted or unsubstituted 5-membered heterocyclic group selected from hetero atoms of oxygen and sulfur;
所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
在一些方面，式(I)化合物选自式(II-b)化合物：In some aspects, the compound of formula (I) is selected from the group consisting of compounds of formula (II-b):
Figure PCTCN2018080787-appb-000005
Figure PCTCN2018080787-appb-000005
其中，among them,
R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
n为0或1；n is 0 or 1;
R 2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基； R 2 is a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrole group. a substituted or unsubstituted furanyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group;
所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基； The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino;
在一些方面，式(I)化合物选自式(III-a)化合物：In some aspects, the compound of formula (I) is selected from the group consisting of compounds of formula (III-a):
Figure PCTCN2018080787-appb-000006
Figure PCTCN2018080787-appb-000006
其中，among them,
R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
n为0或1；n is 0 or 1;
R 2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基； R 2 is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with a covalently bonded carbon atom means substituted or unsubstituted cyclopentyl or 1-2 a substituted or unsubstituted 5-membered heterocyclic group selected from hetero atoms of oxygen and sulfur;
所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基； The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino;
在一些方面，式(I)化合物选自式(III-b)化合物：In some aspects, the compound of formula (I) is selected from the group consisting of compounds of formula (III-b):
Figure PCTCN2018080787-appb-000007
Figure PCTCN2018080787-appb-000007
其中，among them,
R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
n为0或1；n is 0 or 1;
R 2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基； R 2 is a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrole a substituted or unsubstituted furanyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group;
所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基； The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino;
在式(II)和(III)方案中，In the formulas (II) and (III),
n优选为0、1或2；n is preferably 0, 1 or 2;
R 1优选H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)或(＝S)； R 1 is preferably H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN, OH, (=O) or (=S);
当Y为C时，When Y is C,
R 2优选为F、
Figure PCTCN2018080787-appb-000008
Figure PCTCN2018080787-appb-000009
R 2 is preferably F,
Figure PCTCN2018080787-appb-000008
Figure PCTCN2018080787-appb-000009
当Y为N时，When Y is N,
R 2优选为
Figure PCTCN2018080787-appb-000010
Figure PCTCN2018080787-appb-000011
R 2 is preferably
Figure PCTCN2018080787-appb-000010
Figure PCTCN2018080787-appb-000011
Rx为F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基； Rx is F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 - C 3 alkoxy or C 1 -C 3 alkylamino;
本发明中所述的药学上可接受的盐为本发明化合物与选自下列的酸形成的 盐：盐酸、对甲苯磺酸、酒石酸、马来酸、乳酸、甲磺酸、硫酸、磷酸、柠檬酸、乙酸或三氟乙酸。优选为盐酸、对甲苯磺酸或三氟乙酸。The pharmaceutically acceptable salt described in the present invention is a salt of the compound of the present invention and an acid selected from the group consisting of hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, and lemon. Acid, acetic acid or trifluoroacetic acid. It is preferably hydrochloric acid, p-toluenesulfonic acid or trifluoroacetic acid.
根据本发明第一方面任一项的化合物，其为实施例制备的本发明目标化合物(以结构式表示的或以***命名描述的)及其异构体，其药学可接受的盐。A compound according to any one of the first aspects of the invention, which is an object of the invention (expressed by structural formula or by system nomenclature) and an isomer thereof, a pharmaceutically acceptable salt thereof, prepared as an example.
根据本发明第一方面任一项化合物，其为选自下列的化合物：A compound according to any one of the first aspects of the invention, which is a compound selected from the group consisting of:
Figure PCTCN2018080787-appb-000012
Figure PCTCN2018080787-appb-000012
Figure PCTCN2018080787-appb-000013
Figure PCTCN2018080787-appb-000013
Figure PCTCN2018080787-appb-000014
Figure PCTCN2018080787-appb-000014
本发明第二方面提供了制备本发明第一方面任一项所述化合物的方法，其包括以下步骤：A second aspect of the invention provides a process for the preparation of a compound of any of the first aspects of the invention, comprising the steps of:
Figure PCTCN2018080787-appb-000015
Figure PCTCN2018080787-appb-000015
化合物A在合适的溶剂(例如二氯甲烷、四氢呋喃、乙腈，优选二氯甲烷)中，与胺类化合物B，在缩合试剂(例如CDI、DCC、EDCI\HOBT、HATU，优选DCC)的作用下，在空气或惰性气体(Ar或N 2)保护下，置于-10℃-50℃反应1-24小时，其中优选室温反应8-15小时，得到式C所示化合物； Compound A in a suitable solvent (eg dichloromethane, tetrahydrofuran, acetonitrile, preferably dichloromethane) with amine compound B under the action of a condensation reagent (eg CDI, DCC, EDCI\HOBT, HATU, preferably DCC) Under the protection of air or an inert gas (Ar or N 2 ), the reaction is carried out at -10 ° C to 50 ° C for 1-24 hours, wherein preferably at room temperature for 8-15 hours, to obtain a compound of formula C;
式C所示化合物在适当的溶剂(例如DMF、DMSO，优选DMF)中，在碱性条件(例如碳酸钠、碳酸钾或碳酸铯，优选碳酸钾)下，在惰性气体(Ar或N 2)保护下，于20-140℃下反应0.5-12小时，优选110℃条件下反应1-5小时，得到式(II)化合物。 The compound of formula C is in an inert solvent (Ar or N 2 ) in a suitable solvent (for example DMF, DMSO, preferably DMF) under basic conditions (for example sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate). Under the protection, the reaction is carried out at 20 to 140 ° C for 0.5 to 12 hours, preferably at 110 ° C for 1-5 hours to obtain a compound of the formula (II).
本发明中的化合物A参考现有出版物中已知的方法即可容易制得，例如(J. Med.Chem.2007,50,3369-3379)。The compound A in the present invention can be easily produced by referring to a method known in the prior art, for example (J. Med. Chem. 2007, 50, 3369-3379).
Figure PCTCN2018080787-appb-000016
Figure PCTCN2018080787-appb-000016
化合物D与二硫化碳在合适的溶剂(例如甲苯、丙酮、四氢呋喃、DMF、DMSO，优选DMSO)中，在碱性条件(例如NaH、氢氧化钠、甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠，优选氢氧化钠)下，在空气或惰性气体(Ar或N 2)保护下，于-10-30℃下反应10-60分钟，优选15-25℃下反应15-30分钟，随后在15-25℃下加入MeI，反应30-60分钟，得到化合物E； Compound D and carbon disulfide in a suitable solvent (such as toluene, acetone, tetrahydrofuran, DMF, DMSO, preferably DMSO) under basic conditions (such as NaH, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide, tert-butyl) Under sodium alkoxide, preferably sodium hydroxide, under the protection of air or an inert gas (Ar or N 2 ), react at 10-30 ° C for 10-60 minutes, preferably 15-25 ° C for 15-30 minutes, then Adding MeI at 15-25 ° C, the reaction is 30-60 minutes, to obtain the compound E;
化合物E与胺类化合物B，在合适的溶剂(例如叔丁醇、异丙醇、乙二醇、乙二醇二甲醚、DMF、DMSO，优选异丙醇)中，在空气或惰性气体(Ar或N 2)保护下，于80-160℃下反应1-48小时，优选120-140℃反应20-25小时，得到式(III)化合物。 Compound E and amine compound B in a suitable solvent (eg t-butanol, isopropanol, ethylene glycol, ethylene glycol dimethyl ether, DMF, DMSO, preferably isopropanol) in air or an inert gas ( Under the protection of Ar or N 2 ), the reaction is carried out at 80-160 ° C for 1-48 hours, preferably 120-140 ° C for 20-25 hours to obtain a compound of formula (III).
将式(III)化合物于室温或加热条件下，溶解或混悬在合适的溶剂(例如二氯甲烷、四氢呋喃、甲醇、乙醇、异丙醇，优选乙醇、异丙醇)中，在空气或惰性气体(Ar或N 2)保护下，加入相应的酸溶液(例如盐酸、硫酸、盐酸乙醇，优选盐酸乙醇)，于室温或加热条件下搅拌1-48小时，优选室温下搅拌2小时，经过滤，相应溶剂洗涤，干燥后得到式(III)化合物相应的盐。 The compound of formula (III) is dissolved or suspended in a suitable solvent (for example, dichloromethane, tetrahydrofuran, methanol, ethanol, isopropanol, preferably ethanol, isopropanol) at room temperature or under heating, in air or inert Under the protection of gas (Ar or N 2 ), add the corresponding acid solution (such as hydrochloric acid, sulfuric acid, hydrochloric acid ethanol, preferably hydrochloric acid), stir at room temperature or under heating for 1-48 hours, preferably at room temperature for 2 hours, filtered. The corresponding solvent is washed and dried to obtain the corresponding salt of the compound of the formula (III).
本发明第三方面提供了一种药用组合物，其包括治疗有效量的本发明第一方面任一项所述化合物及其药学可接受的盐，以及任选的一种或多种药学可接受的辅料。A third aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of the first aspects of the invention, and a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable Accepted accessories.
本发明第四方面提供了本发明第一方面任一项所述化合物及其药学可接受的盐，或者本发明第三方面任一项所述药物组合物在制备治疗和/或预防结核分枝杆菌引起的感染性疾病药物中的应用。A fourth aspect of the present invention provides the compound according to any one of the first aspects of the present invention, and a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of the third aspects of the present invention for the preparation of a medicament for treating and/or preventing tuberculosis Use in bacilli-induced infectious disease drugs.
前面所述内容只概述了本发明的某些方面，但并不限于这方面。这些方面及其他的方面内容将在下面做更加具体完整的描述。The foregoing description merely summarizes certain aspects of the invention, but is not limited in this respect. These and other aspects will be described in more detail below.
发明详述Detailed description of the invention
下面对本发明的各个方面和特点作进一步的描述。Various aspects and features of the present invention are further described below.
本发明所引述的所有文献，它们的全部内容通过引用并入本文，并且如果这 些文献所表达的含义与本发明不一致时，以本发明的表述为准。此外，本发明使用的各种术语和短语具有本领域技术人员公知的一般含义，即便如此，本发明仍然希望在此对这些术语和短语作更详尽的说明和解释，提及的术语和短语如有与公知含义不一致的，以本发明所表述的含义为准。下面是本发明所用多种术语的定义，这些定义适用于本申请整个说明书中所用的术语，除非在具体情况中另作说明。All documents cited in the present invention are hereby incorporated by reference in their entirety, and if the meanings expressed by these documents are inconsistent with the present invention, the expression of the present invention shall prevail. Moreover, the various terms and phrases used in the present invention have the ordinary meanings well known to those skilled in the art, and even though the present invention is intended to provide a more detailed description and explanation of the terms and phrases herein, such terms and phrases are Inconsistent with the well-known meaning, the meaning expressed in the present invention shall prevail. The following are definitions of various terms used in the present invention, which apply to the terms used throughout the specification of the present application unless otherwise specified in the specific context.
一般而言，术语“取代或未取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个任选的取代基团可以在基团各个可取代的位置进行取代。当所给出的结构始终不只有一个位置能被选自具体基团得一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。In general, the term "substituted or unsubstituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group can be substituted at each substitutable position of the group. When the structure given is always more than one position which can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently.
C i-C j表示具有整数“i”(包含i)至整数“j”(包含j)个碳原子的部分。因此，例如C 1-C 3烷基指具有1至3个(包含1和3)碳原子的烷基。例如C 2-C 9杂芳基指具有2至9个(包含2和9)碳原子的杂芳基，包含四氮唑基、三氮唑基、噻吩基、吡啶基、嘧啶基、喹啉基。 C i -C j represents a moiety having an integer "i" (including i) to an integer "j" (containing j) carbon atoms. Thus, for example, C 1 -C 3 alkyl refers to an alkyl group having 1 to 3 (including 1 and 3) carbon atoms. For example, C 2 -C 9 heteroaryl refers to a heteroaryl group having 2 to 9 (including 2 and 9) carbon atoms, and includes a tetrazolyl group, a triazozolyl group, a thienyl group, a pyridyl group, a pyrimidinyl group, a quinoline group. base.
