WO2013185507A1 - Benzothiazine-4-one derivatives, preparation method therefor and use thereof - Google Patents

Benzothiazine-4-one derivatives, preparation method therefor and use thereof Download PDF

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WO2013185507A1
WO2013185507A1 PCT/CN2013/074497 CN2013074497W WO2013185507A1 WO 2013185507 A1 WO2013185507 A1 WO 2013185507A1 CN 2013074497 W CN2013074497 W CN 2013074497W WO 2013185507 A1 WO2013185507 A1 WO 2013185507A1
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alkyl
substituted
halogen
group
independently
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PCT/CN2013/074497
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余洛汀
魏于全
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四川大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
    • 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
    • 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
    • A61P31/08—Antibacterial agents for leprosy
    • 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
    • C07D417/04—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 directly linked by a ring-member-to-ring-member bond
    • 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 medicine, and particularly relates to a benzothiazin-4-one derivative, a preparation method thereof and use thereof.
  • Tuberculosis is one of the diseases with the highest prevalence and mortality. In the 21st century, tuberculosis continues to be a major cause of death in developing countries and a renewed disease in developed countries. Due to the prevalence of poverty and HIV/AIDS, the emergence of multidrug-resistant (MDR-TB)/broad-spectrum-resistant tuberculosis (XDR-TB), the number of people dying from tuberculosis worldwide continues to increase, and existing anti-tuberculosis drugs are no longer able to meet the cure Demand is currently one-third of the world's population of 2 billion people carrying tubercle bacilli, tuberculosis kills 3 million people each year, and as one of the developing countries, there are about 4.5 million active tuberculosis patients in China.
  • MDR-TB multidrug-resistant
  • XDR-TB broad-spectrum-resistant tuberculosis
  • Tuberculosis has become a serious public health problem
  • the resurgence of tuberculosis has drawn deep concern from all walks of life. It is extremely urgent to develop new, highly effective and low-toxic anti-tuberculosis drugs. And content
  • the first technical problem to be solved by the present invention is to provide a novel class of benzothiazin-4-one derivatives having the structure of formula I:
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri independently is -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkane Substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO Or -CF 3 ;
  • R 6 and R 7 are independently -H, a substituted -C 8 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, and a band a substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is - ⁇ , ⁇ 3 ⁇ 4 alkyl, ⁇ alkoxy, ⁇ alkyl substituted a sulfamoyl group, a substituted ⁇ prime ⁇ C 8 alkyl group, ⁇ ⁇ alkyl substituted carbonyl group, substituted amino ⁇ C 8 alkyl group, ⁇ C 8 alkyl-substituted amide group, a halogen, -N0 2, -OH, -OCF 3 , -CF 3 or phenyl; R 8 to R 16 are independently -H, -C 8
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ⁇ 3 ⁇ 4 alkyl, ⁇ C 8 alkoxy, C 3 ⁇ C 8 cycloalkyl, ⁇ C 8 Alkyl substituted sulfamoyl group, aryl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, ⁇ substituted ⁇ 3 ⁇ 4 alkyl group, ⁇ 3 ⁇ 4 alkyl substituted carbonyl group, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl group a ⁇ 3 ⁇ 4 alkyl-substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a hetero atom containing N, 0 or S a saturated or unsaturated heterocyclic ring;
  • R 27 is ⁇ 3 ⁇ 4 alkyl, C 3 ⁇ C 8 cycloalkyl, substituted phenyl, C 3 ⁇ C 8 cycloalkyl substituted ⁇ 3 ⁇ 4 alkyl or adamantyl; the substituent of the substituted phenyl is Halogen, -1 ⁇ 0 2 or ⁇ 3 ⁇ 4 alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri independently is -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkane Substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ C 8 alkyl substituted amide, ⁇ alkyl substituted sulfamoyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 5 is ⁇ R 9 R" R or 3 ⁇ 4 R,usually ;
  • R 6 and R 7 are independently -H, a substituted -C 8 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, and a band A substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -H, ⁇ .
  • alkyl ⁇ ⁇ alkoxy, substituted sulfamoyl ⁇ C 8 alkyl group, a substituted ⁇ prime ⁇ C 8 alkyl group, ⁇ ⁇ alkyl substituted carbonyl group, substituted amino ⁇ C 8 alkyl group, C ⁇ 8
  • R 8 to R 16 are independently -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 An alkyl substituted aminoacyl group, a ⁇ 3 ⁇ 4 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is - ⁇ , ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy. 3 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ alkyl substituted sulfamoyl group, sulfamoyl group substituted with an aryl group, halogen-substituted Ci ⁇ C 8 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl group, ⁇ 3 ⁇ 4 alkyl substituted amino group, ⁇ 3 ⁇ 4 alkoxy a substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated group containing a hetero atom of N, 0 or S Heterocycle
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ (-8 3 ⁇ 43 ⁇ 43 ⁇ 4, fierce 4 ⁇ tf J Li L alkoxy, -N0 2 -NH 2 -CN or -CF 3 ;
  • R 6 R 7 is independently -H, ⁇ alkyl, substituted C 3 C 8 cycloalkyl, halogen substituted Ci C alkyl, substituted phenyl, substituted benzene a formyl group, a pyridyl group having a substituent, said substituent is - ⁇ , ⁇ ⁇ 3 ⁇ 4 alkyl, halo-substituted ⁇ 3 ⁇ 4 alkyl, -F -Cl -Br -CF 3 -OCF 3 -N0 2 - NH 2 or -CN;
  • R 8 R 16 is independently -H -F -Cl -Br -COOH, ⁇ 3 ⁇ 4 alkyl or halogen substituted ⁇ 3 ⁇ 4 fluorenyl;
  • L is nitrogen, oxygen or sulfur;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, C 3 C 8 cycloalkyl, C 8 alkyl Substituted sulfamoyl, halogen substituted ⁇ . 8 alkyl, ⁇ . 8- alkyl substituted carbonyl, C 8 alkyl substituted aminoacyl, C Cs alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 -OH -CF 3 or substituted phenyl, said substitution
  • the base is a saturated or unsaturated heterocyclic ring containing a N 0 or S hetero atom.
  • R 2 R4 is independently halogen, -N0 2 -NH 2 -OCF 3 -CN, or -CF 3 ;
  • Ri R 3 is independently -H -F -Cl -Br, ⁇ 3 ⁇ 4 alkyl, C 8 -alkoxy, halogen-substituted C 8 alkyl, halogen-substituted C 8 alkoxy, -N M' R 6 W, U ,, ' X "
  • R 5 is R 7 R" R
  • R 6 R 7 is independently -H, ⁇ 3 ⁇ 4 alkyl, halogen-substituted ⁇ 3 ⁇ 4 alkyl, substituted C 3 3 ⁇ 4 cycloalkyl, substituted phenyl, substituted benzoyl
  • An acyl group, a substituted pyridyl group, the substituent is a 3 ⁇ 4 alkyl group, a halogen-substituted ⁇ 3 ⁇ 4 alkyl group, -F-Cl-Br-CF 3 -OCF 3 -N0 2 -NH 2 or -CN ;
  • R 8 R 16 is independently -H-COOH C 8 alkyl or halogen substituted C 8 alkyl
  • M is oxygen, R 17 is -H ; M is nitrogen, R 17 is -HC 8 alkyl, C 8 alkoxy, C 3 C 8 cycloalkyl, C 8 alkyl substituted sulfamoyl, aryl substituted ammonia Sulfonyl, a substituted C 8 alkyl group, an alkyl substituted carbonyl group, a C 8 alkyl substituted amino group, a C 8 alkyl substituted amide group, a compound, a tert-butyloxycarbonyl group, -OCF 3 -OH -CF 3 Or a substituted phenyl group, said substituent being a saturated or unsaturated heterocyclic ring containing a N 0 or S hetero atom;
  • R 2 R 4 is independently halogen, -N0 2 -NH 2 -OCF 3 -CN -OH -CHO or -CF 3;
  • Ri R 3 is independently -H -F -Cl -Br, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2 ; , 6
  • R 5 is 7
  • R 6 and R 7 are independently -H, -3 ⁇ 4 alkyl, substituted phenyl, substituted C 3 -C 8 cycloalkyl, substituted benzoyl, or a pyridyl group of a substituent, which is - ⁇ , ⁇ 3 ⁇ 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
  • R 8 to R 16 are -H, -COOH or methyl; M is oxygen, R 17 is -H; M is nitrogen, and R 17 is t-butyloxycarbonyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 5 is H 7 , ;
  • R 6 and R 7 are independently -H, -C 4 alkyl, substituted phenyl, substituted C 3 -C 8 cycloalkyl, substituted benzoyl, or a pyridyl group having a substituent which is -H, -C 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 ,
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl group, a halogen-substituted alkoxy ⁇ ⁇ ⁇ , -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 5 is R " H 3 , , or r ;
  • R 6 and R 7 are independently -H, a substituted ⁇ 3 ⁇ 4 alkyl group, a substituted C 3 ⁇ C 8 cycloalkyl group, a substituted halogenated ⁇ 3 ⁇ 4 alkyl group, with a substitution a phenyl group, a substituted benzoyl group, a substituted pyridyl group, the substituent is - ⁇ , ⁇ 3 ⁇ 4 alkyl, ⁇ alkoxy, ⁇ alkyl-substituted ammoxime Acyl, n-substituted -3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ C 8 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , CF 3 or phenyl;
  • R 8 to R 16 are independently -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 An alkyl substituted aminoacyl group, a ⁇ 3 ⁇ 4 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ⁇ 3 ⁇ 4 alkyl, ⁇ C 8 alkoxy, 3 ⁇ 4 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ 3 ⁇ 4 substituted alkyl Sulfonyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, cyclin substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 Alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, -CF 3 or substituted a phenyl group, the substituent being a saturated or unsaturated heterocyclic ring containing a N, 0 or S hetero atom;
  • R 27 is -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted The group is halogen, -N0 2 or ⁇ alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ . 4 alkyl, ⁇ . 4 alkoxy, halogen substituted ⁇
  • R 6 and R 7 are independently -H, a substituted -C 4 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 4 alkyl group having a substituent, and a band a substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -H, -C 4 alkyl group, ⁇ C 4 alkoxy group, ⁇ C 4 alkane substituted sulfamoyl group, a halogen-substituted ⁇ C 4 alkyl group, a substituted carbonyl group ⁇ C 4 alkyl group, a substituted amino ⁇ C 4 alkyl group, ⁇ C 4 alkyl substituted amide group, a halogen, -N0 2, -OH, -OCF 3 , -CF 3 or phenyl;
  • R 8 ⁇ R 16 are independent - ⁇ , ⁇ . 4 alkyl, ⁇ . 4 alkoxy, ⁇ . a 4- alkyl substituted sulfamoyl group, a halogen-substituted ⁇ alkyl group, a ⁇ alkyl-substituted carbonyl group, a ⁇ -alkyl-substituted aminoacyl group, a ⁇ alkyl-substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is - ⁇ , ⁇ . 4 alkyl, ⁇ . 4 alkoxy, 3 ⁇ 4 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ alkyl substituted sulfamoyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, halogen substituted ⁇ alkyl, ⁇ alkyl Substituted carbonyl, ⁇ alkyl substituted aminoacyl, ⁇ .
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the base is halogen, -N0 2 or ⁇ C 4 alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 6 and R 7 are independently -H, and have a substituent of ⁇ . 4- alkyl, substituted C 3 -C 8 cycloalkyl, substituted halo-C 4 alkyl, substituted phenyl, substituted benzoyl, with The pyridyl group of the substituent, which is - ⁇ , ⁇ . 4 alkyl, ⁇ . 4 alkoxy, ⁇ . 4- alkyl substituted sulfamoyl, halogen substituted ⁇ . 4 alkyl, ⁇ . 4 alkyl substituted carbonyl, ⁇ . 4 alkyl substituted aminoacyl, ⁇ a C 4 alkyl substituted amide group, a halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or a phenyl group;
  • R 8 to R 16 are independently -H, -C 4 alkyl, ⁇ C 4 alkoxy, -C 4 alkyl substituted sulfamoyl, halogen substituted ⁇ C 4 alkyl, ⁇ C 4 alkyl substituted carbonyl ⁇ C 4 alkyl substituted aminoacyl, ⁇ C 4 alkyl substituted amide group, halogen, —OCF 3 , —OH, —CF 3 , —COOH or phenyl;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 4 alkyl, ⁇ C 4 alkoxy, 3 ⁇ 4 ⁇ 3 ⁇ 4 cycloalkyl, ⁇ alkyl substituted Sulfamoyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, halogen substituted ⁇ alkyl, ⁇ alkyl substituted carbonyl, ⁇ alkyl substituted aminoacyl, ⁇ .
  • R 27 is ⁇ . a 4- alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; the substituent of the substituted phenyl group is a halogen, - 1 ⁇ 0 2 or ⁇ alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 6 and R 7 are independently -H, ⁇ . a 4- alkyl group, a substituted phenyl group, a substituted C 3 -C 8 cycloalkyl group, a substituted benzoyl group, or a substituted pyridyl group, wherein the substituent is - ⁇ , ⁇ alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
  • R 8 to R 16 are -H, -COOH or methyl
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 is - H, ⁇ ⁇ . 4 alkyl, ⁇ . 4 alkoxy, C 3 ⁇ C 8 cycloalkyl group, t-butyloxycarbonyl group, a substituted sulfonyl group R 27 R 27 or a substituted acyl group;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the base is halogen, -N0 2 or ⁇ C 4 alkyl;
  • R 2 and R 4 are independently halogen, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 6 and R 7 are independent of 11, ⁇ .
  • R 8 to Ri 6 are -H, -COOH or methyl; M is oxygen, R 17 is -H ; M is nitrogen, and R 17 is C 3 -C 8 cycloalkyl, tert-butyloxycarbonyl, R 27 -substituted sulfonyl or R 27 -substituted acyl;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the base is halogen, -N0 2 or ⁇ C 4 alkyl;
  • L is sulfur or oxygen
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, halogen, ⁇ C 8 alkane a group, a C 8 alkoxy group, a halogen substituted ⁇ .
  • alkyl halogen substituted ⁇ alkoxy, ⁇ ⁇ alkyl substituted amino, ⁇ ⁇ alkyl substituted carbonyl, ⁇ C 8 alkyl substituted amino, ⁇ C 8 alkyl substituted amide, ⁇ alkyl substituted ammonia Sulfonyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 7 is -H, a substituted -C 8 alkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, a phenyl group having a substituent, a pyridyl group having a substituent, and the substitution
  • the base is -H, ⁇ .
  • alkyl group an alkoxy group ⁇ ⁇ , ⁇ C 8 alkyl-substituted sulfamoyl group, a substituted ⁇ prime ⁇ C 8 alkyl group, ⁇ ⁇ alkyl substituted carbonyl group, substituted amino ⁇ C 8 alkyl group, an alkoxy ⁇ C 8 Substituted amide group, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
  • R 18 to R 22 are independently -H, -C 8 alkyl, ⁇ C 8 alkoxy, -C 8 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, halogen, -N0 2 , -OH, -OCH 3 , -OCF 3 , -CF 3 or phenyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl group, a halogen-substituted alkoxy ⁇ ⁇ ⁇ , -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 7 is -H, ⁇ 3 ⁇ 4 alkyl, halogen-substituted ⁇ 3 ⁇ 4 alkyl, substituted phenyl, substituted pyridyl, and the substituent is -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ⁇ 3 ⁇ 4 alkyl or halogen substituted ⁇ 3 ⁇ 4 alkyl;
  • R 18 to R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -OCH 3 , -N0 2 , ⁇ 3 ⁇ 4 alkyl or halogen-substituted ⁇ 3 ⁇ 4 alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2 ;
  • R 7 is -H, -C 8 alkyl, halogen-substituted ⁇ C 8 alkyl, substituted phenyl, substituted pyridyl, said substituent is -H, -F, - Cl, -Br, -CF 3 , -N0 2 , ⁇ C 8 alkyl or halogen substituted ⁇ C 8 alkyl;
  • R 18 to R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , -OCH 3 , -C 8 alkyl or halogen-substituted ⁇ 3 ⁇ 4 alkyl.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2; R 7 is -H or ⁇ 3 ⁇ 4 alkyl;
  • Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 , ⁇ 3 ⁇ 4 alkyl or halogen-substituted ⁇ alkyl.
  • R 2 and R 4 are independently -F, -N0 2 , -Gu 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • R 7 is -H or ⁇ alkyl;
  • Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 ⁇ . 4 alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri R 3 is independently -H, halogen, ⁇ C 8 alkyl, ⁇ . 8 alkoxy, halogen substituted ⁇ . 8 alkyl, halogen substituted ⁇ alkoxy, ⁇ ⁇ alkyl substituted amino, ⁇ ⁇ alkyl substituted carbonyl, ⁇ C 8 alkyl substituted amino, ⁇ C 8 alkyl substituted amide, ⁇ alkyl substituted ammonia Sulfonyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 7 is -H, a substituted -C 8 alkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, a phenyl group having a substituent, a pyridyl group having a substituent, and the substitution
  • the base is -H, ⁇ .
  • R 23 to R 26 are independently -H, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl, halogen substituted ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 Alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl, halogen-substituted alkoxy ⁇ C 8, -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 7 is -H, -C 8 alkyl or halogen substituted ⁇ C 8 alkyl
  • R 23 to R 26 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ⁇ 3 ⁇ 4 alkyl or halogen substituted d ⁇ Further preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -0CF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, -3 ⁇ 4 alkyl, -CF 3 or -N0 2; R 7 is H or ⁇ C 8 alkyl; R 2 3 to R 2 6 are -H, -F, -Cl, -Br, or ⁇ C 8 alkyl group.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • R 7 is -H or ⁇ alkyl;
  • L is nitrogen, oxygen or sulfur;
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri independently is -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkane Substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO Or -CF 3 ;
  • R 16 is -H, -F, -Cl, -Br, -COOH, ⁇ 3 ⁇ 4 alkyl or halogen substituted ⁇ 3 ⁇ 4 alkyl.
  • L is oxygen or sulfur
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl group, a halogen-substituted alkoxy ⁇ ⁇ ⁇ , -N0 2 , -NH 2 , -CN or -CF 3 ;
  • R 16 is -H, -COOH, -C 8 alkyl or halogen-substituted ⁇ C 8 alkyl.
  • L is oxygen or sulfur
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3
  • Ri R 3 is independently -H, -F, ⁇ 3 ⁇ 4 Alkyl, -CF 3 or -N0 2
  • R 16 is -H or methyl.
  • L is oxygen or sulfur
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, -C 4 alkyl, -CF 3 or -N0 2 ;
  • R 16 is -H or methyl.
  • R 3 is independently -H, halogen, CC 8 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, Halogen-substituted alkoxy group ⁇ ⁇ ⁇ ⁇ alkyl substituted amino, ⁇ ⁇ alkyl substituted carbonyl group, ⁇ C 8 alkyl substituted amino group, ⁇ C 8 alkyl group substituted with an amide group, an alkyl-substituted sulfamoyl group ⁇ , - N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 8 alkyl, ⁇ C 8 alkoxy, C 3 -C 8 cycloalkyl, ⁇ C 8- alkyl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, halogen substituted ⁇ 3 ⁇ 4 alkyl group, ⁇ 3 ⁇ 4 alkyl substituted carbonyl group, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl group, ⁇ 3 ⁇ 4 alkyl group Substituting an amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated group containing a N, 0 or S hetero atom Heterocycle
  • R 27 is a ⁇ 3 ⁇ 4 alkyl group, a C 3 ⁇ C 8 cycloalkyl group, a substituted phenyl group, a C 3 ⁇ C 8 cycloalkyl group-substituted ⁇ 3 ⁇ 4 alkyl group or an adamantyl group; the substituent of the substituted phenyl group is Halogen, -1 ⁇ 0 2 or ⁇ 3 ⁇ 4 alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • Ri is independently -H, halogen, ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halogen substituted ⁇ 3 ⁇ 4 alkyl, halogen substituted ⁇ 3 ⁇ 4 alkoxy, ⁇ 3 ⁇ 4 alkyl substituted amino, ⁇ 3 ⁇ 4 alkyl substituted carbonyl, ⁇ 3 ⁇ 4 alkyl substituted aminoacyl, ⁇ 3 ⁇ 4 alkyl substituted amide group, ⁇ 3 ⁇ 4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
  • R 17 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 8 alkyl, ⁇ C 8 alkoxy, C 3 -C 8 cycloalkyl, ⁇ . 8- alkyl substituted sulfamoyl group, substituted with -C 8 alkyl group, ⁇ alkyl substituted carbonyl group, ⁇ alkyl substituted aminoacyl group, ⁇ alkyl substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated heterocyclic ring containing a N, 0 or S hetero atom.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ 3 ⁇ 4 alkyl, ⁇ C 8 alkoxy, halo-substituted ⁇ C 8 alkyl, halogen-substituted alkoxy ⁇ C 8, - N0 2 , -NH 2 , -CN or -CF 3 ;
  • M is oxygen, R 17 is H; M is nitrogen, and R 17 is -H or tert-butyloxycarbonyl.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ 3 ⁇ 4 alkyl, -CF 3 or -N0 2 ;
  • M is oxygen, R 17 is -H; M is nitrogen and R 17 is tert-butyloxycarbonyl.
  • R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • M is oxygen, R 17 is -H ; M is nitrogen and R 17 is tert-butyloxycarbonyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ ⁇ 3 ⁇ 4 alkyl, ⁇ 3 ⁇ 4 alkoxy, halo-substituted ⁇ ⁇ C 8 alkyl, halogen-substituted alkoxy ⁇ C 8, -N0 2 , -NH 2 , -CN or -CF 3 ;
  • M is oxygen, R 17 is H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is a ⁇ 3 ⁇ 4 alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; a substituent of the substituted phenyl group It is a halogen, -1 ⁇ 0 2 or ⁇ 3 ⁇ 4 alkyl. Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -0CF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ C 4 alkyl group, ⁇ C 4 alkoxy, halo-substituted ⁇ C 4 alkyl, substituted by halogen ⁇ C 4 alkoxy group, -N0 2 , -NH 2 , -CN or -CF 3 ;
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the group is halogen, -1 ⁇ 0 2 or ⁇ alkyl.
  • R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
  • Ri R 3 is independently -H, -F, -Cl, -Br, ⁇ . 4 alkyl, ⁇ . 4 alkoxy, halo-substituted ⁇ ⁇ C 4 alkyl, -N0 2, -CN or -CF 3;
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is ⁇ . a 4- alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; the substituent of the substituted phenyl group is a halogen, - 1 ⁇ 0 2 or ⁇ alkyl.
  • R 2 and R 4 are independently -F, -N0 2 , -Gu 2 , -OCF 3 or -CF 3 ;
  • Ri R 3 is independently -H, -F, ⁇ . 4 alkyl, -CF 3 or -N0 2 ;
  • M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
  • R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ⁇ C 4 alkyl or adamantyl; substituted phenyl substituted
  • the group is halogen, -N0 2 or ⁇ C 4 alkyl.
  • the synthetic route is:
  • Route A The procedure of Route A is as follows: 1 ⁇ 1 4 Substituted benzoyl chloride is reacted with ammonium thiocyanate under the action of a catalyst, and then reacted with R 5 H to finally obtain a ⁇ substituted benzothiazin-4-one.
  • the catalyst described in the A route step is crown ether 18-crown-6 or PEG (polyethylene glycol); the PEG is preferably PEG-400 or PEG-300.
  • the reaction solvent in the reaction with ammonium thiocyanate described in the A route step is dichloromethane or toluene.
  • the solvent used is DMF ( ⁇ , ⁇ -dimethylformamide) or DMSO (dimethyl sulfoxide); preferably DMF.
  • the step of the B route is as follows: the benzoic acid substituted by 1 ⁇ 1 4 is reacted to obtain 1 ⁇ 1 4 substituted benzoyl chloride, and then reacted with ammonium thiocyanate under the action of a catalyst, and then reacted with R 5 H to obtain a Ri.
  • ⁇ R4 replaces benzothiazin-4-one.
  • the catalyst described in the B route step is 18-crown-6 or PEG; and the PEG is preferably PEG-400 or PEG-300.
  • the reaction solvent in the reaction with the ammonium thiocyanate described in the step B is dichloromethane or toluene.
  • the solvent used is DMF or DMSO; preferably DMF.
  • the reaction temperature of each of the above reaction steps is normal temperature.
  • the present invention also provides a pharmaceutically acceptable salt, hydrate or prodrug of the above benzothiazin-4-one derivative.
  • the prodrugs are derivatives of the above compounds which may themselves have weak or even no activity, but after administration, are converted under physiological conditions (for example by metabolism, solvolysis or otherwise) into Corresponding biologically active forms.
  • the present invention also provides the use of the above benzothiazin-4-one derivative for the preparation of a medicament for treating tuberculosis or leprosy.
  • the present invention also provides a pharmaceutical composition prepared by adding the pharmaceutically acceptable auxiliary component to the above benzothiazin-4-one derivative.
  • the pharmaceutical composition can be used to prepare a medicament for treating tuberculosis or leprosy.
  • the benzothiazin-4-one derivative of the present invention is a novel compound obtained on the basis of a large number of screenings, has excellent activity against Mycobacterium tuberculosis, is an anti-tuberculosis drug and is resistant to leprosy.
  • the development and application of drugs offers new options. Specific form
  • 2,3,4,5-tetrafluorobenzoyl chloride (3 g, 14.12 mmol) was dissolved in 20 mL of dichloromethane, ammonium thiocyanate (2.14 g, 28.24 mmol), and PEG-400 (0.2 g) was added dropwise. After reacting at room temperature for two hours, the precipitate was filtered off, and the filtrate was slowly added dropwise to a solution of ethylamine in dichloromethane, and the mixture was reacted at room temperature for three hours.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was morpholine. A yellow needle solid was obtained in a yield of 59%.
  • Example 5 In the same manner as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was ethylamine. A yellow solid was obtained in 44% yield.
  • Example 10 The same procedure as in Example 10 was carried out, and the acid chloride used was m-nitrobenzoyl chloride. A yellow solid was obtained with a yield of 72%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was propylamine. A yellow solid was obtained in a yield of 57%.
  • the starting material was the same as in Example 5, and the starting material was 2-chloro-3nitro-5.
  • Example 20 Compound 20: Preparation of 2-(pyrrolidinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
  • the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was pyrrolidine.
  • a yellow solid was obtained in a yield of 49%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethyl benzoic acid, and the amine used was 1, 4-homopiperazine. A yellow solid was obtained in a yield of 45%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was cyclopentylamine. A yellow solid was obtained in a yield of 56%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was N-BOC piperazine. A yellow solid was obtained in a yield of 54%.
  • the starting material was 2-chloro-3-nitro-5-trifluoromethylbenzoic acid, and the amine used was 4-piperidinone ethanedithiol. A yellow solid was obtained in a yield of 56%.
  • Example 5 The procedure was the same as in Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 2-methyl-1,4-dithia-8 aza snail. [4.5] decane. A yellow solid was obtained in a yield of 58%.
  • the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was piperazine to give the compound 2-(piperazin-1yl)-8-nitrate.
