CN103664996B - Indole derivatives and preparation method thereof - Google Patents

Indole derivatives and preparation method thereof Download PDF

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CN103664996B
CN103664996B CN201310388834.XA CN201310388834A CN103664996B CN 103664996 B CN103664996 B CN 103664996B CN 201310388834 A CN201310388834 A CN 201310388834A CN 103664996 B CN103664996 B CN 103664996B
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stereoisomer
methyl
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CN103664996A (en
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刘宗英
李卓荣
金洁
朱俊泰
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Institute of Medicinal Biotechnology of CAMS
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    • 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
    • C07D495/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/16—Peri-condensed systems
    • 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
    • C07D495/12—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 three hetero rings
    • C07D495/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

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Abstract

The present invention relates to the new antimicrobial compound of a class, i.e. a class indole derivatives, its alloisomerism or their officinal salt or solvate or hydrate；The preparation method of these compounds, the pharmaceutical composition containing these compounds, these compounds are for preparing the purposes in antibacterials.

Description

Indole derivatives and preparation method thereof
Technical field
The present invention relates to the new antimicrobial compound of a class, i.e. a class indole derivatives, its alloisomerism or they can medicine With salt or solvate or hydrate；The preparation method of these compounds, the pharmaceutical composition containing these compounds, these changes Compound is for preparing the purposes in antibacterials, and the antibacterials preferred pin is to bacillus or gram- bacteria, be more preferably directed to Tubercle bacillus or Gram-negative bacteria or gram-positive bacteria.
Background technology
Antibody-resistant bacterium seriously endangers controlling for anti-infective disease to the drug resistance especially multiple drug drug resistance of antibiotic One of treat, and the important public hygiene problem as global concern.In recent years, infection is to cause infectivity caused by antibody-resistant bacterium The one of the main reasons of disease high mortality, such as seriously jeopardizes the methicillin-resistant staphylococcus aureus of clinical treatment（MRSA） And MRSE（MRSE）, penicillin resistance pneumococcus（PRSP）, vancomycin-resistant enterococcus（VRE）, cause antibacterial The use of medicine is very restricted, or even invalid.The clinical demand to new effective antibacterials is very urgent, Ren Menzheng Spare no effort actively to find and exploitation can resist each kind new medicine of drug-fast bacteria.
Creatmycin is that one kind that one plant of actinoplanes generation is isolated from the soil of China's Jinan, Shandong Province has new The antibacterium antibiotic of chemical constitution, has inhibitory action, toxicity is very low to part Gram-positive and negative bacterium, to infection dysentery Bacillus or the mouse of Escherichia coli, abdominal cavity or oral administration have protective effect.Creatmycin clinically causes to Escherichia coli Septicemia, urinary system infection contamination have good therapeutic effect.The molecular structure β monomethyls indolepopionic acid of desulfurization creatmycin is without wound Thiapyran ring in neomycin is identical with creatmycin to E.coli B antibacterial activity.It is mould that Qi Tianqing etc. have studied desulfurization innovation Antibacterial action and antibacterial primary action of the element to E.coli B, it is by suppression as a result to show creatmycin and desulfurization creatmycin The biosynthesis of bacterium tryptophan processed and produce antibacterial activity, its antibacterial action mechanism be antagonism suppress tryptophan pathway enzyme Synthesize (the such as Qi Changqing antibiotic 1984,9（5）：401).This result shows, it appears that thiapyran ring is not in creatmycin molecule Necessary group.The structure of creatmycin is novel, and its main core is a new heterocyclic system in chemistry.But it is still unused so far from finding In clinic, its reason is high outer except fermenting and producing cost, and it is narrower to also reside in its antimicrobial spectrum, is only capable of orally, it is impossible to intramuscular injection, and antibacterial Activity is less than current clinically other antibacterials.Therefore scientific worker has carried out many structure of modification to creatmycin, revives Sheng favour etc. has carried out transformation following aspects according to the chemical structure characteristic of creatmycin：The derivative of some carboxylic acids is synthesized Thing, including ester and acid amides；Some derivatives replaced on the NH of indoles are synthesized；Some take has been carried out in whole ring system Generation.The experiment of these derivatives shows, in addition to the antibacterial action that N- formoxyl creatmycins have close to creatmycin, other derivatives Thing is without obvious antibacterial action [the medical industries such as Su Shenghui, 1984,139（2)：17）].
Therefore, new antimicrobial compound is also needed in the prior art.
The content of the invention
Technical problem underlying solved by the invention, which is to imitate by the structure to Some Derivatives of Chuangxinmycin, to be studied, and is screened and is closed Into going out the new antimicrobial compound of a class.Such compound not only have significant antibacterial activity, and with molecular weight it is small, synthesis Simply, the small advantage of toxic side effect.
Present invention also offers the indole derivatives or the synthetic method of its pharmaceutical salts, pass through the choosing to reaction scheme Select, obtain described compound.
Present invention also offers the indole derivatives or its pharmaceutical salts in the application of antibiosis, study and show that it has Significant antibacterial activity, and then there is provided the antibacterial combination using the indole derivatives as active component.The present invention is also There is provided the compounds of this invention for preparing the purposes in antibacterials, the antibacterials preferred pin is to bacillus or gram Bacterium, more preferably be directed to tubercle bacillus or Gram-negative bacteria or gram-positive bacteria.
On the one hand, the invention provides with formula（I）Indole derivatives, its stereoisomer or they can Pharmaceutical salts or solvate or hydrate：
Wherein,
R1For H, C1-6Alkyl, C1-6Alkanoyl or C1-6Alkylamino；
R2For H, C1-6Alkyl, C3-6Cycloalkyl, C1-6Alkoxy, C1-6Alkanoyl, halogen, cyano group, nitro, CF3, amino, N (R5)2, COR6, CO2R6, or CON (R6)2；
R3For H, C1-6Alkyl, C3-6Cycloalkyl, C1-6Alkoxy, C1-6Alkanoyl, halogen, cyano group, nitro, CF3, amino, N (R5)2, COR6, CO2R6, or CON (R6)2；
R4For H, C1-6Alkyl, C3-6Cycloalkyl, C1-6Alkoxy, C1-6Alkanoyl, halogen, cyano group, nitro, CF3, amino, N (R5)2, COR6, CO2R6, or CON (R6)2；
Each R5It independently is H, C1-6Alkyl, or COCH2N(R7)2；
Each R6It independently is H, or C1-6Alkyl；
Each R7It independently is H, or C1-6Alkyl；
A, B, D are carbon or nitrogen-atoms independently of each other；
X is NH, O, S or is not present；
Y is OR8Or N (R8)2；
Each R8Independently selected from
（1）H or C1-6Alkyl,
Wave represented at bonding,
R11Represent H or C1-6Alkyl；
R12Represent
I) it is unsubstituted or by 1-3 R9Substituted C1-6Alkyl；
II) it is unsubstituted or by halogen, C1-6Alkyl, C1-6 alkyl aminos, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkanes Base；
III) it is unsubstituted or by 1-3 R106 to the 18 yuan of aryl or 5 to 14 unit's heteroaryls of substitution；
Iv) adamantyl；
Each R8Can be independently by 1-3 R9Substitution,
Each R9Independently selected from halogen, C1-6Alkyl, C1-6Alkyl amino, two（C1-6Alkyl）Amino, hydroxyl, hydroxyl C1-6 Alkyl, amino, amino C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl oxy, amino-sulfonyl, carbamoyl, C1-6Alkyl Carbamoyl, C3-8Cycloalkyl；6 to 18 yuan of aryl-carbonyl oxygens；6 to 18 yuan of aryl or 5 to 14 unit's heteroaryls, or R10Substitution 6 to 18 yuan of aryl or 5 to 14 unit's heteroaryls；Non-aromatic heterocycle containing 5 or 6 annular atoms；Butyrolactam -1- bases；And phosphorus Acidic group；
R10Selected from halogen, hydroxyl, amino, C1-6Alkyl-carbonyl, C1-6Alkyl, C1-6 alkoxies, C1-6 alkyl aminos and C1-6 Alkyl carbonyl oxy；
Condition is, the formula（I）Compound does not include following compound：
The substituent of above formula is as shown in the table
2）The compound of following formula 3
Formula 3
R1It is methyl and R2It is hydroxyl；Or
R1It is methyl and R2It is ethyoxyl；With
3）The compound of formula 4
Formula 4
R1It is methyl and R2It is hydroxyl.