如本文所述的，术语“烷基”是指具有指定数目碳原子数的烷基，其为直链或支链的烷基，并且其可包括其子基团，例如提及“C 1-C 3烷基”时，其还可以包括C 1-C 2烷基表示的子范围的基团，以及具体基团例如甲基、乙基、正丙基、异丙基。 As used herein, the term "alkyl" refers to an alkyl group having the specified number of carbon atoms, which is a straight or branched alkyl group, and which may include a subgroup thereof, for example, reference to "C 1 - when C 3 alkyl group ", which may also include sub-ranges of the group represented by C 1 -C 2 alkyl group, and specific groups such as methyl, ethyl, n-propyl, isopropyl.
如本文所述的，术语“烷氧基”和“烷胺基”属于惯用表达，是指分别通过一个氧原子或胺基连接到分子的其余部分的烷基基团，其中的烷基如本发明所述。As used herein, the terms "alkoxy" and "alkylamino" are used conventionally to refer to an alkyl group attached to the remainder of the molecule through an oxygen or amine group, respectively, wherein the alkyl group is Invention.
如本文所述的，术语“卤代烷基”表示烷基基团上的氢被一个或多个卤素原子所取代，这样的实例包含，但并不限于，单氟甲基、单氟甲氧基等。As used herein, the term "haloalkyl" means that the hydrogen on the alkyl group is replaced by one or more halogen atoms, examples of which include, but are not limited to, monofluoromethyl, monofluoromethoxy, and the like. .
如本文所述的，术语“环烷基”是指具有指定数目环碳原子数的环状烷基，并且其可包括其子基团，例如提及“C 3-C 6环烷基”时，其还可以包括C 3-C 5环烷基、C 4-C 6环烷基等表示的子范围的基团，以及具体基团例如环丙基、环丁基、环戊基、环己基。 As used herein the term "cycloalkyl" refers to a cyclic alkyl group having the specified number of number of ring carbon atoms, and which may include a sub-group thereof, for example, reference "C 3 -C 6 cycloalkyl" when It may further include a sub-range group represented by a C 3 -C 5 cycloalkyl group, a C 4 -C 6 cycloalkyl group or the like, and a specific group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. .
如本文所述的，术语“C 3-C 6杂环烷基”，除另有说明或限定外，是指包含3-6个环碳原子的饱和或部分不饱和的单环、双环或三环体系，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被羰基替代。环的硫原子可以任选地被氧化成S-氧化物。杂环基包括但 不限于氧杂环丁烷基、氮杂环丁烷基、四氢呋喃基、四氢吡咯基、四氢噻唑基、哌啶基、哌嗪基、吗啉基、硫代吗啉、高哌嗪基等。 As used herein, the term "C 3 -C 6 heterocycloalkyl", unless otherwise indicated or limited, refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing from 3 to 6 ring carbon atoms. A ring system wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise stated, a heterocyclic group can be a carbyl or a nitrogen group, and a -CH 2 - group can be optionally substituted with a carbonyl group. The sulfur atom of the ring can be optionally oxidized to an S-oxide. Heterocyclyl groups include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiazolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine , high piperazinyl and the like.
如本文所述的，术语“C 6-C 10芳基”表示含有6个环原子或6-10个环原子的单环和双环的碳环体系，其中，至少一个环是芳香族的，其中每一个环包含3-6个原子组成的环，且环体系中有一个或多个附着点与分子的其余部分相连。芳香基团可以包括苯基和萘基。 As used herein, the term "C 6 -C 10 aryl" denotes a monocyclic and bicyclic carbon ring system containing 6 ring atoms or 6-10 ring atoms, wherein at least one ring is aromatic, wherein Each ring contains a ring of 3-6 atoms and one or more attachment points in the ring system are attached to the remainder of the molecule. The aromatic group may include a phenyl group and a naphthyl group.
如本文所述的，术语“C 2-C 9杂芳基”在本文中指具有1至3个杂原子作为环原子，其余的环原子为碳的芳香基团，杂原子包括氧、硫和氮。杂芳基的实例包括但不限于吡啶基、哒嗪基、三氮唑基、四氮唑基、噁唑基、异噁唑基、嘧啶基、咪唑基、呋喃基、噻吩基、吡嗪基等。 As used herein the term "C 2 -C 9 heteroaryl" having 1 to 3 heteroatoms as used herein refers to ring atoms, the remaining ring atoms being carbon of an aromatic group, a hetero atom include oxygen, nitrogen and sulfur, . Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrimidinyl, imidazolyl, furyl, thienyl, pyrazinyl Wait.
如本文所述的，术语“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。环上原子的数目通常被定义为环的元数，例如“C 3-C 6环”是指环绕排列3-6个原子。 As used herein, the term "ring" refers to a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted. Heteroaryl. The so-called ring includes a fused ring. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "C 3 -C 6 ring" means that 3-6 atoms are arranged around.
如本文所述的，术语“杂原子”是指O、S、N，包括N、S的任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式。As used herein, the term "heteroatom" refers to a form of O, S, N, including any oxidation state of N, S; a form of primary, secondary, tertiary, and quaternary ammonium salts; or a nitrogen atom in a heterocyclic ring. The hydrogen is replaced by the form.
如本文所述的，术语“卤素”、“卤代”等表示氟(F)、氯(Cl)或溴(Br)。As used herein, the terms "halogen", "halo" and the like mean fluorine (F), chlorine (Cl) or bromine (Br).
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中，“室温”指的是温度由20℃到30℃；在另一些实施例中，室温指的是25℃。"Room temperature" in the present invention means that the temperature is from 10 ° C to 40 ° C. In some embodiments, "room temperature" refers to a temperature of from 20 ° C to 30 ° C; in other embodiments, room temperature refers to 25 ° C.
如本文所述的，术语“有效量”是指可在受试者中实现所期望的治疗本发明所述疾病或病症的药物用量。As used herein, the term "effective amount" refers to the amount of drug that can be used to achieve the desired treatment of a disease or condition of the invention in a subject.
如本文所述的，术语“药学可接受的”例如在描述“药学可接受的盐”时，表示该盐不但是受试者生理学上可接受，而且还可指在药学上有使用价值的合成物质。As used herein, the term "pharmaceutically acceptable", for example when describing a "pharmaceutically acceptable salt," means that the salt is not only physiologically acceptable to the subject, but may also refer to a pharmaceutically useful synthetic. substance.
如本文所述的，术语“药物组合物”，其还可以是指“组合物”，其可用于在受试者特别是哺乳动物中实现治疗本发明所述疾病或病症。As used herein, the term "pharmaceutical composition", which may also refer to a "composition," which can be used to effect treatment of a disease or condition of the invention in a subject, particularly a mammal.
疾病的“治疗”包括：The "treatment" of the disease includes:
(1)预防该疾病，即，使暴露至或易感染该疾病但未经历或显示该疾病症状的哺乳动物不发生该疾病的临床症状，(1) preventing the disease, that is, causing a mammal exposed to or susceptible to the disease but not experiencing or exhibiting symptoms of the disease to develop clinical symptoms of the disease,
(2)抑制该疾病，即，阻止或减少该疾病或其临床症状的进展，(2) inhibiting the disease, that is, preventing or reducing the progression of the disease or its clinical symptoms,
(3)减轻该疾病，即，引起该疾病或其临床症状的复原。(3) Alleviating the disease, that is, causing recovery of the disease or its clinical symptoms.
“治疗有效量”指为了治疗疾病向哺乳动物施用时足以实现对该疾病的治疗的化合物的量。治疗有效量将根据化合物、待治疗的疾病及其严重性以及哺乳动物的年龄、体重、性别等因素而变化。治疗有效量还可指足以实现所需的有益效果的化合物的任何量，该有益效果包括如以上(1)-(3)所述的预防疾病、抑制疾病或减轻疾病。例如化合物的量可以介于0.1-250mg/kg，或优选地，0.5-100mg/kg，或更优选地，1-50mg/kg，或甚至更优选地，2-20mg/kg。优选地，所述量的化合物每天两次向哺乳动物施用。更优选地，所述量的化合物每天一次向哺乳动物施用。"Therapeutically effective amount" refers to an amount of a compound that is sufficient to effect treatment of the disease when administered to a mammal for the treatment of a disease. The therapeutically effective amount will vary depending on the compound, the condition to be treated and its severity, and the age, weight, sex, etc. of the mammal. A therapeutically effective amount can also refer to any amount of a compound sufficient to achieve the desired beneficial effect, including the prevention of a disease, the suppression of a disease, or the alleviation of a disease as described in (1)-(3) above. For example, the amount of the compound may range from 0.1 to 250 mg/kg, or preferably from 0.5 to 100 mg/kg, or more preferably from 1 to 50 mg/kg, or even more preferably from 2 to 20 mg/kg. Preferably, the amount of the compound is administered to the mammal twice daily. More preferably, the amount of the compound is administered to the mammal once a day.
如本文所述的，术语“疾病和/或病症”是指所述受试者的一种身体状态，该身体状态与本发明所述疾病和/或病症有关。例如，本发明所述疾病和/或病症指结核杆菌感染性疾病。As used herein, the term "disease and/or condition" refers to a physical state of the subject that is associated with the disease and/or condition of the invention. For example, the disease and/or condition of the present invention refers to a Mycobacterium tuberculosis infectious disease.
如本文所述的，术语“受试者”可以指患者或者其它接受本发明式I化合物或其药物组合物以治疗本发明所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。As used herein, the term "subject" can refer to a patient or other animal, particularly a mammal, such as a human, a dog, that receives a compound of formula I of the invention, or a pharmaceutical composition thereof, for the treatment of a disease or condition according to the invention. Monkeys, cows, horses, etc.
本发明再一方面还涉及以本发明中的化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。Still another aspect of the present invention relates to a pharmaceutical composition comprising the compound of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods well known in the art. Any dosage form suitable for human or animal use can be prepared by combining a compound of the invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
本发明中的化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、***、直肠等。The compound of the present invention or the pharmaceutical composition containing the same may be administered in a unit dosage form, which may be enterally or parenterally, such as oral, intravenous, intramuscular, subcutaneous, nasal, oral mucosa, eye, Lung and respiratory tract, skin, vagina, rectum, etc.
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。The dosage form can be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage forms can be solutions (including true and colloidal solutions), emulsions (including o/w type, w/o type and double emulsion), suspensions, injections (including water injections, powder injections and infusions), eye drops Agents, nasal drops, lotions, tinctures, etc.; solid dosage forms may be tablets (including ordinary tablets, enteric tablets, lozenges, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric capsules), granules, powders, pellets, dropping pills, suppositories, films, patches, gas (powder) sprays, sprays, etc.; semi-solid dosage forms can be ointments, Gel, paste, etc.
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制 剂及各种微粒给药***。The compounds of the present invention can be formulated into common preparations, sustained release preparations, controlled release preparations, targeted preparations, and various microparticle delivery systems.
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、***胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。In order to form the compound of the present invention into tablets, various excipients known in the art, including diluents, binders, wetting agents, disintegrating agents, lubricants, and solubilizing agents, can be widely used. The diluent may be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agent may be water, ethanol, or different Propyl alcohol, etc.; the binder may be starch syrup, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic, gelatin syrup, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl group Cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrant can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinyl pyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium hydrogencarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium dodecyl sulfonate, etc.; lubricants and cosolvents It may be talc, silica, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。Tablets may also be further formed into coated tablets, such as sugar coated tablets, film coated tablets, enteric coated tablets, or bilayer tablets and multilayer tablets.