  • Base-6-trifluoromethyl-1,3-benzothiazin-4-one (0.5 g, 1.4 mmol, yield 52%).
  • 2-(piperazin-1yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was dissolved in dichloromethane, and methylsulfonate was added dropwise with stirring at room temperature.
  • the acid chloride (0.2 g, 2.1 mmol) and a catalytic amount of triethylamine were reacted for 2 hours.
  • Example 33 Preparation of 2-(4-cyclopropylsulfonylpiperazinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
  • Example 44 Compound 44: 2-(4-(2-cyclohexylethene)piperazinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one preparation
  • Example 47 Compound 47: 2-(l,5-Dithia-9-azaspiro[5.5]undec-9-yl)-8-nitro-6-trifluoromethyl-1,3- Preparation of benzothiazin-4-one
  • Example 5 According to the operation of Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 1,5-dithia-9-azaspiro[5.5 ] -i ⁇ alkane. A yellow solid was obtained in a yield of 54%.
  • Example 48 Compound 48: 2-(4-Cyclopentyl-3-piperazinone)--8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
  • the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was
  • Experimental method Inoculum preparation 5 to 10 H37Ra colonies (from the National Type Culture Collection, ATCC 25177) and 1 mL of sterile saline prepared in advance were inoculated into the kit using a BBL pump. Due to the slow growth of Mycobacterium tuberculosis, it is grown for 2-3 weeks; ultrasonic and vortex mixing to obtain a suspension of Mycobacterium tuberculosis of about 10 8 CFU/mL. The specific experimental concentration can be diluted.
  • the suspension was diluted 200-fold by the following method: 0.2 mL of H37Ra-containing suspension was added to 40 mL of sterile 7H9 broth containing 2% glycerol and OADC nutritional supplement (about 10 6 CFU/mL from BD, USA) The ⁇ suspension (approximately 5 ⁇ 10 4 cells) was inoculated into the wells of the test wells and 1 ⁇ M of DMSO dissolved in a specific concentration of the compound to be tested was added.
  • Isoniazid and rifampicin were selected as positive controls, and the test compound and positive control were formulated into 10 mM solution in DMSO, and successively diluted to 100 ⁇ , 50 ⁇ , 25 ⁇ , 12.5 ⁇ , 6.3 ⁇ , 3.1 ⁇ , 1.6 ⁇ , 0.8 ⁇ , 0.4. ⁇ , 0.2 ⁇ , 0.1 ⁇ , 0 ⁇ 05 ⁇ , 0 ⁇ 025 ⁇ , 0 ⁇ 0125 ⁇ , 0 ⁇ 008 ⁇ , 0 ⁇ 004 ⁇ , 0.002 ⁇ for use.
  • the inoculated 96-well plates were incubated for 9 days at 37 ° C in a 5% CO 2 incubator.
  • Liquid medium Middlebrook 7H9 medium dry powder and nutritional supplements (OADC) are purchased from the United States BD the company.
  • Test drugs Compounds 9, 15, 17, 19, 21, 24, 26, 27, 28, 29 and 47.
  • test strain was transferred to a liquid medium, and after activation, cultured at 37 ° C for 2 weeks, a small amount of the culture liquid was aspirated, placed in 4 mL of liquid medium, and 10-20 pieces of sterile glass beads having a diameter of 2 - 3 mm were added. Oscillate for 20-30s, static precipitation for 10-20min, absorb the supernatant of the bacterial suspension, adjust the turbidity to 1 Meth's unit with liquid medium, which is equivalent to lxl0 7 CFU/mL.
  • the drug and the positive control isoniazid were dissolved in an appropriate amount of DMSO to a lmg/mL, 0.22 ⁇ filter.
  • the final concentration of the test drug was set as follows: 0.000125 g/mL, 0.00025 g/mL, 0.00049 g/mL, 0.00098 g/mL, 0.00195 g/mL, 0.0039 g/mL, 0.0078 g/mL, 0.0156 g/mL, 0.03125 g /mL, 0.0625 g/mL, 0.125 g/mL, 0.25 g/mL, 0.5 g/mL, lg/mL, 2 g/mL, 4 g/mL, 8 g/mL, 16 g/mL, 32 g/ There are 20 concentration gradients in mL and 64 g/mL.
  • each of the above drug solution 10 (VL was added to a 96-well microplate, and 10 4 CFU/mL (diluted by 10 7 CFU/mL) was added to the bacterial solution 10 (VL) to achieve a drug concentration. 2) The final concentration was set. At 37 ° C, the blank control group was given no drugs, and the same drug dilution was set up with three sets of parallel controls. The minimum inhibitory concentration of each drug against Mycobacterium tuberculosis was observed.
  • Leprosy is a chronic contagious disease caused by M. leprae.
  • Mycobacterium leprae and Mycobacterium tuberculosis belong to the genus Mycobacterium, and they have many commonalities in biological characteristics.
  • Common anti-tuberculosis drugs such as rifampic can also be used for the treatment of leprosy.
  • rifampic can also be used for the treatment of leprosy.
  • Vera cells are African green monkey kidney cells (from the National Key Laboratory of Biotherapy), so Vera cells can be used for cytotoxicity testing. Adjust the cell concentration to 3 ⁇ 10 4 /mL with complete medium, inoculate 96-well plates, 200 uL per well, and culture overnight. The next day, different doses of compound 14-19, compound 21, compound 23-25, compound 27-29 And compound 47 (final concentrations of 500, 400, 300, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125 ⁇ ) were treated with cells, and an equal volume of blank medium control group, solvent control group The concentration of DMSO was 0.5% (0.5% DMSO had no effect on cell proliferation).

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Abstract

Provided are benzothiazine-4-one derivatives and preparation method therefor and use thereof. The benzothiazine-4-one derivatives represented by the formula I have activity of anti-mycobacterium tuberculosis.

Description

苯并噻嗪 -4-酮衍生物及其制备方法和用途  Benzothiazin-4-one derivative, preparation method and use thereof
技术领域 Technical field
本发明属于医药领域， 特别涉及苯并噻嗪 -4-酮衍生物及其制备方法和用途。  The invention belongs to the field of medicine, and particularly relates to a benzothiazin-4-one derivative, a preparation method thereof and use thereof.
背景技术 Background technique
结核病是患病率及死亡率最高的疾病之一。 21 世纪， 结核病仍然是发展中国家引 起死亡的主要疾病和发达国家再度活跃的疾病。 由于贫穷和 HIV/艾滋病的流行， 多重 耐药 （MDR-TB)/广谱耐药结核病 （XDR-TB ) 的出现， 全球死于结核病的人数持续增 加，现有的抗结核病药物已经不能满足治愈需求目前全球三分之一的人口即 20 亿人携 带结核杆菌，肺结核病每年造成 300万人丧生，而作为发展中国家之一的中国现有活动 性肺结核病人约 450 万人， 患病人数居世界第二位。结核病已成为严重的公共卫生问题 结核病的重新席卷之势已引起了社会各界的深切关注。 研发新型、 高效、 低毒的抗结核 病药物已是迫在眉睫。 及明内容  Tuberculosis is one of the diseases with the highest prevalence and mortality. In the 21st century, tuberculosis continues to be a major cause of death in developing countries and a renewed disease in developed countries. Due to the prevalence of poverty and HIV/AIDS, the emergence of multidrug-resistant (MDR-TB)/broad-spectrum-resistant tuberculosis (XDR-TB), the number of people dying from tuberculosis worldwide continues to increase, and existing anti-tuberculosis drugs are no longer able to meet the cure Demand is currently one-third of the world's population of 2 billion people carrying tubercle bacilli, tuberculosis kills 3 million people each year, and as one of the developing countries, there are about 4.5 million active tuberculosis patients in China. The second place in the world. Tuberculosis has become a serious public health problem The resurgence of tuberculosis has drawn deep concern from all walks of life. It is extremely urgent to develop new, highly effective and low-toxic anti-tuberculosis drugs. And content
本发明所要解决的第一个技术问题是提供一类新的苯并噻嗪 -4-酮衍生物，其结构如 式 I：  The first technical problem to be solved by the present invention is to provide a novel class of benzothiazin-4-one derivatives having the structure of formula I:
Figure imgf000003_0001
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3;
Figure imgf000003_0001
Wherein R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri 独立为 -H、 卤素、 〜¾烷基、 ^〜¾烷氧基、 卤素取代的 ^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 〜¾烷基取代氨基、 ^〜¾烷基取代羰基、 〜¾烷基 取代氨酰基、 〜¾烷基取代酰胺基、 ^〜¾烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3;
Figure imgf000003_0002
Ri independently is -H, halogen, ~3⁄4 alkyl, ^~3⁄4 alkoxy, halogen substituted ^~3⁄4 alkyl, halogen substituted ^~3⁄4 alkoxy, ~3⁄4 alkyl substituted amino, ^~3⁄4 alkane Substituted carbonyl, 〜3⁄4 alkyl substituted aminoacyl, 〜3⁄4 alkyl substituted amide group, ^~3⁄4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO Or -CF 3 ;
Figure imgf000003_0002
R6、 R7独立的为 -H、 带有取代基的 〜C8烷基、 带有取代基的 C3〜C8环烷基、 带 有取代基的卤代 〜C8烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代 基的吡啶基， 所述的取代基为 -Η、 ^〜¾烷基、 ^〜^烷氧基、 〜 烷基取代氨磺 酰基、 ^素取代的 〜C8烷基、 〜^烷基取代羰基、 〜C8烷基取代氨酰基、 〜 C8烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R8〜R16独立的为 -H、 〜C8烷基、 〜C8烷氧基、 〜C8烷基取代氨磺酰基、 卤 素取代的 〜 烷基、 〜 ^烷基取代羰基、 〜 烷基取代氨酰基、 〜C8烷基取 代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 6 and R 7 are independently -H, a substituted -C 8 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, and a band a substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -Η, ^~3⁄4 alkyl, ^~^ alkoxy, ~alkyl substituted a sulfamoyl group, a substituted ^ prime ~C 8 alkyl group, ~ ^ alkyl substituted carbonyl group, substituted amino ~C 8 alkyl group, ~ C 8 alkyl-substituted amide group, a halogen, -N0 2, -OH, -OCF 3 , -CF 3 or phenyl; R 8 to R 16 are independently -H, -C 8 alkyl, ~C 8 alkoxy, ~C 8 alkyl substituted sulfamoyl, halogen substituted ~ alkyl, ~ ^ alkyl substituted carbonyl, ~ alkane a substituted amino group, a ~C 8 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为 -H、 〜 ¾烷基、 〜C8烷氧 基、 C3〜C8环烷基、 〜C8烷基取代氨磺酰基、芳基取代氨磺酰基、 R27取代的磺酰基、 R27取代的酰基、 ^素取代的 〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰 基、 〜¾烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的 苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~ ¾ alkyl, ~C 8 alkoxy, C 3 ~C 8 cycloalkyl, ~C 8 Alkyl substituted sulfamoyl group, aryl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, ^ substituted ～3⁄4 alkyl group, 〜3⁄4 alkyl substituted carbonyl group, 〜3⁄4 alkyl substituted aminoacyl group a ~3⁄4 alkyl-substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a hetero atom containing N, 0 or S a saturated or unsaturated heterocyclic ring;
R27为 〜¾烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜¾烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或^〜¾烷基； R 27 is ～3⁄4 alkyl, C 3 ～C 8 cycloalkyl, substituted phenyl, C 3 ～C 8 cycloalkyl substituted ～3⁄4 alkyl or adamantyl; the substituent of the substituted phenyl is Halogen, -1^0 2 or ^~3⁄4 alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。  L is nitrogen, oxygen or sulfur; u = 0 to 1, v = 0 to 1, w = 0 to 1, x = 0 to 1, y = 0 to 1, z = 0 to 1.
优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3;Preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri 独立为 -H、 卤素、 〜¾烷基、 ^〜¾烷氧基、 卤素取代的 ^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 〜¾烷基取代氨基、 ^〜¾烷基取代羰基、 〜¾烷基 取代氨酰基、 〜C8烷基取代酰胺基、 〜 烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri independently is -H, halogen, ~3⁄4 alkyl, ^~3⁄4 alkoxy, halogen substituted ^~3⁄4 alkyl, halogen substituted ^~3⁄4 alkoxy, ~3⁄4 alkyl substituted amino, ^~3⁄4 alkane Substituted carbonyl, ～3⁄4 alkyl substituted aminoacyl, ~C 8 alkyl substituted amide, ~alkyl substituted sulfamoyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
。  .
R5为 Κ
Figure imgf000004_0001
R9 R" R 或 ¾ R,„ ； R 5 is Κ
Figure imgf000004_0001
R 9 R" R or 3⁄4 R, „ ;
R6、 R7独立的为 -H、 带有取代基的 〜C8烷基、 带有取代基的 C3〜C8环烷基、 带 有取代基的卤代 〜C8烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代 基的吡啶基， 所述的取代基为 -H、 〜。8烷基、 〜^^烷氧基、 〜C8烷基取代氨磺 酰基、 ^素取代的 〜C8烷基、 〜^烷基取代羰基、 〜C8烷基取代氨酰基、 〜 C8烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 6 and R 7 are independently -H, a substituted -C 8 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, and a band A substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -H, 〜. 8 alkyl, ~ ^^ alkoxy, substituted sulfamoyl ~C 8 alkyl group, a substituted ^ prime ~C 8 alkyl group, ~ ^ alkyl substituted carbonyl group, substituted amino ~C 8 alkyl group, C ~ 8 An alkyl substituted amide group, a halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or a phenyl group;
R8〜R16独立的为 -H、 〜¾烷基、 〜¾烷氧基、 〜¾烷基取代氨磺酰基、 卤 素取代的^〜¾烷基、 〜¾烷基取代羰基、 ^〜¾烷基取代氨酰基、 〜¾烷基取 代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 to R 16 are independently -H, ~3⁄4 alkyl, ~3⁄4 alkoxy, ~3⁄4 alkyl substituted sulfamoyl, halogen substituted ^~3⁄4 alkyl, ~3⁄4 alkyl substituted carbonyl, ^~3⁄4 An alkyl substituted aminoacyl group, a ~3⁄4 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为 -Η、 ^〜¾烷基、 〜¾烷氧 基、 。3〜¾环烷基、 〜 烷基取代氨磺酰基、 芳基取代氨磺酰基、 卤素取代的 Ci〜 C8烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 〜¾烷基取代酰胺基、 卤 素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0 或 S杂原子的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -Η, ^~3⁄4 alkyl, ~3⁄4 alkoxy. 3 ~¾ cycloalkyl, ~ alkyl substituted sulfamoyl group, sulfamoyl group substituted with an aryl group, halogen-substituted Ci~ C 8 alkyl, ~¾ alkyl substituted carbonyl group, ~¾ alkyl substituted amino group, ~¾ alkoxy a substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated group containing a hetero atom of N, 0 or S Heterocycle
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。  L is nitrogen, oxygen or sulfur; u = 0 to 1, v = 0 to 1, w = 0 to 1, x = 0 to 1, y = 0 to 1, z = 0 to 1.
进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 〜¾烷氧基、 卤素取代的 ^〜 (-8 ¾¾¾、 凶糸 4乂 Ί tf J Li L 烷氧基、 -N02 -NH2 -CN或 -CF3; Ri R 3 is independently -H, -F, -Cl, -Br, ^~3⁄4 alkyl, ~3⁄4 alkoxy, halogen substituted ^~ (-8 3⁄43⁄43⁄4, fierce 4乂Ί tf J Li L alkoxy, -N0 2 -NH 2 -CN or -CF 3 ;
1 DV5— yy
Figure imgf000005_0001
R9 Rl1 Rl3 j¾ F¾ R,„ ； 1 D V5 — yy
Figure imgf000005_0001
R 9 Rl1 Rl3 j3⁄4 F3⁄4 R, „ ;
R6 R7独立的为 -H、 ^〜 烷基、 带有取代基的 C3 C8环烷基、 卤素取代的 Ci C烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代基的吡啶基， 所述的取 代基为 -Η、 ^〜¾烷基、 卤素取代的 〜¾烷基、 -F -Cl -Br -CF3 -OCF3 -N02 -NH2或 -CN; R 6 R 7 is independently -H, ^~ alkyl, substituted C 3 C 8 cycloalkyl, halogen substituted Ci C alkyl, substituted phenyl, substituted benzene a formyl group, a pyridyl group having a substituent, said substituent is -Η, ^ ~¾ alkyl, halo-substituted ~¾ alkyl, -F -Cl -Br -CF 3 -OCF 3 -N0 2 - NH 2 or -CN;
R8 R16独立的为 -H -F -Cl -Br -COOH、 ^〜¾烷基或卤素取代的 ^〜¾浣 基； R 8 R 16 is independently -H -F -Cl -Br -COOH, ^~3⁄4 alkyl or halogen substituted ^~3⁄4 fluorenyl;
L为氮、 氧或硫； u=0 l， v=0 l， w=0 l， x=0 l， y=0 l， z=0 l;  L is nitrogen, oxygen or sulfur; u = 0 l, v = 0 l, w = 0 l, x = 0 l, y = 0 l, z = 0 l;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为 -H、 ^〜¾烷基、 〜¾烷氧 基、 C3 C8环烷基、 C8烷基取代氨磺酰基、 卤素取代的 〜。8烷基、 〜。8烷基 取代羰基、 C8烷基取代氨酰基、 C Cs烷基取代酰胺基、卤素、叔丁基氧羰基、-OCF3 -OH -CF3或带取代基的苯基， 所述的取代基为含有 N 0或 S杂原子的饱和或不饱和 的杂环。 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ^~3⁄4 alkyl, 〜3⁄4 alkoxy, C 3 C 8 cycloalkyl, C 8 alkyl Substituted sulfamoyl, halogen substituted ~. 8 alkyl, ~. 8- alkyl substituted carbonyl, C 8 alkyl substituted aminoacyl, C Cs alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 -OH -CF 3 or substituted phenyl, said substitution The base is a saturated or unsaturated heterocyclic ring containing a N 0 or S hetero atom.
进一步优选的， R2 R4独立的为卤素、 -N02 -NH2 -OCF3 -CN、 或 -CF3; Ri R3独立的为 -H -F -Cl -Br、 〜 ¾烷基、 C8烷氧基、 卤素取代的 C8烷基、 卤素取代的 C8烷氧基、 -N M'R6 W、U、,' X " Further preferably, R 2 R4 is independently halogen, -N0 2 -NH 2 -OCF 3 -CN, or -CF 3 ; Ri R 3 is independently -H -F -Cl -Br, ~ 3⁄4 alkyl, C 8 -alkoxy, halogen-substituted C 8 alkyl, halogen-substituted C 8 alkoxy, -N M' R 6 W, U ,, ' X "
R5为 R7 R" R
Figure imgf000005_0002
R 5 is R 7 R" R
Figure imgf000005_0002
R6 R7独立的为 -H、 〜¾烷基、 卤素取代的 〜¾烷基、 带有取代基的 C3 ¾环烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代基的吡啶基， 所述的 取代基为 ¾烷基、 卤素取代的 ^〜¾烷基、 -F -Cl -Br -CF3 -OCF3 -N02 -NH2或 -CN; R 6 R 7 is independently -H, ~3⁄4 alkyl, halogen-substituted ~3⁄4 alkyl, substituted C 3 3⁄4 cycloalkyl, substituted phenyl, substituted benzoyl An acyl group, a substituted pyridyl group, the substituent is a 3⁄4 alkyl group, a halogen-substituted ^~3⁄4 alkyl group, -F-Cl-Br-CF 3 -OCF 3 -N0 2 -NH 2 or -CN ;
R8 R16独立的为 -H -COOH C8烷基或卤素取代的 C8烷基； R 8 R 16 is independently -H-COOH C 8 alkyl or halogen substituted C 8 alkyl;
M为氧， R17为 -H; M为氮， R17为- H C8烷基、 C8烷氧基、 C3 C8环 烷基、 C8烷基取代氨磺酰基、 芳基取代氨磺酰基、 ^素取代的 C8烷基、 烷基取代羰基、 C8烷基取代氨酰基、 C8烷基取代酰胺基、 ^素、 叔丁基氧 羰基、 -OCF3 -OH -CF3或带取代基的苯基， 所述的取代基为含有 N 0或 S杂原子 的饱和或不饱和的杂环； M is oxygen, R 17 is -H ; M is nitrogen, R 17 is -HC 8 alkyl, C 8 alkoxy, C 3 C 8 cycloalkyl, C 8 alkyl substituted sulfamoyl, aryl substituted ammonia Sulfonyl, a substituted C 8 alkyl group, an alkyl substituted carbonyl group, a C 8 alkyl substituted amino group, a C 8 alkyl substituted amide group, a compound, a tert-butyloxycarbonyl group, -OCF 3 -OH -CF 3 Or a substituted phenyl group, said substituent being a saturated or unsaturated heterocyclic ring containing a N 0 or S hetero atom;
L为硫或氧； u=0 l， v=0 l， w=0 l， x=0 l， y=0 l， z=0 l。  L is sulfur or oxygen; u = 0 l, v = 0 l, w = 0 l, x = 0 l, y = 0 l, z = 0 l.
进一步优选的， R2 R4独立的为卤素、 -N02 -NH2 -OCF3 -CN -OH -CHO 或 -CF3; Further preferably, R 2 R 4 is independently halogen, -N0 2 -NH 2 -OCF 3 -CN -OH -CHO or -CF 3;
Ri R3独立的为 -H -F -Cl -Br、 〜 ¾烷基、 -CF3或 -N02; 、 6 Ri R 3 is independently -H -F -Cl -Br, ~ 3⁄4 alkyl, -CF 3 or -N0 2 ; , 6
R5为 7
Figure imgf000006_0001
R 5 is 7
Figure imgf000006_0001
R6、 R7独立的为 -H、 〜¾烷基、 带有取代基的苯基、 带有取代基的 C3〜C8环烷 基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -Η、 ^〜¾烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R 6 and R 7 are independently -H, -3⁄4 alkyl, substituted phenyl, substituted C 3 -C 8 cycloalkyl, substituted benzoyl, or a pyridyl group of a substituent, which is -Η, ^~3⁄4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜R16为 -H、 -COOH 或甲基； M为氧， R17为- H; M为氮， R17为叔丁基氧羰基；R 8 to R 16 are -H, -COOH or methyl; M is oxygen, R 17 is -H; M is nitrogen, and R 17 is t-butyloxycarbonyl;
L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。 L is sulfur or oxygen; u = v = 0, z = 0 to 1, x = 0 to 1, w = y = 1.
最优的， R2、 R4独立的为卤素、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 -CF3或 -N02; Most preferably, R 2 and R 4 are independently halogen, -N0 2 , -2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
R5为 H7 、
Figure imgf000006_0002
； R 5 is H 7 ,
Figure imgf000006_0002
;
R6、 R7独立的为 -H、 〜C4烷基、 带有取代基的苯基、 带有取代基的 C3〜C8环烷 基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -H、 〜C4烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R 6 and R 7 are independently -H, -C 4 alkyl, substituted phenyl, substituted C 3 -C 8 cycloalkyl, substituted benzoyl, or a pyridyl group having a substituent which is -H, -C 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜Ri6为 -H、 -COOH 或甲基； M为氧， R17为 -H; M为氮， R17为叔丁基氧羰基； L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。 R 8 ～Ri6 are -H, -COOH or methyl; M is oxygen, R 17 is -H; M is nitrogen, R 17 is tert-butyloxycarbonyl; L is sulfur or oxygen; u=v=0, z =0~l, x=0~l, w= y=l.
上述的苯并噻嗪 -4-酮衍生物， 优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、The above benzothiazin-4-one derivative, preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 ,
-CN、 -OH、 -CHO或 -CF3; -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 〜¾烷氧基、 卤素取代的 ^〜 C8烷基、 卤素取代的 ^〜^烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^ ~¾ alkyl, ~¾ alkoxy, halo-substituted ^ ~ C 8 alkyl group, a halogen-substituted alkoxy ^ ~ ^, -N0 2 , -NH 2 , -CN or -CF 3 ;
。  .
, Y- H r R B b R^ ¾ , Y- H r R B b R ^ 3⁄4
R5为 R" H 3 、 、 或 r ； R 5 is R " H 3 , , or r ;
R6、 R7独立的为 -H、 带有取代基的 〜¾烷基、 带有取代基的 C3〜C8环烷基、 带 有取代基的卤代 〜¾烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代 基的吡啶基， 所述的取代基为 -Η、 ^〜¾烷基、 ^〜^烷氧基、 〜 烷基取代氨磺 酰基、 ^素取代的 〜¾烷基、 ^〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 〜 C8烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 6 and R 7 are independently -H, a substituted ～3⁄4 alkyl group, a substituted C 3 ～C 8 cycloalkyl group, a substituted halogenated ～3⁄4 alkyl group, with a substitution a phenyl group, a substituted benzoyl group, a substituted pyridyl group, the substituent is -Η, ^~3⁄4 alkyl, ^~^ alkoxy, ~alkyl-substituted ammoxime Acyl, n-substituted -3⁄4 alkyl, ^~3⁄4 alkyl substituted carbonyl, 〜3⁄4 alkyl substituted aminoacyl, ~C 8 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , CF 3 or phenyl;
R8〜R16独立的为 -H、 〜¾烷基、 〜¾烷氧基、 〜¾烷基取代氨磺酰基、 卤 素取代的^〜¾烷基、 〜¾烷基取代羰基、 ^〜¾烷基取代氨酰基、 〜¾烷基取 代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 to R 16 are independently -H, ~3⁄4 alkyl, ~3⁄4 alkoxy, ~3⁄4 alkyl substituted sulfamoyl, halogen substituted ^~3⁄4 alkyl, ~3⁄4 alkyl substituted carbonyl, ^~3⁄4 An alkyl substituted aminoacyl group, a ~3⁄4 alkyl substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or a phenyl group;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为 -H、 〜 ¾烷基、 〜C8烷氧 基、 ¾〜¾环烷基、 〜¾烷基取代氨磺酰基、芳基取代氨磺酰基、 R27取代的磺酰基、 R27取代的酰基、 ^素取代的 〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰 基、 〜¾烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的 苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~ ¾ alkyl, ~C 8 alkoxy, ¾~¾ cycloalkyl, ~¾ substituted alkyl Sulfonyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, cyclin substituted ～3⁄4 alkyl, 〜3⁄4 alkyl substituted carbonyl, 〜3⁄4 alkyl substituted aminoacyl, ~3⁄4 Alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, -CF 3 or substituted a phenyl group, the substituent being a saturated or unsaturated heterocyclic ring containing a N, 0 or S hetero atom;
R27为 〜C8烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜C4烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜 烷基； R 27 is -C 8 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ~C 4 alkyl or adamantyl; substituted phenyl substituted The group is halogen, -N0 2 or ~alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。  L is nitrogen, oxygen or sulfur; u = 0 to 1, v = 0 to 1, w = 0 to 1, x = 0 to 1, y = 0 to 1, z = 0 to 1.