In a preferred embodiment, formula（I）Compound has below general formula（Ⅱ）
R1、R2、R3、R4, A, B, D, X, Y such as formula（I）Defined.
In a further preferred embodiment, R3It is substituted on A.
In a further preferred embodiment, R3It is substituted on B.
In a further preferred embodiment, R3It is substituted on D.
In a further preferred embodiment, formula（I）Compound has below general formula XV
R1、R2、R3、R4, A, B, D, Y such as formula（I）Defined.
In a further preferred embodiment, in formula（I）Or formula（II）In compound,
A, B and D are carbon atom；
B and D is carbon atom, and A is nitrogen-atoms；
D is carbon atom, and A and B are nitrogen-atoms；
A and D is carbon atom, and B is nitrogen-atoms；
A and B is carbon atom, and D is nitrogen-atoms；Or
B is carbon atom, and A and D are nitrogen-atoms.
In a further preferred embodiment, in formula（I）Or formula（II）In compound,
R1For H, C1-4Alkyl, C1-4Alkanoyl or C1-4Alkylamino；
R2For H, C1-4Alkyl, C3-4Cycloalkyl, C1-4Alkoxy, C1-4Alkanoyl, halogen, cyano group, nitro, CF3, amino, N (R5)2, COR6, CO2R6, or CON (R6)2；
R3For H, C1-4Alkyl, C3-6Cycloalkyl, C1-6Alkoxy, C1-4Alkanoyl, halogen, cyano group, nitro, CF3, amino, N (R5)2, COR6, CO2R6, or CON (R6)2；
R4For H, C1-4Alkyl, C3-4Cycloalkyl, C1-4Alkoxy, C1-4Alkanoyl, halogen, cyano group, nitro, CF3, amino, N (R5)2, COR6, CO2R6, or CON (R6)2；
Each R5It independently is H, C1-4Alkyl, or COCH2N(R7)2；
Each R6It independently is H, C1-4Alkyl；
Each R7It independently is H, C1-4Alkyl；
A, B, D are carbon or nitrogen-atoms；
X is NH, O, S or is not present；
Y is OR8Or N (R8)2；
Each R8Independently selected from
（1）H or C1-6Alkyl,
Wave represented at bonding,
R11Represent H or C1-6Alkyl；
R12Represent
I) it is unsubstituted or by 1-3 R9Substituted C1-6Alkyl；
II) it is unsubstituted or by halogen, C1-6Alkyl, C1-6 alkyl aminos, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkanes Base；
III) it is unsubstituted or by 1-3 R106 to the 18 yuan of aryl or 5 to 14 unit's heteroaryls of substitution；
Iv) adamantyl；
Each R8Can be independently by 1-3 R9Substitution,
Each R9Independently selected from halogen, C1-6Alkyl, C1-6Alkyl amino, two（C1-6Alkyl）Amino, hydroxyl, hydroxyl C1-6 Alkyl, amino, amino C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl oxy, amino-sulfonyl, carbamoyl, C1-6Alkyl Carbamoyl, C3-8Cycloalkyl；6 to 18 yuan of aryl-carbonyl oxygens, 6 to 18 yuan of aryl or 5 to 14 unit's heteroaryls, or R10The 6 of substitution To 18 yuan of aryl or 5 to 14 unit's heteroaryls；Non-aromatic heterocycle containing 5 or 6 annular atoms；Butyrolactam -1- bases and phosphate；
R10Selected from halogen, hydroxyl, amino, C1-6Alkyl-carbonyl, C1-6Alkyl, C1-6 alkoxies, C1-6 alkyl aminos and C1-6 Alkyl carbonyl oxy.
In a further preferred embodiment, Y is OR8, R8For C1-6Alkyl, each R8Can be independently by 1-3 R9Take Generation, each R9Independently selected from halogen, C1-6Alkyl, C1-6Alkyl amino, two（C1-6Alkyl）Amino, hydroxyl, hydroxyl C1-6Alkyl, Amino, amino C1-6Alkyl, C1-6Alkyl-carbonyl, C1-6Alkyl carbonyl oxy, amino-sulfonyl, carbamoyl, C1-6Alkyl amino Formoxyl, C3-8Cycloalkyl；6 to 18 yuan of aryl-carbonyl oxygens, 6 to 18 yuan of aryl or 5 to 14 unit's heteroaryls, or R10The 6 to 18 of substitution First aryl or 5 to 14 unit's heteroaryls；Non-aromatic heterocycle containing 5 or 6 annular atoms；Butyrolactam -1- bases and phosphate.
In a further preferred embodiment, Y is OR8, R8For C1-6Alkyl, each R8Can be independently by 1-3 R9Take Generation, each R9Independently selected from 6 to 18 yuan of aryl-carbonyl oxygens.
In a further preferred embodiment, in formula（I）Or formula（II）In compound, R12Represent unsubstituted C3-8Ring Alkyl, each R8Can be independently by 1-3 R9Substitution, each R9Independently selected from hydroxyl, and C1-6Alkyl amino, it is preferable that R9It is substituted in R12On.
In a further preferred embodiment, the present invention relates to one kind such as formula（I）Shown indole derivatives or its solid Isomers or their officinal salt or solvate or hydrate：
Wherein,
R1For H, C1-6Alkyl, or C1-6Alkanoyl；
R2For H, C1-6Alkyl or halogen；
R3For H, C1-6Alkyl, C1-6Alkoxy, halogen, CF3, or N (R5)2；
R4For C1-6Alkyl；
Each R5It independently is H, or C1-6Alkyl；
A, B, D are carbon or nitrogen-atoms independently of each other；
X is O, S, or is not present；
Y is OR8, or N (R8)2；
Each R8Independently selected from
（1）H, or C1-6Alkyl,
Wave represented at bonding,
R11Represent H or C1-6Alkyl；
R12Represent
I) it is unsubstituted or by 1-3 R9Substituted C1-6Alkyl；
II) it is unsubstituted or by halogen, C1-6Alkyl, C1-6Alkyl amino, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkanes Base；
III) it is unsubstituted or by 1-3 R106 to 18 yuan of aryl of substitution,
Iv) adamantyl；
V) unsubstituted 5 to 14 unit's heteroaryl；
Each R8Can be independently by 1-3 R9Substitution,
Each R9Independently selected from halogen, C1-6Alkyl, C1-6Alkyl amino, two（C1-6Alkyl）Amino, hydroxyl, 6 to 18 yuan Aryl-carbonyl oxygen, the non-aromatic heterocycle containing 5 or 6 annular atoms, butyrolactam -1- bases and phosphate；
R10Selected from halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy, C1-6Alkyl amino and C1-6Alkyl amino；
Condition is, the formula（I）Compound does not include following compound：
1）The compound of formula 2
Formula 2
The substituent of above formula is as shown in the table
2）The compound of following formula 3
Formula 3
R1It is methyl and R2It is hydroxyl；Or
R1It is methyl and R2It is ethyoxyl；With
3）The compound of following formula 4
Formula 4
R1It is methyl and R2It is hydroxyl.
In a further preferred embodiment, R1For H, C1-6Alkyl, or C1-6Alkanoyl.
In a further preferred embodiment, R2For H, C1-6Alkyl or halogen.