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助溶剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。In order to prepare the administration unit as a capsule, the active ingredient of the present compound may be mixed with a diluent, a co-solvent, and the mixture may be directly placed in a hard capsule or a soft capsule. The active ingredient can also be formulated into a granule or pellet with a diluent, a binder, a disintegrant, and then placed in a hard or soft capsule. The various diluents, binders, wetting agents, disintegrating agents, and solubilizing agents used in the preparation of the tablets of the present invention are also useful in the preparation of capsules of the compounds of the present invention.
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。In order to prepare the compound of the present invention as an injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof may be used as a solvent, and an appropriate amount of a solubilizer, a solubilizer, a pH adjuster, an osmotic pressure adjusting agent which is commonly used in the art may be added. The solubilizer or cosolvent may be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster may be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; osmotic pressure regulator may It is sodium chloride, mannitol, glucose, phosphate, acetate, and the like. For preparing a lyophilized powder injection, mannitol, glucose or the like may also be added as a proppant.
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。In addition, coloring agents, preservatives, perfumes, flavoring agents or other additives may also be added to the pharmaceutical preparations as needed.
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。The pharmaceutical or pharmaceutical composition of the present invention can be administered by any known administration method for the purpose of administration and enhancing the therapeutic effect.
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它 的剂量。The compounds or compositions of the invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention synergizes with other therapeutic agents, its dosage should be adjusted according to the actual situation.
有益技术效果Beneficial technical effect
本申请的发明人经过广泛的研究，合成了一系列化合物，并通过MABA(Microplate alamar blue assay)法以M.tuberculosis H 37Rv菌株进行最低抑菌浓度MIC(Minimum inhibitory concentration)测定，显示出较好的抗结核分枝杆菌活性，其中获得MIC<0.5μg/mL的化合物14个，13个化合物的MIC达到10 -8g/mL，与抗结核一线药物异烟肼相当，此外对Vero细胞毒性低(IC 50大于64μg/mL)显示出良好的安全性，并且在HepG2细胞毒性测试中显示出相较苯并噻嗪酮类化合物PBTZ169(EMBO Mol.Med.2014,6,372-383)更高的安全性。本发明中部分化合物在肝微粒体及肝细胞代谢稳定性试验中均显示出较PBTZ169具有更优的代谢性质。小鼠体内药代动力学结果显示，化合物11和化合物22具有较优于PBTZ169的体内药代动力学性质。本发明提供了一类结构新颖、体内抗结核活性强、药代性质良好的新化合物，其母核结构为苯并吡喃酮或苯并硫代吡喃酮结构，可用于由细菌引起的感染性疾病，特别是由结核分枝杆菌引起的结核病的治疗或预防性治疗，同时也可用于克服与耐药性有关的问题。 The inventors of the present application have conducted extensive research to synthesize a series of compounds, and the minimum inhibitory concentration MIC (Minimum inhibitory concentration) of M. tuberculosis H 37 Rv strain by MABA (Microplate alamar blue assay) method shows that Good anti-tuberculous mycobacterial activity, in which 14 compounds with MIC <0.5μg/mL were obtained, and the MIC of 13 compounds reached 10 -8 g/mL, which is equivalent to the anti-tuberculosis first-line drug isoniazid, in addition to Vero cytotoxicity Low (IC 50 greater than 64 μg/mL) showed good safety and showed higher in the HepG2 cytotoxicity test than the benzothiazinone compound PBTZ169 (EMBO Mol. Med. 2014, 6, 372-383) safety. Some of the compounds of the present invention showed superior metabolic properties compared to PBTZ169 in both liver microsome and hepatocyte metabolic stability assays. The pharmacokinetic results in mice showed that Compound 11 and Compound 22 had better in vivo pharmacokinetic properties than PBTZ169. The invention provides a novel compound with novel structure, strong anti-tuberculosis activity in vivo and good pharmacokinetic properties, and the mother core structure is benzopyrone or benzothiopyranone structure, which can be used for infection caused by bacteria. Sexual diseases, especially the treatment or prophylaxis of tuberculosis caused by M. tuberculosis, can also be used to overcome problems related to drug resistance.
Figure PCTCN2018080787-appb-000017
Figure PCTCN2018080787-appb-000017
具体实施方式detailed description
通过下面的实施例可以对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。The invention may be described in detail by the following examples, which are not to be construed as limiting. The present invention has been described in detail herein, and the specific embodiments thereof are disclosed, and various changes and modifications of the embodiments of the present invention are possible without departing from the spirit and scope of the invention. Obvious.
对于以下全部实施例，可使用本领域技术人员已知的标准操作和纯化方法。除非另有说明，所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振谱(NMR)来确定的。For all of the following examples, standard procedures and purification methods known to those skilled in the art can be used. All temperatures are expressed in ° C (degrees Celsius) unless otherwise stated. The structure of the compound was determined by nuclear magnetic resonance spectroscopy (NMR).
制备实施例部分Preparation Example Section
化合物的结构是通过核磁共振氢谱( 1H NMR)来确定的。核磁共振氢谱及碳 谱位移(δ)以百万分之一(ppm)的单位给出。耦合常数(J)以赫兹(Hz)为单位。核磁共振谱用Mercury-400型核磁共振仪测定，氘代氯仿(CDCl 3)或氘代二甲基亚砜(DMSO-d 6)作溶剂，四甲基硅烷(TMS)为内标。 The structure of the compound was determined by nuclear magnetic resonance spectroscopy ( 1 H NMR). The nuclear magnetic resonance spectrum and the carbon spectral shift (δ) are given in units of parts per million (ppm). The coupling constant (J) is in Hertz (Hz). The nuclear magnetic resonance spectrum was measured by a Mercury-400 nuclear magnetic resonance spectrometer, deuterated chloroform (CDCl 3 ) or deuterated dimethyl sulfoxide (DMSO-d 6 ) as a solvent, and tetramethylsilane (TMS) as an internal standard.
电子天平采用日本Yanaco LY-300型电子天平。The electronic balance uses the Japanese Yanaco LY-300 electronic balance.
柱层析一般使用200～300目硅胶为载体。Column chromatography generally uses 200 to 300 mesh silica gel as a carrier.
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯。Anhydrous solvents are treated by standard methods. All other reagents were of commercially available analytical grade.
本发明采用下述缩略词：The present invention uses the following abbreviations:
CDI为羰基二咪唑。CDI is carbonyl diimidazole.
DCC为二环己基碳二亚胺。DCC is dicyclohexylcarbodiimide.
DMF为N,N-二甲基甲酰胺。DMF is N,N-dimethylformamide.
DMSO为二甲基亚砜。DMSO is dimethyl sulfoxide.
EDCI为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
HOBT为1-羟基苯并***。HOBT is 1-hydroxybenzotriazole.
HATU为2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯。HATU is 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.
实施例Example
实施例1Example 1
Figure PCTCN2018080787-appb-000018
Figure PCTCN2018080787-appb-000018
(S)-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮(S)-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro-benzo Pyran-4-one
路线：route:
Figure PCTCN2018080787-appb-000019
Figure PCTCN2018080787-appb-000019
实验步骤：Experimental steps:
第一步(S)-1-(2-氯-3-硝基-5-(三氟甲基)苯基)-3-(2-甲基-1,4-二氧杂-8-氮杂螺 [4.5]癸烷-8-基)丙烷-1,3-二酮B-1的制备First step (S)-1-(2-chloro-3-nitro-5-(trifluoromethyl)phenyl)-3-(2-methyl-1,4-dioxa-8-nitrogen Preparation of heterospiro[4.5]decane-8-yl)propane-1,3-dione B-1
于25mL反应瓶中，将化合物3-(2-氯-3-硝基-5-(三氟甲基)苯基)-3-氧代丙酸A(311mg，1.0mmol)、DCC(201mg，1.0mmol)溶于干燥二氯甲烷中(5mL)，Ar气保护，加入(S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷(157mg，1.0mmol)，室温下搅拌12小时。过滤掉不溶固体，浓缩，硅胶(200-300目)柱色谱分离，乙酸乙酯-石油醚(V：V＝5～15:100)混合液为洗脱剂。得中间体B-1，浅黄色固体250mg，收率55.5％。In a 25 mL reaction flask, the compound 3-(2-chloro-3-nitro-5-(trifluoromethyl)phenyl)-3-oxopropanoic acid A (311 mg, 1.0 mmol), DCC (201 mg, 1.0 mmol) dissolved in dry dichloromethane (5 mL), protected with Ar gas, (S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]decane (157 mg, 1.0) Methyl), stirred at room temperature for 12 hours. The insoluble solid was filtered off, concentrated, and subjected to silica gel (200-300 mesh) column chromatography, and ethyl acetate- petroleum ether (V:V = 5 to 15:100) mixture as an eluent. Intermediate B-1 was obtained as a pale yellow solid, 250 mg, yield 55.5%.
1H NMR(400MHz,CDCl 3)δ:15.64(brs,1H),8.01(s,1H),8.00(s,1H),5.72(s,1H),4.30-4.13(m,1H),4.12-4.08(m,1H),3.75-3.47(m,5H),1.79-1.75(m,4H),1.30(m,3H). 1 H NMR (400MHz, CDCl 3 ) δ: 15.64 (brs, 1H), 8.01 (s, 1H), 8.00 (s, 1H), 5.72 (s, 1H), 4.30-4.13 (m, 1H), 4.12- 4.08 (m, 1H), 3.75-3.47 (m, 5H), 1.79-1.75 (m, 4H), 1.30 (m, 3H).
第二步(S)-2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮II-1(化合物1)的制备The second step (S)-2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-6-trifluoromethyl-8-nitro -Preparation of benzopyran-4-one II-1 (Compound 1)
于10mL反应瓶中，将化合物(S)-1-(2-氯-3-硝基-5-(三氟甲基)苯基)-3-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)丙烷-1,3-二酮B-1(90mg，0.2mmol)、碳酸钾(28mg，0.2mmol)溶于DMF中(2mL)，Ar气保护，升温至110℃反应1小时。蒸干溶剂，加入25mL二氯甲烷，依次用水和盐水洗，无水硫酸钠干燥，过滤，浓缩，硅胶(200-300目)柱色谱分离，甲醇-二氯甲烷(V：V＝1:100)混合液为洗脱剂。得化合物II-1(化合物1)，浅黄色固体58mg，收率69.9％。Compound (S)-1-(2-chloro-3-nitro-5-(trifluoromethyl)phenyl)-3-(2-methyl-1,4-dioxo) in a 10 mL reaction flask Hetero-8-azaspiro[4.5]decane-8-yl)propane-1,3-dione B-1 (90 mg, 0.2 mmol), potassium carbonate (28 mg, 0.2 mmol) dissolved in DMF (2 mL) , Ar gas protection, heating to 110 ° C for 1 hour. Evaporate the solvent, add 25 mL of dichloromethane, washed with water and brine, dried over anhydrous sodium sulfate, dried, filtered, concentrated, silica gel (200-300 mesh) column chromatography, methanol-dichloromethane (V:V = 1:100) The mixture is an eluent. Compound II-1 (Compound 1) was obtained as a pale yellow solid (yield: 69%).
1H NMR(400MHz,CDCl 3)δ:8.74(s,1H),8.51(s,1H),5.66(s,1H),4.32-4.27(m,1H),4.14-4.10(m,1H),3.77-3.71(m,4H),3.53-3.49(m,1H),1.88-1.85(m,4H),1.31(d,J＝6.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ: 8.74 (s, 1H), 8.51 (s, 1H), 5.66 (s, 1H), 4.32-4.27 (m, 1H), 4.14-4.10 (m, 1H), 3.77-3.71 (m, 4H), 3.53-3.49 (m, 1H), 1.88-1.85 (m, 4H), 1.31 (d, J = 6.0 Hz, 3H).