优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜。4烷基、 〜。4烷氧基、 卤素取代的 ^〜Ri R 3 is independently -H, -F, -Cl, -Br, ^~. 4 alkyl, ~. 4 alkoxy, halogen substituted ^~
C4烷基、 卤素取代的 〜。4烷氧基、 -N02、 -NH2、 -CN或 -CF3 ;
Figure imgf000007_0001
C 4 alkyl, halogen substituted ~. 4 alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
Figure imgf000007_0001
R6、 R7独立的为 -H、 带有取代基的 〜C4烷基、 带有取代基的 C3〜C8环烷基、 带 有取代基的卤代 〜C4烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代 基的吡啶基， 所述的取代基为 -H、 〜C4烷基、 〜C4烷氧基、 〜C4烷基取代氨磺 酰基、 卤素取代的 〜C4烷基、 〜C4烷基取代羰基、 〜C4烷基取代氨酰基、 〜 C4烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 6 and R 7 are independently -H, a substituted -C 4 alkyl group having a substituent, a C 3 -C 8 cycloalkyl group having a substituent, a halogenated to C 4 alkyl group having a substituent, and a band a substituted phenyl group, a substituted benzoyl group, a substituted pyridyl group, and the substituent is -H, -C 4 alkyl group, ~C 4 alkoxy group, ~C 4 alkane substituted sulfamoyl group, a halogen-substituted ~C 4 alkyl group, a substituted carbonyl group ~C 4 alkyl group, a substituted amino ~C 4 alkyl group, ~ C 4 alkyl substituted amide group, a halogen, -N0 2, -OH, -OCF 3 , -CF 3 or phenyl;
R8〜R16独立的为 -Η、 〜。4烷基、 〜。4烷氧基、 〜。4烷基取代氨磺酰基、 卤 素取代的^〜 烷基、 〜 烷基取代羰基、 ^〜 烷基取代氨酰基、 〜 烷基取 代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 ~ R 16 are independent - Η, ~. 4 alkyl, ~. 4 alkoxy, ~. a 4- alkyl substituted sulfamoyl group, a halogen-substituted ^~ alkyl group, a ~alkyl-substituted carbonyl group, a ^-alkyl-substituted aminoacyl group, a ~alkyl-substituted amide group, a halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为 -Η、 ^〜。4烷基、 〜。4烷氧 基、 ¾〜¾环烷基、 〜 烷基取代氨磺酰基、芳基取代氨磺酰基、 R27取代的磺酰基、 R27取代的酰基、 卤素取代的 〜 烷基、 〜 烷基取代羰基、 〜 烷基取代氨酰 基、 〜。4烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的 苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -Η, ^~. 4 alkyl, ~. 4 alkoxy, 3⁄4~3⁄4 cycloalkyl, ~alkyl substituted sulfamoyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, halogen substituted ~ alkyl, ~ alkyl Substituted carbonyl, ~ alkyl substituted aminoacyl, ~. a 4- alkyl substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being saturated or containing a hetero atom of N, 0 or S Unsaturated heterocyclic ring;
R27为 〜C4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜C4烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C4烷基； R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ~C 4 alkyl or adamantyl; substituted phenyl substituted The base is halogen, -N0 2 or ~C 4 alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。  L is nitrogen, oxygen or sulfur; u = 0 to 1, v = 0 to 1, w = 0 to 1, x = 0 to 1, y = 0 to 1, z = 0 to 1.
进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO 或 -CF3 ; Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
R5
Figure imgf000007_0002
R9 Ri3 . R5
Figure imgf000007_0002
R 9 Ri 3 .
R6、 R7独立的为 -H、 带有取代基的 〜。4烷基、 带有取代基的 C3〜C8环烷基、 带 有取代基的卤代 〜C4烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代 基的吡啶基， 所述的取代基为 -Η、 ^〜。4烷基、 〜。4烷氧基、 〜。4烷基取代氨磺 酰基、 卤素取代的 〜。4烷基、 ^〜。4烷基取代羰基、 〜。4烷基取代氨酰基、 〜 C4烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 6 and R 7 are independently -H, and have a substituent of ~. 4- alkyl, substituted C 3 -C 8 cycloalkyl, substituted halo-C 4 alkyl, substituted phenyl, substituted benzoyl, with The pyridyl group of the substituent, which is -Η, ^~. 4 alkyl, ~. 4 alkoxy, ~. 4- alkyl substituted sulfamoyl, halogen substituted ~. 4 alkyl, ^~. 4 alkyl substituted carbonyl, ~. 4 alkyl substituted aminoacyl, ~ a C 4 alkyl substituted amide group, a halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or a phenyl group;
R8〜R16独立的为 -H、 〜C4烷基、 〜C4烷氧基、 〜C4烷基取代氨磺酰基、 卤 素取代的 〜C4烷基、 〜C4烷基取代羰基、 〜C4烷基取代氨酰基、 〜C4烷基取 代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 to R 16 are independently -H, -C 4 alkyl, ~C 4 alkoxy, -C 4 alkyl substituted sulfamoyl, halogen substituted ~C 4 alkyl, ~C 4 alkyl substituted carbonyl ～C 4 alkyl substituted aminoacyl, ～C 4 alkyl substituted amide group, halogen, —OCF 3 , —OH, —CF 3 , —COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为 -H、 〜C4烷基、 〜C4烷氧 基、 ¾〜¾环烷基、 〜 烷基取代氨磺酰基、芳基取代氨磺酰基、 R27取代的磺酰基、 R27取代的酰基、 卤素取代的 〜 烷基、 〜 烷基取代羰基、 〜 烷基取代氨酰 基、 〜。4烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的 苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 4 alkyl, ~C 4 alkoxy, 3⁄4~3⁄4 cycloalkyl, ~alkyl substituted Sulfamoyl, aryl substituted sulfamoyl, R 27 substituted sulfonyl, R 27 substituted acyl, halogen substituted ~ alkyl, ~ alkyl substituted carbonyl, ~ alkyl substituted aminoacyl, ~. a 4- alkyl substituted amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being saturated or containing a hetero atom of N, 0 or S Unsaturated heterocyclic ring;
R27为 〜。4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 ^〜^烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或^〜 烷基； R 27 is ~. a 4- alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; the substituent of the substituted phenyl group is a halogen, - 1^0 2 or ^~ alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。  L is nitrogen, oxygen or sulfur; u = 0 to 1, v = 0 to 1, w = 0 to 1, x = 0 to 1, y = 0 to 1, z = 0 to 1.
进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO 或 -CF3 ; Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
R5
Figure imgf000008_0001
R5
Figure imgf000008_0001
R6、 R7独立的为 -H、 〜。4烷基、 带有取代基的苯基、 带有取代基的 C3〜C8环烷 基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -Η、 ^〜 烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R 6 and R 7 are independently -H, ~. a 4- alkyl group, a substituted phenyl group, a substituted C 3 -C 8 cycloalkyl group, a substituted benzoyl group, or a substituted pyridyl group, wherein the substituent is -Η, ^~ alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜R16为 -H、 -COOH 或甲基； R 8 to R 16 are -H, -COOH or methyl;
M为氧， R17为 -H; M为氮， R17为- H、 ^〜。4烷基、 〜。4烷氧基、 C3〜C8环烷 基、 叔丁基氧羰基、 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is -H; M is nitrogen, R 17 is - H, ^ ~. 4 alkyl, ~. 4 alkoxy, C 3 ~C 8 cycloalkyl group, t-butyloxycarbonyl group, a substituted sulfonyl group R 27 R 27 or a substituted acyl group;
R27为 〜C4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜C4烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C4烷基； R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ~C 4 alkyl or adamantyl; substituted phenyl substituted The base is halogen, -N0 2 or ~C 4 alkyl;
L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。  L is sulfur or oxygen; u = v = 0, z = 0 to 1, x = 0 to 1, w = y = 1.
最优的， R2、 R4独立的为卤素、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3;Most preferably, R 2 and R 4 are independently halogen, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, -Cl, -Br, -C 4 alkyl, -CF 3 or -N0 2 ;
R5
Figure imgf000008_0002
R5
Figure imgf000008_0002
R6、 R7独立的为11、 〜。4烷基、 带有取代基的苯基、 带有取代基的 C3〜C8环烷 基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -H、 〜C4烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R 6 and R 7 are independent of 11, ~. a 4- alkyl group, a substituted phenyl group, a substituted C 3 -C 8 cycloalkyl group, a substituted benzoyl group, or a substituted pyridyl group, wherein the substituent is -H, ~C 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜Ri6为 -H、 -COOH 或甲基； M为氧， R17为 -H; M为氮， R17 为 C3〜C8环烷基、 叔丁基氧羰基、 R27取代的磺 酰基或 R27取代的酰基； R 8 to Ri 6 are -H, -COOH or methyl; M is oxygen, R 17 is -H ; M is nitrogen, and R 17 is C 3 -C 8 cycloalkyl, tert-butyloxycarbonyl, R 27 -substituted sulfonyl or R 27 -substituted acyl;
R27为 〜C4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜C4烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C4烷基； R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ~C 4 alkyl or adamantyl; substituted phenyl substituted The base is halogen, -N0 2 or ~C 4 alkyl;
L为硫或氧； u=v=0, z=0〜l， x=0〜  L is sulfur or oxygen; u=v=0, z=0~l, x=0~
上述的苯并噻嗪 -4-酮衍 其结构如式 II所示: The above benzothiazin-4-one derivative has the structure shown in formula II:
Figure imgf000009_0001
Figure imgf000009_0001
II  II
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R3独立为 -H、 卤素、 〜C8烷基、 C广 8烷氧基、 卤素取代的 〜。8烷基、 卤素取代的 〜^烷氧基、 〜^烷基取代氨基、 〜^烷基取代羰基、 〜C8烷基 取代氨酰基、 〜C8烷基取代酰胺基、 〜 烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Wherein R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, halogen, ~C 8 alkane a group, a C 8 alkoxy group, a halogen substituted ~. 8 alkyl, halogen substituted ~ alkoxy, ~ ^ alkyl substituted amino, ~ ^ alkyl substituted carbonyl, ~ C 8 alkyl substituted amino, ~ C 8 alkyl substituted amide, ~ alkyl substituted ammonia Sulfonyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R7为- H、带有取代基的 〜C8烷基、带有取代基的卤代 〜C8烷基、带有取代基 的苯基、 带有取代基的吡啶基， 所述的取代基为 -H、 〜。8烷基、 〜^烷氧基、 〜 C8烷基取代氨磺酰基、 ^素取代的 〜C8烷基、 〜^烷基取代羰基、 〜C8烷基取 代氨酰基、 〜C8烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 7 is -H, a substituted -C 8 alkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, a phenyl group having a substituent, a pyridyl group having a substituent, and the substitution The base is -H, ~. 8 alkyl group, an alkoxy group ^ ~, ~ C 8 alkyl-substituted sulfamoyl group, a substituted ^ prime ~C 8 alkyl group, ~ ^ alkyl substituted carbonyl group, substituted amino ~C 8 alkyl group, an alkoxy ~C 8 Substituted amide group, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R18〜R22独立的为 -H、 〜C8烷基、 〜C8烷氧基、 〜C8烷基取代氨磺酰基、 卤素取代的 ^〜¾烷基、 〜¾烷基取代羰基、 ^〜¾烷基取代氨酰基、 〜¾烷基 取代酰胺基、 卤素、 -N02、 -OH、 -OCH3、 -OCF3、 -CF3或苯基。 R 18 to R 22 are independently -H, -C 8 alkyl, ~C 8 alkoxy, -C 8 alkyl substituted sulfamoyl, halogen substituted ^~3⁄4 alkyl, 〜3⁄4 alkyl substituted carbonyl, ^~3⁄4 alkyl substituted aminoacyl, 〜3⁄4 alkyl substituted amide group, halogen, -N0 2 , -OH, -OCH 3 , -OCF 3 , -CF 3 or phenyl.
优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 〜¾烷氧基、 卤素取代的 ^〜 C8烷基、 卤素取代的 ^〜^烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^ ~¾ alkyl, ~¾ alkoxy, halo-substituted ^ ~ C 8 alkyl group, a halogen-substituted alkoxy ^ ~ ^, -N0 2 , -NH 2 , -CN or -CF 3 ;
R7为 -H、 〜¾烷基、 卤素取代的 〜¾烷基、 带有取代基的苯基、 带有取代基 的吡啶基， 所述的取代基为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 〜¾烷基或卤素取代的 〜¾烷基； R 7 is -H, ～3⁄4 alkyl, halogen-substituted ～3⁄4 alkyl, substituted phenyl, substituted pyridyl, and the substituent is -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ~3⁄4 alkyl or halogen substituted ~3⁄4 alkyl;
R18〜R22独立的为 -H、 -F、 -Cl、 -Br、 -CF3、 -OCH3、 -N02、 〜¾烷基或卤素取 代的 ^〜¾烷基。 R 18 to R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -OCH 3 , -N0 2 , ~3⁄4 alkyl or halogen-substituted ^~3⁄4 alkyl.
进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO 或 -CF3; Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜 ¾烷基、 -CF3或 -N02; Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ~ 3⁄4 alkyl, -CF 3 or -N0 2 ;
R7为- H、 〜C8烷基、 卤素取代的 〜C8烷基、 带有取代基的苯基、 带有取代基 的吡啶基， 所述的取代基为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 〜C8烷基或卤素取代的 〜C8烷基； R 7 is -H, -C 8 alkyl, halogen-substituted ~C 8 alkyl, substituted phenyl, substituted pyridyl, said substituent is -H, -F, - Cl, -Br, -CF 3 , -N0 2 , ~C 8 alkyl or halogen substituted ~C 8 alkyl;
R18〜R22独立的为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 -OCH3、 〜C8烷基或卤素取 代的 ^〜¾烷基。 R 18 to R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , -OCH 3 , -C 8 alkyl or halogen-substituted ^~3⁄4 alkyl.
进一步优选的， R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; Further preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜¾烷基、 -CF3或 -N02; R7为 -H或 〜¾烷基；Ri R 3 is independently -H, -F, ^~3⁄4 alkyl, -CF 3 or -N0 2; R 7 is -H or ~3⁄4 alkyl;
Ri8〜R22为 -H、 -N02、 -OCH3、 -CF3、 ^〜¾烷基或卤素取代的 ^〜 烷基。 最优的， R2、 R4独立的为 -F、 -N02、 -顧2、 -OCF3或 -CF3; Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 , ^~3⁄4 alkyl or halogen-substituted ^~ alkyl. Optimally, R 2 and R 4 are independently -F, -N0 2 , -Gu 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜。4烷基、 -CF3或 -N02; R7为 -H或 〜 烷基；Ri R 3 is independently -H, -F, ^~. 4 alkyl, -CF 3 or -N0 2 ; R 7 is -H or ~alkyl;
Ri8〜R22为 -H、 -N02、 -OCH3、 -CF3 ^〜。4烷基。 Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 ^~. 4 alkyl.
上述苯并噻嗪 -4-酮衍生物， 结构如式 III所示: The above benzothiazin-4-one derivative has the structure shown in Formula III:
Figure imgf000010_0001
Figure imgf000010_0001
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3;Wherein R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立为 -H、 卤素、 〜C8烷基、 〜。8烷氧基、 卤素取代的 〜。8烷基、 卤素取代的 〜^烷氧基、 〜^烷基取代氨基、 〜^烷基取代羰基、 〜C8烷基 取代氨酰基、 〜C8烷基取代酰胺基、 〜 烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R 3 is independently -H, halogen, ~C 8 alkyl, ~. 8 alkoxy, halogen substituted ~. 8 alkyl, halogen substituted ~ alkoxy, ~ ^ alkyl substituted amino, ~ ^ alkyl substituted carbonyl, ~ C 8 alkyl substituted amino, ~ C 8 alkyl substituted amide, ~ alkyl substituted ammonia Sulfonyl, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R7为- H、带有取代基的 〜C8烷基、带有取代基的卤代 〜C8烷基、带有取代基 的苯基、 带有取代基的吡啶基， 所述的取代基为 -H、 〜。8烷基、 〜^烷氧基、 〜 C8烷基取代氨磺酰基、 ^素取代的 〜¾烷基、 ^〜¾烷基取代羰基、 〜¾烷基取 代氨酰基、 〜¾烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 7 is -H, a substituted -C 8 alkyl group having a substituent, a halogenated to C 8 alkyl group having a substituent, a phenyl group having a substituent, a pyridyl group having a substituent, and the substitution The base is -H, ~. 8 alkyl, ~ alkoxy, ~ C 8 alkyl substituted sulfamoyl, ^ substituted by -3⁄4 alkyl, ^~3⁄4 alkyl substituted carbonyl, ~3⁄4 alkyl substituted aminoacyl, ~3⁄4 alkyl substituted Amido, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R23〜R26独立的为 -H、 〜¾烷基、 〜¾烷氧基、 〜¾烷基取代氨磺酰基、 卤素取代的 ^〜¾烷基、 〜¾烷基取代羰基、 ^〜¾烷基取代氨酰基、 〜¾烷基 取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基。 R 23 to R 26 are independently -H, ~3⁄4 alkyl, ~3⁄4 alkoxy, 〜3⁄4 alkyl substituted sulfamoyl, halogen substituted ^~3⁄4 alkyl, 〜3⁄4 alkyl substituted carbonyl, ^~3⁄4 Alkyl substituted aminoacyl, 〜3⁄4 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl.
优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 〜¾烷氧基、 卤素取代的 ^〜 C8烷基、 卤素取代的 〜C8烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^ ~¾ alkyl, ~¾ alkoxy, halo-substituted ^ ~ C 8 alkyl, halogen-substituted alkoxy ~C 8, -N0 2 , -NH 2 , -CN or -CF 3 ;
R7为 -H、 〜C8烷基或卤素取代的 〜C8烷基； R 7 is -H, -C 8 alkyl or halogen substituted ~C 8 alkyl;
R23〜R26独立的为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 〜¾烷基或卤素取代的 d〜 进一步优选的， R2、 R4独立的为 -F、 -N02、 -NH2、 -0CF3或 -CF3; R 23 to R 26 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ~3⁄4 alkyl or halogen substituted d~ Further preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -0CF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜 ¾烷基、 -CF3或 -N02; R7为 H或 〜C8烷基; R23〜R26为 -H、 -F、 -Cl、 -Br或 〜C8烷基。 Ri R 3 is independently -H, -F, -3⁄4 alkyl, -CF 3 or -N0 2; R 7 is H or ~C 8 alkyl; R 2 3 to R 2 6 are -H, -F, -Cl, -Br, or ~C 8 alkyl group.
最优选的， R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; Most preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜。4烷基、 -CF3或 -N02; R7为 -H或 〜 烷基; Ri R 3 is independently -H, -F, ^~. 4 alkyl, -CF 3 or -N0 2 ; R 7 is -H or ~alkyl;
结构如式 V所示: The structure is as shown in the formula V:
Figure imgf000011_0001
Figure imgf000011_0001
其中， L为氮、 氧或硫； R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Wherein L is nitrogen, oxygen or sulfur; R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri 独立为 -H、 卤素、 〜¾烷基、 ^〜¾烷氧基、 卤素取代的 ^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 〜¾烷基取代氨基、 ^〜¾烷基取代羰基、 〜¾烷基 取代氨酰基、 〜¾烷基取代酰胺基、 ^〜¾烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri independently is -H, halogen, ~3⁄4 alkyl, ^~3⁄4 alkoxy, halogen substituted ^~3⁄4 alkyl, halogen substituted ^~3⁄4 alkoxy, ~3⁄4 alkyl substituted amino, ^~3⁄4 alkane Substituted carbonyl, 〜3⁄4 alkyl substituted aminoacyl, 〜3⁄4 alkyl substituted amide group, ^~3⁄4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO Or -CF 3 ;
R16为 -H、 -F、 -Cl、 -Br、 -COOH、 〜¾烷基或卤素取代的 〜¾烷基。 R 16 is -H, -F, -Cl, -Br, -COOH, ~3⁄4 alkyl or halogen substituted ~3⁄4 alkyl.
优选的， L为氧或硫； R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3 ; Preferably, L is oxygen or sulfur; R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 〜¾烷氧基、 卤素取代的 ^〜 C8烷基、 卤素取代的 ^〜^烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^ ~¾ alkyl, ~¾ alkoxy, halo-substituted ^ ~ C 8 alkyl group, a halogen-substituted alkoxy ^ ~ ^, -N0 2 , -NH 2 , -CN or -CF 3 ;
R16为 -H、 -COOH、 〜C8烷基或卤素取代的 〜C8烷基。 R 16 is -H, -COOH, -C 8 alkyl or halogen-substituted ~C 8 alkyl.
进一步优选的， L为氧或硫； R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; Ri R3独立的为 -H、 -F、 〜 ¾烷基、 -CF3或 -N02; R16为 -H或甲基。 Further preferably, L is oxygen or sulfur; R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ; Ri R 3 is independently -H, -F, ~3⁄4 Alkyl, -CF 3 or -N0 2; R 16 is -H or methyl.
最优选的， L为氧或硫； R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; Most preferably, L is oxygen or sulfur; R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜C4烷基、 -CF3或 -N02; R16为 -H或甲基。 上述苯并噻嗪 -4-酮衍生物， 当 -¾-NC^M— R17时， 其结构如式 IV所示：
Figure imgf000011_0002
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R 3 is independently -H, -F, -C 4 alkyl, -CF 3 or -N0 2 ; R 16 is -H or methyl. The above benzothiazin-4-one derivative, when -3⁄4 - N C^ M - R17 , has the structure shown in Formula IV:
Figure imgf000011_0002
Wherein R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R3独立为 -H、 卤素、 C C8烷基、 ^〜¾烷氧基、 卤素取代的 ^〜¾烷基、 卤素取代的 〜^烷氧基、 〜^烷基取代氨基、 〜^烷基取代羰基、 〜C8烷基 取代氨酰基、 〜C8烷基取代酰胺基、 〜 烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R 3 is independently -H, halogen, CC 8 alkyl, ^~3⁄4 alkoxy, halogen substituted ^~3⁄4 alkyl, Halogen-substituted alkoxy group ~ ^ ~ ^ alkyl substituted amino, ~ ^ alkyl substituted carbonyl group, ~C 8 alkyl substituted amino group, ~C 8 alkyl group substituted with an amide group, an alkyl-substituted sulfamoyl group ~, - N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C8烷基、 〜C8烷氧基、 C3〜C8环烷基、 〜C8烷基取代氨磺酰基、 R27取代的磺酰基、 R27取代的酰基、 卤素 取代的 ^〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 ^〜¾烷基取代 酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基 为含有 N、 0或 S杂原子的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 8 alkyl, ~C 8 alkoxy, C 3 -C 8 cycloalkyl, ~C 8- alkyl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, halogen substituted ^~3⁄4 alkyl group, 〜3⁄4 alkyl substituted carbonyl group, 〜3⁄4 alkyl substituted aminoacyl group, ^~3⁄4 alkyl group Substituting an amide group, a halogen, a tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated group containing a N, 0 or S hetero atom Heterocycle
R27为 〜¾烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜¾烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或^〜¾烷基。 R 27 is a ～3⁄4 alkyl group, a C 3 ～C 8 cycloalkyl group, a substituted phenyl group, a C 3 ～C 8 cycloalkyl group-substituted ～3⁄4 alkyl group or an adamantyl group; the substituent of the substituted phenyl group is Halogen, -1^0 2 or ^~3⁄4 alkyl.
优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri 独立为 -H、 卤素、 〜¾烷基、 ^〜¾烷氧基、 卤素取代的 ^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 〜¾烷基取代氨基、 ^〜¾烷基取代羰基、 〜¾烷基 取代氨酰基、 〜¾烷基取代酰胺基、 ^〜¾烷基取代氨磺酰基、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri is independently -H, halogen, ~3⁄4 alkyl, ^~3⁄4 alkoxy, halogen substituted ^~3⁄4 alkyl, halogen substituted ^~3⁄4 alkoxy, ~3⁄4 alkyl substituted amino, ^~3⁄4 alkyl substituted carbonyl, ~3⁄4 alkyl substituted aminoacyl, ~ 3⁄4 alkyl substituted amide group, ^~3⁄4 alkyl substituted sulfamoyl group, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C8烷基、 〜C8烷氧基、 C3〜C8环烷基、 〜。8烷基取代氨磺酰基、 ^素取代的 〜C8烷基、 〜^烷基取代 羰基、 〜 烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和 的杂环。 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, -C 8 alkyl, ~C 8 alkoxy, C 3 -C 8 cycloalkyl, ~. 8- alkyl substituted sulfamoyl group, substituted with -C 8 alkyl group, ~^alkyl substituted carbonyl group, ~ alkyl substituted aminoacyl group, ~ alkyl substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, said substituent being a saturated or unsaturated heterocyclic ring containing a N, 0 or S hetero atom.
进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜 ¾烷基、 〜C8烷氧基、 卤素取代的 〜 C8烷基、 卤素取代的 〜C8烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ~ ¾ alkyl, ~C 8 alkoxy, halo-substituted ~ C 8 alkyl, halogen-substituted alkoxy ~C 8, - N0 2 , -NH 2 , -CN or -CF 3 ;
M为氧， R17为 H; M为氮， R17为 -H或叔丁基氧羰基。 M is oxygen, R 17 is H; M is nitrogen, and R 17 is -H or tert-butyloxycarbonyl.
更进一步优选的， R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; Still more preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜¾烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, ^~3⁄4 alkyl, -CF 3 or -N0 2 ;
M为氧， R17为 -H; M为氮， R17为叔丁基氧羰基。 M is oxygen, R 17 is -H; M is nitrogen and R 17 is tert-butyloxycarbonyl.
更进一步优选的， R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; Still more preferably, R 2 and R 4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜。4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, ^~. 4 alkyl, -CF 3 or -N0 2 ;
M为氧， R17为 -H; M为氮， R17为叔丁基氧羰基。 M is oxygen, R 17 is -H ; M is nitrogen and R 17 is tert-butyloxycarbonyl.
优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 〜¾烷氧基、 卤素取代的 ^〜 C8烷基、 卤素取代的 〜C8烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^ ~¾ alkyl, ~¾ alkoxy, halo-substituted ^ ~ C 8 alkyl, halogen-substituted alkoxy ~C 8, -N0 2 , -NH 2 , -CN or -CF 3 ;
M为氧， R17为 H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
R27为 〜¾烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 ^〜^烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或^〜¾烷基。 进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -0CF3、 -CN、 或 -CF3; R 27 is a ~3⁄4 alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; a substituent of the substituted phenyl group It is a halogen, -1^0 2 or ^~3⁄4 alkyl. Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -0CF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 〜C4烷氧基、 卤素取代的 〜 C4烷基、 卤素取代的 〜C4烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ~C 4 alkyl group, ~C 4 alkoxy, halo-substituted ~ C 4 alkyl, substituted by halogen ~C 4 alkoxy group, -N0 2 , -NH 2 , -CN or -CF 3 ;
M为氧， R17为 -H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
R27为 〜C4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜C4烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或^〜 烷基。 R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ~C 4 alkyl or adamantyl; substituted phenyl substituted The group is halogen, -1^0 2 or ^~ alkyl.