In a further preferred embodiment, R3For H, C1-6Alkyl, C1-6Alkoxy, halogen, CF3, or N (R5)2。
In a further preferred embodiment, R4For C1-6Alkyl.
In a further preferred embodiment, each R5It independently is H, or C1-6Alkyl.
In a further preferred embodiment, A, B, D are carbon or nitrogen-atoms independently of each other.
In a further preferred embodiment, X is O, S, or is not present.
In a further preferred embodiment, Y is OR8, or N (R8)2,
Each R8Independently selected from
（1）H, or C1-6Alkyl,
Wave represented at bonding,
R11Represent H or C1-6Alkyl.
In a further preferred embodiment, R12Represent
I) it is unsubstituted or by 1-3 R9Substituted C1-6Alkyl；
II) it is unsubstituted or by halogen, C1-6Alkyl, C1-6Alkyl amino, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkanes Base；
III) it is unsubstituted or by 1-3 R106 to 18 yuan of aryl of substitution,
Iv) adamantyl；
V) unsubstituted 5 to 14 unit's heteroaryl.
In a further preferred embodiment, each R8Independently selected from
（1）H, or C1-6Alkyl,
Wave represented at bonding,
R11Represent H or C1-6Alkyl.
In a further preferred embodiment, R12Represent
I) it is unsubstituted or by 1-3 R9Substituted C1-6Alkyl；
II) it is unsubstituted or by halogen, C1-6Alkyl, C1-6Alkyl amino, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkanes Base；
III) it is unsubstituted or by 1-3 R106 to 18 yuan of aryl of substitution,
Iv) adamantyl；
V) unsubstituted 5 to 14 unit's heteroaryl.
In a further preferred embodiment, each R8Independently selected from
（1）H, or C1-6Alkyl,
Wave represented at bonding,
R11Represent H or C1-6Alkyl；
R12Represent
I) it is unsubstituted or by 1-3 R9Substituted C1-6Alkyl；
II) it is unsubstituted or by halogen, C1-6Alkyl, C1-6Alkyl amino, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkanes Base；
III) it is unsubstituted or by 1-3 R106 to 18 yuan of aryl of substitution,
Iv) adamantyl；
V) unsubstituted 5 to 14 unit's heteroaryl.
In a further preferred embodiment, each R8Can be independently by 1-3 R9Substitution, each R9Independently selected from Halogen, C1-6Alkyl, C1-6Alkyl amino, two（C1-6Alkyl）Amino, hydroxyl, 6 to 18 yuan of aryl-carbonyl oxygens, contain 5 or 6 rings Non-aromatic heterocycle, butyrolactam -1- bases and the phosphate of atom.Preferred in terms of, R9It is substituted in R12On.
In a further preferred embodiment, R10Selected from halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxy, C1-6Alkoxy, C1-6Alkyl amino and C1-6Alkyl amino.
In a further preferred embodiment, formula (I) compound has the structure of Formula VIII
Wherein R1、R2、R3、R4, A, B, D such as formula (I) defined, X be NH, O or S.
In a further preferred embodiment, formula (I) compound has Formula IX structure
Wherein R1、R2、R3、R4, A, B, D such as formula (I) defined.
In a further preferred embodiment, formula (I) compound has Formula X structure
Wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R4、R9, A, B, D such as Formulas I institute Definition, X is NH, O or S.
In a further preferred embodiment, formula (I) compound has Formula X I structures
Wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R4、R9, A, B, D such as Formulas I institute Definition.
In a further preferred embodiment, formula (I) compound has Formula X III structures
Wherein, R1、R2、R3、R4、R11、R12, A, B, D and X such as Formulas I defined.
In a further preferred embodiment, formula (I) compound has Formula X IV structures
Wherein, R1、R2、R3、R4、R11、R12, A, B and D such as Formulas I defined.
Preferred compounds of the invention is pharmaceutically acceptable with theirs for the compound or stereoisomer in following Tables 1 and 2 Salt and solvate or hydrate.
Table 1
Table 2
Term related definition of the present invention is as follows.
Term " alkyl " use herein means the straight chain or branched alkyl of saturation, and referring in particular to carbon number is The alkyl of 1-6 straight or branched.Instantiation includes, but are not limited to methyl, ethyl, isopropyl, n-propyl, cyclopropyl, just Butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, n-hexyl, isohesyl.Preferably methyl, ethyl or propyl group. Substituted alkyl can be dihalo or tri haloalkyl, such as trifluoromethyl, trifluoroethyl, trichloromethyl, trichloroethyl, tribromo Methyl, three bromomethyl etc..
Term " halogen ", " halo " and " halogen " represents F, Cl, Br or I.
Term " cycloalkyl " refers to that non-aromatic monocyclic contains carbocyclic ring, and it can be saturation, with 3-8 ring carbon atom.Specifically Example includes, but are not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.
Term " heterocyclic radical " used herein or " heterocycle " refer to the aromatics as ring memberses with least one hetero atom With non-aromatic cyclic group.It is preferred that heterocyclic radical for those contain 5 or 6 annular atoms to include at least one heteroatomic miscellaneous Ring group, the more preferably 5 or 6 circle heterocycles bases containing 1 nitrogen-atoms and 1 oxygen atom, or contain 1 nitrogen-atoms or 1 oxygen 5 or 6 circle heterocycles bases of atom, 5 or 6 yuan of non-aromatic heterocycles either containing 1 nitrogen-atoms and 1 oxygen atom or contain 1 5 or 6 yuan of non-aromatic heterocycles of individual nitrogen-atoms or 1 oxygen atom, and " heterocyclic radical " include：Cyclic amine group, it is all Such as morpholinyl, preferably morpholino, preferably piperidyl, piperidino, preferably pyrrolidinyl, pyrrolidino；With cyclic ethers class base Group, tetrahydrofuran base, THP trtrahydropyranyl etc..Aromatic heterocyclic radical, is that can include 1-3 miscellaneous originals also referred to as " heteroaryl " List-ring of son is miscellaneous-aromatic group, such as pyrroles, furans, thiophene, imidazoles, oxazoles, thiazole, triazole, pyrazoles, pyridine, pyrazine, rattle away Piperazine, pyrimidine group etc..Term " hetero atom " used herein includes nitrogen-atoms, oxygen atom and sulphur atom.Term used herein Heteroaryl also includes polycyclic miscellaneous-aromatic systems with two or more rings, and two atoms therein are that two adjacent rings are total to Such as with (these rings are " fusions "), at least one in its middle ring is heteroaryl, and other rings can be cycloalkyl, cyclenes Base, aryl, heterocycle and/or heteroaryl.Heteroaryl includes 5 or 6 yuan containing 1 or 2 nitrogen-atoms, oxygen atom or sulphur atom List-ring is miscellaneous-aromatic group.Polycyclic miscellaneous-aromatic systems with two rings include benzo five-membered heteroaryl, the quinary heteroaryl Contain a nitrogen-atoms, oxygen atom or sulphur atom.The example of polycyclic hetero-aromatic system include quinoline, isoquinolin, tetrahydroisoquinoline, Quinoxaline, benzimidazole, benzofuran, purine, imidazopyridine, BTA etc..The example of heteroaryl also includes pyridine radicals, Pyrazinyl, pyrimidine radicals, pyridazinyl, imidazole radicals, pyrrole radicals, pyrazolyl, triazolyl, tetrazole radical,It is oxazolyl, differentOxazolyl, Di azoly, thiazolyl, isothiazolyl or thiadiazolyl group, including for example, 2- furyls, 3- furyls, TMSIM N imidazole base, 2- imidazoles Base, 4- imidazole radicals, 5- imidazole radicals, 3- are differentOxazolyl, 4- are differentOxazolyl, 5- are differentOxazolyl, 2-Di azoly, 5-Two Oxazolyl, 2-Oxazolyl, 4-Oxazolyl, 5-Oxazolyl, 3- pyrazolyls, 4- pyrazolyls, 1- pyrrole radicals, 2- pyrrole radicals, 3- pyrroles Base, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, 3- pyridazinyls, 2- thiazolyls, 4- Thiazolyl, 5- thiazolyls, 2- triazolyls, 5- triazolyls, tetrazole radical, 2- thienyls, 3- thienyls, carbazyl, benzimidazolyl, Benzothienyl, benzofuranyl, indyl, BTA base, benzothiazolyl, benzoIt is oxazolyl, benzimidazolyl, different Quinolyl, indyl, isoindolyl, acridinyl, benzisoxaOxazolyl, isothiazolyl, 1,2,3-Di azoly, 1,2,5-Di azoly, 1,2,4-Di azoly, 1,2,3- triazolyls, 1,2,3- thiadiazolyl groups, 1,3,4- thiadiazolyl groups, 1,2,5- thiophenes Di azoly, purine radicals, pyrazinyl, cyanuro 1,3,5, quinolyl (such as 2- quinolyls, 3- quinolyls, 4- quinolyls) and different Quinolyl (such as 1- isoquinolyls, 3- isoquinolyls or 4- isoquinolyls).