实施例2Example 2
Figure PCTCN2018080787-appb-000020
Figure PCTCN2018080787-appb-000020
2-(4-(环己基甲基)哌嗪-1-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-trifluoromethyl-8-nitro-benzopyran-4-one
路线：route:
Figure PCTCN2018080787-appb-000021
Figure PCTCN2018080787-appb-000021
实验步骤：Experimental steps:
第一步1-(2-氯-3-硝基-5-三氟甲基苯基)-3-(4-(环己基甲基)哌嗪-1-基)丙烷-1,3-二酮B-2的制备The first step is 1-(2-chloro-3-nitro-5-trifluoromethylphenyl)-3-(4-(cyclohexylmethyl)piperazin-1-yl)propane-1,3-di Preparation of ketone B-2
以1-(环己基甲基)哌嗪(182mg，1.0mmol)为原料，采用实施例1中第一步相似操作步骤，得到中间体B-2，浅黄色固体272mg，收率57.1％。Using 1-(cyclohexylmethyl)piperazine (182 mg, 1.0 mmol) as a starting material, using the procedure of the first step of Example 1 to afford Intermediate B-2 as a pale yellow solid (yield: 57.1%).
1H NMR(400MHz,CDCl 3)δ:15.62(brs,1H),8.01(s,1H),8.00(s,1H),5.67(s,1H),3.73-3.49(m,4H),2.45(m,4H),2.17(m,2H),1.79-1.71(m,5H),1.26-1.20(m,4H),0.90-0.87(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ: 15.62 (brs, 1H), 8.01 (s, 1H), 8.00 (s, 1H), 5.67 (s, 1H), 3.73-3.49 (m, 4H), 2.45 ( m, 4H), 2.17 (m, 2H), 1.79-1.71 (m, 5H), 1.26-1.20 (m, 4H), 0.90-0.87 (m, 2H).
第二步2-(4-(环己基甲基)哌嗪-1-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮II-2(化合物2)的制备The second step of 2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-trifluoromethyl-8-nitro-benzopyran-4-one II-2 (Compound 2) preparation
以1-(2-氯-3-硝基-5-三氟甲基苯基)-3-(4-(环己基甲基)哌嗪-1-基)丙烷-1,3-二酮(95mg，0.2mmol)为原料，采用实施例1中第二步相似操作步骤，得到化合物II-2(化合物2)，浅黄色固体46mg，收率52.3％。1-(2-Chloro-3-nitro-5-trifluoromethylphenyl)-3-(4-(cyclohexylmethyl)piperazin-1-yl)propane-1,3-dione ( 95 mg, 0.2 mmol) was used as a starting material, and a similar procedure of the second step of Example 1 was used to obtain Compound II-2 (Compound 2) as a pale yellow solid (yield: 52.3%).
1H NMR(400MHz,CDCl 3)δ:8.74(d,J＝2.0Hz,1H),8.50(d,J＝2.0Hz,1H),5.59(s,1H),3.65(m,4H),2.55(m,4H),2.20(m,2H),1.80-1.62(m,5H),1.28-1.19(m,4H),0.91-0.86(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ: 8.74 (d, J = 2.0Hz, 1H), 8.50 (d, J = 2.0Hz, 1H), 5.59 (s, 1H), 3.65 (m, 4H), 2.55 (m, 4H), 2.20 (m, 2H), 1.80-1.62 (m, 5H), 1.28-1.19 (m, 4H), 0.91-0.86 (m, 2H).
实施例3Example 3
Figure PCTCN2018080787-appb-000022
Figure PCTCN2018080787-appb-000022
2-(4-(环己基甲基)哌嗪-2-酮-1-基)-6-三氟甲基-8-硝基-苯并吡喃-4-酮2-(4-(cyclohexylmethyl)piperazin-2-one-1-yl)-6-trifluoromethyl-8-nitro-benzopyran-4-one
以1-(环己基甲基)哌嗪-2-酮(39mg，0.2mmol)为原料，采用实施例2中相似操作步骤，得到化合物II-3(化合物3)，浅黄色固体42mg，收率46.4％。1-(cyclohexylmethyl)piperazin-2-one (39 mg, 0.2 mmol) was used as a starting material to give compound II-3 (Compound 3) as a pale yellow solid. 46.4%.
1H NMR(400MHz,CDCl 3)δ:8.76(d,J＝2.0Hz,1H),8.55(d,J＝2.0Hz,1H), 5.54(s,1H),4.14(s,2H),3.98-3.96(m,2H),3.58-3.56(m,2H),3.34(d,J＝7.2Hz,2H),1.77-1.66(m,5H),1.29-1.19(m,4H),1.02-0.99(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ: 8.76 (d, J = 2.0Hz, 1H), 8.55 (d, J = 2.0Hz, 1H), 5.54 (s, 1H), 4.14 (s, 2H), 3.98 -3.96 (m, 2H), 3.58-3.56 (m, 2H), 3.34 (d, J = 7.2 Hz, 2H), 1.77-1.66 (m, 5H), 1.29-1.19 (m, 4H), 1.02-0.99 (m, 2H).
实施例4Example 4
Figure PCTCN2018080787-appb-000023
Figure PCTCN2018080787-appb-000023
2-(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-6-(trifluoromethyl)-8-nitro-benzothio Pyran-4-one
路线route
Figure PCTCN2018080787-appb-000024
Figure PCTCN2018080787-appb-000024
实验步骤：Experimental steps:
第一步2-甲硫基-8-硝基-6-(三氟甲基)-4H-硫代色烯-4-酮D的制备Preparation of 2-methylthio-8-nitro-6-(trifluoromethyl)-4H-thiochromene-4-one D
于50mL反应瓶中，将NaOH(800mg，20mmol)溶于DMSO(5mL)，在20℃下加入二硫化碳(2.34g，30mmol)，将2-氯-3-硝基-5-三氟甲基苯乙酮(2.67g，10mmol)分次加入其中，15分钟后，在20℃的温度下加入碘甲烷(10mmol)，反应30分钟。加入100mL乙酸乙酯，依次用100mL水和盐水洗，无水硫酸钠干燥，过滤，浓缩，硅胶(200-300目)柱色谱分离，乙酸乙酯-石油醚(V：V＝7:100)混合液为洗脱剂。得中间体D，浅黄色固体1.83g，收率60.0％。In a 50 mL reaction flask, NaOH (800 mg, 20 mmol) was dissolved in DMSO (5 mL), and carbon disulfide (2.34 g, 30 mmol) was added at 20 ° C to give 2-chloro-3-nitro-5-trifluoromethylbenzene Ethyl ketone (2.67 g, 10 mmol) was added portionwise, and after 15 minutes, methyl iodide (10 mmol) was added at a temperature of 20 ° C for 30 minutes. Add 100 mL of ethyl acetate, wash with 100 mL of water and brine, dry over anhydrous sodium sulfate, filtered, concentrated, silica gel (200-300 mesh) column chromatography, ethyl acetate- petroleum ether (V:V=7:100) The mixture is an eluent. Intermediate D was obtained, pale yellow solid 1.83 g, yield 60.0%.
1H NMR(400MHz,CDCl 3)δ:9.12(d,J＝2.0Hz,1H),8.84(d,J＝2.0Hz,1H),6.91(s,1H),2.70(s,3H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.12 (d, J = 2.0Hz, 1H), 8.84 (d, J = 2.0Hz, 1H), 6.91 (s, 1H), 2.70 (s, 3H).
第二步(2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮III-1(化合物4)的制备The second step (2-methyl-1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-6-(trifluoromethyl)-8-nitro-benzosulfur Preparation of pyran-4-one III-1 (Compound 4)
于25mL反应瓶中，将2-甲硫基-8-硝基-6-(三氟甲基)-4H-硫代色烯-4-酮(64mg，0.2mmol)、(S)-2-甲基-1,4-二氧杂-8-氮杂螺[4.5]癸烷(157mg，1.0mmol)溶于异丙醇(5mL)，Ar保护下，于140℃反应24小时，得到化合物III-1(化合物4)，浅黄色固体57mg，收率66.3％。2-Methylthio-8-nitro-6-(trifluoromethyl)-4H-thiochromene-4-one (64 mg, 0.2 mmol), (S)-2- in a 25 mL reaction flask Methyl-1,4-dioxa-8-azaspiro[4.5]decane (157 mg, 1.0 mmol) was dissolved in isopropanol (5 mL), and treated under Ar for 24 hours at 140 ° C to give compound III. -1 (Compound 4), 57 mg of pale yellow solid, yield 66.3%.
1H NMR(300MHz,CDCl 3)δ:9.13(s,1H),8.77(s,1H),6.45(s,1H),4.28(m,1H),4.12(m,1H),3.82(m,4H),3.51(m,1H),1.88(m,4H),1.32(d,J＝6Hz,3H). 1 H NMR (300MHz, CDCl 3 ) δ: 9.13 (s, 1H), 8.77 (s, 1H), 6.45 (s, 1H), 4.28 (m, 1H), 4.12 (m, 1H), 3.82 (m, 4H), 3.51 (m, 1H), 1.88 (m, 4H), 1.32 (d, J = 6 Hz, 3H).
实施例5Example 5
Figure PCTCN2018080787-appb-000025
Figure PCTCN2018080787-appb-000025
2-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(1,4-Dioxa-8-azaspiro[4.5]decane-8-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4- ketone
以1,4-二氧杂-8-氮杂螺[4.5]癸烷(143mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-2(化合物5)，浅黄色固体60mg，收率72.2％。Using 1,4-dioxa-8-azaspiro[4.5]decane (143 mg, 1.0 mmol) as a starting material, using the similar procedure of the second step of Example 4, to obtain compound III-2 (compound 5), Light yellow solid 60 mg, yield 72.2%.
1H NMR(400MHz,CDCl 3)δ:9.13(s,1H),8.76(s,1H),6.41(s,1H),4.03(s,4H),3.81(m,4H),1.88(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.13 (s, 1H), 8.76 (s, 1H), 6.41 (s, 1H), 4.03 (s, 4H), 3.81 (m, 4H), 1.88 (m, 4H).
实施例6Example 6
Figure PCTCN2018080787-appb-000026
Figure PCTCN2018080787-appb-000026
2-(1,4-二硫杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(1,4-Dithia-8-azaspiro[4.5]decane-8-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4- ketone
以1,4-二硫杂-8-氮杂螺[4.5]癸烷(175mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-3(化合物6)，浅黄色固体70mg，收率77.8％。Using 1,4-dithia-8-azaspiro[4.5]decane (175 mg, 1.0 mmol) as the starting material, using the similar procedure of the second step of Example 4, to obtain compound III-3 (compound 6), Light yellow solid 70 mg, yield 77.8%.
1H NMR(400MHz,CDCl 3)δ:9.12(d,J＝1.6Hz,1H),8.78(d,J＝1.6Hz,1H),6.54(s,1H),3.83(m,4H),3.39(s,4H),2.28(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.12 (d, J = 1.6Hz, 1H), 8.78 (d, J = 1.6Hz, 1H), 6.54 (s, 1H), 3.83 (m, 4H), 3.39 (s, 4H), 2.28 (m, 4H).
实施例7Example 7
Figure PCTCN2018080787-appb-000027
Figure PCTCN2018080787-appb-000027
2-(1-氧杂-4-硫杂-8-氮杂螺[4.5]癸烷-8-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(1-oxa-4-thia-8-azaspiro[4.5]decane-8-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran- 4-ketone
以1-氧杂-4-硫杂-8-氮杂螺[4.5]癸烷(159mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-4(化合物7)，浅黄色固体52mg，收率60.5％。Using 1-oxa-4-thia-8-azaspiro[4.5]decane (159 mg, 1.0 mmol) as the starting material, using the similar procedure of the second step in Example 4 to give compound III-4 (Compound 7) ), pale yellow solid 52 mg, yield 60.5%.