进一步优选的， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Further preferably, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜。4烷基、 〜。4烷氧基、 卤素取代的 ^〜 C4烷基、 -N02、 -CN或 -CF3; Ri R 3 is independently -H, -F, -Cl, -Br, ^~. 4 alkyl, ~. 4 alkoxy, halo-substituted ^ ~ C 4 alkyl, -N0 2, -CN or -CF 3;
M为氧， R17为 -H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
R27为 〜。4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 ^〜^烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或^〜 烷基。 R 27 is ~. a 4- alkyl group, a C 3 -C 8 cycloalkyl group, a substituted phenyl group, a C 3 -C 8 cycloalkyl group-substituted alkyl group or an adamantyl group; the substituent of the substituted phenyl group is a halogen, - 1^0 2 or ^~ alkyl.
最优的， R2、 R4独立的为 -F、 -N02、 -顧2、 -OCF3或 -CF3; Optimally, R 2 and R 4 are independently -F, -N0 2 , -Gu 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜。4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, ^~. 4 alkyl, -CF 3 or -N0 2 ;
M为氧， R17为 -H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is -H; M is nitrogen, R 17 R 27 is a substituted sulfonyl group or a substituted acyl group R 27;
R27为 〜C4烷基、 C3〜C8环烷基、 取代的苯基、 C3〜C8环烷基取代的 〜C4烷 基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C4烷基。 R 27 is -C 4 alkyl, C 3 -C 8 cycloalkyl, substituted phenyl, C 3 -C 8 cycloalkyl substituted ~C 4 alkyl or adamantyl; substituted phenyl substituted The group is halogen, -N0 2 or ~C 4 alkyl.
上述苯并噻嗪 -4-酮衍生物的名称为：  The above benzothiazin-4-one derivatives are named:
2-乙氨基 -6,7,8-三氟 -1,3-苯并噻嗪 -4-酮、 2-吗啉 -6,7,8-三氟 -1,3-苯并噻嗪 -4-酮、 2-(5- 溴吡啶 -2-氨基) -6,7,8-三氟 -1,3-苯并噻嗪 -4-酮、 2-(5-氯吡啶 -2-氨基) -6,7,8-三氟 -1,3-苯并 噻嗪 -4-酮、 2- (哌啶 -1-基) -6,8-二硝基 -1,3-苯并噻嗪 -4-酮、 2-吗啉 -6,8-二硝基 -1,3-苯并噻 嗪 -4-酮、 2-(5-溴吡啶 -2-氨基) - 6,8-二硝基 -1,3-苯并噻嗪 -4-酮、 2-吗啉 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-乙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 N-乙基 -N-(8-硝基 -4酮 -6-三氟甲基 -1,3-苯并噻嗪 -2基） -4- (氯甲基)苯甲酰胺、 N-乙基 -N-(8-硝基 -4酮 -6-三 氟甲基 -1,3-苯并噻嗪 -2基) -2- (三氟甲基)苯甲酰胺、 N-乙基 -N-(8-硝基 -4 酮 -6-三氟甲基 -1,3-苯并噻嗪 -2基) -3- (硝基)苯甲酰胺、 2-甲氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-丙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-丁氨基 -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪—4-酮、 2-异丙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-二乙氨基 -8-硝基 -6-三 氟甲基 -1,3-苯并噻嗪 -4-酮、 2-异丁氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-环丙氨 基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2- (吡咯烷 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪 -4-酮、 2- (哌啶 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 1-(8-硝基 -4-酮 -6-三氟 甲基 -1,3-苯并噻嗪 -2-基)哌啶 -4-羧酸、 2- ( 1,4-高哌嗪 -1-基） -8-硝基 -6-三氟甲基 -1,3-苯 并噻嗪—4-酮、 2-(4-甲基哌啶 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-环戊氨基 -8- 硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 4-(8-硝基 -4-酮 -6-三氟甲基 -1,3-苯并噻嗪 -2-基)哌嗪 小羧酸 -叔丁醇酯、 2-(1,4-二硫杂 -8-氮杂螺 [4.5]癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(2 甲基 -1,4-二硫杂 -8氮杂螺 [4.5] 癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮、 2-(l-氧杂 -4-硫杂 -8氮杂螺 [4.5] 癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4- 甲磺酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丙基磺酰基哌嗪 -1- 基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丁基磺酰基哌嗪 -1-基) -8-硝基 -6-三氟甲 基 -1,3-苯并噻嗪 -4-酮、 2-(4-环丙基磺酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮、 2-(4-(4-叔丁基苯磺酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(2- 硝基苯磺酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(4-硝基苯磺酰基) 哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(3-硝基苯磺酰基)哌嗪 -1-基) -8- 硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-乙酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪 -4-酮、 2-(4-丙酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-新戊酰基 哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丁酰基哌嗪 -1-基) -8-硝基 -6-三氟 甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-环丙甲酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮、 2-(4-环己烷甲酰基哌嗪小基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(2-环己基 乙酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(2-氯苯甲酰基)哌嗪 -1- 基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-金刚烷甲酰基哌嗪 -1-基) -8-硝基 -6-三氟 甲基 -1,3-苯并噻嗪 -4-酮、 2-(1,5-二硫杂 -9-氮杂螺 [5.5] ^—烷 -9-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮或 2-(4-环戊基 -3-哌嗪酮 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮。 2-ethylamino-6,7,8-trifluoro-1,3-benzothiazin-4-one, 2-morpholine-6,7,8-trifluoro-1,3-benzothiazine- 4-keto, 2-(5-bromopyridin-2-amino)-6,7,8-trifluoro-1,3-benzothiazin-4-one, 2-(5-chloropyridin-2-amino -6,7,8-trifluoro-1,3-benzothiazin-4-one, 2-(piperidin-1-yl)-6,8-dinitro-1,3-benzothiazide Pyrazin-4-one, 2-morpholine-6,8-dinitro-1,3-benzothiazin-4-one, 2-(5-bromopyridin-2-amino)-6,8-di Nitro-1,3-benzothiazin-4-one, 2-morpholine-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-ethylamino -8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, N-ethyl-N-(8-nitro-4 keto-6-trifluoromethyl-1 , 3-benzothiazin-2-yl)-4-(chloromethyl)benzamide, N-ethyl-N-(8-nitro-4keto-6-trifluoromethyl-1,3- Benzothiazin-2-yl)-2-(trifluoromethyl)benzamide, N-ethyl-N-(8-nitro-4-keto-6-trifluoromethyl-1,3-benzoate Thiazin-2-yl)-3-(nitro)benzamide, 2-methylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-propane Amino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-butylamino-8-nitro-6-trifluoromethyl-1,3-benzo Thiazide- 4-ketone 2-Isopropylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-diethylamino-8-nitro-6-trifluoromethyl-1 , 3-benzothiazin-4-one, 2-isobutylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-cyclopropylamino-8 -nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(pyrrolidin-1-yl)-8-nitro-6-trifluoromethyl-1,3 -Benzothiazine-4-one, 2-(piperidin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 1-(8 -nitro-4-keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)piperidine-4-carboxylic acid, 2-(1,4-homopiperazin-1-yl -8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-methylpiperidin-1-yl)-8-nitro-6-three Fluoromethyl-1,3-benzothiazin-4-one, 2-cyclopentylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 4- (8-Nitro-4-keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)piperazine small carboxylic acid-tert-butanol ester, 2-(1,4-disulfide Hetero-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(2-methyl-1 ,4-dithia-8-oxaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazide-4- Ketone, 2-(l-oxa-4-thia-8azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazine- 4-keto, 2-(4-methanesulfonylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4- Propylsulfonyl piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-butylsulfonylpiperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-cyclopropylsulfonylpiperazin-1-yl)-8-nitrate -6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-(4-tert-butylphenylsulfonyl)piperazin-1-yl)-8-nitro- 6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-(2-nitrophenylsulfonyl)piperazin-1-yl)-8-nitro-6-tri Fluoromethyl-1,3-benzothiazin-4-one, 2-(4-(4-nitrophenylsulfonyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl -1,3-benzothiazin-4-one, 2-(4-(3-nitrophenylsulfonyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1, 3-benzothiazin-4-one, 2-(4-acetylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one 2-(4-propionylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-pivaloyl Pyrazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-butyrylpiperazin-1-yl)-8-nitrate -6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-cyclopropionylpiperazin-1-yl)-8-nitro-6-trifluoromethyl -1,3-benzothiazin-4-one, 2-(4-cyclohexaneformylpiperazine small)-8-nitro-6-trifluoromethyl-1,3-benzothiazine 4-keto, 2-(4-(2-cyclohexylacetyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one , 2-(4-(2-chlorobenzoyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-( 4-adamantyl-piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(1,5-dithia- 9-Azaspiro[5.5]^-alkan-9-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one or 2-(4-cyclopentyl) 3-piperazinone-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one.
上述苯并噻嗪 -4-酮衍生物的合成方法：  The synthesis method of the above benzothiazin-4-one derivative:
合成路线为：  The synthetic route is:
Figure imgf000014_0001
Figure imgf000014_0001
其中， 〜 的定义与式 I〜 中 〜 的定义相同。  Wherein, the definition of ~ is the same as the definition of the formula I~.
A路线的步骤为： 1^〜1 4取代的苯甲酰氯在催化剂作用下与硫氰酸铵反应， 再与 R5H反应， 最后关环得到 〜 取代的苯并噻嗪 -4-酮。 The procedure of Route A is as follows: 1^~1 4 Substituted benzoyl chloride is reacted with ammonium thiocyanate under the action of a catalyst, and then reacted with R 5 H to finally obtain a ~substituted benzothiazin-4-one.
其中， A路线步骤所述的催化剂为冠醚 18-冠 -6 或 PEG (聚乙二醇）； PEG优选为 PEG-400或 PEG-300。  Wherein the catalyst described in the A route step is crown ether 18-crown-6 or PEG (polyethylene glycol); the PEG is preferably PEG-400 or PEG-300.
其中， A路线步骤所述的与硫氰酸铵反应时的反应溶剂为二氯甲烷或甲苯。  The reaction solvent in the reaction with ammonium thiocyanate described in the A route step is dichloromethane or toluene.
其中， A 路线步骤所述的关环反应， 所用溶剂为 DMF (Ν,Ν-二甲基甲酰胺） 或 DMSO (二甲基亚砜）； 优选为 DMF。 Wherein, the ring-closing reaction described in the A route step, the solvent used is DMF (Ν, Ν-dimethylformamide) or DMSO (dimethyl sulfoxide); preferably DMF.
B路线的步骤为： 由 1^〜1 4取代的苯甲酸反应得到 1^〜1 4取代苯甲酰氯，再在催 化剂作用下与硫氰酸铵反应， 再与 R5H反应关环得到 Ri〜R4取代苯并噻嗪 -4-酮。 The step of the B route is as follows: the benzoic acid substituted by 1^~1 4 is reacted to obtain 1^~1 4 substituted benzoyl chloride, and then reacted with ammonium thiocyanate under the action of a catalyst, and then reacted with R 5 H to obtain a Ri. ~R4 replaces benzothiazin-4-one.
其中， B路线步骤所述的催化剂为 18-冠 -6或 PEG; PEG优选为 PEG-400或 PEG-300。 其中， B路线步骤所述的与硫氰酸铵反应时的反应溶剂为二氯甲烷或甲苯。  Wherein, the catalyst described in the B route step is 18-crown-6 or PEG; and the PEG is preferably PEG-400 or PEG-300. The reaction solvent in the reaction with the ammonium thiocyanate described in the step B is dichloromethane or toluene.
其中， B路线步骤所述的关环反应， 所用溶剂为 DMF或 DMSO; 优选为 DMF。 上述各个反应步骤的反应温度均为常温。  Wherein, in the ring-closing reaction described in the step B, the solvent used is DMF or DMSO; preferably DMF. The reaction temperature of each of the above reaction steps is normal temperature.
本发明还提供了上述苯并噻嗪 -4-酮衍生物在药学上可接受的盐、水合物或前药。所 述的前药是上述化合物的衍生物， 它们自身可能具有较弱的活性或甚至没有活性， 但是 在给药后， 在生理条件下 （例如通过代谢、 溶剂分解或另外的方式）被转化成相应的生 物活性形式。  The present invention also provides a pharmaceutically acceptable salt, hydrate or prodrug of the above benzothiazin-4-one derivative. The prodrugs are derivatives of the above compounds which may themselves have weak or even no activity, but after administration, are converted under physiological conditions (for example by metabolism, solvolysis or otherwise) into Corresponding biologically active forms.
本发明还提供了上述苯并噻嗪 -4-酮衍生物在制备治疗结核病或麻风病药物中的用 途。  The present invention also provides the use of the above benzothiazin-4-one derivative for the preparation of a medicament for treating tuberculosis or leprosy.
本发明还提供了一种药物组合物， 是由上述苯并噻嗪 -4-酮衍生物， 添加药学上可以 接受的辅助性成分制备而成的。 该药物组合物可用于制备治疗结核病或麻风病的药物。  The present invention also provides a pharmaceutical composition prepared by adding the pharmaceutically acceptable auxiliary component to the above benzothiazin-4-one derivative. The pharmaceutical composition can be used to prepare a medicament for treating tuberculosis or leprosy.
实验结果显示式 I所示的苯并噻嗪 -4-酮衍生物具有明显的抑制结核分枝杆菌作用， 并且有部分化合物的抑菌效果远超过了阳性对照异烟肼（Μ =0.8μΜ)和利福平（MIC =0.1μΜ) ο 而麻风病是由麻风分枝杆菌引起的一种慢性接触性传染病。 麻风分枝杆菌同 结核分枝杆菌同属分枝杆菌属， 二者在生物特性上具有很多共性， 常见的抗结核药物如 利福平等也能用于麻风病的治疗。 鉴于此， 本领域技术人员容易推断出本发明化合物具 有抗麻风分枝杆菌的作用， 有开发成抗麻风病药物的潜力。  The experimental results show that the benzothiazin-4-one derivative represented by the formula I has a significant inhibitory effect on Mycobacterium tuberculosis, and the bacteriostatic effect of some compounds far exceeds that of the positive control isoniazid (Μ = 0.8 μΜ). And rifampicin (MIC = 0.1 μΜ) ο And leprosy is a chronic contagious disease caused by M. leprae. Mycobacterium leprae and Mycobacterium tuberculosis belong to the genus Mycobacterium, and they have many commonalities in biological characteristics. Common anti-tuberculosis drugs such as rifampic can also be used for the treatment of leprosy. In view of this, those skilled in the art can easily infer that the compound of the present invention has an action against M. leprae and has the potential to be developed into a drug against leprosy.
本发明的有益效果为：本发明的苯并噻嗪 -4-酮衍生物是在大量筛选的基础上得到的 新化合物， 具有很好的抗结核分枝杆菌活性， 为抗结核药物和抗麻风药物的开发和应用 提供了新的选择。 具体实 式  The beneficial effects of the present invention are that the benzothiazin-4-one derivative of the present invention is a novel compound obtained on the basis of a large number of screenings, has excellent activity against Mycobacterium tuberculosis, is an anti-tuberculosis drug and is resistant to leprosy. The development and application of drugs offers new options. Specific form
以下结合实施例对本发明作进一步的阐述。 实施例仅用于说明本发明， 而不是以任 何方式来限制本发明。  The invention is further illustrated by the following examples. The examples are merely illustrative of the invention and are not intended to limit the invention in any way.
实施例 1 化合物 1: 2-乙氨基 -6,7,8- 噻嗪 -4-酮的制备
Figure imgf000015_0001
Example 1 Preparation of Compound 1: 2-Ethylamino-6,7,8-thiazin-4-one
Figure imgf000015_0001
将 2,3,4,5-四氟苯甲酰氯（3g,14.12mmol)溶于 20mL 二氯甲烷， 硫氰酸铵 (2.14g,28.24mmol), 再滴加 PEG-400 (0.2g), 常温反应两小时， 滤去沉淀， 滤液缓慢滴 加入乙胺的二氯甲烷溶液， 常温反应三小时。 室温下向反应液加入水和二氯甲烷， 收集 有机层，旋干得到淡黄色中间体，将其置于干燥烧瓶中，加入 DMF20mL和三乙胺 0.5mL， 回流 40分钟， 待反应液冷却过滤， 滤液旋干， 柱层析得到白色固体 2.1g (产率 57.2%)。 1H NMR: (DMSO-d6, 400MHz): 0.98 (m, 3H)， 3.92(m 2H)， 4.43(s 1H)， 7.21( s, 1H)。 MS-ESI(m/s): 259舉 -1)。 2,3,4,5-tetrafluorobenzoyl chloride (3 g, 14.12 mmol) was dissolved in 20 mL of dichloromethane, ammonium thiocyanate (2.14 g, 28.24 mmol), and PEG-400 (0.2 g) was added dropwise. After reacting at room temperature for two hours, the precipitate was filtered off, and the filtrate was slowly added dropwise to a solution of ethylamine in dichloromethane, and the mixture was reacted at room temperature for three hours. Water and dichloromethane were added to the reaction mixture at room temperature, and the organic layer was collected and evaporated to give a pale yellow intermediate, which was placed in a dry flask, and DMF 20 mL and triethylamine 0.5 mL were added. After refluxing for 40 minutes, the reaction solution was cooled and filtered, and the filtrate was evaporated to dryness. 1H NMR: (DMSO-d6, 400 MHz): 0.98 (m, 3H), 3.92 (m 2H), 4.43 (s 1H), 7.21 (s, 1H). MS-ESI (m/s): 259 -1).
实施例 2化合物 2: 2-吗啉 -6,7,8-三 -4-酮的制备
Figure imgf000016_0001
Example 2 Compound 2: Preparation of 2-morpholine-6,7,8-tri-4-one
Figure imgf000016_0001
与实施例 1的操作过程相同， 所用的胺为吗啉。 得到白色固体， 产率 55% < MS-ESI(m/s):301.0(M-l) 303·0(Μ+1)。  As in the operation of Example 1, the amine used was morpholine. Obtained as a white solid, yield 55% < MS-ESI (m/s): 301.0 (M-1) 303.
实施例 3化合物 3： 2-(5-溴吡啶 -2- 1,3-苯并噻嗪 -4-酮的制备
Figure imgf000016_0002
Example 3 Compound 3: Preparation of 2-(5-bromopyridine-2-1,3-benzothiazin-4-one
Figure imgf000016_0002
与实施例 1 的操作过程相同， 所用的胺为 2-氨基 -5溴吡啶。 得到白色固体， 产率 43%  As in the operation of Example 1, the amine used was 2-amino-5 bromopyridine. Obtained a white solid, yield 43%
1H NMR: (DMSO-d6, 400MHz): 7.30(sbr, 1H)， 8.12(dd J=8.4, 2.0Hz, 1H)， 8.51(t, J=8.4Hz 1H)， 8.64(s,lH) o MS-ESI(m/s):385.9(M-l) 387.9(M+1)。  </ RTI> <RTIgt; - ESI (m/s): 385.9 (Ml) 387.9 (M + 1).
实施例 4 化合物 4: 2-(5-氯吡啶 -2 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000016_0003
Example 4 Compound 4: Preparation of 2-(5-chloropyridine-2 -1,3-benzothiazin-4-one
Figure imgf000016_0003
与实施例 1 的操作过程相同， 所用的胺为 2-氨基 -5氯吡啶。 得到白色固体， 产率 45%  As in the operation of Example 1, the amine used was 2-amino-5chloropyridine. Obtained a white solid, yield 45%
1H NMR: (DMSO-d6, 400MHz): 7.32(sbr, 1H)， 8.21(dd J=8.4, 2.0Hz, 1H)， 8.61(t, J=8.4Hz 1H)， 8.74(s,lH) o MS-ESI(m/s):341.9(M-l) 343.9(M+1)。  </ RTI> <RTIgt; - ESI (m/s): 341.9 (Ml) 343.9 (M + 1).
实施例 5 化合物 5: 2- (哌啶 -1-基) -6,8-二硝基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000016_0004
Example 5 Preparation of Compound 5: 2-(piperidin-1-yl)-6,8-dinitro-1,3-benzothiazin-4-one
Figure imgf000016_0004
向 2-氯 -3,5-二硝基苯甲酸 （3g 12.2mmol) 中加入 20mL二氯甲烷， 常温搅拌下缓 慢滴加入草酰氯 （3.9g 30.5mmol) 禾 B 0.05mL DMF， 反应两小时。 反应结束后将反应 液旋干， 加 15mL 二氯甲烷溶解， 缓慢滴加入硫氰酸铵 （2.8g 36.6mmol) ，再加入 PEG-400(0.2g), 常温搅拌 1.5小时； 过滤， 将滤液滴加入哌啶二氯甲烷溶液中， 常温搅 拌 40分钟。 反应完成后将反应液旋干， 柱层析， 得到黄色固体 2.6g (产率 63% )。  To 2-chloro-3,5-dinitrobenzoic acid (3 g, 12.2 mmol), 20 mL of dichloromethane was added, and oxalyl chloride (3.9 g, 30.5 mmol) and B 0.05 mL of DMF were slowly added dropwise under stirring at room temperature for two hours. After the reaction was completed, the reaction solution was sparged, dissolved in 15 mL of dichloromethane, and slowly added dropwise with ammonium thiocyanate (2.8 g, 36.6 mmol), then PEG-400 (0.2 g), and stirred at room temperature for 1.5 hours; It was added to a piperidine dichloromethane solution and stirred at room temperature for 40 minutes. After the completion of the reaction, the reaction mixture was evaporated to dryness, mjjjjjj
1H NMR: (DMSO-d6, 400MHz): 1.71(s, 6H)， 3.85(s 2H)， 4.09(s 2H)， 9.07(s, 1H)， 9.71(s, 1H)。 MS-ESI(m/s): 335.0(M-1) 337.0(M+1)。  1H NMR: (DMSO-d6, 400 MHz): 1.71 (s, 6H), 3.85 (s 2H), 4.09 (s 2H), 9.07 (s, 1H), 9.71 (s, 1H). MS-ESI (m/s): 335.0 (M-1)
实施例 6 化合物 6: 2-吗啉 -6,8-二硝基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000017_0001
Example 6 Preparation of Compound 6: 2-morpholine-6,8-dinitro-1,3-benzothiazin-4-one
Figure imgf000017_0001
与实施例 5的操作过程相同， 所用的胺为吗啉。 得到黄色针状固体， 产率 47%。 1H NMR: (DMSO-d6, 400MHz): 3.77(s, 4H) ， 3.88(s， 2H) ， 4.03(s， 2H) ， 9.09(s， 1H) ， 9.70(s, 1H)。 MS-ESI(m/s): 337.0(M-1) 339.0(M+1)。  As in the operation of Example 5, the amine used was morpholine. A yellow needle solid was obtained in a yield of 47%. 1H NMR: (DMSO-d6, 400 MHz): 3.77 (s, 4H), 3.88 (s, 2H), 4.03 (s, 2H), 9.09 (s, 1H), 9.70 (s, 1H). MS-ESI (m/s): 337.0 (M-1)
实施例 7 化合物 7: 2-(5-溴吡啶 -2 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000017_0002
Example 7 Compound 7: Preparation of 2-(5-bromopyridine-2 -1,3-benzothiazin-4-one)
Figure imgf000017_0002
与实施例 5 的操作过程相同， 所用的胺为 2-氨基 -5-溴吡啶。 得到黄色固体， 产率 39%。  The same procedure as in Example 5, the amine used was 2-amino-5-bromopyridine. A yellow solid was obtained in a yield of 39%.
MS-ESI(m/s): 424.0(M+1)。  MS-ESI (m/s): 424.0 (M-1).
实施例 8 化合物 8: 2-吗啉 -8-硝基 - 3-苯并噻嗪 -4-酮的制备
Figure imgf000017_0003
Example 8 Preparation of Compound 8: 2-morpholine-8-nitro-3-benzothiazin-4-one
Figure imgf000017_0003
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为吗啉。 得到黄色针状固体， 产率 59%。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was morpholine. A yellow needle solid was obtained in a yield of 59%.
1H NMR: (DMSO-d6, 400MHz): 3.73(s, 4H)， 3.92(s， 4H)， 8.80(s， 1H)， 8.86(s， lH MS-ESI(m/s): 360.0(M-1) 362.0(M+1)。  1H NMR: (DMSO-d6, 400MHz): 3.73 (s, 4H), 3.92 (s, 4H), 8.80 (s, 1H), 8.86 (s, lH MS-ESI (m/s): 360.0 (M- 1) 362.0 (M+1).
实施例 9 化合物 9: 2-乙氨基 -8-硝 ,3-苯并噻嗪 -4-酮的制备
Figure imgf000017_0004
Example 9 Preparation of Compound 9: 2-Ethylamino-8-nitrol, 3-benzothiazin-4-one
Figure imgf000017_0004
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为乙胺。 得到黄色固体， 产率 44%。  In the same manner as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was ethylamine. A yellow solid was obtained in 44% yield.
1H NMR: (DMSO-d6, 400MHz): 1.13(m, 3H)， 3.92(m， 2H)， 4.43(s， 1H)， 8.80(s， 1H)， 8.85(s, 1H)。 MS-ESI(m/s): 320.0 +l  1H NMR: (DMSO-d6, 400 MHz): 1.13 (m, 3H), 3.92 (m, 2H), 4.43 (s, 1H), 8.80 (s, 1H), 8.85 (s, 1H). MS-ESI(m/s): 320.0 +l
实施例 10 化合物 10: N-乙基 -N-(8-硝基 -4酮 -6-三氟甲基 -1,3-苯并噻嗪 -2基) -4- (氯甲 基）苯甲酰胺的制备
Figure imgf000017_0005
Example 10 Compound 10: N-ethyl-N-(8-nitro-4 keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)-4-(chloromethyl)benzene Preparation of formamide
Figure imgf000017_0005
将化合物 9溶于二氯甲烷， 加入对氯甲基苯甲酰氯， 以及少量三乙胺， 常温搅拌 2 小时。 反应结束后加水， 用二氯甲烷萃取， 合并有机层， 旋干， 柱层析得到黄色固体。 产率 75%。  Compound 9 was dissolved in dichloromethane, p-chloromethylbenzoyl chloride was added, and a small amount of triethylamine was stirred at room temperature for 2 hours. After the reaction, water was added, and the mixture was extracted with dichloromethane. The yield was 75%.
1H NMR: (DMSO-d6, 400MHz): 0.83(m, 3H)， 4.05(m， 2H)， 4.55(s， 2H)， 7.54(m, 2H)， 7.94(m, 2H)， 8.78(s, 1H)， 8.84(s, 1H)。 MS-ESI(m/s): 470.0(M-1) 472.0(M+1)。 实施例 11 化合物 11 ： Ν-乙基 -Ν-(8-硝基 -4酮 -6-三氟甲基 -1,3-苯并噻嗪 -2基) -2- (三 氟甲基）苯甲酰胺的制备
Figure imgf000018_0001
1H NMR: (DMSO-d6, 400MHz): 0.83 (m, 3H), 4.05 (m, 2H), 4.55 (s, 2H), 7.54 (m, 2H), 7.94 (m, 2H), 8.78 (s, 1H), 8.84 (s, 1H). MS-ESI (m/s): 47. Example 11 Compound 11 : Ν-ethyl-fluorene-(8-nitro-4 keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)-2-(trifluoromethyl) Preparation of benzamide
Figure imgf000018_0001
与实施例 10的操作步骤相同， 所用的酰氯为邻三氟甲基苯甲酰氯。 得到黄色固体， 产率 78%。  As in the procedure of Example 10, the acid chloride used was o-trifluoromethylbenzoyl chloride. A yellow solid was obtained in a yield of 78%.