Term " phosphate " expression-PO (OH) used in application2。
Term " alkoxy " use herein represents to pass through oxygen（" alkoxy ", such as-O- alkyl）Atom and molecule The alkyl as defined hereinabove of connection.Instantiation includes, but are not limited to methoxyl group, ethyoxyl, isopropoxy, positive third oxygen Base, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isoamoxy, positive hexyloxy, dissident's epoxide etc., When for substituted alkoxy, substituent can be such as halogen or amino.
Term " alkanoyl " means that-C (O) R, wherein R is alkyl defined herein.Instantiation includes, but not It is limited to formoxyl, acetyl group, isopropyl acyl group, n-propyl acyl group, normal-butyl acyl group, isobutyl group acyl group, sec-butyl acyl group, uncle Butyl acyl group, n-pentyl acyl group, isopentyl acyl group, n-hexyl acyl group, isohesyl acyl group etc..
Term " aryl " refers to carbocyclic aromatic cyclic group.The carbocyclic aromatic cyclic group only has carboatomic ring atom (generally 6-18) and including monocyclic aromatic ring such as phenyl and the polycyclic aromatic ring system condensed, one of carbocyclic aromatic ring and one Individual or multiple aromatic ring fusions, wherein the group or point that connect are on carbocyclic aromatic ring.Example includes 1- naphthyls, 2- naphthyls, 1- Anthryl and 2- anthryls.In this application in use, also including such group, wherein aromatics in the range of term " carbocyclic aromatic ring " Ring is fused to one or more non-aromatic rings (carbocyclic ring or heterocycle), such as in indanyl, phthalimide group, naphthalimide (naphthimidyl), phenanthridinyl or tetralyl, wherein the group or point that connect are located on carbocyclic aromatic ring.
Term DMAP is DMAP.
Term DIC is N, N- DICs.
Term DMF is dimethylformamide.
Term " racemic mixture " indicates the equimolar mixing of two or more enantiomter materials of no optical activity Thing.The present invention includes all stereoisomers of compound described herein.
The present invention includes the salt or solvate of compound described herein, including combinations thereof, the solvation of such as salt Thing.The compound of the present invention can exist with solvate forms (such as hydrate forms) and unsolvated thing form, this Invention includes all such forms.
Generally, but be not that utterly, salt of the invention is pharmaceutically acceptable salt.Term is included in " pharmaceutically may be used Salt in the salt of receiving " represents the nontoxic salts of the compound of the present invention.
The example of suitable pharmaceutically acceptable salt includes inorganic acid addition salt, such as hydrochloride, bromate, sulfuric acid Salt, phosphate and nitrate；Organic acid addition salt, such as acetate, galactosaccharic acid salt, propionate, succinate, lactic acid Salt, glycollate, malate, tartrate, citrate, maleate, fumarate, mesylate, p-methyl benzenesulfonic acid Salt and ascorbate；With the salt of acidic amino acid formation, such as aspartate and glutamate；Alkali metal salt, such as sodium Salt and sylvite；Alkali salt, such as magnesium salts and calcium salt；Ammonium salt；Organic alkali salt, such as front three amine salt, triethylamine salt, pyridine Salt, picoline salt, dicyclohexyl amine salt and N, N'- dibenzylethylenediamine salt；With the salt formed with basic amino acid, such as Lysine salt and arginine salt.In some cases, the salt can be hydrate or alcohol solvent compound.
The qualifier " about " being used together with quantity including described value, and specify with context implication (for example, Including the error degree relevant with certain amount of measurement).
Present invention also offers the synthetic method of formula (I) compound.
Methods described can be reacted according to following scheme, so as to prepare the formula (I) compound.
Wherein, R1、R2、R3, A, B, D, Y be as defined above text formula (I) is defined, wherein each R '1Independently be- COR4, R4As formula (I) is defined, X is NH, O or S.
The inventive method can be reacted according to following scheme, and formula (I) compound with Formula VIII structure is converted For formula (I) compound with Formula IX structure
Wherein, R1、R2、R3、R4, A, B, D definition such as formula (I) defined.
The inventive method can also be reacted according to following scheme, so that Formula VIII compound is converted into Formula X chemical combination Thing
Wherein, wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R1、R2、R3、R4、 R9, A, B, D such as formula (I) defined, X be NH, O or S.
The inventive method can also be reacted according to following scheme, so that Formula IX compound is converted into Formula X I
Wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R1、R2、R3、R4、R9、A、B、 D such as formulas (I) are defined.
The inventive method can also be reacted according to following scheme, so that Formula VIII compound is converted into XIII chemical combination Thing
Wherein, R1、R2、R3、R4、R11、R12, A, B and D such as formula (I) defined, X be NH, O or S.
The inventive method can also be reacted according to following scheme, so that Formula IX compound is converted into XIV chemical combination Thing
Wherein, R1、R2、R3、R4、R11、R12, A, B and D such as formula (I) defined.
The method of the invention may include steps of：
Step 1）Make formula III compound
Reacted with the compound of formula 1,
(R’1)2O formulas 1
So as to production IV compounds,
Wherein each R '1It independently is-COR4, R1、R2、R3、R4, A, B, D such as formula (I) defined, R13For halogen or nitro；
Step 2）Make formula IV compound and HXCH2COY ' reacts, and obtains Formula V compound,
Wherein Y ' is C1-6Alkoxy, R1、R2、R3、R4, A, B, D such as formula (I) defined, X be NH, O or S；
Step 3）By Formula V compound and acid and its reactant salt, Formula IV compound is obtained
Wherein Y ' such as Formula V is defined, R1、R2、R3、R4, A, B, D such as formula (I) defined, X be NH, O or S；
Step 4）By Formula IV hydrogenation of compounds, Formula VII compound is obtained
Wherein Y ' such as Formula V is defined, R1、R2、R3、R4, A, B, D such as formula (I) defined, X be NH, O or S；
Step 5）Formula VII compound and alkali are reacted, formula (I) compound is obtained, it has the structure of Formula VIII
Wherein R1、R2、R3、R4, A, B, D such as formula (I) defined, X be NH, O or S.
Method of the present invention can also comprise the following steps：
Step 6）In the presence of a catalyst, by formula (I) compound with Formula VIII structure
It is converted into formula (I) compound with Formula IX structure
Wherein R1、R2、R3、R4, A, B, D such as formula (I) defined.
Method of the present invention can also comprise the following steps：
Step 7）In the presence of appropriate alkali, by Formula VIII compound
With R8ZH reacts, and obtains Formula X compound
Wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R1、R2、R3、R4、R9、A、B、 D such as formulas (I) are defined, and X is NH, O or S.
The method that the present invention is stated can also comprise the following steps：
Step 8）By Formula IX compound
With R8ZH reacts, and obtains Formula X I.
Wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R1、R2、R3、R4、R9、A、B、 D such as formulas (I) are defined.
Method of the present invention can also comprise the following steps：
Step 9）By Formula VIII compound
WithReaction, obtains Formula X III compounds
Wherein, R1、R2、R3、R4、R11、R12, A, B, D and X such as formula (I) defined.
Method of the present invention can also comprise the following steps：
Step 10）By Formula IX compound
WithReaction, obtains Formula X IV compounds
Wherein, R1、R2、R3、R4、R11、R12, A, B and D such as formula (I) defined.
In an embodiment of the method for the present invention, step 1）It is carried out as follows, in inert gas, preferably nitrogen is present Under, in organic solvent, preferably in dichloromethane, in catalyst, preferably in the presence of butter of tin, and/or nitromethane, preferably exist At room temperature, formula III compound is reacted with the compound of formula 1, so that production IV compounds.
In an embodiment of the method for the present invention, step 2）It is carried out as follows, in inert gas, preferably nitrogen is present Under, by formula IV compound, HXCH2COY ' and appropriate alkali, such as anhydrous pyridine are excellent in appropriate solvent, such as absolute methanol Preference temperature, e.g., from about 90 DEG C reaction appropriate times, such as 48h are selected in, Formula V compound is obtained.
In an embodiment of the method for the present invention, step 3）It is carried out as follows, in inert gas, preferably nitrogen is present Under, by Formula V compound and acid and its salt, preferably ammonium acetate and glacial acetic acid reaction, obtain Formula IV compound.
In an embodiment of the method for the present invention, step 4）It is carried out as follows, in catalyst, such as 10% Pd-C In the presence of, in organic solvent, such as ethyl acetate, preferably in appropriate pressure, such as 45 atmospheric pressure, by Formula IV compound hydrogen Change, obtain Formula VII compound.
In an embodiment of the method for the present invention, step 5）It is carried out as follows, by Formula VII compound and suitably Alkali, such as sodium hydroxide, in appropriate solvent, such as ethanol, water and/or tetrahydrofuran, preferably in proper temperature, such as room temperature Appropriate time, such as 5h are reacted, formula (I) compound is obtained, it has the structure of Formula VIII.
In an embodiment of the method for the present invention, 6) described method also comprises the following steps：
In the presence of catalyst, such as Raney's nickel, preferably in appropriate alkali, such as sodium hydroxide, in appropriate solvent, for example In water, formula (I) compound with Formula VIII structure is converted into formula (I) compound with Formula IX structure.
In an embodiment of the method for the present invention, 7) described method also comprises the following steps：
In the presence of DIC and DMAP, by Formula VIII compound and R8ZH reacts, and obtains Formula X compound.
In an embodiment of the method for the present invention, 8) described method also comprises the following steps：
In the presence of inert gas such as nitrogen, appropriate alkali such as triethylamine, in appropriate solvent such as DMF, by Formula IX Compound and R8ZH reacts, and obtains Formula X I.
In an embodiment of the method for the present invention, 9) described method also comprises the following steps：
In inert gas, preferably in the presence of nitrogen, in the presence of appropriate alkali, such as triethylamine, in appropriate solvent, for example In DMF, preferably in proper temperature, for example react at room temperature appropriate time such as 5min, by Formula VIII compound withReaction, obtains Formula X III compounds.
In an embodiment of the method for the present invention, 10) described method also comprises the following steps：
In inert gas, preferably in the presence of nitrogen, in the presence of appropriate alkali, such as triethylamine, in appropriate solvent, for example In DMF, preferably in proper temperature, such as room temperature, by Formula IX compound withAppropriate time such as 5min is reacted, Obtain Formula X IV compounds.
The preparation of stereoisomer
Prepared by the conventional technical means that the stereoisomer of the compounds of this invention is referred to prior art, for example, Guo Xia The exploration and its research of stereoisomer of the fully synthetic route of creatmycin of icepro etc.（Acta Pharmaceutica Sinica, 1987,22（9）：671- 678）.Specifically, according to the above method, the stereoisomer for the compound being prepared in table 1, it has such as formula（II）Or XV Described spatial configuration, the especially compound of table 2.
Those skilled in the art know how to prepare the salt or solvate of compound of the present invention.
The present invention also provide contain in formula defined above (I) compound or its pharmacodynamics acceptable salt as activity into The bactericidal composition divided.The weight ratio of the indole derivatives that pharmaceutical composition contains in the composition is 0.7-99.9%, and medicine can The weight ratio of the carrier of receiving in the composition is 0.1-99.9%.Pharmaceutical composition exists to be adapted to medicinal dosage form. Medicinal dosage form can be tablet, sugar coated tablet, film coated tablet, enteric coated tablet, sustained-release tablet, capsule, ebonite Wafer, soft capsule, Duracaps, oral liquid, mixture, mouth containing agent, granule, electuary, pill, powder, paste, sublimed preparation, Supensoid agent, solution, injection, powder-injection, freeze drying powder injection, cachet, suppository, ointment, emplastrum, creme, spray, Aerosol, drops, patch.
The pharmaceutical composition of the present invention, as dosage form, the effective dose of the invention compound contained in every dose is 0.1- 1000mg, described every dose refers to each preparation unit, such as every of tablet, every of capsule, can also refer to each taking dosage, Such as each taking 100mg.
The pharmaceutical composition of the present invention is being prepared into pulvis, tablet, dispersible pulvis, capsule, cachet, suppository and ointment When the solid or semisolid pharmaceutical formulation of form, solid carrier can be used.Workable solid carrier be preferably selected from diluent, One or more materials in flavor enhancement, solubilizer, lubricant, suspending agent, adhesive, exapnsion agent etc., or can be encapsulating substance In powderous preparations, in the carrier containing 5% to 70% micronised active composition.Suitable solid carrier include magnesium carbonate, Magnesium stearate, talcum powder, sucrose, lactose, fructose, dextrin, starch, gelatin, methylcellulose, sodium carboxymethylcellulose, low boiling Point wax, cocoa butter etc..Because they are easy to administration, tablet, pulvis, cachet and the best oral administration solid system of Capsules representative Profit.
The liquid preparation of the present invention includes solution, suspension and emulsion.For example, the ejection preparation of parenteral administration can be water Or water-propylene glycol solution form, and its isotonic degree is adjusted, pH etc. makes the physiological condition suitable for live body；Liquid preparation can also be made Into the solution form in polyethylene glycol, the aqueous solution.Can be by the way that active component be dissolved in water, appropriate coloring is added Agent, flavor enhancement, stabilizer and thickener, to prepare oral aqueous solution.The active component of micronized can be dispersed in stickum Hanged as prepared in natural and rubber polymer, methylcellulose, sodium carboxymethylcellulose and other known suspending agent suitable for oral water Liquid.
Homogeneous for ease of administration and dosage, it is particularly advantageous that said medicine preparation is configured into dosage unit form. The dosage unit form of preparation refers to the physical separation unit for being adapted as single dose, and each unit, which contains, produces desired control The active component of the scheduled volume calculated of therapeutic effect.This dosage unit form can be packaged form, such as tablet, capsule or dress Pulvis in tubule or bottle or the ointment in pipe or bottle, gel or creme.
Although the amount of contained active component can change in dosage unit form, the general active component selected by Effect, is adjusted in the range of 1-800mg.
When formula (I) reactive compound of the present invention is used as the medicine for the treatment of bacterium infection, preferably with 6-14mg/kg body weight Amount be administered.But dosage can with patient the need for, seriousness, the selected compounds of infection to be treated etc. and become Change.
Those skilled in the art can determine the preferred dose suitable for certain situation according to a conventional method.Typically, treatment is started Amount is then gradually increased dosage, until reaching optimum therapeuticing effect less than the optimal dose of active component.Rise for convenience See, total daily dose can be divided into several parts, fraction time administration.