1H NMR(400MHz,CDCl 3)δ:9.13(s,1H),8.80(s,1H),6.78(s,1H),4.23(m,2H),3.86(m,4H),3.16(m,2H),2.17(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.13 (s, 1H), 8.80 (s, 1H), 6.78 (s, 1H), 4.23 (m, 2H), 3.86 (m, 4H), 3.16 (m, 2H), 2.17 (m, 4H).
实施例8Example 8
Figure PCTCN2018080787-appb-000028
Figure PCTCN2018080787-appb-000028
2-(4-(环己基甲基)-3-氧代-哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4-(cyclohexylmethyl)-3-oxo-piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以1-(环己基甲基)-哌嗪-2-酮(196mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-5(化合物8)，浅黄色固体61mg，收率64.8％。Using 1-(cyclohexylmethyl)-piperazin-2-one (196 mg, 1.0 mmol) as a starting material, using the similar procedure from the second step of Example 4 to give Compound III-5 (Compound 8) as a pale yellow solid 61 mg, yield 64.8%.
1H NMR(400MHz,CDCl 3)δ:9.16(s,1H),8.80(s,1H),6.19(s,1H),4.24(m,2H),3.90(m,2H),3.59(m,2H),3.36(m,2H),1.73-1.66(m,6H),1.26-1.21(m,3H),1.02-1.00(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.16 (s, 1H), 8.80 (s, 1H), 6.19 (s, 1H), 4.24 (m, 2H), 3.90 (m, 2H), 3.59 (m, 2H), 3.36 (m, 2H), 1.73-1.66 (m, 6H), 1.26-1.21 (m, 3H), 1.02-1.00 (m, 2H).
实施例9Example 9
Figure PCTCN2018080787-appb-000029
Figure PCTCN2018080787-appb-000029
2-(4,4-二氟哌啶-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4,4-Difluoropiperidin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以4,4-二氟哌啶(121mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-6(化合物9)，浅黄色固体63mg，收率79.7％。Using 4,4-difluoropiperidine (121 mg, 1.0 mmol) as a starting material, a similar procedure of the second step of Example 4 was used to afford compound III-6 (Compound 9) as a pale yellow solid (yield: 79.7%).
1H NMR(400MHz,CDCl 3)δ:9.13(s,1H),8.80(s,1H),6.41(s,1H),3.83(m,4H),2.20(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.13 (s, 1H), 8.80 (s, 1H), 6.41 (s, 1H), 3.83 (m, 4H), 2.20 (m, 4H).
实施例10Example 10
Figure PCTCN2018080787-appb-000030
Figure PCTCN2018080787-appb-000030
2-(4-(噻唑-2-基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4-(thiazol-2-yl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以(哌嗪-1-基)噻唑(169mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-7(化合物10)，浅黄色固体43mg，收率48.9％。Using (piperazin-1-yl)thiazole (169 mg, 1.0 mmol) as a starting material, using a similar procedure from the second step of Example 4 to give Compound III-7 (Compound 10) as a pale yellow solid, 43. .
1H NMR(400MHz,CDCl 3)δ:9.14(s,1H),8.80(s,1H),7.28(d,J＝3.6Hz,1H),6.70(d,J＝3.6Hz,1H),6.31(s,1H),3.84(m,8H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.14 (s, 1H), 8.80 (s, 1H), 7.28 (d, J = 3.6Hz, 1H), 6.70 (d, J = 3.6Hz, 1H), 6.31 (s, 1H), 3.84 (m, 8H).
实施例11Example 11
Figure PCTCN2018080787-appb-000031
Figure PCTCN2018080787-appb-000031
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4-(cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以1-(环己基甲基)哌嗪(182mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-8(化合物11)，橙色固体66mg，收率72.5％。1-(cyclohexylmethyl)piperazine (182 mg, 1.0 mmol) was used as the starting material, using the procedure of the second step of Example 4 to give compound III-8 (Compound 11), 66 mg of orange solid, yield 72.5% .
1H NMR(400MHz,CDCl 3)δ:9.12(s,1H),8.75(s,1H),6.25(s,1H),3.66(m,4H),2.56(m,4H),2.20(m,2H),1.80-1.67(m,5H),1.51(m,1H),1.26-1.16(m,3H),0.94-0.88(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.12 (s, 1H), 8.75 (s, 1H), 6.25 (s, 1H), 3.66 (m, 4H), 2.56 (m, 4H), 2.20 (m, 2H), 1.80-1.67 (m, 5H), 1.51 (m, 1H), 1.26-1.16 (m, 3H), 0.94-0.88 (m, 2H).
实施例12Example 12
Figure PCTCN2018080787-appb-000032
Figure PCTCN2018080787-appb-000032
2-(4-(环己基甲基)-3-甲基-哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4-(Cyclohexylmethyl)-3-methyl-piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以1-(环己基甲基)-2-甲基哌嗪(196mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-9(化合物12)，浅黄色固体67mg，收率71.3％。Using 1-(cyclohexylmethyl)-2-methylpiperazine (196 mg, 1.0 mmol) as a starting material, using a similar procedure from the second step of Example 4 to give compound III-9 (Compound 12) as a pale yellow solid 67 mg, yield 71.3%.
1H NMR(400MHz,CDCl 3)δ:9.12(s,1H),8.74(s,1H),6.24(s,1H),3.80-3.77 (m,2H),3.47(m,1H),3.19(m,1H),2.95(m,1H),2.58(m,1H),2.50(m,1H),2.36(m,1H),2.01(m,1H),1.87(m,1H),1.71(m,4H),1.46(m,1H),1.25-1.11(m,6H),0.91-0.88(m,2H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.12 (s, 1H), 8.74 (s, 1H), 6.24 (s, 1H), 3.80-3.77 (m, 2H), 3.47 (m, 1H), 3.19 ( m, 1H), 2.95 (m, 1H), 2.58 (m, 1H), 2.50 (m, 1H), 2.36 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.71 (m) , 4H), 1.46 (m, 1H), 1.25-1.11 (m, 6H), 0.91-0.88 (m, 2H).
实施例13Example 13
Figure PCTCN2018080787-appb-000033
Figure PCTCN2018080787-appb-000033
2-(4-(苄基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4-(benzyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以N-苄基哌嗪(176mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-10(化合物13)，浅黄色固体55mg，收率61.1％。Using N-benzylpiperazine (176 mg, 1.0 mmol) as a starting material, a similar procedure from the second step of Example 4 was used to afford compound III-10 (Comp. 13) as a pale yellow solid (yield: 61.1%).
1H NMR(400MHz,CDCl 3)δ:9.12(s,1H),8.75(s,1H),7.35(m,5H),6.24(s,1H),3.68(m,4H),3.60(s,2H),2.63(m,4H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.12 (s, 1H), 8.75 (s, 1H), 7.35 (m, 5H), 6.24 (s, 1H), 3.68 (m, 4H), 3.60 (s, 2H), 2.63 (m, 4H).
实施例14Example 14
Figure PCTCN2018080787-appb-000034
Figure PCTCN2018080787-appb-000034
2-(4-苄基-3-甲基-哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮2-(4-Benzyl-3-methyl-piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one
以1-苄基-2-甲基哌嗪(190mg，1.0mmol)为原料，采用实施例4中第二步相似操作步骤，得到化合物III-11(化合物21)，浅黄色固体47mg，收率50.7％。Using 1-benzyl-2-methylpiperazine (190 mg, 1.0 mmol) as a starting material, using a similar procedure from the second step of Example 4 to give Compound III-11 (Comp. 50.7%.
1H NMR(400MHz,CDCl 3)δ:9.12(s,1H),8.75(s,1H),7.35-7.26(m,5H),6.23(s,1H),4.06(d,J＝13.2Hz,1H),3.84(t,J＝15.2Hz,2H),3.40(t,J＝9.6Hz,1H),3.27-3.20(m,2H),2.85(d,J＝12.4Hz,1H),2.71(brs,1H),2.32(t,J＝9.2Hz,1H),1.26(d,J＝6.0Hz,3H). 1 H NMR (400MHz, CDCl 3 ) δ: 9.12 (s, 1H), 8.75 (s, 1H), 7.35-7.26 (m, 5H), 6.23 (s, 1H), 4.06 (d, J = 13.2Hz, 1H), 3.84 (t, J = 15.2 Hz, 2H), 3.40 (t, J = 9.6 Hz, 1H), 3.27-3.20 (m, 2H), 2.85 (d, J = 12.4 Hz, 1H), 2.71 ( Brs, 1H), 2.32 (t, J = 9.2 Hz, 1H), 1.26 (d, J = 6.0 Hz, 3H).
实施例15Example 15
Figure PCTCN2018080787-appb-000035
Figure PCTCN2018080787-appb-000035
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮盐酸盐2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one hydrochloride
将2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮(46mg，0.1mmol)置于5mL乙醇中，加热至溶解，搅拌下滴加1N的盐酸乙醇溶液0.1mL，滴加完毕后搅拌2小时，冷却过滤，少量冷乙醇洗，干燥得到化合物III-12(化合物22)，黄色固体47mg，收率95.6％。2-(4-(Cyclohexylmethyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one (46 mg, 0.1 mmol) Placed in 5 mL of ethanol, heated to dissolve, and 0.1 mL of 1N hydrochloric acid ethanol solution was added dropwise with stirring. After the completion of the dropwise addition, the mixture was stirred for 2 hours, cooled and filtered, washed with a small amount of cold ethanol, and dried to give Compound III-12 (Compound 22), yellow 47 mg solid, 95.6% yield.
1H NMR(400MHz,DMSO-d 6)δ:10.48(brs,1H),8.87(s,1H),8.86(s,1H),6.44(s,1H),4.31-4.28(m,2H),3.77-3.70(m,2H),3.61-3.58(m,2H),3.19-3.17(m,2H),2.99(brs,2H),1.83-1.80(m,3H),1.70-1.67(m,2H),1.64-1.60(m,1H),1.26-1.12(m,3H),0.98-0.95(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ: 10.48 (brs, 1H), 8.87 (s, 1H), 8.86 (s, 1H), 6.44 (s, 1H), 4.31-4.28 (m, 2H), 3.77-3.70 (m, 2H), 3.61-3.58 (m, 2H), 3.19-3.17 (m, 2H), 2.99 (brs, 2H), 1.83-1.80 (m, 3H), 1.70-1.67 (m, 2H) ), 1.64-1.60 (m, 1H), 1.26-1.12 (m, 3H), 0.98-0.95 (m, 2H).
实施例16Example 16
Figure PCTCN2018080787-appb-000036
Figure PCTCN2018080787-appb-000036
2-(4-(苄基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮盐酸盐2-(4-(Benzyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one hydrochloride
将2-(4-(苄基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮(45mg，0.1mmol)置于5mL乙醇中，加热至溶解，搅拌下滴加1N的盐酸乙醇溶液0.1mL，滴加完毕后搅拌2小时，冷却过滤，少量冷乙醇洗，干燥得到化合物III-13(化合物26)，黄色固体46mg，收率94.7％。2-(4-(Benzyl)piperazin-1-yl)-6-(trifluoromethyl)-8-nitro-benzothiopyran-4-one (45 mg, 0.1 mmol) was placed In 5 mL of ethanol, it was heated to dissolve, and 0.1 mL of 1N hydrochloric acid ethanol solution was added dropwise with stirring. After the completion of the dropwise addition, the mixture was stirred for 2 hours, cooled and filtered, washed with a small amount of cold ethanol, and dried to give Compound III-13 (Compound 26), a yellow solid 46 mg. The yield was 94.7%.