1H NMR: (DMSO-d6, 400MHz): 1.15(m， 3H)， 4.05(m， 2H)， 7.54(m, 2H)， 8.03(m， 2H)， 8.78(s, 1H)， 8.84(s, 1H)。 MS-ESI(m/s): 490.0(M-1) 514.0(M+23)。  1H NMR: (DMSO-d6, 400MHz): 1.15 (m, 3H), 4.05 (m, 2H), 7.54 (m, 2H), 8.03 (m, 2H), 8.78 (s, 1H), 8.84 (s, 1H). MS-ESI (m/s): 49.
实施例 12 化合物 12: N-乙基 -N-(8-硝基 -4酮 -6-三氟甲基 -1,3-苯并噻嗪 -2基) -3- (硝 基）苯甲酰胺的制备
Figure imgf000018_0002
Example 12 Compound 12: N-ethyl-N-(8-nitro-4 keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)-3-(nitro)benzene Preparation of amide
Figure imgf000018_0002
与实施例 10的操作步骤相同， 所用的酰氯为间硝基苯甲酰氯。 得到黄色固体， 产 率 72%。  The same procedure as in Example 10 was carried out, and the acid chloride used was m-nitrobenzoyl chloride. A yellow solid was obtained with a yield of 72%.
MS-ESI(m/s): 467舉 -1)、 469舉 +1)。  MS-ESI (m/s): 467, -1), 469, +1).
实施例 13 化合物 13： 2-甲氨基 -8- -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000018_0003
Example 13 Preparation of Compound 13: 2-Methylamino-8-1,3-1,3-benzothiazin-4-one
Figure imgf000018_0003
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为甲胺。 得到黄色固体， 产率 47%。 MS-ESI(m/s): 304.0(M-1) 306.0(M+1)。  The same procedure as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was methylamine. A yellow solid was obtained in 47% yield. MS-ESI (m/s): 304.0 (M-1)
实施例 14 化合物 14： 2-丙氨基 -8 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000018_0004
Example 14 Preparation of Compound 14: 2-Propyl-8-1,3-benzothiazin-4-one
Figure imgf000018_0004
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为丙胺。 得到黄色固体， 产率 57%。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was propylamine. A yellow solid was obtained in a yield of 57%.
1H NMR: (DMSO-d6, 400MHz): 0.94(m, 3H)， 1.60(m， 2H)， 3.43(m， 2H)， 3.81(s, 1H)， 8.80(s， 1H)， 8.85(s， 1H)。 MS-ESI(m/s): 332.0(M-1) 334.0(M+1)。  1H NMR: (DMSO-d6, 400MHz): 0.94 (m, 3H), 1.60 (m, 2H), 3.43 (m, 2H), 3.81 (s, 1H), 8.80 (s, 1H), 8.85 (s, 1H). MS-ESI (m/s): 3321. (M-1)
实施例 15 化合物 15： 2-丁氨基 -8 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000018_0005
Example 15 Preparation of Compound 15: 2-Butylamino-8-1,3-benzothiazin-4-one
Figure imgf000018_0005
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5  The starting material was the same as in Example 5, and the starting material was 2-chloro-3nitro-5.
为丁胺。 得到黄色固体， 产率 56%。 'H NMR: (DMSO-d6, 400MHz): 0.93(m, 3H)， 1.36(m 2H)， 1.55(m 2H)， 3.30(s, 1H)， 3.47(m, 2H)， 8.80(s, 1H)， 8.85(s, 1H)。 MS-ESI(m/s): 370.0(M+23)。 It is butylamine. A yellow solid was obtained in a yield of 56%. 'H NMR: (DMSO-d6, 400MHz): 0.93 (m, 3H), 1.36 (m 2H), 1.55 (m 2H), 3.30 (s, 1H), 3.47 (m, 2H), 8.80 (s, 1H) ), 8.85(s, 1H). MS-ESI (m/s): 370.0 (M+23).
实施例 16 化合物 16： 2-异丙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000019_0001
Example 16 Preparation of Compound 16: 2-Isopropylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000019_0001
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为异丙胺。 得到黄色固体， 产率 61%  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was isopropylamine. Obtained a yellow solid, yield 61%
1H NMR: (DMSO-d6, 400MHz): 1.22(d, J=8 6H)， 4.34(m 1H)， 8.79(s, 1H)， 8.86(s 1H)， 9.54(s 1H)。 MS-ESI(m/s): 356.0(M+23)。  1H NMR: (DMSO-d6, 400 MHz): 1.22 (d,J=8 6H), 4.34 (m 1H), 8.79 (s, 1H), 8.86 (s 1H), 9.54 (s 1H). MS-ESI (m/s): 356.0 (M+23).
实施例 17 化合物 17： 2-二乙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000019_0002
Example 17 Preparation of Compound 17: 2-Diethylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000019_0002
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为二乙胺。 得到黄色固体， 产率 54%  The same procedure as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was diethylamine. Obtained a yellow solid, yield 54%
1H NMR: (DMSO-d6, 400MHz): 1.25(m, 6H)， 3.75(m, 4H)， 8.80(s 1H)， 8.85(s 1H)。 MS-ESI(m/s): 346.0(M-1) 348.0(M+1)。  1H NMR: (DMSO-d6, 400 MHz): 1.25 (m, 6H), 3.75 (m, 4H), 8.80 (s 1H), 8.85 (s 1H). MS-ESI (m/s): 346.0 (M-1)
实施例 18 化合物 18: 2-异丁氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000019_0003
Example 18 Preparation of Compound 18: 2-Isobutylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000019_0003
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为异丁胺。 得到黄色固体， 产率 53%  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was isobutylamine. Obtained a yellow solid, yield 53%
1H NMR: (DMSO-d6, 400MHz): 0.92(d, J=6.8, 6H)， 1.92(m 1H)， 3.32 (m 2H)， 8.80(s, 1H)， 8.85(s, 1H)， 9.62(t J=5.2, 1H)。 MS-ESI(m/s): 346.0(M-1) 348.0(M+1)。 实施例 19 化合物 19： 2-环丙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制备  1H NMR: (DMSO-d6, 400MHz): 0.92 (d, J = 6.8, 6H), 1.92 (m 1H), 3.32 (m 2H), 8.80 (s, 1H), 8.85 (s, 1H), 9.62 ( t J=5.2, 1H). MS-ESI (m/s): 346.0 (M-1) Example 19 Compound 19: Preparation of 2-cyclopropylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Ο  Ο
I ^f"S入 iL N  I ^f"S into iL N
N 2 H N 2 H
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为环丙胺。 得到黄色固体， 产率 58%  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was cyclopropylamine. Obtained a yellow solid, yield 58%
1H NMR: (DMSO-d6, 400MHz): 0.65(m, 2H)， 0.82(m 2H)， ,3.14 (m, 1H)， 8.80(s 1H NMR: (DMSO-d6, 400MHz): 0.65 (m, 2H), 0.82 (m 2H), , 3.14 (m, 1H), 8.80 (s
1H)， 8.86(s, 1H)， 9.54(s, 1H)。 MS-ESI(m/s): 330.0(M-1) 332.0(M+1)。 1H), 8.86(s, 1H), 9.54(s, 1H). MS-ESI (m/s): 330.0 (M-1)
实施例 20 化合物 20: 2- (吡咯烷小基） -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000019_0004
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为吡咯烷。 得到黄色固体， 产率 49%。 Example 20 Compound 20: Preparation of 2-(pyrrolidinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000019_0004
In the same manner as in Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was pyrrolidine. A yellow solid was obtained in a yield of 49%.
1H NMR: (DMSO-d6, 400MHz): 1.95(m, 2H)， 2.06(m， 2H)， 3.66(m， 4H)， 8.77(s, 1H)， (s, 1H)。 MS-ESI(m/s):  1H NMR: (DMSO-d6, 400MHz): 1.95 (m, 2H), 2.06 (m, 2H), 3.66 (m, 4H), 8.77 (s, 1H), (s, 1H). MS-ESI (m/s):
实施例 21 化合物 21: 2- (哌啶 -1-基 甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000020_0001
Example 21 Compound 21: Preparation of 2-(piperidin-1-ylmethyl-1,3-benzothiazin-4-one)
Figure imgf000020_0001
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为哌啶。 得到黄色固体， 产率 52%。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was piperidine. A yellow solid was obtained in a yield of 52%.
1H NMR: (DMSO-d6, 400MHz): 1.71(s, 6H)， 3.85(s， 2H)， 4.09(s， 2H)， 8.73(s, 1H)， (s, 1H)。 MS-ESI(m/s):  1H NMR: (DMSO-d6, 400 MHz): 1.71 (s, 6H), 3.85 (s, 2H), 4.09 (s, 2H), 8.73 (s, 1H), (s, 1H). MS-ESI (m/s):
实施例 22 化合物 22: 1- (8-硝基 -4-酮 -6-三氟甲基 -1,3-苯并噻嗪 -2-基）哌啶 -4-羧酸的 制备
Figure imgf000020_0002
Example 22 Compound 22: Preparation of 1-(8-nitro-4-keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)piperidine-4-carboxylic acid
Figure imgf000020_0002
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 哌啶甲酸。 得到黄色固体， 产率 。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethylbenzoic acid, and the amine used was piperidinic acid. Obtained a yellow solid in a yield.
1H NMR: (DMSO-d6, 400MHz): 1.63(m, 2H)， 2.02(m， 2H)， 2.70(m, 1H)， 3.42(m， 2H)， 4.35(m， 2H)， 8.78(s, 1H)， 8.85(s, 1H)， 12.44(s, 1H)。 MS-ESI(m/s):402.0(M-l) 404.0(M+l  1H NMR: (DMSO-d6, 400MHz): 1.63 (m, 2H), 2.02 (m, 2H), 2.70 (m, 1H), 3.42 (m, 2H), 4.35 (m, 2H), 8.78 (s, 1H), 8.85 (s, 1H), 12.44 (s, 1H). MS-ESI (m/s): 402.0 (M-l) 404.0 (M+l
实施例 23 化合物 23: 2-(l,4省哌 -三氟甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000020_0003
Example 23 Compound 23: Preparation of 2-(1,4 province pipera-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000020_0003
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 1， 4-高哌嗪。 得到黄色固体， 产率 45%。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 -trifluoromethyl benzoic acid, and the amine used was 1, 4-homopiperazine. A yellow solid was obtained in a yield of 45%.
1H NMR: (DMSO-d6, 400MHz): 1.18(m, 2H)， 2.02(m， 2H)， 2.20(s， 1H)， 4.05(m， 3H)， 4.24(m， 3H)， 8.71(s, 1H)， 8.80(s, 1H)。 MS-ESI(m/s):373.1(M-l) 375.1(M+1)。 实施例 24 化合物 24： 2-(4-甲基哌啶小基 )-8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制 备
Figure imgf000020_0004
1H NMR: (DMSO-d6, 400MHz): 1.18 (m, 2H), 2.02 (m, 2H), 2.20 (s, 1H), 4.05 (m, 3H), 4.24 (m, 3H), 8.71 (s, 1H), 8.80(s, 1H). MS-ESI (m/s): 3721. (Ml) Example 24 Preparation of Compound 24: 2-(4-Methylpiperidinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000020_0004
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 4-甲基哌啶。 得到黄色固体， 产率 63%。 H NMR: (DMSO-d6, 400MHz): 0.94(d， J=8， 3H)， 1.81(m, 5H)， 3.15(m, 4H)， 1H)， 8.84(s, 1H)。 MS-ESI(m/s):372.1(M-l) 374.1(M+1)。 In the same manner as in Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 4-methylpiperidine. A yellow solid was obtained in a yield of 63%. H NMR: (DMSO-d6, 400 MHz): 0.94 (d, J=8, 3H), 1.81 (m, 5H), 3.15 (m, 4H), 1H), 8.84 (s, 1H). MS-ESI (m/s): 3721. (Ml)
实施例 25 化合物 25: 2-环戊氨基 - 基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000021_0001
Example 25 Compound 25: Preparation of 2-cyclopentylamino-yl-1,3-benzothiazin-4-one
Figure imgf000021_0001
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为环戊胺。 得到黄色固体， 产率 56%。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was cyclopentylamine. A yellow solid was obtained in a yield of 56%.
1H NMR: (DMSO-d6, 400MHz): 1.56(m, 6H)， 1.95(m， 2H)， 4.47(s, 1H)， 8.77(s, 1H)， 8.82(s, 1H)， 9.48(s, 1H)。 MS-ESI(m/s): 382.1(M+23)。  </ RTI> <RTIgt; 1H). MS-ESI (m/s): 3821. (M+23).
实施例 26 化合物 26: 4-(8-硝基 -4-酮 -6-三氟甲基 -1,3-苯并噻嗪 -2-基)哌嗪 -1-羧酸 -叔丁 醇酯的制备
Figure imgf000021_0002
Example 26 Compound 26: 4-(8-Nitro-4-keto-6-trifluoromethyl-1,3-benzothiazin-2-yl)piperazine-1-carboxylic acid-tert-butanol ester Preparation
Figure imgf000021_0002
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 N-BOC哌嗪。 得到黄色固体， 产率 54%。  The procedure was the same as in Example 5, the starting material was 2-chloro -3 nitro -5 trifluoromethylbenzoic acid, and the amine used was N-BOC piperazine. A yellow solid was obtained in a yield of 54%.
1H NMR: (DMSO-d6, 400MHz): 1.43(s, 9H)， 3.53(s， 4H)， 3.95(s， 4H)， 8.73(s, 1H)， 8.84(s, 1H)。 MS-ESI(m/s): 459.1(M-1) 461.1(M+1)。  1H NMR: (DMSO-d6, 400 MHz): 1.43 (s, 9H), 3.53 (s, 4H), 3.95 (s, 4H), 8.73 (s, 1H), 8.84 (s, 1H). MS-ESI (m/s): 459.1 (M-1)
实施例 27 化合物 27： 2-(l,4-二硫杂 -8-氮杂螺 [4.5]癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪 -4-酮的制备
Figure imgf000021_0003
Example 27 Compound 27: 2-(l,4-dithia-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3-benzo Preparation of thiazin-4-one
Figure imgf000021_0003
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 4-哌啶酮縮乙二硫醇。 得到黄色固体， 产率 56%。  In the same manner as in Example 5, the starting material was 2-chloro-3-nitro-5-trifluoromethylbenzoic acid, and the amine used was 4-piperidinone ethanedithiol. A yellow solid was obtained in a yield of 56%.
1H NMR: (DMSO-d6, 400MHz): 2.19(s, 4H)， 3.38(s， 4H)， 4.05(s， 4H)， 8.78(s, 1H)， 8.85(s, 1H)。 MS-ESI(m/s):448.0(M-l) 450.0(M+1)。  1H NMR: (DMSO-d6, 400 MHz): 2.19 (s, 4H), 3.38 (s, 4H), 4.05 (s, 4H), 8.78 (s, 1H), 8.85 (s, 1H). MS-ESI (m/s): 448.0 (M-1)
实施例 28 化合物 28: 2-(2甲基 -1,4-二硫杂 -8氮杂螺 [4.5]癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮的制备
Figure imgf000021_0004
Example 28 Compound 28: 2-(2methyl-1,4-dithia-8azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3 -Preparation of benzothiazin-4-one
Figure imgf000021_0004
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 2-甲基 -1,4-二硫杂 -8氮杂螺 [4.5] 癸烷。 得到黄色固体， 产率 58%。  The procedure was the same as in Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 2-methyl-1,4-dithia-8 aza snail. [4.5] decane. A yellow solid was obtained in a yield of 58%.
1H NMR: (DMSO-d6, 400MHz):1.23(d, J=6.0, 3H)， 1.804(s, 4H)， 3.45(m， 1H)， 4.10(m, 4H)， 4.25(m， 2H)， 8.78(s, 1H)， 8.85(s, 1H)。 MS-ESI(m/s):462.0(M-l)、 464.0(M+1)。 实施例 29 化合物 29: 2-(l-氧杂 -4-硫杂 -8氮杂螺 [4.5]癸 -8-基) -8-硝基 -6-三氟甲基 -1,3- 苯并噻嗪 -4-酮的制备
Figure imgf000022_0001
1H NMR: (DMSO-d6, 400MHz): 1.23 (d, J = 6.0, 3H), 1.804 (s, 4H), 3.45 (m, 1H), 4.10 (m, 4H), 4.25 (m, 2H), 8.78 (s, 1H), 8.85 (s, 1H). MS-ESI (m/s): 462.0 (Ml) Example 29 Compound 29: 2-(l-oxa-4-thia-8azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3-benzene Preparation of thiazin-4-one
Figure imgf000022_0001
与实施例 5的操作过程相同，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺 为 1-氧杂 -4-硫杂 -8氮杂螺 [4.5] 癸烷。 得到黄色固体， 产率 54%  The same procedure as in Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 1-oxa-4-thia-8 azaspiro[4.5] Decane. Obtained a yellow solid, yield 54%
1H NMR: (DMSO-d6, 400MHz):2.08(s, 4H)， 3.12(t， J=6， 2H)， 3.95(m， 6H)， 4.10(m， 4H)， 4.25(m， 2H)， 8.77(s, 1H)， 8.84(s, 1H)。 MS-ESI(m/s):432.0(M-l) 434.0(M+1)。 实施例 30 化合物 30： 2-(4-甲磺酰基哌嗪小基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮 的制备
Figure imgf000022_0002
1H NMR: (DMSO-d6, 400MHz): 2.08 (s, 4H), 3.12 (t, J=6, 2H), 3.95 (m, 6H), 4.10 (m, 4H), 4.25 (m, 2H), 8.77 (s, 1H), 8.84 (s, 1H). MS-ESI (m/s): 4321. Example 30 Compound 30: Preparation of 2-(4-methanesulfonylpiperazine small group)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000022_0002
按实施例 5的操作过程，起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸，所用的胺为哌 嗪， 得到化合物 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮 （0.5g， 1.4mmol, 产率 52% )。 再将 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮溶于二氯甲烷， 常 温搅拌下滴加入甲基磺酰氯 （0.2g， 2.1mmol) 和催化量的三乙胺， 反应 2 小时后， 向 反应体系加入 20mL饱和碳酸氢钠水溶液， 搅拌 1小时， 用二氯甲烷萃取旋干有机相， 柱层析得到黄色固体 0.52g， 产率 85%  According to the procedure of Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was piperazine to give the compound 2-(piperazin-1yl)-8-nitrate. Base-6-trifluoromethyl-1,3-benzothiazin-4-one (0.5 g, 1.4 mmol, yield 52%). Further 2-(piperazin-1yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was dissolved in dichloromethane, and methylsulfonate was added dropwise with stirring at room temperature. The acid chloride (0.2 g, 2.1 mmol) and a catalytic amount of triethylamine were reacted for 2 hours. Then, 20 mL of a saturated aqueous sodium hydrogencarbonate solution was added to the reaction system, and the mixture was stirred for 1 hour, and the organic phase was extracted with dichloromethane and then purified by column chromatography. Yellow solid 0.52g, yield 85%
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 2.86(s, 3H)， 3.43(s, 4H)， 4.16(s, 4H)， 8.80(s, 1H)， 9.11(s, 1H)。 MS-ESI(m/s): 439.0 (M+l)。  1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 2.86 (s, 3H), 3.43 (s, 4H), 4.16 (s, 4H), 8.80 (s, 1H), 9.11 (s, 1H). MS-ESI (m/s): 439.0 (M+l).
实施例 31 化合物 31： 2-(4-丙基磺藤哌嗪小基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮的制备
Figure imgf000022_0003
Example 31 Compound 31: Preparation of 2-(4-propylsulfonazine piperazine)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000022_0003
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与丙 基磺酰氯反应得到黄色固体， 产率 87%  2-(Piperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was reacted with propylsulfonyl chloride according to the procedure of Example 30 to give yellow Solid, yield 87%
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 1.08(t， J = 8.0 Hz , 3H)， 1.86 (m， 2H)， 2.94(m, 2H)， 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 1.08 (t, J = 8.0 Hz, 3H), 1.86 (m, 2H), 2.94 (m, 2H),
3.48(s, 4H)， 4.11(s, 4H)， 8.79(s, 1H)， 9.10(s, 1H)。 MS-ESI(m/s): 467.1 (M+l)。 3.48(s, 4H), 4.11(s, 4H), 8.79(s, 1H), 9.10(s, 1H). MS-ESI (m/s): 467.1 (M+l).
实施例 32 化合物 32： 2-(4-丁基磺藤哌嗪小基 )-8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮的制备
Figure imgf000023_0001
Example 32 Compound 32: Preparation of 2-(4-butylsulfonazine piperazine)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000023_0001
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与丁 基磺酰氯反应得到黄色固体， 产率 83%。  2-(Piperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was reacted with butylsulfonyl chloride to give a yellow color. Solid, yield 83%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 0.94(t, J = 8.0 Hz , 3H)， 1.44 (m， 2H)， 1.77(m, 2H)， 2.94(t, J = 8.0 Hz , 2H)， 3.48(s, 4H)， 4.13(s, 4H)， 8.80(s, 1H)， 9.11(s, 1H)。 MS-ESI(m/s): 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 0.94 (t, J = 8.0 Hz, 3H), 1.44 (m, 2H), 1.77 (m, 2H), 2.94 (t, J = 8.0 Hz, 2H), 3.48(s, 4H), 4.13(s, 4H), 8.80(s, 1H), 9.11(s, 1H). MS-ESI (m/s):
481.1 (M+l)。 481.1 (M+l).
实施例 33 化合物 33: 2-(4-环丙基磺鶴哌嗪小基 )-8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮的制备
Figure imgf000023_0002
Example 33 Compound 33: Preparation of 2-(4-cyclopropylsulfonylpiperazinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000023_0002
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与环 丙基磺酰氯反应得到黄色固体， 产率 90%。  2-(Piperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was reacted with cyclopropylsulfonyl chloride according to the procedure of Example 30. Yellow solid, yield 90%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 1.04(m, 2H)， 1.21 (m， 2H)， 2.28(m, 1H)， 3.50(s, 4H)， 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 1.04 (m, 2H), 1.21 (m, 2H), 2.28 (m, 1H), 3.50 (s, 4H),
4.15(s, 4H)， 8.80(s, 1H)， 9.11(s, 1H)。 MS-ESI(m/s): 487.0 (M+23)。 4.15(s, 4H), 8.80(s, 1H), 9.11(s, 1H). MS-ESI (m/s): 487.0 (M+23).
实施例 34 化合物 34： 2-(4- (4-叔丁基苯磺鶴）哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3- 苯并噻嗪 -4-酮的制备
Figure imgf000023_0003
Example 34 Compound 34: 2-(4-(4-tert-Butylbenzenesulfonamide) piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazine- Preparation of 4-ketone
Figure imgf000023_0003
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与对 叔丁基苯磺酰氯反应得到黄色固体， 产率 84%。  2-(Piperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one and p-tert-butylbenzenesulfonyl chloride as in Example 30 The reaction gave a yellow solid in a yield of 84%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 1.29(s, 9H)， 3.10 (s， 4H)， 4.02(s, 4H)， 7.67(s, 4H)， 8.75(s, 1H)， 8.84(s, 1H)。 MS-ESI(m/s): 555.1 (M-l) o  1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 1.29 (s, 9H), 3.10 (s, 4H), 4.02 (s, 4H), 7.67 (s, 4H), 8.75 (s, 1H), 8.84 (s) , 1H). MS-ESI (m/s): 555.1 (M-l) o
实施例 35 化合物 35： 2-(4- (2-硝基苯磺雌）哌嗪小基) -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪 -4-酮的制备
Figure imgf000023_0004
Example 35 Compound 35: 2-(4-(2-Nitrobenzenesulfonyl)piperazine small base)-8-Nitro-6-trifluoromethyl-1,3-benzothiazin-4-one Preparation
Figure imgf000023_0004
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与邻 硝基苯磺酰氯反应得到黄色固体， 产率 91%。  Reaction of 2-(piperazin-1yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one with o-nitrobenzenesulfonyl chloride according to the procedure of Example 30 A yellow solid was obtained in a yield of 91%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 3.51(s, 4H)， 4.13 (s， 4H)， 7.67(d, J = 8.0 Hz, 1H)， 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 3.51 (s, 4H), 4.13 (s, 4H), 7.67 (d, J = 8.0 Hz, 1H),
7.76(m, 2H)， 8.04(d, J = 8.0 Hz, 1H)， 8.78(s, 1H)， 9.08(s, 1H)。 MS-ESI(m/s): 568.0 (M+23)。 M^stfu難:^ *-ε'ι-¾ώ 三 -9- οε m i
Figure imgf000024_0001
7.76 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 8.78 (s, 1H), 9.08 (s, 1H). MS-ESI (m/s): 568.0 (M+23). M^stfu is difficult: ^ *-ε'ι-3⁄4ώ three-9- οε mi
Figure imgf000024_0001
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Figure imgf000024_0004
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塞藝  Saiyi
^¾*滅ϋi^««is匾ώ川寸ε98 ΐζ οε --- ------ ^ 己基甲酰氯反应得到黄色固体， 产率 84%。 ^3⁄4*ϋϋi^««is匾ώ川寸ε98 ΐζ οε --- ------ ^ The hexylcarbonyl chloride reaction gave a yellow solid in a yield of 84%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 1.25(m, 3H)， 1.51 (m， 2H)， 1.72(m, 5H)， 2.46(t, J = 12.0 Hz, IH )， 3.70(s, 2H)， 3.82(s, 2H)， 4.11(s, 2H)， 4.13(s, 2H)， 8.80(s, 1H)， 9.12(s, 1H)。 MS-ESI(m/s): 471.1 (M+l)。 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 1.25 (m, 3H), 1.51 (m, 2H), 1.72 (m, 5H), 2.46 (t, J = 12.0 Hz, IH ), 3.70 (s, 2H ), 3.82(s, 2H), 4.11(s, 2H), 4.13(s, 2H), 8.80(s, 1H), 9.12(s, 1H). MS-ESI (m/s): 471.1 (M+l).
实施例 44 化合物 44: 2-(4- (2-环己基乙鶴）哌嗪小基) -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪 -4-酮的制备
Figure imgf000026_0001
Example 44 Compound 44: 2-(4-(2-cyclohexylethene)piperazinyl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one preparation
Figure imgf000026_0001
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与环 己基乙酰氯反应得到黄色固体， 产率 80%。 1H NMR: (DMSO-d6, 400ΜΗζ) δ: 0.95(m, 2H)， 1.14 (m, 1H)， 1.31(m, 2H)， 1.74(m, According to the procedure of Example 30, 2-(piperazin-1yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was reacted with cyclohexylacetyl chloride to give a yellow color. Solid, yield 80%. 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 0.95 (m, 2H), 1.14 (m, 1H), 1.31 (m, 2H), 1.74 (m,
6H ), 2.26(d, J = 8.0 Hz, 2H), 3.68(s, 2H), 3.84(s, 2H), 3.98(s, 2H), 4.09 ( s, 2H) , 8.80(s, IH), 9.11(s, 1H)。 MS-ESI(m/s): 485.1 (M+l)。 6H ), 2.26(d, J = 8.0 Hz, 2H), 3.68(s, 2H), 3.84(s, 2H), 3.98(s, 2H), 4.09 ( s, 2H) , 8.80(s, IH), 9.11 (s, 1H). MS-ESI (m/s): 485.1 (M+l).