Embodiment
Below by the further details of explanation present invention of embodiment, these embodiments can make those skilled in the art more The present invention is apparent from, but the implementation of the present invention is not limited in these embodiments, and these embodiments can not be with any side The formula limitation present invention.The related datas such as corresponding nuclear-magnetism, mass spectrometric data, the racemic mixing are write exactly below corresponding product The specific isomers that the title compound of thing form is corresponding has identical nuclear-magnetism and mass spectrometric data.Implementation is prepared below The related specific isomer structure of the title compound that refers to is represented compound in table 2, the title compound in example The numbering of specific isomers corresponding with its is specified as follows：The upper right corner of the numbering of title compound is added " ' ", so as to obtain institute State the corresponding specific isomers numbering of title compound.For example, the specific isomers numbering of compound 1 is compound 1 '.
Embodiment 1：2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles (compound C)
Step 1）Under nitrogen protection, to 0 DEG C of 4- iodine indoles（7.5g, 30mmol）Dichloromethane (75ml) solution in it is slow It is slow to add butter of tin（4.5ml,36mmol）, 30min is reacted at room temperature, Ac is then added2O（2.9g,30mmol）With nitro first Alkane（46.5ml）, 1h is reacted at room temperature, is quenched with frozen water, is filtered, filter cake is washed with a small amount of ether, and organic layer is carried with ethyl acetate Take, anhydrous Na2SO4Dry, be spin-dried for after solvent obtaining compound 3- acetyl -4- iodine Yin with after ethyl acetate and petroleum ether recrystallization Diindyl (6.9g, 78%).
1HNMR(500MHz,DMSO-d6）δ:12.07(s,1H),8.32(d,J=3.0Hz,1H),7.67(dd,J= 7.5Hz, 1.0Hz, 1H), 7.49 (dd, J=8.0Hz, 1.0Hz, 1H), 6.92 (t, J=8.0Hz, 1H), 2.49 (s, 3H).MS (ESI+)m/z:286.0[M+H]+。
Step 2）Under nitrogen protection, by 3- acetyl -4- iodine indoles（2.85g, 10mmol）, ethyl thioglycolate（3.84g, 16mmol）And anhydrous pyridine（2.61g, 17mmol）Absolute methanol (100ml) solution 48h is reacted at 90 DEG C, reaction terminates After be evaporated methanol, add 100ml ethyl acetate dissolving residue, wash ethyl acetate layer（80ml×3）, ethyl acetate layer is used Anhydrous Na2SO4Dry, be spin-dried for after solvent being recrystallized to give compound 3- acetyl -4- ethoxy carbonyl first sulphur with ethyl acetate and petroleum ether Base indoles (1.93g, 70%).
1HNMR(500MHz,DMSO-d6）δ:12.00 (s, 1H), 8.28 (s, 1H), 7.24 (d, J=8.0Hz, 1H), 7.14 (t, J=8.0Hz, 1H), 6.96 (d, J=8.0Hz, 1H), 4.08 (q, J=7.5Hz, 2H), 3.80 (s, 2H), 2.45 (s, 3H), 1.13(t,J=7.5Hz,3H)。MS(ESI+)m/z:278.1[M+H]+。
Step 3）Under nitrogen protection, by 3- acetyl -4- ethoxy carbonyl methylthioindoles（2.63g, 10mmol）, ammonium acetate （3.51g, 46mmol）And glacial acetic acid（5.54g, 93mmol）15h is reacted at 110 DEG C, reaction adds water after terminating, uses acetic acid Ethyl ester extracts water layer（80ml×3）, wash ethyl acetate layer（80ml×3）, by ethyl acetate layer anhydrous Na2SO4Dry, rotation Compound 3- methyl -5H- sulphur pyrans simultaneously [4,3,2-cd] Yin is obtained after dry solvent with petroleum ether and ethyl acetate column chromatography for separation Diindyl -2- carboxylic acid, ethyl esters (1.23g, 50%).
1HNMR(500MHz,DMSO-d6）δ:11.20 (s, 1H), 7.32 (s, 1H), 6.84 (d, J=8.0Hz, 1H), 6.77 (t,J=8.0Hz,1H),6.44(d,J=7.0Hz,1H),4.18(q,J=7.5Hz,2H),2.49(s,3H),1.24(t,J= 7.5Hz,3H)。MS(ESI+)m/z:259.1[M]+。
Step 4）To 3- methyl -5H- sulphur pyrans simultaneously [4,3,2-cd] indole -2-carboxylic ethyl ester（1.23g, 5mmol）Second Acetoacetic ester（50ml）The Pd-C of addition 10% in solution（324mg, 0.30mmol）, then catalytic hydrogenation is anti-under 45 atmospheric pressure 20h, reaction is answered to be filtered after terminating through diatomite, ethyl acetate, which is washed, uses petroleum ether and acetic acid second after filter cake, filtrate concentrated solvent Ester column chromatography for separation obtains compound 3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole -2-carboxylic ethyl ester (0.74g, 60%).1HNMR(500MHz,DMSO-d6）δ:12.85 (s, 1H), 10.80 (s, 1H), 7.15 (d, J=2.0Hz, 1H),7.12(d,J=8.0Hz,1H),6.92(t,J=7.5Hz,1H),6.73(d,J=7.0Hz,1H),4.29(d,J=3.0Hz, 1H),4.16(q,J=7.5Hz,2H),3.66(dq,J=3.5Hz,7.0Hz,1H),1.23(t,J=7.0Hz,3H)。MS(ESI+) m/z:261.3[M]+。
Step 5）By 3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole -2-carboxylic ethyl ester（0.5g, 2mmol）And sodium hydroxide（1.21g, 30mmol）Ethanol（30ml）, water（18ml）And tetrahydrofuran（80ml）Solution room temperature is anti- Answer 5h.Reaction terminates to add salt solution dilution in backward reaction solution, then adds 2M hydrochloric acid solution（20ml）, carried with dichloromethane Take（80ml×3）, anhydrous magnesium sulfate dry, ethyl acetate washing filter cake, be spin-dried for after solvent use dichloromethane and re crystallization from toluene Obtain racemic mixture 2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles (0.30g, 66%).
By above-mentioned gained racemic mixture 2- carboxylic acids -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles (0.3g) is dissolved in absolute methanol（8ml）, boiling is heated to, (-)-α-phenylethylamine is added dropwise（0.18ml）, filter while hot, after cooling Separate out (S)-α-phenylethylamine (2R, 3S) -2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles, white Rod crystalline substance 0.20g.Mother liquor is retained.The crystallization secondary rear weight 0.17g of absolute methanol recrystallization.