1H NMR(400MHz,DMSO-d 6)δ:11.3(brs,1H),8.88(s,1H),8.85(s,1H),7.58(brs,2H),7.47(brs,3H),6.42(s,1H),4.37-4.33(m,4H),3.66-3.60(m,2H),3.41-3.39(m,2H),3.23-3.21(m,2H). 1 H NMR (400MHz, DMSO- d 6) δ: 11.3 (brs, 1H), 8.88 (s, 1H), 8.85 (s, 1H), 7.58 (brs, 2H), 7.47 (brs, 3H), 6.42 ( s, 1H), 4.37-4.33 (m, 4H), 3.66-3.60 (m, 2H), 3.41-3.39 (m, 2H), 3.23 - 3.21 (m, 2H).
生物活性测试Biological activity test
1、体外抗结核活性测试1. In vitro anti-tuberculosis activity test
测定方法：Microplate Alamar Blue Assay(MABA)法测定体外抗结核活性。Assay method: The antiplatelet activity in vitro was determined by Microplate Alamar Blue Assay (MABA) method.
实验原理：Alamar Blue加入培养基可作为氧化还原指示剂，颜色由蓝色向红色转变，反映所研究的微生物对氧分子的消耗。Alamar Blue的颜色改变可用光度计测定，其发射波长为590nm。Experimental principle: Alamar Blue is added to the medium as a redox indicator, and the color changes from blue to red, reflecting the consumption of oxygen molecules by the microorganisms studied. The color change of Alamar Blue can be measured with a luminometer with an emission wavelength of 590 nm.
实验方法：无菌96孔板(Falcon3072；Becton Dickinson,Lincoln Park,N.J.)，实验化合物以DMSO溶解，制成浓度为5mg/mL的初溶液，最高浓度孔加入199μL 7H9 培养基，1μL化合物初溶液，混合均匀后，向其余各孔依次2倍稀释，化合物终浓度为：25、12.5、6.25、3.125、1.56、0.78、0.39、0.2、0.1、0.05、0.025μg/mL。选取结核分枝杆菌H 37R v(或临床分离耐药菌株)培养2～3周的培养物制成菌悬液，接种到含0.05％吐温80、10％ADC的7H9培养基中，37℃静止培养1～2周，生长至浊度为McFarland 1(相当于10 7CFU/mL)时，1：20稀释后，加入各孔100μL，菌液的终浓度为10 6CFU/mL。每板上均设2个不含抗菌药的生长对照孔，96孔板于37℃孵育。7天后加入生长对照孔20μL 10×Alamar Blue和5％Tween80 50μL的混合液，37℃孵育24小时，如果颜色从蓝色变为粉色，则在各实验药物的孔内加入上述量的Alamar Blue和Tween 80混合液，37℃孵育24小时记录各孔的颜色，并应用酶标仪测定590nm荧光值，计算MIC 90。 Experimental method: sterile 96-well plate (Falcon3072; Becton Dickinson, Lincoln Park, NJ), the test compound was dissolved in DMSO to prepare a primary solution at a concentration of 5 mg/mL, and the highest concentration well was added to 199 μL of 7H9 medium, 1 μL of the initial solution of the compound. After mixing well, the remaining wells were diluted 2-fold sequentially, and the final concentrations of the compounds were: 25, 12.5, 6.25, 3.125, 1.56, 0.78, 0.39, 0.2, 0.1, 0.05, 0.025 μg/mL. The cultures of Mycobacterium tuberculosis H 37 R v (or clinically isolated drug-resistant strains) were cultured for 2 to 3 weeks to prepare a bacterial suspension, and inoculated into 7H9 medium containing 0.05% Tween 80 and 10% ADC, 37 The cells were cultured at °C for 1 to 2 weeks and grown to a turbidity of McFarland 1 (corresponding to 10 7 CFU/mL). After dilution at 1:20, 100 μL of each well was added, and the final concentration of the bacterial solution was 10 6 CFU/mL. Two growth control wells containing no antibacterial agents were placed on each plate, and 96-well plates were incubated at 37 °C. After 7 days, 20 μL of 10×Alamar Blue and 5% Tween80 50 μL mixture of growth control wells were added and incubated at 37° C. for 24 hours. If the color changed from blue to pink, the above amount of Alamar Blue and the above amount were added to the wells of each experimental drug. The Tween 80 mixture was incubated at 37 ° C for 24 hours to record the color of each well, and the 590 nm fluorescence value was measured using a microplate reader to calculate the MIC 90 .
表1、本发明部分化合物体外抗结核分枝杆菌H 37R v活性 Table 1. In vitro anti-tuberculous mycobacterial H 37 R v activity of some compounds of the present invention
Figure PCTCN2018080787-appb-000037
Figure PCTCN2018080787-appb-000037
表2、本发明部分化合物体外抗耐药结核分枝杆菌活性Table 2. In vitro anti-drug resistant Mycobacterium tuberculosis activity of some compounds of the present invention
Figure PCTCN2018080787-appb-000038
Figure PCTCN2018080787-appb-000038
Figure PCTCN2018080787-appb-000039
Figure PCTCN2018080787-appb-000039
a耐异烟肼，利福平，链霉素，乙胺丁醇，利福喷丁，利福布丁和苯甲酰氨基水杨酸。 a isoniazid resistant, rifampicin, streptomycin, ethambutol, rifapentine, rifabutin and benzoylaminosalicylic acid.
b耐异烟肼，乙胺丁醇，利福平，利福喷丁，利福布丁，阿米卡星和卷曲霉素。 b resistant to isoniazid, ethambutol, rifampin, rifapentine, rifabutin, amikacin and capreomycin.
由表1及表2数据可知，本发明中的化合物具有很强的体外抗结核敏感菌和耐药菌的活性。As is apparent from the data of Tables 1 and 2, the compounds of the present invention have strong activity against anti-tuberculosis-sensitive bacteria and resistant bacteria in vitro.
2、细胞毒性测试2, cytotoxicity test
测定方法：MTT法Determination method: MTT method
实验原理：细胞活性通过线粒体内脱氢酶(如琥珀酸脱氢酶)将氧化态的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐(商品名：噻唑蓝)/MTT[3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide]还原为难溶的蓝色甲臜(formazan)化合物，经DMSO溶解后显色来测定，转化量与活细胞数量呈正性相关。Experimental principle: Cellular activity 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium in the oxidized state by mitochondrial dehydrogenase (such as succinate dehydrogenase) Bromine salt (trade name: thiazolyl blue)/MTT[3-(4,5-dimethylthiazo-2-yl)-2,5-diphenyl tetrazolium bromide] reduced to insoluble blue formazan compound, dissolved in DMSO After color development, the amount of conversion was positively correlated with the number of viable cells.
实验方法：1.细胞悬液的制备。将已培养至对数生长期的Vero/HepG2细胞用0.25％胰酶消化2～3min，吸弃消化液，加入适量培养液，混匀后取20μL用血球计数仪在显微镜下计数，配制成合适浓度的细胞悬液，备用。同时用PBS(phosphate buffered solution)配制5g/L的MTT溶液，过滤除菌，备用。2.药物配制与细胞毒性检测。将受试药物溶于DMSO中，以培养基稀释50倍，制成受试的最高浓度，然后用培养基在96孔板上按1∶3进行系列稀释，每个化合物设6个浓度，最高浓度64μg/mL,每个浓度设6个平行孔，50μL/孔。将制备好的细胞悬液接种于96孔板内，50μL/孔，细胞浓度4×10 5个/mL.。同时设不含药的细胞对照孔及培养基空白对照孔。培养48小时后，加入MTT 10μL/孔，继续培养4小时。取出培养板，小心弃去孔内培养基，每孔加DMSO100μL，振荡至甲臜颗粒完全溶解后，用酶联免疫检测仪在570nm波长处测定其光密度值(OD 570)。3.数据处理。细胞抑制百分率(％)＝[(细胞对照OD 570值－加药组OD 570值)/(细胞对照OD 570值－空白OD 570值)]×100％。用Origin7.0软件进行剂量－反应关系曲线拟合，计算各种化合物对细胞抑制率50％时的浓度(IC 50)。 Experimental methods: 1. Preparation of cell suspension. The Vero/HepG2 cells that have been cultured to logarithmic growth phase are digested with 0.25% trypsin for 2 to 3 minutes, the digestive juice is aspirated, and the appropriate amount of the culture solution is added. After mixing, 20 μL is counted under a microscope using a hemocytometer to prepare a suitable one. Concentration of cell suspension, spare. At the same time, a 5 g/L MTT solution was prepared by using PBS (phosphate buffered solution), and the cells were removed by filtration and used. 2. Drug preparation and cytotoxicity test. The test drug was dissolved in DMSO, diluted 50 times with the medium to prepare the highest concentration of the test, and then serially diluted with 1:3 in a 96-well plate, and each compound was set to 6 concentrations, the highest. The concentration was 64 μg/mL, and each concentration was set to 6 parallel wells, 50 μL/well. The prepared cell suspension was inoculated into a 96-well plate at 50 μL/well with a cell concentration of 4 × 10 5 /mL. At the same time, a cell control well containing no drug and a blank control well of the medium were set. After 48 hours of incubation, MTT 10 μL/well was added and incubation was continued for 4 hours. The culture plate was taken out, the medium in the well was carefully discarded, and 100 μL of DMSO was added to each well, and the mixture was shaken until the formazan particles were completely dissolved, and the optical density value (OD 570 ) was measured at a wavelength of 570 nm by an enzyme-linked immunosorbent assay. 3. Data processing. Percent inhibition of cells (%) = [(cell control OD 570 value - dosing group OD 570 value) / (cell control OD 570 value - blank OD 570 value)] x 100%. Dose-response curve fitting was performed using Origin 7.0 software, and the concentration (IC 50 ) of each compound at a cell inhibition rate of 50% was calculated.
表3、本发明部分化合物Vero细胞毒性Table 3. Vero cytotoxicity of some compounds of the present invention
Figure PCTCN2018080787-appb-000040
Figure PCTCN2018080787-appb-000040
表4、本发明部分化合物HepG2细胞毒性Table 4. HepG2 cytotoxicity of some compounds of the present invention
Figure PCTCN2018080787-appb-000041
Figure PCTCN2018080787-appb-000041
由表3，表4数据可知，本发明的化合物的细胞毒性低，表现出了较阳性药PBTZ169具有更高的安全性。From the data of Table 3 and Table 4, the compound of the present invention has low cytotoxicity and exhibits higher safety than the positive drug PBTZ169.
3、肝微粒体代谢稳定性测试3, liver microsomal metabolism stability test
实验方法：experimental method:
选取目标化合物进行肝微粒体(混合的人源(Bioreclamation))的代谢稳定性研究，具体方法如下：分别取合成的目标化合物配制成1μM测试液。微粒体蛋白浓度为1mg/mL。通过添加NADPH(1mM)来引发反应，并将样品在振荡培养箱中于37℃孵育至多60分钟。通过添加含内标的冰冷的乙腈/甲醇(50:50)使反应终止于0,5,15和30分钟。分别于0,5,15,30和60分钟取出等份试样的反应混合物，然后加入含内标的冰冷的乙腈/甲醇(50:50，v/v)。将样品在4℃离心15分钟(4,000转/分)，并通过LC-MS/MS分析上清液。色谱条件：色谱柱：Kinetex C18 100A(30mm×3.0mm，2.6μm)；柱温：室温，流动相：乙腈-水(含0.1％甲酸)梯度；流速：0.9mL/min。通过测量在有或没有NADPH辅因子的情况下化合物的残余量来评估化合物的代谢稳定性。The target compound was selected for the metabolic stability study of liver microsomes (Bioreclamation). The specific method was as follows: The synthesized target compound was separately prepared into a 1 μM test solution. The microsomal protein concentration was 1 mg/mL. The reaction was initiated by the addition of NADPH (1 mM) and the samples were incubated in a shaking incubator at 37 °C for up to 60 minutes. The reaction was terminated at 0, 5, 15 and 30 minutes by the addition of an ice-cold acetonitrile/methanol (50:50) containing an internal standard. Aliquots of the reaction mixture were taken at 0, 5, 15, 30 and 60 minutes, respectively, followed by ice-cold acetonitrile/methanol (50:50, v/v) containing an internal standard. The sample was centrifuged at 4 ° C for 15 minutes (4,000 rpm), and the supernatant was analyzed by LC-MS/MS. Chromatographic conditions: column: Kinetex C18 100A (30 mm x 3.0 mm, 2.6 μm); column temperature: room temperature, mobile phase: acetonitrile-water (containing 0.1% formic acid) gradient; flow rate: 0.9 mL/min. The metabolic stability of the compounds was assessed by measuring the residual amount of the compound with or without the NADPH cofactor.