实施例 45 化合物 45: 2-(4- (2-氯苯甲鶴）哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻 嗪 -4-酮的制备 Example 45 Compound 45: 2-(4-(2-Chlorobenzylidene)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazide-4- Preparation of ketone
^Y 人 ^Y people
k 、  k,
<  <
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与邻 氯苯甲酰氯反应得到黄色固体， 产率 73%。  2-(Piperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was reacted with o-chlorobenzoyl chloride according to the procedure of Example 30. Yellow solid, yield 73%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 3.87(s, 2H)， 3.92 (s， 2H)， 4.06(s, 4H)， 7.47(s, 2H )， 7.49(s, 1H)， 7.57(s, 1H)， 8.81(s, 1H)， 8.88(s, 1H)。 MS-ESI(m/s): 499.0 (M+l)。 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 3.87 (s, 2H), 3.92 (s, 2H), 4.06 (s, 4H), 7.47 (s, 2H), 7.49 (s, 1H), 7.57 (s , 1H), 8.81(s, 1H), 8.88(s, 1H). MS-ESI (m/s): 499.0 (M+l).
实施例 46 化合物 46: 2-(4-金刚烷甲雌哌嗪小基 )-8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮的制备
Figure imgf000026_0002
Example 46 Compound 46: Preparation of 2-(4-adamantanepiperazine small base)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000026_0002
按实施例 30的操作过程， 2- (哌嗪 -1基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮与金 刚烷酰氯反应得到黄色固体， 产率 87%。 1H NMR: (DMSO-d6, 400ΜΗζ) δ: 1.74(d, J = 8.0 Hz, 6H)， 2.01(s, 6H)， 2.09(s, 3H)， 2-(Piperazine-1 -yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one was reacted with adamantyl chloride according to the procedure of Example 30 to give a yellow solid. , yield 87%. 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 1.74 (d, J = 8.0 Hz, 6H), 2.01 (s, 6H), 2.09 (s, 3H),
8.79(s, 1H)， 9.11(s, 1H)。 MS-ESI(m/s): 545.1 (M+23)。 8.79(s, 1H), 9.11(s, 1H). MS-ESI (m/s): 545.1 (M+23).
实施例 47 化合物 47： 2-(l,5-二硫杂 -9-氮杂螺 [5.5]十一垸 -9-基) -8-硝基 -6-三氟甲基 -1,3- 苯并噻嗪 -4-酮的制备
Figure imgf000027_0001
Example 47 Compound 47: 2-(l,5-Dithia-9-azaspiro[5.5]undec-9-yl)-8-nitro-6-trifluoromethyl-1,3- Preparation of benzothiazin-4-one
Figure imgf000027_0001
按实施例 5的操作过禾 '王， 起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸， 所用的胺为 1,5-二硫杂 -9-氮杂螺 [5.5] -i ^一烷。 得到黄色固体， 产率 54%。  According to the operation of Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was 1,5-dithia-9-azaspiro[5.5 ] -i ^ alkane. A yellow solid was obtained in a yield of 54%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 2.06(m, 2H)， 2.22(s, 4H)， 2.88(m, 4H)， 4.01(s, 2H)， 4.26(s, 2H)， 8.77(s, 1H)， 9.11(s, 1H)。 MS-ESI(m/s): 486.0 (M+23)。 1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 2.06 (m, 2H), 2.22 (s, 4H), 2.88 (m, 4H), 4.01 (s, 2H), 4.26 (s, 2H), 8.77 (s , 1H), 9.11(s, 1H). MS-ESI (m/s): 486.0 (M+23).
实施例 48化合物 48： 2-(4-环戊基 -3-哌嗪酮小基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮
Figure imgf000027_0002
Example 48 Compound 48: 2-(4-Cyclopentyl-3-piperazinone)--8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one
Figure imgf000027_0002
按实施例 5的操作过程， 起始原料为 2-氯 -3硝基 -5三氟甲基苯甲酸， 所用的胺为 According to the procedure of Example 5, the starting material was 2-chloro-3nitro-5-trifluoromethylbenzoic acid, and the amine used was
1-环戊基哌嗪 -2-酮。 得到黄色固体， 产率 56%。 1-cyclopentylpiperazine-2-one. A yellow solid was obtained in a yield of 56%.
1H NMR: (DMSO-d6, 400ΜΗζ) δ: 1.51(m, 2H)， 1.65(m, 2H)， 1.76(m, 2H)， 1.93(m, 2H)， 3.47(s, 2H)， 4.29(s, 2H)， 4.50(s, 2H)， 4.97 ( m， 1H)， 8.81(s, 1H)， 9.13(s, 1H)。 MS-ESI(m/s): 465.1(M+23  1H NMR: (DMSO-d6, 400 ΜΗζ) δ: 1.51 (m, 2H), 1.65 (m, 2H), 1.76 (m, 2H), 1.93 (m, 2H), 3.47 (s, 2H), 4.29 (s , 2H), 4.50 (s, 2H), 4.97 (m, 1H), 8.81 (s, 1H), 9.13 (s, 1H). MS-ESI (m/s): 465.1 (M+23)
实施例 49 药物体外抑制结核分枝杆菌（H37Ra)实验 Example 49 Inhibition of Mycobacterium tuberculosis (H37Ra) in vitro
1、 实验方法接种物准备： 用 BBL泵将事先准备好的 5〜10个 H37Ra菌落 （来自美国 国家菌种保藏中心， ATCC 25177)和 lmL无菌盐水接种到试剂盒中。 因结核分支杆菌生 长缓慢，待其生长 2-3周待用；超声，涡旋混合得到约 108CFU/mL的结核分支杆菌混悬液， 具体试验操作浓度可稀释得到。 将混悬液稀释 200倍， 具体方法如下： 将 0.2mL含 H37Ra 的混悬液加入 40mL含有 2%甘油和 OADC营养添加剂（约 106 CFU/mL，来自美国 BD公司） 的无菌 7H9肉汤中； 将 ΙΟΟμΙ混悬液 （细胞数目约 5 Χ 104个） 接种到测试的微孔板孔中， 并加入 1 μΐ溶有特定浓度待测试化合物的 DMSO。 1. Experimental method Inoculum preparation: 5 to 10 H37Ra colonies (from the National Type Culture Collection, ATCC 25177) and 1 mL of sterile saline prepared in advance were inoculated into the kit using a BBL pump. Due to the slow growth of Mycobacterium tuberculosis, it is grown for 2-3 weeks; ultrasonic and vortex mixing to obtain a suspension of Mycobacterium tuberculosis of about 10 8 CFU/mL. The specific experimental concentration can be diluted. The suspension was diluted 200-fold by the following method: 0.2 mL of H37Ra-containing suspension was added to 40 mL of sterile 7H9 broth containing 2% glycerol and OADC nutritional supplement (about 10 6 CFU/mL from BD, USA) The ΙΟΟμΙ suspension (approximately 5 Χ 10 4 cells) was inoculated into the wells of the test wells and 1 μM of DMSO dissolved in a specific concentration of the compound to be tested was added.
稀释化合物、 接种、 MIC测试：  Diluted compounds, inoculation, MIC test:
选择异烟肼和利福平作为阳性对照， 待测试化合物以及阳性对照用 DMSO配制成 10mM溶液，逐次稀释成 100μΜ、 50μΜ、 25μΜ、 12.5μΜ、 6.3μΜ、 3.1μΜ、 1.6μΜ、 0.8μΜ、 0.4μΜ、 0.2μΜ、 0.1μΜ、 0·05μΜ、 0·025μΜ、 0·0125μΜ、 0·008μΜ、 0·004μΜ、 0.002μΜ 待用。  Isoniazid and rifampicin were selected as positive controls, and the test compound and positive control were formulated into 10 mM solution in DMSO, and successively diluted to 100 μΜ, 50 μΜ, 25 μΜ, 12.5 μΜ, 6.3 μΜ, 3.1 μΜ, 1.6 μΜ, 0.8 μΜ, 0.4. μΜ, 0.2μΜ, 0.1μΜ, 0·05μΜ, 0·025μΜ, 0·0125μΜ, 0·008μΜ, 0·004μΜ, 0.002μΜ for use.
将稀释好的不同浓度的化合物 DMSO溶液 1μ L加入 96孔板中， 随后加入 ΙΟΟμί稀释 后的结核杆菌悬液， 并用排枪手动混合均匀。  1 μL of the diluted various concentrations of the compound DMSO solution was added to the 96-well plate, followed by the ΙΟΟμί diluted M. tuberculosis suspension, and mixed by hand with a lance.
接种好的 96孔板在 37°C， 5%C02孵化箱中孵化 9天。 The inoculated 96-well plates were incubated for 9 days at 37 ° C in a 5% CO 2 incubator.
9天后， 每个孔中加入 30μΙ 01%的 7-羟 -3H-吩噁嗪 -3-酮 -10-氧， 在 492nm下测其背 景荧光， 记录数据， 并将 96孔板放回孵化箱中孵化 24小时。 24小时后再次在 492nm下测定每孔的荧光， 记录数据。 After 9 days, 30 μΙ of 01% 7-hydroxy-3H-phenoxazin-3-one-10-oxo was added to each well, the background fluorescence was measured at 492 nm, data was recorded, and the 96-well plate was returned to the incubator. Incubate for 24 hours. The fluorescence of each well was measured again at 492 nm after 24 hours, and data was recorded.
2、 实验结果 2, the experimental results
化合物 1~47对结核分枝杆菌 （H37Ra) 的最小抑菌浓度 ΜΚ[μ Μ]见表 1 :  The minimum inhibitory concentration of compounds 1~47 against Mycobacterium tuberculosis (H37Ra) ΜΚ[μ Μ] is shown in Table 1:
表 1  Table 1
Figure imgf000028_0001
Figure imgf000028_0001
结果显示： 大多数化合物均显示出了明显的抑菌效果， 其中化合物 26、 27、 28、 29、 32、 33、 34、 35、 36、 37、 40、 43、 44、 45、 47 的抑菌效果远超过 （10倍以上） 了阳 性对照异烟肼和利福平。  The results showed that most of the compounds showed significant bacteriostatic effects, in which the compounds 26, 27, 28, 29, 32, 33, 34, 35, 36, 37, 40, 43, 44, 45, 47 were bacteriostatic. The effect was far more than (more than 10 times) the positive controls of isoniazid and rifampicin.
实施例 50 药物体外抑制结核分枝杆菌 (H37Rv)实验 Example 50 Inhibition of Mycobacterium tuberculosis (H37Rv) in vitro
1、 材料  1, material
1 ) 菌株： 结核分枝杆菌标准株 H37Rv来自美国国家菌种保藏中心 （ATCC 27294) 。 1) Strain: Mycobacterium tuberculosis standard strain H37Rv is from the National Collection of National Cultures (ATCC 27294).
2) 液体培养基： Middlebrook 7H9培养基干粉和营养添加剂 （OADC) 均购自美国 BD 公司。 2) Liquid medium: Middlebrook 7H9 medium dry powder and nutritional supplements (OADC) are purchased from the United States BD the company.
3) 受试药物： 化合物 9、 15、 17、 19、 21、 24、 26、 27、 28、 29和 47。  3) Test drugs: Compounds 9, 15, 17, 19, 21, 24, 26, 27, 28, 29 and 47.
2、 实验方法  2, the experimental method
1) 受试菌株的制备  1) Preparation of test strains
将受试菌株转入液体培养基， 经活化后， 于 37°C培养 2周， 吸取培养菌液少许， 置 于 4mL液体培养基中， 加入直径 2— 3mm无菌玻璃珠 10— 20粒， 振荡 20— 30s， 静止 沉淀 10— 20min， 吸取菌悬液上清， 用液体培养基调整比浊至 1 个麦氏单位， 相当于 lxl07CFU/mL备用。 The test strain was transferred to a liquid medium, and after activation, cultured at 37 ° C for 2 weeks, a small amount of the culture liquid was aspirated, placed in 4 mL of liquid medium, and 10-20 pieces of sterile glass beads having a diameter of 2 - 3 mm were added. Oscillate for 20-30s, static precipitation for 10-20min, absorb the supernatant of the bacterial suspension, adjust the turbidity to 1 Meth's unit with liquid medium, which is equivalent to lxl0 7 CFU/mL.
2) 受试药物的准备  2) Preparation of test drugs
药物和阳性对照异烟肼用适量的 DMSO溶解至 lmg/mL， 0.22μηι滤器过滤。 受试 药物终浓度设置如下： 0.000125 g/mL、 0.00025 g/mL、 0.00049 g/mL、 0.00098 g/mL、 0.00195 g/mL、 0.0039 g/mL、 0.0078 g/mL、 0.0156 g/mL、 0.03125 g/mL、 0.0625 g/mL、 0.125 g/mL、 0.25 g/mL、 0.5 g/mL、 l g/mL、 2 g/mL、 4 g/mL、 8 g/mL、 16 g/mL、 32 g/mL和 64 g/mL， 共 20个浓度梯度。  The drug and the positive control isoniazid were dissolved in an appropriate amount of DMSO to a lmg/mL, 0.22 μηι filter. The final concentration of the test drug was set as follows: 0.000125 g/mL, 0.00025 g/mL, 0.00049 g/mL, 0.00098 g/mL, 0.00195 g/mL, 0.0039 g/mL, 0.0078 g/mL, 0.0156 g/mL, 0.03125 g /mL, 0.0625 g/mL, 0.125 g/mL, 0.25 g/mL, 0.5 g/mL, lg/mL, 2 g/mL, 4 g/mL, 8 g/mL, 16 g/mL, 32 g/ There are 20 concentration gradients in mL and 64 g/mL.
3) 操作步骤 3) Operation steps
检测时， 各取上述药物溶液 10(VL， 加到 96孔微孔板中， 再加入 104CFU/mL (由 107CFU/mL稀释获得） 浓度的菌液 10(VL， 使药物浓度达到 2) 设置的终浓度。 37°C培 养， 空白对照组不加任何药物， 同一药物稀释度设三组平行对照。 观察各药对结核分枝 杆菌的最低抑菌浓度。 At the time of detection, each of the above drug solution 10 (VL was added to a 96-well microplate, and 10 4 CFU/mL (diluted by 10 7 CFU/mL) was added to the bacterial solution 10 (VL) to achieve a drug concentration. 2) The final concentration was set. At 37 ° C, the blank control group was given no drugs, and the same drug dilution was set up with three sets of parallel controls. The minimum inhibitory concentration of each drug against Mycobacterium tuberculosis was observed.
3、 实验结果： 化合物 9、 15、 17、 19、 21、 24、 26、 27、 28、 29和 47对结核分枝杆菌 (H37Rv) 的最小抑菌浓度 MIC^g/mL]见表 2 3. Experimental results: The minimum inhibitory concentration of compounds 9, 15, 17, 19, 21, 24, 26, 27, 28, 29 and 47 against Mycobacterium tuberculosis (H37Rv) MIC^g/mL] is shown in Table 2.
表 2  Table 2
Figure imgf000029_0001
Figure imgf000029_0001
结果显示： 所测化合物均显示出明显的抑菌效果。 其中化合物 27 的抑菌效果是异 烟肼的 230倍， 化合物 28、 47对结核杆菌标准株活性更是达到了皮摩尔水平， 其活性 是异烟肼的一万倍 （以 μ Μ计算） 。  The results showed that the tested compounds showed significant bacteriostatic effects. Among them, compound 27 has a bacteriostatic effect 230 times that of isoniazid, and compounds 28 and 47 have a picomolar level of activity against Mycobacterium tuberculosis standard strain, and its activity is 10,000 times that of isoniazid (calculated as μ Μ).
而麻风病是由麻风分枝杆菌引起的一种慢性接触性传染病。麻风分枝杆菌同结核分 枝杆菌同属分枝杆菌属， 二者在生物特性上具有很多共性， 常见的抗结核药物如利福平 等也能用于麻风病的治疗。 鉴于此， 本领域技术人员容易推断出本发明化合物具有开发 为抗麻风病药物的潜力。 Leprosy is a chronic contagious disease caused by M. leprae. Mycobacterium leprae and Mycobacterium tuberculosis belong to the genus Mycobacterium, and they have many commonalities in biological characteristics. Common anti-tuberculosis drugs such as rifampic can also be used for the treatment of leprosy. In view of this, those skilled in the art can easily infer that the compound of the present invention has been developed. The potential for anti-leprosy drugs.
实施例 50 细胞毒性实验 Example 50 Cytotoxicity experiment
1、 实验方法 （MTT法）  1. Experimental method (MTT method)
Vera细胞是非洲绿猴肾细胞（来自生物治疗国家重点实验室）， 因此可用 Vera细胞 进行细胞毒性试验测试。 用完全培养液调整细胞浓度为 3xl04/mL， 接种于 96孔板， 每 孔 200uL，培养过夜，次日，分别用不同剂量的化合物 14~19、化合物 21、化合物 23~25、 化合物 27~29和化合物 47 (终浓度分别为 500、 400、 300、 200、 100、 50、 25、 12.5、 6.25、 3.125、 1.5625、 0.78125μΜ) 处理细胞， 同时设等体积的空白培养基对照组， 溶 剂对照组， DMSO浓度为 0.5% ( 0.5%的 DMSO对细胞增殖无影响）。 每个组设 4个复 孔， 37 °C , 5%C02培养。 培养 48小时后， 每孔加入 5mg/mL MTT试剂 20μί， 继续培 养 2h， 弃上清， 再加 DMS015(^L， 振荡混匀 15min， 用酶标仪 （OD=570nm) 测定吸 光度 （A) 值 （A值与活细胞数成正比）， 取其平均值。 细胞增殖抑制率 （％) = (溶剂 对照组 A570-实验组 A570) /溶剂对照组 A570xl00%。 以下各化合物对细胞增殖抑制作 用， 均采用细胞增殖抑制率 （％) 表示。 Vera cells are African green monkey kidney cells (from the National Key Laboratory of Biotherapy), so Vera cells can be used for cytotoxicity testing. Adjust the cell concentration to 3×10 4 /mL with complete medium, inoculate 96-well plates, 200 uL per well, and culture overnight. The next day, different doses of compound 14-19, compound 21, compound 23-25, compound 27-29 And compound 47 (final concentrations of 500, 400, 300, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625, 0.78125 μΜ) were treated with cells, and an equal volume of blank medium control group, solvent control group The concentration of DMSO was 0.5% (0.5% DMSO had no effect on cell proliferation). Four replicate wells were set in each group, cultured at 37 °C and 5% CO 2 . After 48 hours of culture, add 5 mg/mL MTT reagent 20 μί per well, continue to culture for 2 h, discard the supernatant, add DMS015 (^L, shake and mix for 15 min, and measure the absorbance (A) value with a microplate reader (OD=570nm). (A value is proportional to the number of viable cells), and the average value is taken. Cell proliferation inhibition rate (%) = (solvent control group A570 - experimental group A570) / solvent control group A570x100%. The following compounds inhibit cell proliferation, Both were expressed by cell proliferation inhibition rate (%).
2、 实验结果 2, the experimental results
化合物 14~19、 化合物 21、 化合物 23~25、 化合物 27~29和化合物 47对 Vera细胞 的半抑制浓度 IC50 见表 -3。  The semi-inhibitory concentration of compound 14-19, compound 21, compound 23-25, compound 27-29 and compound 47 on Vera cells is shown in Table -3.
表 3  table 3
Figure imgf000030_0001
Figure imgf000030_0001
结果显示： 所测化合物未体现出明显细胞毒性。  The results showed that the tested compounds did not show significant cytotoxicity.

Claims

权利要求书 claims
1、 苯并噻嗪 -4-酮衍生物， 其结构如式 I所示: 1. Benzothiazin-4-one derivatives, whose structure is shown in Formula I:
Figure imgf000031_0001
Figure imgf000031_0001
I I
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Among them, R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri 独立为 -H、 卤素、 〜¾烷基、 〜¾烷氧基、 卤素取代的 〜¾ 烷基、 ^素取代的 〜¾烷氧基、 〜¾烷基取代氨基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 ^〜¾烷基取代酰胺基、 〜¾烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri is independently -H, halogen, ~¾ alkyl, ~¾ alkoxy, halogen-substituted ~¾ alkyl, ^ alkyl-substituted ~¾ alkoxy, ~¾ alkyl-substituted amino, ~¾ alkyl-substituted carbonyl , ~¾ alkyl substituted aminoacyl group, ~¾ alkyl substituted amide group, ~¾ alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R6 R 6
'R，
Figure imgf000031_0002
 'R,
Figure imgf000031_0002
R6、 R7独立的为 -H、带有取代基的 〜。8烷基、带有取代基的 C3〜C8环烷 基、 带有取代基的卤代 〜C8烷基、 带有取代基的苯基、 带有取代基的苯甲酰 基、 带有取代基的吡啶基， 所述的取代基为 -H、 〜¾烷基、 〜¾烷氧基、 〜¾烷基取代氨磺酰基、卤素取代的 ^〜¾烷基、 ^〜¾烷基取代羰基、 d~ C8烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3 或苯基； R 6 and R 7 are independently -H and ~ with a substituent. 8 alkyl group, C 3 ~ C 8 cycloalkyl group with substituent, halogenated ~ C 8 alkyl group with substituent, phenyl group with substituent, benzoyl group with substituent, with The substituent is pyridyl, the substituent is -H, -H alkyl, -H alkoxy, -H alkyl substituted sulfamoyl, halogen substituted H - H alkyl, H - H alkyl substituted Carbonyl, d~ C 8 alkyl substituted aminoacyl, ~ alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R8〜R16独立的为 -H、 C Cs烷基、 C^Cs烷氧基、 C Cs烷基取代氨磺 酰基、 ^素取代的 〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 〜¾烷基取代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 ~ R 16 are independently -H, C Cs alkyl, C Cs alkoxy, C Cs alkyl substituted sulfamoyl, C alkyl substituted ~H alkyl, ~ C alkyl substituted carbonyl, ~ H Alkyl substituted aminoacyl, ~¾ alkyl substituted amide, halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜 烷基、 〜 ¾烷氧基、 ¾〜¾环烷基、 ^〜¾烷基取代氨磺酰基、 芳基取代氨磺酰基、 R27 取代的磺酰基、 R27取代的酰基、卤素取代的 〜 烷基、 〜 ^烷基取代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述取代苯基的取代基为含有1^、 0或 S杂原子 的饱和或不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~ alkyl, ~ ¾ alkoxy, ¾ ~ ¾ cycloalkyl, ^ ~ ¾ alkyl substituted amino Sulfonyl group, aryl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, halogen substituted ~ alkyl group, ~ C alkyl substituted carbonyl group, ~ C 8 alkyl substituted aminoacyl group, ~ alkyl substituted Amide group, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, -CF 3 or a substituted phenyl group, the substituent of the substituted phenyl group is a saturated or substituted phenyl group containing R, O or S heteroatoms. Unsaturated heterocycle;
R27为 〜C8烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 〜 C8烷基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C8烷基； R 27 is ~C 8 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted ~ C 8 alkyl or adamantyl; the substitution of the substituted phenyl The base is halogen, -N0 2 or ~C 8 alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。 L is nitrogen, oxygen or sulfur; u=0~1, v=0~1, w=0~1, x=0~1, y=0~1, z=0~1.
2、 根据权利要求 1所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 2. The benzothiazin-4-one derivative according to claim 1, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R3独立为 -H、 卤素、 〜C8烷基、 〜C8烷氧基、 卤素取代的 〜C8 烷基、 ^素取代的 〜^烷氧基、 〜^烷基取代氨基、 〜^烷基取代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 〜C8烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, halogen, ~C 8 alkyl, ~C 8 alkoxy, halogen-substituted ~C 8 alkyl, halogen-substituted ~C alkoxy, ~C alkyl-substituted amino , ~ ^Alkyl substituted carbonyl group, ~C 8 alkyl substituted aminoacyl group, ~ alkyl substituted amide group, ~C 8 alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R5为 H7 、
Figure imgf000032_0001
； R 5 is H 7 ,
Figure imgf000032_0001
;
R6、 R7独立的为 -H、带有取代基的 ^〜¾烷基、带有取代基的 C3〜C8环烷 基、 带有取代基的卤代 〜¾烷基、 带有取代基的苯基、 带有取代基的苯甲酰 基、 带有取代基的吡啶基， 所述的取代基为 -H、 〜¾烷基、 〜¾烷氧基、 〜¾烷基取代氨磺酰基、卤素取代的 ^〜¾烷基、 ^〜¾烷基取代羰基、 d~ C8烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3 或苯基； R 6 and R 7 are independently -H, a substituted ^~¾ alkyl group, a substituted C 3 ~ C 8 cycloalkyl group, a substituted halogenated ~ ¾ alkyl group, a Phenyl group with substituent, benzoyl group with substituent, pyridyl group with substituent, the substituent is -H, ~¾ alkyl, ~¾ alkoxy group, ~¾ alkyl substituted sulfamate Acyl group, halogen substituted ^~¾ alkyl group, ^~¾ alkyl substituted carbonyl group, d~C 8 alkyl substituted aminoacyl group, ~ alkyl substituted amide group, halogen, -N0 2 , -OH, -OCF 3 , - CF 3 or phenyl;
R8〜R16独立的为 -H、 C Cs烷基、 C^Cs烷氧基、 C Cs烷基取代氨磺 酰基、 ^素取代的 〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 〜C8烷基取代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 ~ R 16 are independently -H, C Cs alkyl, C Cs alkoxy, C Cs alkyl substituted sulfamoyl, C alkyl substituted ~H alkyl, ~ C alkyl substituted carbonyl, ~ H Alkyl substituted aminoacyl group, ~C 8 alkyl substituted amide group, halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C8烷基、 〜 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~C 8 alkyl, ~
。8烷氧基、 C3〜C8环烷基、 〜C8烷基取代氨磺酰基、 芳基取代氨磺酰基、 卤 素取代的 〜 烷基、 〜 ^烷基取代羰基、 〜 烷基取代氨酰基、 〜C8 烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环； . 8 alkoxy, C 3 ~ C 8 cycloalkyl, ~ C 8 alkyl substituted sulfamoyl, aryl substituted sulfamoyl, halogen substituted ~ alkyl, ~ ^ alkyl substituted carbonyl, ~ alkyl substituted amino Acyl group, ~C 8 alkyl substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or phenyl group with substituent, the substituent is containing N, 0 or S hetero Atomically saturated or unsaturated heterocycles;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。 L is nitrogen, oxygen or sulfur; u=0~1, v=0~1, w=0~1, x=0~1, y=0~1, z=0~1.