By the crystallization and H2O（9ml）Mixture with 49%H2SO4—H2O processing, with extracted by ether, is washed to pH5, nothing Water MgSO4Dry.Concentration, chloroform-Diethyl ether recrystallization once, obtains (2R, 3S) -2- carboxylic acid -3- methyl -3,5- dihydros -2H- Sulphur pyrans simultaneously [4,3,2-cd] indoles 0.1g, is white-amorphous crystallization.Related data is as follows：
1HNMR(500MHz,DMSO-d6）δ:12.99 (s, 1H), 10.89 (s, 1H), 7.14 (d, J=2.0Hz, 1H), 7.09(d,J=8.0Hz,1H),6.98(t,J=7.5Hz,1H),6.77(d,J=7.0Hz,1H),4.24(d,J=3.0Hz,1H), 3.66(dq,J=3.5Hz,7.0Hz,1H),1.21(d,J=7.0Hz,3H)。MS(ESI+)m/z:233.1[M]+。
Embodiment 2：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid benzoyloxymethy Ester (CV2)
Under nitrogen protection, by racemic mixture 2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] Yin Diindyl or (2R, 3S) -2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles（0.23g, 1mmol）With three Ethamine（0.10g, 1mmol）It is dissolved in DMF solution (6ml) solution, reacts at room temperature 5min, then adds benzoic acid chloromethane base ester （0.17g, 1mmol）, 24h is reacted at room temperature, reaction adds ethyl acetate 50ml after terminating, washes ethyl acetate layer（80ml×3）, By ethyl acetate layer anhydrous Na2SO4Dry, be spin-dried for after solvent being recrystallized to give racemic mixture 3- first with ethanol and petroleum ether Base -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid benzoyloxymethy ester or (2R, 3S) -3- methyl -3, 5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid benzoyloxymethy ester (0.22g, 60%), related data is such as Under：
1HNMR(500MHz,DMSO-d6）δ:10.91 (s, 1H), 7.94 (d, J=7.5Hz2H), 7.71 (d, J=7.5Hz, 2H),7.56(t,J=7.5Hz,1H),7.18(s,1H),7.11(d,J=8.5Hz,1H),6.98(t,J=7.5Hz,1H),6.76 (d, J=7.0Hz, 1H), 6.01 (t, J=6.5Hz, 1H), 5.94 (d, J=6.5Hz, 1H), 4.42 (d, J=3.5Hz, 1H), 3.61 (dd,J=3.5Hz,6.5Hz,1H),1.23(d,J=7.0Hz,3H)。MS(ESI+)m/z:367.1[M+H]+。
Embodiment 3：3- (indol-3-yl)-butyric acid (compound 20)
Sodium hydroxide (0.19g, 4.8mmol) is dissolved in water (50ml), racemic mixture 2- carboxylics are added under agitation Acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles or (2R, 3S) -2- carboxylic acid -3- methyl -3,5- dihydros - 2H- sulphur pyrans simultaneously [4,3,2-cd] indoles (1g, 4.3mmol), adds freshly prepd Raney's nickel (Raney nickel) thereto（10g, Weight in wet base, containing absolute ethyl alcohol）With water（50ml）, it is heated to reflux 1 hour, cold filtration is washed with 0.02% sodium hydroxide solution （20ml×2）, washing lotion merges with filtrate, plus 0.2 gram of activated carbon decolorizing, and filtering, filtrate uses extracted by ether after being acidified with concentrated hydrochloric acid （20ml×3）, ether extracted liquid is washed with water（10ml×3）, anhydrous sodium sulfate drying is stayed overnight, with ether and stone after concentrated solvent Yellow crystal is obtained after oily ether recrystallization, it is racemic mixture 3- (indol-3-yls）- butyric acid or (S) -3- (indol-3-yls）- Butyric acid（0.46g, 52%）, related data is as follows：
1HNMR(400MHz,DMSO-d6）δ:12.00 (s, 1H), 10.76 (s, 1H), 7.53 (d, J=8.0Hz, 1H), 7.31(d,J=8.0Hz,1H),7.09(d,J=2.4Hz,1H),7.04(t,J=7.2Hz,1H),6.95(t,J=7.2Hz,1H), 3.42(m,1H),2.65(m,1H),2.46(m,1H),1.31(d,J=6.8Hz,3H)。MS(ESI+)m/z:204.3[M+H]+。
Embodiment 4：3- (indol-3-yls）- butyric acid benzoyloxymethy ester (compound DSCV)
Under nitrogen protection, by racemic mixture 3- (indol-3-yls）- butyric acid or (S) -3- (indol-3-yls）- butyric acid （0.20g, 1mmol）And triethylamine（0.10g, 1mmol）It is dissolved in DMF solution (6ml) solution, reacts at room temperature 5min, then Add benzoic acid chloromethane base ester（0.17g, 1mmol）, 24h is reacted at room temperature, reaction adds ethyl acetate 50ml after terminating, washes second Ethyl acetate layer（80ml×3）, by ethyl acetate layer anhydrous Na2SO4Dry, target is obtained after being spin-dried for the separation of solvent rear pillar level Compound 3- (indol-3-yls）- butyric acid benzoyloxymethy ester (0.23g, 70%), it is racemic mixture or (S) isomery Body, related data is as follows：
1HNMR（400MHz,DMSO-d6）δ:10.79 (s, 1H), 7.90 (d, J=8.4Hz, 1H), 7.69 (t, J=7.6Hz, 1H),7.53(t,J=7.6Hz,1H),7.16(d,J=8.0Hz,1H),7.12(d,J=2.4Hz,1H),7.03(m,1H),6.93 (m,1H),5.92(q,2H),3.45(m,1H),2.84(m,1H),2.69(m,1H),1.30(d,J=6.8Hz,3H)。MS(ESI+)m/z:338.1[M+H]+。
Embodiment 5：2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6- azaindole (chemical combination Thing 1)
With iodo- 1H- pyrrolo-es [3, the 2-c] pyridines of 4- for raw material, title compound is prepared according to the method similar to embodiment 1 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.73 (s, 1H), 7.63 (s, 1H), 7.31 (s, 1H), 6.93 (s, 1H), 6.37(s,1H),4.04(s,1H),3.50(m,1H),1.44(d,J=6.5Hz,3H)。MS(ESI+)m/z:234.05[M]+。
Embodiment 6：2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,7- diaza indoles (compound 2)
With iodo- 1H- pyrrolo-es [3, the 2-d] pyridazines of 4- for raw material, title compound is prepared according to the method similar to embodiment 1 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.77 (s, 1H), 8.96 (s, 1H), 7.92 (s, 1H), 6.37 (s, 1H), 4.04 (s,1H),3.50(m,1H),1.46(d,J=6.5Hz,3H)。MS(ESI+)m/z:235.04[M]+。
Embodiment 7：2- carboxylic acid -3- methyl -3,5- dihydro -2H- pyrans simultaneously (change by [4,3,2-cd] -6,7- diazas indoles Compound 3)
Think iodo- 1H- pyrrolo-es [3,2-d] the pyridazine raw materials of 4-, title compound is prepared by the method similar to embodiment 1 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.78 (s, 1H), 8.90 (s, 1H), 7.88 (s, 1H), 6.37 (s, 1H), 4.47 (s,1H),3.70(m,1H),1.53(d,J=6.5Hz,3H)。MS(ESI+)m/z:219.06[M]+。
Embodiment 8：3- methyl -6- methoxyl group -3,5- dihydro -2H- sulphur pyrans simultaneously (change by [4,3,2-cd] indole-2-carboxylic acid Compound 4)
Think the iodo- 7- methoxyl groups -1H- indoles raw materials of 4-, title compound prepared by the method similar to embodiment 1, It is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 12.53 (s, 1H), 11.68 (s, 1H), 9.82 (s, 1H), 7.15 (s, 1H), 6.89(s,1H),4.13(s,1H),4.07(s,3H),3.50(m,1H),1.41(d,J=6.5Hz,3H)。MS(ESI+)m/z: 263.06[M]+。
Embodiment 9：3- methyl -6- methylamino -3,5- dihydro -2H- sulphur pyrans simultaneously (change by [4,3,2-cd] indole-2-carboxylic acid Compound 5)
Using the iodo- N- Methyl-1H-indoles -7- amine of 4- as raw material, title compound is prepared by the method similar to embodiment 1 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 12.78 (s, 1H), 11.31 (s, 1H), 9.86 (s, 1H), 7.02 (s, 1H), 6.97(s,1H),4.04(s,1H),3.50(m,1H),2.88(s,3H),1.54(d,J =6.5Hz,3H)。MS(ESI+)m/z: 262.08[M]+。
Embodiment 11：2- carboxylic acid -3,4- dimethyl -7- trifluoromethyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] Yin Diindyl (compound 7)
Using 2- methyl -4- iodo- 6- (trifluoromethyl) -1H- indoles as raw material, prepared by the method similar to embodiment 1 Title compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 12.17 (s, 1H), 11.86 (s, 1H), 8.37 (s, 1H), 6.92 (s, 1H), 4.47(s,1H),3.70(m,1H),2.49(s,3H),1.45(d,J=6.5Hz,3H)。MS(ESI+)m/z:299.08[M]+。