表5、本发明部分化合物的人源肝微粒体代谢稳定性数据Table 5. Metabolic stability data of human liver microsomes of some compounds of the present invention
Figure PCTCN2018080787-appb-000042
Figure PCTCN2018080787-appb-000042
由表5数据可知，本发明的化合物具有较高的肝微粒体代谢稳定性。As can be seen from the data in Table 5, the compounds of the present invention have high metabolic stability of liver microsomes.
4、肝细胞代谢稳定性测试4, liver cell metabolism stability test
实验方法：experimental method:
使用来自混合的CD-1小鼠(Bioreclamation IVT)，混合的SD大鼠(Bioreclamation IVT)，混合的雄性狗(Bioreclamation IVT)，混合的雄性食蟹猴(RILD)和混合的人(Bioreclamation IVT)的肝细胞进行测定。在1μM浓度下测试化合物(化合物11和PBTZ169)，最终肝细胞浓度为1百万个细胞/mL。通过向化合物溶液(2μM)中加入预热的肝细胞溶液(200万细胞/mL)来引发反应。将反应混合物在100转/分钟的CO 2培养箱中于37℃孵育120分钟。在预定的时间点(0,15,30,60,90和120分钟)，取出30μL反应混合物，通过加入200μL含内标的冰冷的ACN/MeOH(50:50)终止反应。将样品充分混合，在4℃离心15分钟(4,000转/分)，并通过LC-MS/MS分析上清液。色谱条件：色谱柱：Kinetex C18100A(30mm×3.0mm，2.6μm)；柱温：室温，流动相：乙腈-水(含0.1％甲酸)梯度；流速：0.9mL/min。通过测定化合物的剩余量来评估化合物在肝细胞中的代谢稳定性。 Using mixed CD-1 mice (Bioreclamation IVT), mixed SD rats (Bioreclamation IVT), mixed male dogs (Bioreclamation IVT), mixed male cynomolgus monkeys (RILD) and mixed humans (Bioreclamation IVT) The liver cells were assayed. Compounds (Compound 11 and PBTZ169) were tested at a concentration of 1 μM with a final hepatocyte concentration of 1 million cells/mL. The reaction was initiated by adding a preheated hepatocyte solution (2 million cells/mL) to the compound solution (2 μM). The reaction mixture was incubated at 37 ° C for 120 minutes in a 100 rpm CO 2 incubator. At predetermined time points (0, 15, 30, 60, 90 and 120 minutes), 30 μL of the reaction mixture was taken out and the reaction was stopped by the addition of 200 μL of ice-cold ACN/MeOH (50:50) containing an internal standard. The samples were thoroughly mixed, centrifuged at 4 ° C for 15 minutes (4,000 rpm), and the supernatant was analyzed by LC-MS/MS. Chromatographic conditions: column: Kinetex C18100A (30 mm x 3.0 mm, 2.6 μm); column temperature: room temperature, mobile phase: acetonitrile-water (containing 0.1% formic acid) gradient; flow rate: 0.9 mL/min. The metabolic stability of the compound in hepatocytes was assessed by measuring the remaining amount of the compound.
表6、化合物11和PBTZ169的肝细胞代谢稳定性Table 6. Hepatocyte metabolic stability of compound 11 and PBTZ169
Figure PCTCN2018080787-appb-000043
Figure PCTCN2018080787-appb-000043
Figure PCTCN2018080787-appb-000044
Figure PCTCN2018080787-appb-000044
由表6数据可知，本发明的化合物11较阳性对照药PBTZ169在五种种属肝细胞中具有更长的半衰期，代谢稳定性显著优于PBTZ169。As can be seen from the data in Table 6, the compound 11 of the present invention has a longer half-life than the positive control drug PBTZ169 in five species of hepatocytes, and the metabolic stability is significantly superior to that of PBTZ169.
5、化合物11，化合物22和PBTZ169小鼠体内药代动力学试验5. Pharmacokinetics test of compound 11, compound 22 and PBTZ169 mice
实验方法：experimental method:
每组采用三只重量为22-23克的Balb/c小鼠(雄性)进行化合物11，化合物22和PBTZ169的药代动力学研究。将化合物11以0.5％羧甲基纤维素和0.5％吐温80配制成2.5mg/mL悬液，化合物22以0.5％羧甲基纤维素配制成2.5mg/mL悬液，PBTZ169以0.5％羧甲基纤维素和4摩尔当量的1N盐酸配制成2.5mg/mL悬液，所有化合物给予25mg/kg的剂量。在口服给药后5,15,30分钟，以及1,2,4,7,24小时收集血浆样本。收集的血浆样本储存在-80℃直到用于分析。血浆样本用含有特非那丁内标的乙腈进行提取，提取剂与血浆比率为20:1。通过LC/TSQ Quantum Access质谱仪(AB Sciex 5500)进行分析物定量。色谱条件：色谱柱：Kinetex C18 100A(30mm×3.0mm，2.6μm)；柱温：室温，流动相：乙腈/水(80:20，v/v)(含0.1％甲酸)；流速：0.8mL/min。质谱仪上的化合物检测以电喷雾正离子化模式进行。MRM方式检测m/z 456.17/359.80(化合物11)，456.17/359.80(化合物22)，m/z 457.16/344.20(PBTZ169)。应用WinNonlin软件(6.3Pharsight Corporation,Mountain View,USA)计算药代动力学参数。Three groups of 22-23 g Balb/c mice (male) were used for pharmacokinetic studies of Compound 11, Compound 22 and PBTZ169. Compound 11 was formulated as a 2.5 mg/mL suspension with 0.5% carboxymethylcellulose and 0.5% Tween 80. Compound 22 was formulated as a 2.5 mg/mL suspension with 0.5% carboxymethylcellulose and 0.5% carboxylate with PBTZ169. Methylcellulose and 4 molar equivalents of 1 N hydrochloric acid were formulated into a 2.5 mg/mL suspension, and all compounds were administered at a dose of 25 mg/kg. Plasma samples were collected at 5, 15, 30 minutes, and 1, 2, 4, 7, 24 hours after oral administration. The collected plasma samples were stored at -80 °C until used for analysis. Plasma samples were extracted with acetonitrile containing the terfenadine internal standard with a ratio of extractant to plasma of 20:1. Analyte quantification was performed by LC/TSQ Quantum Access mass spectrometer (AB Sciex 5500). Chromatographic conditions: column: Kinetex C18 100A (30 mm × 3.0 mm, 2.6 μm); column temperature: room temperature, mobile phase: acetonitrile / water (80:20, v / v) (containing 0.1% formic acid); flow rate: 0.8mL /min. Compound detection on the mass spectrometer was performed in electrospray positive ionization mode. m/z 456.17/359.80 (Compound 11), 456.17/359.80 (Compound 22), m/z 457.16/344.20 (PBTZ 169). Pharmacokinetic parameters were calculated using WinNonlin software (6.3 Pharsight Corporation, Mountain View, USA).
表7小鼠口服化合物11，化合物22及PBTZ169后血浆药代动力学参数Table 7 Plasma pharmacokinetic parameters after oral administration of Compound 11, Compound 22 and PBTZ169 in mice
参数parameter 单位unit 化合物11Compound 11 化合物22Compound 22 PBTZ169PBTZ169
t 1/2 t 1/2 hh 7.257.25 6.726.72 2.702.70
T max T max hh 0.500.50 0.420.42 0.330.33
C max C max ng/mLNg/mL 588588 502502 10431043
AUC (0-24) AUC (0-24) ng·h/mLNg·h/mL 15811581 22512251 22702270
AUC (0-∞) AUC (0-∞) ng·h/mLNg·h/mL 16951695 24122412 24512451
MRT (0-∞) MRT (0-∞) hh 6.596.59 7.187.18 3.233.23
由表7可知本发明的化合物11和化合物22较PBTZ169在小鼠体内具有更长的半衰期，其药代动力学性质优于PBTZ169，预示在临床使用时可以减少给药次数，从而提高患者用药的依从性。It can be seen from Table 7 that the compound 11 and the compound 22 of the present invention have a longer half-life than the PBTZ169 in mice, and their pharmacokinetic properties are superior to those of PBTZ169, indicating that the number of administrations can be reduced in clinical use, thereby improving the patient's medication. Compliance.
6、化合物11，化合物22和PBTZ169稳定性考察6. Stability of compound 11, compound 22 and PBTZ169
采用HPLC考察化合物11，化合物22和PBTZ169在光照、高温、高湿条件下放置10天的稳定性，结果如表8所示。The stability of Compound 11, Compound 22 and PBTZ169 under light, high temperature and high humidity conditions for 10 days was examined by HPLC, and the results are shown in Table 8.
表8化合物11，化合物22和PBTZ169稳定性考察结果Table 8 Results of stability study of compound 11, compound 22 and PBTZ169
Figure PCTCN2018080787-appb-000045
Figure PCTCN2018080787-appb-000045
采用Waters e2695-PDA HPLC***检测化合物纯度。色谱条件：色谱柱：Kromasil C18(250mm×4.6mm，5μm)；柱温：30℃，流动相：乙腈/水(84:16，v/v)等梯度；流速：1.0mL/min。由表8可知本发明的化合物11和化合物22在光照条件下的稳定性显著好于PBTZ169。相比PBTZ169，化合物11和化合物22具有更优的理化性质。Compound purity was measured using a Waters e2695-PDA HPLC system. Chromatographic conditions: column: Kromasil C18 (250 mm x 4.6 mm, 5 μm); column temperature: 30 ° C, mobile phase: acetonitrile / water (84:16, v / v) gradient; flow rate: 1.0 mL / min. From Table 8, it is understood that the stability of the compound 11 and the compound 22 of the present invention under light conditions is remarkably better than that of PBTZ169. Compound 11 and Compound 22 have superior physicochemical properties compared to PBTZ169.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described, it is understood that the above-described embodiments are illustrative and are not to be construed as limiting the scope of the invention. The embodiments are subject to variations, modifications, substitutions and variations.

Claims (13)

  1. 如式(I)所示的化合物及其异构体、或其药学上可接受的盐：a compound represented by formula (I), and an isomer thereof, or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2018080787-appb-100001
    Figure PCTCN2018080787-appb-100001
    其中，among them,
    X为O或S；X is O or S;
    Y为C或N；Y is C or N;
    R 1为H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)或(＝S)； R 1 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN, OH, (=O) or (=S);
    n为0、1或2；n is 0, 1 or 2;
    R 2为F、取代或未取代的C 3-C 6环烷基、取代或未取代的C 3-C 6杂环基、取代或未取代的C 6-C 10芳基、取代或未取代的C 2-C 9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基； R 2 is F, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, a substituted or unsubstituted C 3 -C 6 heterocyclic group, a substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted a C 2 -C 9 heteroaryl group, or together with a carbon atom to which it is attached, denotes a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms or 1 to 3 hetero atoms selected from oxygen and sulfur. a substituted or unsubstituted 4-6 membered heterocyclic group;
    所述的C 3-C 6杂环基、C 2-C 9杂芳基至少含有一个选自N、O、S中的杂原子； The C 3 -C 6 heterocyclic group, C 2 -C 9 heteroaryl group contains at least one hetero atom selected from N, O, S;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkoxy group.