3、 根据权利要求 2所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 3. The benzothiazin-4-one derivative according to claim 2, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 ^〜¾烷氧基、 卤素取代 的^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, -F, -Cl, - Br, ^~¾ alkyl, ^~¾ alkoxy, halogen-substituted ^~¾ alkyl, halogen-substituted ^~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
R5为 "
Figure imgf000032_0002
R 5 is "
Figure imgf000032_0002
R6、 R7独立的为 -H、 〜¾烷基、 带有取代基的 C3〜C8环烷基、 卤素取代 的 〜C烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代基的吡 啶基， 所述的取代基为 -H、 〜¾烷基、 卤素取代的 ^〜¾烷基、 -F、 -Cl、 -Br、 -CF3、 -OCF3、 -N02、 -NH2或 -CN; R 6 and R 7 are independently -H, ~¾ alkyl, C 3 ~ C 8 cycloalkyl with substituent, halogen substituted ~C alkyl, phenyl with substituent, substituent benzoyl, pyridyl with substituents, the substituents are -H, -Halkyl, halogen-substituted -Halkyl, -F, -Cl, -Br, -CF 3 , - OCF 3 , -N0 2 , -NH 2 or -CN;
R8〜R16独立的为 -H、 -F、 -Cl、 -Br、 -COOH、 〜C8烷基或卤素取代的 〜 焼基 ^ R 8 ~ R 16 are independently -H, -F, -Cl, -Br, -COOH, ~C 8 alkyl or halogen substituted ~ alkyl group ^
L为氮、 氧或 ¾£; u=0〜l， ν=0〜1， w=0〜l， χ=0〜1， y=0〜l， ζ=0〜1 ; 当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C8烷基、 〜 。8烷氧基、 C3〜C8环烷基、 〜。8烷基取代氨磺酰基、卤素取代的 〜。8烷基、 〜^烷基取代羰基、 〜 烷基取代氨酰基、 〜C8烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环。 L is nitrogen, oxygen or nitrogen; u=0~l, ν=0~1, w=0~l, χ=0~1, y=0~l, ζ=0~1; When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~C 8 alkyl, ~. 8 alkoxy, C 3 ~ C 8 cycloalkyl, ~. 8 Alkyl substituted sulfamoyl, halogen substituted ~. 8 alkyl, ~^ alkyl substituted carbonyl, ~ alkyl substituted aminoacyl, ~ C 8 alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, -CF 3 or substituted Phenyl, the substituent is a saturated or unsaturated heterocyclic ring containing N, 0 or S heteroatoms.
4、 根据权利要求 3所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 4. The benzothiazin-4-one derivative according to claim 3, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜 烷基、 〜¾烷氧基、 卤素取 代的 ^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -N -CF3 ; R R 3 is independently -H, -F, -Cl, -Br, -alkyl, -alkoxy, halogen-substituted -alkyl, halogen-substituted -alkoxy, -N0 2 , -N -CF 3;
R5 n7 Λ
Figure imgf000033_0001
R 5 n 7 Λ
Figure imgf000033_0001
R6、 R7独立的为 -H、 〜C8烷基、 卤素取代的 〜C8烷基、 带有取代基的 C3〜C8环烷基、 带有取代基的苯基、 带有取代基的苯甲酰基、 带有取代基的吡 啶基， 所述的取代基为15、 〜。8烷基、 卤素取代的 〜。8烷基、 -F、 -Cl、 -Br、 -CF3、 -OCF3、 -N02、 -NH2或 -CN; R 6 and R 7 are independently -H, ~C 8 alkyl, halogen-substituted ~C 8 alkyl, substituted C 3 ~ C 8 cycloalkyl, substituted phenyl, with The benzoyl group with substituent and the pyridinyl group with substituent, the substituent is 15, ~. 8 alkyl, halogen substituted ~. 8Alkyl , -F, -Cl, -Br, -CF 3 , -OCF 3 , -N0 2 , -NH 2 or -CN;
R8〜R16独立的为 -H、 -COOH、 〜C8烷基或卤素取代的 〜C8烷基； R 8 ~ R 16 are independently -H, -COOH, ~C 8 alkyl or halogen-substituted ~C 8 alkyl;
M为氧， R17为 -H; M为氮， R17为- H、 〜C8烷基、 〜 ¾烷氧基、 C3〜 C8环烷基、 ^〜¾烷基取代氨磺酰基、 芳基取代氨磺酰基、 ^素取代的 ^〜¾ 烷基、 〜¾烷基取代羰基、 ^〜¾烷基取代氨酰基、 〜¾烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为 含有 N、 0或 S杂原子的饱和或不饱和的杂环； M is oxygen, R 17 is -H ; M is nitrogen, R 17 is -H, ~C 8 alkyl, ~ ¾ alkoxy, C 3 ~ C 8 cycloalkyl, ^ ~ ¾ alkyl substituted sulfamoyl, aromatic Alkyl-substituted sulfamoyl, alkyl-substituted alkyl, alkyl-substituted carbonyl, alkyl-substituted aminoacyl, alkyl-substituted amido, halogen, tert-butyloxycarbonyl, -OCF 3. -OH, -CF 3 or a phenyl group with a substituent, the substituent being a saturated or unsaturated heterocyclic ring containing N, 0 or S heteroatoms;
L为硫或氧； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。 L is sulfur or oxygen; u=0~l, v=0~l, w=0~l, x=0~l, y=0~l, z=0~l.
5、 根据权利要求 2所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 5. The benzothiazin-4-one derivative according to claim 2, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R3独立的 -H、 -F、 -Cl、 -Br 〜¾烷基、 - ;
Figure imgf000033_0002
 R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, -F, -Cl, -Br ~¾Alkyl, -;
Figure imgf000033_0002
R6、 R7独立的为 -H、 〜¾烷基、 带有取代基的苯基、 带有取代基的 C3〜 ¾环烷基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -H、 〜¾烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R 6 and R 7 are independently -H, ~¾ alkyl, substituted phenyl, substituted C 3 ~ ¾ cycloalkyl, substituted benzoyl, or substituted pyridyl group, the substituent is -H, -H alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜Ri6为 -H、 -COOH 或甲基； M为氧， R17为 -H; M为氮， R17为叔丁基 R 8 ~ Ri6 are -H, -COOH or methyl; M is oxygen, R 17 is -H; M is nitrogen, R 17 is tert-butyl
L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。 L is sulfur or oxygen; u=v=0, z=0~l, x=0~l, w= y=l.
6、 根据权利要求 5所述的苯并噻嗪 -4-酮衍生物， 其特征在于： R4独立的为卤素、 -N02. NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3 ; R3独立的为 -H、 -F、 -CI -Br、 〜C4烷基、 -CF3或 -N02; 6. The benzothiazin-4-one derivative according to claim 5, characterized in that: R4 is independently halogen, -N0 2 . NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; R 3 is independently -H, -F, -CI -Br, ~C 4 alkane Base, -CF 3 or -N0 2 ;
R5
Figure imgf000034_0001
R 5
Figure imgf000034_0001
R6、 R7独立的为 -H、 〜C4烷基、 带有取代基的苯基、 带有取代基的 C3〜 C8环烷基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -H、 〜C4烷基、 -N02、 -F、 -Cl、 -Br或 -CF3 ; R 6 and R 7 are independently -H, ~C 4 alkyl, substituted phenyl, substituted C 3 ~ C 8 cycloalkyl, substituted benzoyl, or substituted A pyridyl group with a substituent, the substituent is -H, ~C 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜Ri6为 -H、 -COOH 或甲基； M为氧， R17为 -H; M为氮， R17为叔丁基 R 8 ~ Ri6 are -H, -COOH or methyl; M is oxygen, R 17 is -H; M is nitrogen, R 17 is tert-butyl
L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。 L is sulfur or oxygen; u=v=0, z=0~l, x=0~l, w= y=l.
7、 根据权利要求 1所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 7. The benzothiazin-4-one derivative according to claim 1, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3 ; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C8烷基、 〜C8烷氧基、 卤素取 代的 ^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; R R 3 is independently -H, -F, -Cl, -Br, ~C 8 alkyl, ~C 8 alkoxy, halogen-substituted ^~¾ alkyl, halogen-substituted ^~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
R8 R10 R12 s R16 ¾ ？ R 8 R 10 R 12 s R 16 ¾ ?
R5为 7、 、 、
Figure imgf000034_0002
R5 is 7, , ,
Figure imgf000034_0002
R6、 R7独立的为 -H、 带有取代基的 〜。8烷基、 带有取代基的 C3〜C8环 烷基、 带有取代基的卤代 〜C8烷基、 带有取代基的苯基、 带有取代基的苯甲 酰基、 带有取代基的吡啶基， 所述的取代基为 -H、 〜 烷基、 〜^烷氧基、 〜C8烷基取代氨磺酰基、 ^素取代的 〜。8烷基、 〜。8烷基取代羰基、 〜 C8烷基取代氨酰基、 〜C8烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3 或苯基； R 6 and R 7 are independently -H and ~ with a substituent. 8 alkyl group, C 3 ~ C 8 cycloalkyl group with substituent, halogenated ~ C 8 alkyl group with substituent, phenyl group with substituent, benzoyl group with substituent, with The substituent is pyridyl, and the substituent is -H, ~alkyl, ~alkoxy, ~ C8 alkyl substituted sulfamoyl, or ~C substituted. 8 alkyl, ~. 8 alkyl substituted carbonyl group, ~C 8 alkyl substituted aminoacyl group, ~C 8 alkyl substituted amide group, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R8〜R16独立的为 -H、 C Cs烷基、 C^Cs烷氧基、 C Cs烷基取代氨磺 酰基、 ^素取代的 〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 〜¾烷基取代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 ~ R 16 are independently -H, C Cs alkyl, C Cs alkoxy, C Cs alkyl substituted sulfamoyl, C alkyl substituted ~H alkyl, ~ C alkyl substituted carbonyl, ~ H Alkyl substituted aminoacyl, ~¾ alkyl substituted amide, halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜 烷基、 〜 ¾烷氧基、 ¾〜¾环烷基、 ^〜¾烷基取代氨磺酰基、 芳基取代氨磺酰基、 R27 取代的磺酰基、 R27取代的酰基、卤素取代的 ^〜 烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 ^〜¾烷基取代酰胺基、 卤素、叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或 不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~ alkyl, ~ ¾ alkoxy, ¾ ~ ¾ cycloalkyl, ^ ~ ¾ alkyl substituted amino Sulfonyl group, aryl substituted sulfamoyl group, R 27 substituted sulfonyl group, R 27 substituted acyl group, halogen substituted alkyl group, alkyl substituted carbonyl group, alkyl substituted aminoacyl group, alkyl group Substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or phenyl group with substituent, the substituent is saturated or unsaturated containing N, 0 or S heteroatom of heterocycle;
R27为 〜C8烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜¾烷基； R 27 is ~C 8 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted ~ C 4 alkyl or adamantyl; the substitution of the substituted phenyl The base is halogen, O or ~¾ alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。 L is nitrogen, oxygen or sulfur; u=0~1, v=0~1, w=0~1, x=0~1, y=0~1, z=0~1.
8、 根据权利要求 7所述的苯并噻嗪 -4-酮衍生物， 其特征在于： R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; 8. The benzothiazin-4-one derivative according to claim 7, characterized in that: R4 is independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 〜C4烷氧基、 卤素取 C4烷基、 卤素取代的 〜C 、 -N02、 -NH2、 -CN或 -CF3 ; R 3 is independently -H, -F, -Cl, -Br, ~C 4 alkyl, ~C 4 alkoxy, halogen is C 4 alkyl, halogen substituted ~C, -N0 2 , -NH 2 , -CN or -CF 3 ;
R5为 7、 RG R" KL 3 R15 、
Figure imgf000035_0001
R9 R10 或 9 R,, R ； R6、 R7独立的为 -H、 带有取代基的 ^〜。4烷基、 带有取代基的 C3〜C8环 烷基、 带有取代基的卤代 〜 烷基、 带有取代基的苯基、 带有取代基的苯甲 酰基、 带有取代基的吡啶基， 所述的取代基为 -Η、 ^〜 烷基、 〜 烷氧基、 〜。4烷基取代氨磺酰基、卤素取代的 ^〜。4烷基、 ^〜。4烷基取代羰基、 Ci〜 C4烷基取代氨酰基、 〜C4烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3 或苯基； R5 is 7, RG R " KL 3 R 15 ,
Figure imgf000035_0001
R 9 R 10 or 9 R,, R; R 6 and R 7 are independently -H, ^~ with substituents. 4 alkyl group, C 3 ~ C 8 cycloalkyl group with substituent, halo~alkyl group with substituent, phenyl group with substituent, benzoyl group with substituent, substituent Pyridyl, the substituents are -H, ^~alkyl, ~alkoxy, ~. 4Alkyl substituted sulfamoyl, halogen substituted ^~. 4 alkyl, ^~. 4 alkyl substituted carbonyl, Ci~C 4 alkyl substituted aminoacyl, ~C 4 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R8〜R16独立的为 -H、 〜C4烷基、 〜C4烷氧基、 〜C4烷基取代氨磺 酰基、 卤素取代的 〜C4烷基、 〜C4烷基取代羰基、 〜C4烷基取代氨酰基、 〜C4烷基取代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 8 ~ R 16 are independently -H, ~C 4 alkyl, ~C 4 alkoxy, ~C 4 alkyl substituted sulfamoyl, halogen substituted ~C 4 alkyl, ~C 4 alkyl substituted carbonyl , ~C 4 alkyl substituted aminoacyl group, ~C 4 alkyl substituted amide group, halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C4烷基、 〜 C4烷氧基、 C3〜C8环烷基、 〜 烷基取代氨磺酰基、 芳基取代氨磺酰基、 R27 取代的磺酰基、 R27取代的酰基、卤素取代的 〜C4烷基、 〜C4烷基取代羰基、 〜C4烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或 不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~C 4 alkyl, ~C 4 alkoxy, C 3 ~C 8 cycloalkyl, ~ alkyl Alkyl-substituted sulfamoyl, aryl-substituted sulfamoyl, R 27- substituted sulfonyl, R 27 -substituted acyl, halogen-substituted ~C 4 alkyl, ~C 4 alkyl-substituted carbonyl, ~C 4 alkyl-substituted amino Acyl group, ~alkyl substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or phenyl group with substituent, the substituent is containing N, 0 or S heteroatom Saturated or unsaturated heterocycle;
R27为 〜。4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 Ci〜 R 27 is ~. 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted Ci~
C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜 烷基；C 4 alkyl or adamantyl; the substituent of the substituted phenyl is halogen, C 2 or ~ alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。 L is nitrogen, oxygen or sulfur; u=0~1, v=0~1, w=0~1, x=0~1, y=0~1, z=0~1.
9、 根据权利要求 7所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 9. The benzothiazin-4-one derivative according to claim 7, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜。4烷基、 -CF3或 -N02; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri R 3 is independently -H, -F, -Cl, - Br, ^~. 4alkyl , -CF 3 or -N0 2 ;
D R5 ¾ R7、
Figure imgf000035_0002
；DR 5 ¾ R 7.
Figure imgf000035_0002
;
R6、 R7独立的为 -H、 带有取代基的 〜C4烷基、 带有取代基的 C3〜C8环 烷基、 带有取代基的卤代 〜C4烷基、 带有取代基的苯基、 带有取代基的苯甲 酰基、 带有取代基的吡啶基， 所述的取代基为 -Η、 ^〜 烷基、 〜 烷氧基、 〜。4烷基取代氨磺酰基、卤素取代的 ^〜。4烷基、 ^〜。4烷基取代羰基、 ^〜 C4烷基取代氨酰基、 〜C4烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3 或苯基； R8〜R16独立的为 -H、 〜C4烷基、 〜C4烷氧基、 〜C4烷基取代氨磺 酰基、 卤素取代的 〜C4烷基、 〜C4烷基取代羰基、 〜C4烷基取代氨酰基、 〜C4烷基取代酰胺基、 卤素、 -OCF3、 -OH、 -CF3、 -COOH或苯基； R 6 and R 7 are independently -H, a substituted ~C 4 alkyl group, a substituted C 3 ~ C 8 cycloalkyl group, a substituted halogenated ~ C 4 alkyl group, A phenyl group with a substituent, a benzoyl group with a substituent, and a pyridyl group with a substituent, and the substituents are -H, ^~alkyl, ~alkoxy, ~. 4Alkyl substituted sulfamoyl, halogen substituted ^~. 4 alkyl, ^~. 4 alkyl substituted carbonyl, ^~C 4 alkyl substituted aminoacyl, ~C 4 alkyl substituted amide, halogen, -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl; R 8 ~ R 16 are independently -H, ~C 4 alkyl, ~C 4 alkoxy, ~C 4 alkyl substituted sulfamoyl, halogen substituted ~C 4 alkyl, ~C 4 alkyl substituted carbonyl , ~C 4 alkyl substituted aminoacyl group, ~C 4 alkyl substituted amide group, halogen, -OCF 3 , -OH, -CF 3 , -COOH or phenyl;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C4烷基、 〜 C4烷氧基、 C3〜C8环烷基、 〜 烷基取代氨磺酰基、 芳基取代氨磺酰基、 R27 取代的磺酰基、 R27取代的酰基、卤素取代的 ^〜 烷基、 〜 烷基取代羰基、 〜 烷基取代氨酰基、 ^〜 烷基取代酰胺基、 卤素、叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或 不饱和的杂环； When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~C 4 alkyl, ~C 4 alkoxy, C 3 ~C 8 cycloalkyl, ~ alkyl Alkyl-substituted sulfamoyl, aryl-substituted sulfamoyl, R 27- substituted sulfonyl, R 27- substituted acyl, halogen-substituted ^~ alkyl, ~ alkyl-substituted carbonyl, ~ alkyl-substituted aminoacyl, ^~ alkyl Substituted amide group, halogen, tert-butyloxycarbonyl group, -OCF 3 , -OH, -CF 3 or phenyl group with substituent, the substituent is saturated or unsaturated containing N, 0 or S heteroatom of heterocycle;
R27为 〜。4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 Ci〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜 烷基； R 27 is ~. 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted Ci ~ C 4 alkyl or adamantyl; the substituent of the substituted phenyl is halogen, 0 2 or ~ alkyl;
L为氮、 氧或硫； u=0〜l， v=0〜l， w=0〜l， x=0〜l， y=0〜l， z=0〜l。 L is nitrogen, oxygen or sulfur; u=0~1, v=0~1, w=0~1, x=0~1, y=0~1, z=0~1.
10、 根据权利要求 9所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 10. The benzothiazin-4-one derivative according to claim 9, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, -Cl, -Br, ~C 4 alkyl, -CF 3 or -N0 2 ;
R5为 7、 RG R" KL 3 R15 、
Figure imgf000036_0001
R9 R10 或 9 R,, R ；R5 is 7, RG R " KL 3 R 15 ,
Figure imgf000036_0001
R 9 R 10 or 9 R,, R;
R6、 R7独立的为 -H、 〜C4烷基、 带有取代基的苯基、 带有取代基的 C3〜 ¾环烷基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -H、 〜。4烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R 6 and R 7 are independently -H, ~C 4 alkyl, substituted phenyl, substituted C 3 ~ ¾ cycloalkyl, substituted benzoyl, or substituted The substituent is pyridyl, and the substituent is -H, ~. 4Alkyl , -N0 2 , -F, -Cl, -Br or -CF 3 ;
R8〜Ri6为 -H、 -COOH 或甲基； R 8 ~ Ri6 are -H, -COOH or methyl;
M为氧， R17为 -H; M为氮， R17为 -H、 〜。4烷基、 〜。4烷氧基、 C3〜 ¾环烷基、 叔丁基氧羰基、 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is -H ; M is nitrogen, R 17 is -H, ~. 4 alkyl, ~. 4 alkoxy, C 3 ~ ¾ cycloalkyl, tert-butyloxycarbonyl, R 27- substituted sulfonyl or R 27- substituted acyl;
R27为 〜。4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 Ci〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜 烷基； R 27 is ~. 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted Ci ~ C 4 alkyl or adamantyl; the substituent of the substituted phenyl is halogen, 0 2 or ~ alkyl;
L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。 L is sulfur or oxygen; u=v=0, z=0~l, x=0~l, w= y=l.
11、 根据权利要求 10所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 11. The benzothiazin-4-one derivative according to claim 10, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, -Cl, -Br, ~C 4 alkyl, -CF 3 or -N0 2 ;
R5为 7、 RG R" KL 3 R15 、
Figure imgf000036_0002
R9 R10 或 9 R,, R ；R5 is 7, RG R " KL 3 R 15 ,
Figure imgf000036_0002
R 9 R 10 or 9 R,, R;
R6、 R7独立的为 -H、 〜。4烷基、 带有取代基的苯基、 带有取代基的 C3〜 C8环烷基、带有取代基的苯甲酰基、或带有取代基的吡啶基，所述的取代基为 -H、 〜C4烷基、 -N02、 -F、 -Cl、 -Br或 -CF3; R8〜Ri6为 -H、 -COOH 或甲基； R 6 and R 7 are independently -H, ~. 4 alkyl group, phenyl group with substituent, C 3 ~ C 8 cycloalkyl group with substituent, benzoyl group with substituent, or pyridyl group with substituent, the substituent is -H, ~C 4 alkyl, -N0 2 , -F, -Cl, -Br or -CF 3 ; R 8 ~ Ri6 are -H, -COOH or methyl;
M为氧， R17为 -H; M为氮， R17 为 C3〜C8环烷基、 叔丁基氧羰基、 R27取 代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is -H ; M is nitrogen, R 17 is C 3 ~ C 8 cycloalkyl, tert-butyloxycarbonyl, R 27 -substituted sulfonyl or R 27- substituted acyl;
R27为 〜C4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C4烷基； R 27 is ~C 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted ~ C 4 alkyl or adamantyl; the substitution of the substituted phenyl The base is halogen, -N0 2 or ~C 4 alkyl;
L为硫或氧； u=v=0, z=0〜l， x=0〜l， w= y=l。 L is sulfur or oxygen; u=v=0, z=0~l, x=0~l, w= y=l.
12、 根据权利要求 2所述的苯并噻嗪酮衍生物， 其特征在于：
Figure imgf000037_0001
12. The benzothiazinone derivative according to claim 2, characterized in that:
Figure imgf000037_0001
其结构如式 II所示： Its structure is shown in Formula II:
Figure imgf000037_0002
Figure imgf000037_0002
II II
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 Among them, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or
-CF3; -CF 3 ;
Ri 独立为 -H、 卤素、 〜¾烷基、 〜¾烷氧基、 卤素取代的 〜¾ 烷基、 ^素取代的 〜¾烷氧基、 〜¾烷基取代氨基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 ^〜¾烷基取代酰胺基、 〜¾烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri is independently -H, halogen, ~¾ alkyl, ~¾ alkoxy, halogen-substituted ~¾ alkyl, ^ alkyl-substituted ~¾ alkoxy, ~¾ alkyl-substituted amino, ~¾ alkyl-substituted carbonyl , ~¾ alkyl substituted aminoacyl group, ~¾ alkyl substituted amide group, ~¾ alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R7为- H、 带有取代基的 〜C8烷基、 带有取代基的卤代 〜。8烷基、 带 有取代基的苯基、带有取代基的吡啶基， 所述的取代基为 -H、 〜C8烷基、 〜 。8烷氧基、 〜C8烷基取代氨磺酰基、 ^素取代的 〜C8烷基、 〜C8烷基取 代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； R 7 is -H, a substituted ~C 8 alkyl group, a substituted halogenated ~. 8 alkyl group, phenyl group with substituent, pyridyl group with substituent, the substituent is -H, ~C 8 alkyl group, ~. 8 alkoxy, ~C 8 alkyl substituted sulfamoyl, ^ plain substituted ~C 8 alkyl, ~ C 8 alkyl substituted carbonyl, ~C 8 alkyl substituted aminoacyl, ~ alkyl substituted amide group, halogen , -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R18〜R22独立的为 -H、 〜C8烷基、 〜C8烷氧基、 〜C8烷基取代氨磺 酰基、 ^素取代的 〜C8烷基、 〜^烷基取代羰基、 〜C8烷基取代氨酰基、 〜C8烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCH3、 -OCF3、 -CF3或苯基。 R 18 ~ R 22 are independently -H, ~C 8 alkyl, ~C 8 alkoxy, ~ C 8 alkyl substituted sulfamoyl, ^ plain substituted ~C 8 alkyl, ~ ^ alkyl substituted carbonyl , ~C 8 alkyl substituted aminoacyl group, ~C 8 alkyl substituted amide group, halogen, -N0 2 , -OH, -OCH 3 , -OCF 3 , -CF 3 or phenyl.
13、 根据权利要求 12所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 13. The benzothiazin-4-one derivative according to claim 12, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 ^〜¾烷氧基、 卤素取代 的^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; R R 3 is independently -H, -F, -Cl, -Br, ^~¾ alkyl, ^~¾ alkoxy, halogen-substituted ^~¾ alkyl, halogen-substituted ^~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
R7为 -H、 〜¾烷基、 卤素取代的 ^〜¾烷基、 带有取代基的苯基、 带有 取代基的吡啶基， 所述的取代基为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 〜。8烷基 或卤素取代的 〜。8烷基； R18〜R22独立的为 -H、 -F、 -Cl、 -Br、 -CF3、 -OCH3、 -N02、 〜C8烷基或 卤素取代的 〜。8烷基。 R 7 is -H, -H alkyl, halogen-substituted H - H alkyl, phenyl with a substituent, pyridyl with a substituent, the substituent is -H, -F, -Cl , -Br, -CF 3 , -N0 2 , ~. 8Alkyl or halogen substituted ~. 8 alkyl; R 18 ~ R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -OCH 3 , -N0 2 , ~C 8 alkyl or halogen substituted ~. 8 alkyl.
14、 根据权利要求 12所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 14. The benzothiazin-4-one derivative according to claim 12, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜 ¾烷基、 -CF3或 -N02; R R 3 is independently -H, -F, -Cl, -Br, ~¾ alkyl, -CF 3 or -N0 2 ;
R7为 -H、 〜¾烷基、 卤素取代的 ^〜¾烷基、 带有取代基的苯基、 带有 取代基的吡啶基， 所述的取代基为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 ^〜¾烷基 或卤素取代的 ^〜¾烷基； R 7 is -H, -H alkyl, halogen-substituted H - H alkyl, phenyl with a substituent, pyridyl with a substituent, the substituent is -H, -F, -Cl , -Br, -CF 3 , -N0 2 , ^~¾ alkyl or halogen-substituted ^~¾ alkyl;
R18〜R22独立的为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 -OCH3、 〜¾烷基或 卤素取代的 ^〜¾烷基。 R 18 ~ R 22 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , -OCH 3 , ~¾ alkyl or halogen-substituted H~¾ alkyl.
15、 根据权利要求 14所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 15. The benzothiazin-4-one derivative according to claim 14, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜¾烷基、 -CF3或 -N02; R7为 -H或 ^〜 烷 基； Ri R 3 is independently -H, -F, ^~¾ alkyl, -CF 3 or -N0 2; R 7 is -H or ^~ alkyl;
Ri8〜R22为- H、 -N02、 -OCH3、 -CF3、 〜。8烷基或卤素取代的 〜C8烷 基。 Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 , ~. 8 alkyl or halogen substituted ~C 8 alkyl.
16、 根据权利要求 15所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 16. The benzothiazin-4-one derivative according to claim 15, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜C4烷基、 -CF3或 -N02; R7为 -H或 〜C4烷 基； Ri R 3 is independently -H, -F, ~C 4 alkyl, -CF 3 or -N0 2; R 7 is -H or ~C 4 alkyl;
Ri8〜R22为- H、 -N02、 -OCH3、 -CF3、 〜C4烷基或卤素取代的 〜C4烷 基。 Ri 8 to R 22 are -H, -N0 2 , -OCH 3 , -CF 3 , ~C 4 alkyl or halogen-substituted ~C 4 alkyl.
17、 根据权利要求 2所述的苯并噻嗪酮衍生物， 其特征在于： 为
Figure imgf000038_0001
17. The benzothiazinone derivative according to claim 2, characterized in that:
Figure imgf000038_0001
结构如式 III所示:
Figure imgf000038_0002
The structure is shown in Formula III:
Figure imgf000038_0002
III III
其中， R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 Among them, R 2 and R 4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or
-CF3; -CF 3 ;
Ri 独立为 -H、 卤素、 〜¾烷基、 〜¾烷氧基、 卤素取代的 〜¾ 烷基、 ^素取代的 〜¾烷氧基、 〜¾烷基取代氨基、 〜¾烷基取代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 〜C8烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R7为- H、 带有取代基的 〜C8烷基、 带有取代基的卤代 〜。8烷基、 带 有取代基的苯基、带有取代基的吡啶基， 所述的取代基为 -H、 〜C8烷基、 〜 。8烷氧基、 〜C8烷基取代氨磺酰基、 ^素取代的 〜C8烷基、 〜C8烷基取 代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基； Ri is independently -H, halogen, ~¾ alkyl, ~¾ alkoxy, halogen-substituted ~¾ alkyl, ^ alkyl-substituted ~¾ alkoxy, ~¾ alkyl-substituted amino, ~¾ alkyl-substituted carbonyl , ~C 8 alkyl substituted aminoacyl group, ~ alkyl substituted amide group, ~ C 8 alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; R 7 is -H, a substituted ~C 8 alkyl group, a substituted halogenated ~. 8 alkyl group, phenyl group with substituent, pyridyl group with substituent, the substituent is -H, ~C 8 alkyl group, ~. 8 alkoxy, ~C 8 alkyl substituted sulfamoyl, ^ plain substituted ~C 8 alkyl, ~ C 8 alkyl substituted carbonyl, ~C 8 alkyl substituted aminoacyl, ~ alkyl substituted amide group, halogen , -N0 2 , -OH, -OCF 3 , -CF 3 or phenyl;
R23〜R26独立的为 -H、 〜¾烷基、 〜¾烷氧基、 〜¾烷基取代氨磺 酰基、 ^素取代的 〜¾烷基、 〜¾烷基取代羰基、 〜¾烷基取代氨酰基、 〜¾烷基取代酰胺基、 卤素、 -N02、 -OH、 -OCF3、 -CF3或苯基。 R 23 ~ R 26 are independently -H, ~Alkyl, ~Alkoxy, ~Alkyl substituted sulfamoyl, ~Alkyl substituted ~Alkyl, ~Alkyl substituted carbonyl, ~Alkyl A substituted aminoacyl group, alkyl substituted amide group, halogen, -NO 2 , -OH, -OCF 3 , -CF 3 or phenyl.
18、 根据权利要求 17所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 18. The benzothiazin-4-one derivative according to claim 17, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 ^〜¾烷氧基、 卤素取代 的^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; R R 3 is independently -H, -F, -Cl, -Br, ^~¾ alkyl, ^~¾ alkoxy, halogen-substituted ^~¾ alkyl, halogen-substituted ^~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
R7为 -H、 〜¾烷基或卤素取代的 〜¾烷基； R is -H, ~¾ alkyl or halogen-substituted ~¾ alkyl;
R23〜R26独立的为 -H、 -F、 -Cl、 -Br、 -CF3、 -N02、 ^〜¾烷基或卤素取代 的 〜。8烷基。 R 23 ~ R 26 are independently -H, -F, -Cl, -Br, -CF 3 , -N0 2 , ^~¾ alkyl or halogen substituted ~. 8 alkyl.
19、 根据权利要求 18所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 19. The benzothiazin-4-one derivative according to claim 18, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜。8烷基、 -CF3或 -N02; R7为 H或 〜C8烷 基； Ri R 3 independently is -H, -F, ~. 8 alkyl, -CF 3 or -N0 2; R 7 is H or ~C 8 alkyl;
R23〜R26为 -H、 -F、 -Cl、 -Br或 〜C8烷基。 R 2 3 ~ R 2 6 are -H, -F, -Cl, -Br or ~C 8 alkyl.
20、 根据权利要求 19所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 20. The benzothiazin-4-one derivative according to claim 19, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜。8烷基、 -CF3或 -N02; R7为 H或 〜C4烷 基； Ri R 3 independently is -H, -F, ~. 8 alkyl, -CF 3 or -N0 2; R 7 is H or ~C 4 alkyl;
R23〜R26为 -H、 -F、 -Cl、 -Br或 〜。4烷基。 R 2 3 to R 2 6 are -H, -F, -Cl, -Br or ~. 4 alkyl.
21、 根据权利要求 2所述的苯并噻嗪酮衍生物， 其特征在于： R5
Figure imgf000039_0001
21. The benzothiazinone derivative according to claim 2, characterized in that: R 5
Figure imgf000039_0001
结构如式 V所示：
Figure imgf000039_0002
The structure is shown in Formula V:
Figure imgf000039_0002
V V
其中， L为氮、 氧或硫； R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Among them, L is nitrogen, oxygen or sulfur; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立为 -H、 卤素、 〜C8烷基、 〜C8烷氧基、 卤素取代的 〜C8 烷基、 ^素取代的 〜¾烷氧基、 〜¾烷基取代氨基、 〜¾烷基取代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 〜C8烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R R 3 is independently -H, halogen, ~C 8 alkyl, ~C 8 alkoxy, halogen substituted ~C 8 alkyl, halogen substituted ~C alkoxy, ~C alkyl substituted amino, ~ ¾Alkyl substituted carbonyl, ~C 8 alkyl substituted aminoacyl group, ~ alkyl substituted amide group, ~ C 8 alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
R16为 -H、 -F、 -Cl、 -Br、 -COOH、 〜C8烷基或卤素取代的 〜C8烷基。 R 16 is -H, -F, -Cl, -Br, -COOH, ~C alkyl or halogen-substituted ~C alkyl .
22、 根据权利要求 21所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 22. The benzothiazin-4-one derivative according to claim 21, characterized in that:
L为氧或硫； R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; L is oxygen or sulfur; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 ^〜¾烷氧基、 卤素取代 的^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^~¾ alkyl, ^~¾ alkoxy, halogen-substituted ^~¾ alkyl, halogen-substituted ^~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
R16为 -H、 -COOH、 〜¾烷基或卤素取代的 〜¾烷基。 R 16 is -H, -COOH, ~Halkyl or halogen-substituted ~Halkyl.
23、 根据权利要求 22所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 23. The benzothiazin-4-one derivative according to claim 22, characterized in that:
L为氧或硫； R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; L is oxygen or sulfur; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜¾烷基、 -CF3或 -N02; R16为 -H或甲基。 R R 3 is independently -H, -F, ^~¾ alkyl, -CF 3 or -N0 2; R 16 is -H or methyl.
24、 根据权利要求 23所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 24. The benzothiazin-4-one derivative according to claim 23, characterized in that:
L为氧或硫； R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; L is oxygen or sulfur; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜。4烷基、 -CF3或 -N02; R16为 -H或甲基。 Ri R 3 independently is -H, -F, ^~. 4 alkyl, -CF 3 or -N0 2; R 16 is -H or methyl.
25、 根据权利要求 1所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 为^^— R"， 其结构如式 IV所示：
Figure imgf000040_0001
其中， R2、 R4独立的为卤素、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri 独立为 -H、 卤素、 〜C8烷基、 〜C8烷氧基、 卤素取代的 〜C8 烷基、 ^素取代的 〜^烷氧基、 〜^烷基取代氨基、 〜^烷基取代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 〜C8烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; 25. The benzothiazin-4-one derivative according to claim 1, characterized in that: is ^^- R ", and its structure is shown in formula IV:
Figure imgf000040_0001
Among them, R 2 and R4 are independently halogen, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ; Ri is independently -H, halogen, ~C 8 alkyl, ~C 8 alkoxy, halogen-substituted ~C 8 alkyl, hydroxyl-substituted ~C alkoxy, ~C alkyl-substituted amino, ~C alkyl-substituted carbonyl, ~C 8 alkyl-substituted aminoacyl, ~ Alkyl substituted amide group, ~C 8 alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C8烷基、 〜 烷氧基、 C3〜C8环烷基、 〜C8烷基取代氨磺酰基、 R27取代的磺酰基、 R27 取代的酰基、 卤素取代的 〜。8烷基、 〜^烷基取代羰基、 〜^烷基取代 氨酰基、 〜¾烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 或 带取代基的苯基，所述的取代基为含有 N、0或 S杂原子的饱和或不饱和的杂环; When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~C 8 alkyl, ~ alkoxy, C 3 ~ C 8 cycloalkyl, ~ C 8 alkyl Substituted sulfamoyl group, R 27- substituted sulfonyl group, R 27- substituted acyl group, halogen-substituted ~. 8 alkyl, ~^ alkyl substituted carbonyl, ~ ~ alkyl substituted aminoacyl, ~ ~ alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, or substituted phenyl, The substituent is a saturated or unsaturated heterocycle containing N, 0 or S heteroatoms;
R27为 〜¾烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 〜 C8烷基或金刚烷基； 所述取代苯基的取代基为卤素、 -1^02或 〜¾烷基。 R 27 is ~C alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted ~ C 8 alkyl or adamantyl; the substituent of the substituted phenyl Is halogen, -1^0 2 or ~3 alkyl.
26、 根据权利要求 25所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 26. The benzothiazin-4-one derivative according to claim 25, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
Ri R3独立为 -H、 卤素、 〜C8烷基、 〜C8烷氧基、 卤素取代的 〜C8 烷基、 ^素取代的 〜^烷氧基、 〜^烷基取代氨基、 〜^烷基取代羰基、 〜C8烷基取代氨酰基、 〜 烷基取代酰胺基、 〜C8烷基取代氨磺酰基、 -N02、 -顧2、 -OCF3、 -CN、 -OH、 -CHO或 -CF3; Ri R 3 is independently -H, halogen, ~C 8 alkyl, ~C 8 alkoxy, halogen-substituted ~C 8 alkyl, halogen-substituted ~C alkoxy, ~C alkyl-substituted amino , ~ ^Alkyl substituted carbonyl, ~C 8 alkyl substituted aminoacyl group, ~ alkyl substituted amide group, ~ C 8 alkyl substituted sulfamoyl group, -N0 2 , -Gu 2 , -OCF 3 , -CN, -OH, -CHO or -CF 3 ;
当 M为氧或硫时， R17为 -H; 当 M为氮时， R17为- H、 〜C8烷基、 〜 。8烷氧基、 C3〜C8环烷基、 〜。8烷基取代氨磺酰基、卤素取代的 〜。8烷基、 〜 ^烷基取代羰基、 〜 烷基取代氨酰基、 〜C8烷基取代酰胺基、 卤素、 叔丁基氧羰基、 -OCF3、 -OH、 -CF3或带取代基的苯基， 所述的取代基为含有 N、 0或 S杂原子的饱和或不饱和的杂环。 When M is oxygen or sulfur, R 17 is -H; when M is nitrogen, R 17 is -H, ~C 8 alkyl, ~. 8 alkoxy, C 3 ~ C 8 cycloalkyl, ~. 8 Alkyl substituted sulfamoyl, halogen substituted ~. 8 alkyl, ~ ^ alkyl substituted carbonyl, ~ alkyl substituted aminoacyl, ~ C 8 alkyl substituted amide, halogen, tert-butyloxycarbonyl, -OCF 3 , -OH, -CF 3 or substituted Phenyl, the substituent is a saturated or unsaturated heterocyclic ring containing N, 0 or S heteroatoms.
27、 根据权利要求 26所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 27. The benzothiazin-4-one derivative according to claim 26, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 ^〜¾烷基、 ^〜¾烷氧基、 卤素取代 的^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ^~¾ alkyl, ^~¾ alkoxy, halogen-substituted ^~¾ alkyl, halogen-substituted ^~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3 ;
M为氧， R17为 H; M为氮， R17为 -H或叔丁基氧羰基。 M is oxygen, R 17 is H; M is nitrogen, R 17 is -H or tert-butyloxycarbonyl.
28、 根据权利要求 27所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 28. The benzothiazin-4-one derivative according to claim 27, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜 ¾烷基、 -CF3或 -N02; R R 3 is independently -H, -F, ~¾ alkyl, -CF 3 or -N0 2 ;
M为氧， R17为 -H; M为氮， R17为叔丁基氧羰基。 M is oxygen, R 17 is -H; M is nitrogen, R 17 is tert-butyloxycarbonyl.
29、 根据权利要求 28所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 29. The benzothiazin-4-one derivative according to claim 28, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 〜C4烷基、 -CF3或 -N02; Ri R 3 is independently -H, -F, ~C 4 alkyl, -CF 3 or -N0 2 ;
M为氧， R17为 -H; M为氮， R17为叔丁基氧羰基。 M is oxygen, R 17 is -H ; M is nitrogen, R 17 is tert-butyloxycarbonyl.
30、 根据权利要求 26所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 30. The benzothiazin-4-one derivative according to claim 26, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜 ¾烷基、 〜 ¾烷氧基、 卤素取代 的^〜¾烷基、 卤素取代的 ^〜¾烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; R R 3 is independently -H, -F, -Cl, -Br, ~¾ alkyl, ~¾ alkoxy, halogen-substituted ~¾ alkyl, halogen-substituted ~¾ alkoxy, -N0 2 , -NH 2 , -CN or -CF 3;
M为氧， R17为 H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； M is oxygen, R 17 is H; M is nitrogen, R 17 is a sulfonyl group substituted by R 27 or an acyl group substituted by R 27 ;
R27为 〜¾烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 Ci〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜¾烷基。R 27 is ~C alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted Ci ~ C 4 alkyl or adamantyl; the substitution of the substituted phenyl The radical is halogen, O or -alkyl.
31、 根据权利要求 30所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 31. The benzothiazin-4-one derivative according to claim 30, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ;
Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜 烷基、 〜 烷氧基、 卤素取 代的 ^〜。4烷基、 卤素取代的 ^〜。4烷氧基、 -N02、 -NH2、 -CN或 -CF3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ~alkyl, ~alkoxy, halogen-substituted ^~. 4Alkyl , halogen substituted ^~. 4Alkoxy , -N0 2 , -NH 2 , -CN or -CF 3 ;
M为氧， R17为 -H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； R27为 〜C4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜 烷基。 M is oxygen, R 17 is -H; M is nitrogen, R 17 is a sulfonyl group substituted by R 27 or an acyl group substituted by R 27 ; R 27 is ~C 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted Phenyl, C 3 ~ C 8 cycloalkyl substituted ~ C 4 alkyl or adamantyl; the substituent of the substituted phenyl is halogen, C 2 or ~ alkyl.
32、 根据权利要求 31所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 32. The benzothiazin-4-one derivative according to claim 31, characterized in that:
R2、 R4独立的为卤素、 -N02、 -NH2、 -OCF3、 -CN、 或 -CF3; Ri R3独立的为 -H、 -F、 -Cl、 -Br、 〜C4烷基、 〜C4烷氧基、 卤素取 代的 〜C4烷基、 -N02、 -CN或 -CF3; R 2 and R4 are independently halogen, -N0 2 , -NH 2 , -OCF 3 , -CN, or -CF 3 ; Ri R 3 is independently -H, -F, -Cl, -Br, ~C 4 alkyl, ~C 4 alkoxy, halogen substituted ~C 4 alkyl, -N0 2 , -CN or -CF 3 ;
M为氧， R17为 -H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； R27为 〜C4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 〜 C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 -N02或 〜C4烷基。 M is oxygen, R 17 is -H ; M is nitrogen, R 17 is a sulfonyl group substituted by R 27 or an acyl group substituted by R 27 ; R 27 is ~C 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted Phenyl, C 3 ~ C 8 cycloalkyl substituted ~ C 4 alkyl or adamantyl; the substituent of the substituted phenyl is halogen, -N0 2 or ~ C 4 alkyl.
33、 根据权利要求 32所述的苯并噻嗪 -4-酮衍生物， 其特征在于： 33. The benzothiazin-4-one derivative according to claim 32, characterized in that:
R2、 R4独立的为 -F、 -N02、 -NH2、 -OCF3或 -CF3; R 2 and R4 are independently -F, -N0 2 , -NH 2 , -OCF 3 or -CF 3 ;
Ri R3独立的为 -H、 -F、 ^〜。4烷基、 -CF3或 -N02; Ri R 3 independently is -H, -F, ^~. 4alkyl , -CF 3 or -N0 2 ;
M为氧， R17为 -H; M为氮， R17为 R27取代的磺酰基或 R27取代的酰基； R27为 〜。4烷基、 C3〜C8环烷基、取代的苯基、 C3〜C8环烷基取代的 ^〜 M is oxygen, R 17 is -H; M is nitrogen, R 17 is a sulfonyl group substituted by R 27 or an acyl group substituted by R 27 ; R 27 is ~. 4 alkyl, C 3 ~ C 8 cycloalkyl, substituted phenyl, C 3 ~ C 8 cycloalkyl substituted ^~
C4烷基或金刚烷基； 所述取代苯基的取代基为卤素、 02或 〜 烷基。C 4 alkyl or adamantyl; the substituent of the substituted phenyl is halogen, C 2 or ~ alkyl.
34、 苯并噻嗪 -4-酮衍生物， 其特征在于： 34. Benzothiazin-4-one derivatives, characterized by:
其名称为 2-乙氨基 -6,7,8-三氟 -1,3-苯并噻嗪 -4-酮、 2-吗啉 -6,7,8-三氟 -1,3-苯 并噻嗪 -4-酮、 2-(5-溴吡啶 -2-氨基) -6,7,8-三氟 -1,3-苯并噻嗪 -4-酮、 2-(5-氯吡啶 -2- 氨基) -6,7,8-三氟 -1,3-苯并噻嗪 -4-酮、 2- (哌啶 -1-基) -6,8-二硝基 -1,3-苯并噻嗪 -4- 酮、 2-吗啉 -6,8-二硝基 -1,3-苯并噻嗪 -4-酮、 2-(5-溴吡啶 -2-氨基) - 6,8-二硝基 -1,3- 苯并噻嗪 -4-酮、 2-吗啉 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-乙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 N-乙基 -N-(8-硝基 -4酮 -6-三氟甲基 -1,3-苯并噻嗪 -2基） -4- (氯甲基)苯甲酰胺、 N-乙基 -N-(8-硝基 -4酮 -6-三氟甲基 -1,3-苯并噻嗪 -2 基) -2- (三氟甲基)苯甲酰胺、 N-乙基 -N-(8-硝基 -4 酮 -6-三氟甲基 -1,3-苯并噻嗪 -2 基) -3- (硝基)苯甲酰胺、 2-甲氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-丙氨 基—8—硝基—6—三氟甲基 -;1,3-苯并噻嗪—4—酮、 2-丁氨基 -8-硝基 -6-三氟甲基 -1,3-苯并 噻嗪 -4-酮、 2-异丙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-二乙氨基 -8-硝 基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-异丁氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-环丙氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2- (吡咯烷 -1-基) -8-硝 基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2- (哌啶 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻 嗪 -4-酮、 1-(8-硝基 -4-酮 -6-三氟甲基 -1,3-苯并噻嗪 -2-基)哌啶 -4-羧酸、 2- ( 1,4-高 哌嗪 -1-基） -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-甲基哌啶 -1-基) -8-硝基 -6- 三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-环戊氨基 -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 4-(8-硝基 -4-酮 -6-三氟甲基 -1,3-苯并噻嗪 -2-基)哌嗪 -1-羧酸 -叔丁醇酯、 2-(1,4-二硫 杂 -8-氮杂螺 [4.5]癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(2 甲基 -1,4- 二硫杂 -8氮杂螺 [4.5] 癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(1-氧杂 -4-硫杂 -8氮杂螺 [4.5] 癸 -8-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-甲磺 酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丙基磺酰基哌嗪 -1- 基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丁基磺酰基哌嗪 -1-基) -8-硝基 -6- 三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-环丙基磺酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(4-叔丁基苯磺酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3- 苯并噻嗪 -4-酮、 2-(4-(2-硝基苯磺酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻 嗪—4-酮、 2-(4-(4-硝基苯磺酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(3-硝基苯磺酰基)哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-乙 酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丙酰基哌嗪 -1-基) -8- 硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-新戊酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-丁酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4- 酮、 2-(4-环丙甲酰基哌嗪小基 )-8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-环己 烷甲酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(2-环己基乙酰基) 哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-(2-氯苯甲酰基)哌嗪 -1- 基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(4-金刚烷甲酰基哌嗪 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮、 2-(1,5-二硫杂 -9-氮杂螺 [5.5] ^—烷 -9-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮或 2-(4-环戊基 -3-哌嗪酮 -1-基) -8-硝基 -6-三氟甲基 -1,3-苯并噻嗪 -4-酮。 Its names are 2-ethylamino-6,7,8-trifluoro-1,3-benzothiazin-4-one, 2-morpholine-6,7,8-trifluoro-1,3-benzo Thiazin-4-one, 2-(5-bromopyridin-2-amino)-6,7,8-trifluoro-1,3-benzothiazin-4-one, 2-(5-chloropyridin- 2-Amino)-6,7,8-trifluoro-1,3-benzothiazin-4-one, 2-(piperidin-1-yl)-6,8-dinitro-1,3- Benzothiazin-4-one, 2-morpholin-6,8-dinitro-1,3-benzothiazin-4-one, 2-(5-bromopyridin-2-amino)-6, 8-dinitro-1,3-benzothiazin-4-one, 2-morpholin-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2 -Ethylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, N-ethyl-N-(8-nitro-4-one-6-trifluoromethyl (1,3-benzothiazin-2-yl)-4-(chloromethyl)benzamide, N-ethyl-N-(8-nitro-4-one-6-trifluoromethyl-1) ,3-benzothiazin-2-yl)-2-(trifluoromethyl)benzamide, N-ethyl-N-(8-nitro-4-one-6-trifluoromethyl-1,3 -benzothiazin-2-yl)-3-(nitro)benzamide, 2-methylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-propylamino-8-nitro-6-trifluoromethyl-;1,3-benzothiazin-4-one, 2-butylamino-8-nitro-6-trifluoromethyl-1, 3-benzothiazin-4-one, 2-isopropylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-diethylamino-8- Nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-isobutylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazine- 4-one, 2-cyclopropylamino-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(pyrrolidin-1-yl)-8-nitro -6-Trifluoromethyl-1,3-benzothiazin-4-one, 2-(piperidin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzo Thiazin-4-one, 1-(8-nitro-4-one-6-trifluoromethyl-1,3-benzothiazin-2-yl)piperidine-4-carboxylic acid, 2-( 1,4-homopiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-methylpiperidine-1- base) -8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-cyclopentylamino-8-nitro-6-trifluoromethyl-1,3- Benzothiazin-4-one, 4-(8-nitro-4-one-6-trifluoromethyl-1,3-benzothiazin-2-yl)piperazine-1-carboxylic acid-tert. Butanol ester, 2-(1,4-dithia-8-azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazine -4-one, 2-(2methyl-1,4-dithia-8azaspiro[4.5]dec-8-yl) -8-nitro-6-trifluoromethyl-1,3- Benzothiazin-4-one, 2-(1-oxa-4-thia-8azaspiro[4.5]dec-8-yl)-8-nitro-6-trifluoromethyl-1, 3-benzothiazin-4-one, 2-(4-methanesulfonylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazine-4- Ketone, 2-(4-propylsulfonylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-butanone (Sulfonylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-cyclopropylsulfonylpiperazine-1) -base) -8-nitro-6-trifluoromethyl -1,3-benzothiazin-4-one, 2-(4-(4-tert-butylbenzenesulfonyl)piperazin-1-yl) -8-nitro-6-trifluoromethyl-1 ,3-benzothiazin-4-one, 2-(4-(2-nitrobenzenesulfonyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3- Benzothiazin-4-one, 2-(4-(4-nitrobenzenesulfonyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazine Azin-4-one, 2-(4-(3-nitrobenzenesulfonyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazine-4 -Ketone, 2-(4-acetylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-propionyl) Piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-pivaloylpiperazin-1-yl)-8 -Nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-butyrylpiperazin-1-yl) -8-nitro-6-trifluoromethyl -1,3-benzothiazin-4-one, 2-(4-cyclopropylpiperazine)-8-nitro-6-trifluoromethyl-1,3-benzothiazine- 4-one, 2-(4-cyclohexaneformylpiperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-( 4-(2-cyclohexylacetyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-(2 -Chlorobenzoyl)piperazin-1-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(4-adamantanoylpiperazine) -1-yl) -8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one, 2-(1,5-dithia-9-azaspiro[5.5] ^—alk-9-yl)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one or 2-(4-cyclopentyl-3-piperazinone-1 -base)-8-nitro-6-trifluoromethyl-1,3-benzothiazin-4-one.
35、 权利要求 1〜34任一项所述的苯并噻嗪 -4-酮衍生物在药学上可接受的盐、 水合物或前药。 35. A pharmaceutically acceptable salt, hydrate or prodrug of the benzothiazin-4-one derivative according to any one of claims 1 to 34.
36、权利要求 1〜34任一项所述的苯并噻嗪 -4-酮衍生物或权利要求 35所述的盐、 水合物或前药在制备治疗结核病或麻风病药物中的用途。 36. Use of the benzothiazin-4-one derivative according to any one of claims 1 to 34 or the salt, hydrate or prodrug according to claim 35 in the preparation of drugs for the treatment of tuberculosis or leprosy.
37、 药物组合物， 是由权利要求 1〜34任一项所述的苯并噻嗪 -4-酮衍生物或权 利要求 35所述的盐、 水合物或前药添加药学上可以接受的辅助性成分制备而成 的。 37. A pharmaceutical composition consisting of the benzothiazin-4-one derivative according to any one of claims 1 to 34 or the salt, hydrate or prodrug according to claim 35 with the addition of a pharmaceutically acceptable auxiliary agent Made from sexual ingredients.
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US10358442B2 (en) * 2015-03-23 2019-07-23 Ecole Polytechnique Federale De Lausanne (Epfl) 2-homopiperazine-1-yl-4H-1,3-benzothiazine-4-one derivatives and process for the preparation of 2-(homo)piperazine 1,3-benzothiazine-4-one hydrochlorides
US11155542B2 (en) 2016-09-22 2021-10-26 University Of Notre Dame Du Lac Antimicrobial compounds, their use for the treatment of mammalian infections and a new metabolic mechanism
CN108947952A (en) * 2017-05-24 2018-12-07 中国医学科学院药物研究所 2- substituted-amino -5- trifluoromethyl -8- nitro benzo (thio) pyrans -4- ketone compounds and its preparation method and application
CN108947952B (en) * 2017-05-24 2021-09-21 中国医学科学院药物研究所 2-substituted amino-5-trifluoromethyl-8-nitrobenz (thio) pyran-4-ketone compound and preparation method and application thereof

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