  2. 根据权利要求1所述的化合物及其异构体、或其药学上可接受的盐，所述的化合物由通式(II)所示；The compound according to claim 1 or an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (II);
    Figure PCTCN2018080787-appb-100002
    Figure PCTCN2018080787-appb-100002
    其中，among them,
    Y为C或N；Y is C or N;
    R 1为H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)或(＝S)； R 1 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN, OH, (=O) or (=S);
    n为0、1或2；n is 0, 1 or 2;
    R 2为F、取代或未取代的C 3-C 6环烷基、取代或未取代的C 3-C 6杂环基、取代或未取代的C 6-C 10芳基、取代或未取代的C 2-C 9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基； R 2 is F, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, a substituted or unsubstituted C 3 -C 6 heterocyclic group, a substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted a C 2 -C 9 heteroaryl group, or together with a carbon atom to which it is attached, denotes a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms or 1 to 3 hetero atoms selected from oxygen and sulfur. a substituted or unsubstituted 4-6 membered heterocyclic group;
    所述的C 3-C 6杂环基、C 2-C 9杂芳基至少含有一个选自N、O、S中的杂原子； The C 3 -C 6 heterocyclic group, C 2 -C 9 heteroaryl group contains at least one hetero atom selected from N, O, S;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  3. 根据权利要求1所述的化合物及其异构体、或其药学上可接受的盐，所述的化合物由通式(III)所示；The compound according to claim 1 or an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (III);
    Figure PCTCN2018080787-appb-100003
    Figure PCTCN2018080787-appb-100003
    其中，among them,
    Y为C或N；Y is C or N;
    R 1为H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)或(＝S)； R 1 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN, OH, (=O) or (=S);
    n为0、1或2；n is 0, 1 or 2;
    R 2为F、取代或未取代的C 3-C 6环烷基、取代或未取代的C 3-C 6杂环基、取代或未取代的C 6-C 10芳基、取代或未取代的C 2-C 9杂芳基、或和共同连接的碳原子一起表示含有3-8个碳原子的取代或未取代的环烷基或含1-3个选自氧、硫的杂原子的取代或未取代的4-6元杂环基； R 2 is F, a substituted or unsubstituted C 3 -C 6 cycloalkyl group, a substituted or unsubstituted C 3 -C 6 heterocyclic group, a substituted or unsubstituted C 6 -C 10 aryl group, substituted or unsubstituted a C 2 -C 9 heteroaryl group, or together with a carbon atom to which it is attached, denotes a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms or 1 to 3 hetero atoms selected from oxygen and sulfur. a substituted or unsubstituted 4-6 membered heterocyclic group;
    所述的C 3-C 6杂环基、C 2-C 9杂芳基至少含有一个选自N、O、S中的杂原子； The C 3 -C 6 heterocyclic group, C 2 -C 9 heteroaryl group contains at least one hetero atom selected from N, O, S;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  4. 根据权利要求1或2所述的化合物及其异构体、或其药学上可接受的盐，所述的化合物由通式(II-a)所示：The compound according to claim 1 or 2, and an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (II-a):
    Figure PCTCN2018080787-appb-100004
    Figure PCTCN2018080787-appb-100004
    其中，among them,
    R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
    n为0或1；n is 0 or 1;
    R 2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基； R 2 is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with a covalently bonded carbon atom means substituted or unsubstituted cyclopentyl or 1-2 a substituted or unsubstituted 5-membered heterocyclic group selected from hetero atoms of oxygen and sulfur;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  5. 根据权利要求1或2所述的化合物及其异构体、或其药学上可接受的盐，所述的化合物由通式(II-b)所示：The compound according to claim 1 or 2, and an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (II-b):
    Figure PCTCN2018080787-appb-100005
    Figure PCTCN2018080787-appb-100005
    其中，among them,
    R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
    n为0或1；n is 0 or 1;
    R 2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基或取代或未取代的噻唑基； R 2 is a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrole group. a substituted, unsubstituted or unsubstituted thiophenyl group or a substituted or unsubstituted thiazolyl group;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  6. 根据权利要求1或3所述的化合物及其异构体、或其药学上可接受的盐，所述的化合物由通式(III-a)所示：The compound according to claim 1 or 3, and an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (III-a):
    Figure PCTCN2018080787-appb-100006
    Figure PCTCN2018080787-appb-100006
    其中，among them,
    R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
    n为0或1；n is 0 or 1;
    R 2为F、取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基、或和共同连接的碳原子一起表示取代或未取代的环戊基或含1-2个选自氧、硫的杂原子的取代或未取代的5元杂环基； R 2 is F, substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted quinolyl, substituted or unsubstituted Pyrrolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, or together with a covalently bonded carbon atom means substituted or unsubstituted cyclopentyl or 1-2 a substituted or unsubstituted 5-membered heterocyclic group selected from hetero atoms of oxygen and sulfur;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  7. 根据权利要求1或3所述的化合物及其异构体、或其药学上可接受的盐，所述的化合物由通式(III-b)所示：The compound according to claim 1 or 3, and an isomer thereof, or a pharmaceutically acceptable salt thereof, which is represented by the formula (III-b):
    Figure PCTCN2018080787-appb-100007
    Figure PCTCN2018080787-appb-100007
    其中，among them,
    R 1为H、C 1-C 3烷基、F、Cl或(＝O)； R 1 is H, C 1 -C 3 alkyl, F, Cl or (=O);
    n为0或1；n is 0 or 1;
    R 2为取代或未取代的环己基、取代或未取代的苯基、取代或未取代的萘基、取代或未取代的吡啶基、取代或未取代的喹啉基、取代或未取代的吡咯基、取代或未取代的呋喃基、取代或未取代的噻吩基、取代或未取代的噻唑基； R 2 is a substituted or unsubstituted cyclohexyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted quinolyl group, a substituted or unsubstituted pyrrole a substituted or unsubstituted furanyl group, a substituted or unsubstituted thienyl group, a substituted or unsubstituted thiazolyl group;
    所述R 2中取代或未取代的取代基可任选自以下基团：F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 The substituted or unsubstituted substituent in R 2 may be selected from the group consisting of F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 - C 3 alkyl, halo C 1 -C 3 alkyl, C 1 -C 3 alkoxy or C 1 -C 3 alkylamino.
  8. 根据权利要求2所述的化合物及其异构体、或其药学上可接受的盐，The compound according to claim 2, and an isomer thereof, or a pharmaceutically acceptable salt thereof,
    其中，among them,
    R 1为H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)或(＝S)； R 1 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN, OH, (=O) or (=S);
    n为0、1或2；n is 0, 1 or 2;
    当Y为C时，When Y is C,
    R 2为F、
    Figure PCTCN2018080787-appb-100008
    Figure PCTCN2018080787-appb-100009
    R 2 is F,
    Figure PCTCN2018080787-appb-100008
    Figure PCTCN2018080787-appb-100009
    当Y为N时，When Y is N,
    R 2为
    Figure PCTCN2018080787-appb-100010
    Figure PCTCN2018080787-appb-100011
    R 2 is
    Figure PCTCN2018080787-appb-100010
    Figure PCTCN2018080787-appb-100011
    Rx为F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 Rx is F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 - C 3 alkoxy or C 1 -C 3 alkylamino.
  9. 根据权利要求3所述的化合物及其异构体、或其药学上可接受的盐，The compound according to claim 3, and an isomer thereof, or a pharmaceutically acceptable salt thereof,
    其中，among them,
    R 1为H、C 1-C 3烷基、C 1-C 3烷氧基、F、Cl、Br、CN、OH、(＝O)或(＝S)； R 1 is H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, F, Cl, Br, CN, OH, (=O) or (=S);
    n为0、1或2；n is 0, 1 or 2;
    当Y为C时，When Y is C,
    R 2为F、
    Figure PCTCN2018080787-appb-100012
    Figure PCTCN2018080787-appb-100013
    R 2 is F,
    Figure PCTCN2018080787-appb-100012
    Figure PCTCN2018080787-appb-100013
    当Y为N时，When Y is N,
    R 2为
    Figure PCTCN2018080787-appb-100014
    Figure PCTCN2018080787-appb-100015
    R 2 is
    Figure PCTCN2018080787-appb-100014
    Figure PCTCN2018080787-appb-100015
    Rx为F、Cl、Br、羟基、氨基、硝基、氰基、三氟甲基、三氟甲氧基、C 1-C 3烷基、卤代C 1-C 3烷基、C 1-C 3烷氧基或C 1-C 3烷胺基。 Rx is F, Cl, Br, hydroxy, amino, nitro, cyano, trifluoromethyl, trifluoromethoxy, C 1 -C 3 alkyl, halogenated C 1 -C 3 alkyl, C 1 - C 3 alkoxy or C 1 -C 3 alkylamino.
  10. 根据权利要求1至9任一项的化合物及其异构体，或其药学上可接受的盐，其选自下列化合物：A compound according to any one of claims 1 to 9 and an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds:
    Figure PCTCN2018080787-appb-100016
    Figure PCTCN2018080787-appb-100016
    Figure PCTCN2018080787-appb-100017
    Figure PCTCN2018080787-appb-100017
    Figure PCTCN2018080787-appb-100018
    Figure PCTCN2018080787-appb-100018
  11. 制备权利要求1至10任一项所述化合物的方法，其包括以下步骤：A method of preparing a compound of any one of claims 1 to 10, comprising the steps of:
    (1)(1)
    Figure PCTCN2018080787-appb-100019
    Figure PCTCN2018080787-appb-100019
    化合物A与氮杂环侧链B经缩合得到式C化合物，然后在碱性条件下关环得到式(II)所示化合物；Compound A is condensed with a nitrogen heterocyclic side chain B to obtain a compound of formula C, which is then subjected to ring closure under basic conditions to give a compound of formula (II);
    或(2)Or (2)
    Figure PCTCN2018080787-appb-100020
    Figure PCTCN2018080787-appb-100020
    化合物D先与二硫化碳在碱性条件下反应，然后经甲基化得到化合物E，随后与氮杂环侧链B发生取代反应得到式(III)所示化合物，式(III)所示化合物可在已知的合适溶剂中用相应的酸处理，转化为药学上可接受的盐，其中，可接受的盐选自盐酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、乳酸盐、甲磺酸盐、硫酸盐、磷酸盐、柠檬酸盐、乙酸盐或三氟乙酸盐，Compound D is first reacted with carbon disulfide under basic conditions, and then methylated to obtain compound E, followed by substitution reaction with nitrogen heterocyclic side chain B to obtain a compound of formula (III), and the compound of formula (III) can be It is converted to a pharmaceutically acceptable salt by treatment with the corresponding acid in a suitable solvent, wherein the acceptable salt is selected from the group consisting of hydrochloride, p-toluenesulfonate, tartrate, maleate, lactate. , mesylate, sulfate, phosphate, citrate, acetate or trifluoroacetate,
    其中，Y、R 1、R 2、n定义同权利要求1-9中任一项。 Wherein Y, R 1 , R 2 , n are as defined in any one of claims 1-9.
  12. 一种药物组合物，其包括治疗和/或预防有效量的权利要求1至10任一项所述的化合物及其异构体，或其药学上可接受的盐以及任选的一种或多种药学上可接受的载体、赋形剂、稀释剂、辅料和媒介物。A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound according to any one of claims 1 to 10, and an isomer thereof, or a pharmaceutically acceptable salt thereof, and optionally one or more A pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
  13. 权利要求1-10任一项所述化合物及其异构体或其药学可接受的盐或者权利要求12所述组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。The compound according to any one of claims 1 to 10, and an isomer thereof, or a pharmaceutically acceptable salt thereof, or the composition according to claim 12, for the preparation of a medicament for treating and/or preventing an infectious disease caused by Mycobacterium tuberculosis Application in .
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