Embodiment 12：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid（3 '-morpholino） Propyl ester（Compound 75）
By 2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles or (2R, 3S) -2- carboxylic acids -3- Methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles（2.55g, 11mmol）It is dissolved in dichloromethane（50ml）, add DMAP (0.24g, 1.96mmol) and 3- morpholinoes-propyl alcohol are added after DIC (1.51g, 11.98mmol), stirring at normal temperature 1h (1.59g, 10.95mmol), is heated to reflux after 6h washing reaction solution with water and saturated common salt, anhydrous magnesium sulfate is dried, after filtering Be evaporated, ethyl acetate petroleum ether system recrystallization, obtain 3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles - 2- carboxylic acids（3 '-morpholino）Propyl ester or (2R, 3S) -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- carboxylics Acid（3 '-morpholino）Propyl ester 2.97g（75%）, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.86 (s, 1H), 9.65 (s, 1H), 7.18 (s, 1H), 7.11 (s, 1H), 7.02 (s,1H),4.18(m,2H),4.00(s,1H),3.81(m,1H),3.69(m,2H),2.62(m,2H),2.49(s,2H),2.39 (m,2H),1.78(s,2H),1.57(d,J=6.5Hz,3H)。MS(ESI+)m/z:360.15[M]+。
Embodiment 13：The fluoro- 3,5- dihydros -2H- sulphur pyrans of 3- methyl -7- simultaneously [4,3,2-cd] indole-2-carboxylic acid（2 '- Quinoline generation）Ethyl ester (compound 76)
With compound 2- morpholinoes ethanol and the fluoro- 3,5- dihydros -2H- sulphur pyrans of 2- carboxylic acid -3- methyl -7- simultaneously [4,3,2- Cd] indoles be raw material, its be racemic mixture or (2R, 3S) isomers, prepare title according to the method for similar embodiment 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.84 (s, 1H), 9.79 (s, 1H), 7.02 (s, 1H), 6.89 (s, 1H), 4.27 (s,2H),4.00(s,1H),3.81(m,1H),3.71(m,4H),2.83(m,4H),2.59(m,2H),1.52(d,J=6.5Hz, 3H)。MS(ESI+)m/z:364.13[M]+。
Embodiment 14：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid（2 '-morpholino）Second Ester (compound 77)
With compound 2- morpholinoes ethanol and 2- carboxylic acid -3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indoles For raw material, it is racemic mixture or (2R, 3S) isomers, and title compound is prepared according to the method for similar embodiment 12, It is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.36 (s, 1H), 9.80 (s, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 6.80 (s,1H),4.31(s,2H),4.30(s,1H),4.01(m,1H),3.70(m,4H),2.86(s,4H),2.82(m,2H),1.40 (d,J=6.5Hz,3H)。MS(ESI+)m/z:330.16[M]+。
Embodiment 15：3- methyl -7- methoxyl group -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid （2 '-dimethylamino）Ethyl ester (compound 78)
With compound 2- methylaminoethanols and 2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] Yin Diindyl is raw material, and it is racemic mixture or (2R, 3S) isomers, is prepared according to the method reaction of similar embodiment 12 titled Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.66 (s, 1H), 9.78 (s, 1H), 7.02 (s, 1H), 6.79 (s, 1H), 4.23 (m,2H),4.00(s,1H),3.88(s,3H),3.81(m,1H),3.16(m,2H),2.81(s,6H),1.41(d,J=6.0Hz, 3H)。MS(ESI+)m/z:334.14[M]+。
Embodiment 16：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diazas indoles -2- formyls （2 '-dimethylaminoethyl）Amine (compound 79)
With compound N, N- dimethyl-ethylenediamines and 2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2- Cd] -6,8- diazas indoles be raw material, its be racemic mixture or (2R, 3S) isomers, according to the side of similar embodiment 12 Method prepares title compound, and it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.53 (s, 1H), 9.05 (s, 1H), 7.30 (s, 1H), 4.11 (s, 1H), 3.48(s,1H),3.40(m,1H),3.35(m,2H),2.64(m,2H),2.32(s,6H),1.61(d,J=6.5Hz,3H)。MS (ESI+)m/z:305.13[M]+。
Embodiment 17：2- (3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -8- azaindoles -2- carbonyl oxygen Base) ethylphosphonic acid (compound 80)
By 2- carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -8- azaindoles or (2R, 3S) -2- Carboxylic acid -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -8- azaindoles（2.57g, 11mmol）It is dissolved in dichloromethane Alkane（50ml）, add and DMAP (0.24g, 1.96mmol) and hydroxyl second added after DIC (1.51g, 11.98mmol), stirring at normal temperature 1h Base dimethyl phosphonate (1.84g, 10.95mmol), is heated to reflux after 6h, and reaction solution, anhydrous slufuric acid are washed with water and saturated common salt Magnesium dry, be evaporated after filtering, ethyl acetate petroleum ether system recrystallization, obtain 3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4, 3,2-cd] -8- azaindole -2- carboxylic acids（2 '-dimethyl phosphonate）Ethyl ester 3.50g, is dissolved in dichloromethane（50ml）, add Bromotrimethylsilane (9.85g, 64.8mmol) stirring at normal temperature 3h, uses methanol terminating reaction, is evaporated, obtain product 2- (3- methyl- 3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -8- azaindole -2- carbonyloxy groups) ethylphosphonic acid 2.53g（68%）, it is outer Racemic mixture or (2R, 3S) isomers, related data are as follows：
1H NMR (500MHz, chloroform) δ 11.58 (s, 1H), 8.12 (s, 1H), 7.21 (s, 1H), 6.37 (s, 1H), 4.31 (m,2H),4.00(s,1H),3.81(m,3H),2.02(m,2H),1.42(d,J=6.0Hz,3H)。MS(ESI+)m/z:342.04 [M]+。
Embodiment 18：N- methyl -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -7- azaindole -2- carboxylics Sour methyl esters (compound 8)
With iodo- 1- methyl isophthalic acids H- pyrrolo-es [3, the 2-c] pyridines of 4- for raw material, pass through the method similar to embodiment 1 and 12 Title compound is prepared, it is racemic mixture or (2R, 3S) isomers, related data is as follows：
1H NMR (500MHz, chloroform) δ 7.71 (s, 1H), 6.90 (s, 1H), 6.29 (s, 1H), 5.32 (m, 1H), 4.00 (s,1H),3.78(m,1H),3.62(s,3H),1.42(d,J=6.5Hz,3H)。MS(ESI+)m/z:262.08[M]+。
Embodiment 19：N- acetyl group -3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -7- azaindoles -2- Carboxylic acid, ethyl ester (compound 9)
With 1- (iodo- 1H- pyrrolo-es [2, the 3-c] pyridine -1- bases of 4-) ethyl ketone for raw material, by similar to embodiment 1 and 12 Method prepare title compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 8.65 (s, 1H), 8.30 (s, 1H), 7.12 (s, 1H), 4.12 (m, 2H), 4.01 (s,1H),3.81(m,1H),2.70(s,3H),1.54(d,J=6.5Hz,3H),1.01(m,3H)。MS(ESI+)m/z:304.09 [M]+。
Embodiment 20：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -6,7- diaza indole-2-carboxylic acid second Ester (compound 10)
With iodo- 1H- pyrrolo-es [3, the 2-d] pyridazines of 4- for raw material, title is prepared by the method similar to embodiment 1 and 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.32 (s, 1H), 8.88 (s, 1H), 6.28 (s, 1H), 4.15 (m, 2H), 3.98 (s,1H),3.84(m,1H),1.53(d,J=6.5Hz,3H),0.99(m,3H)。MS(ESI+)m/z:247.10[M]+。
Embodiment 21：3- methyl -3,5- dihydro -2H- pyrans simultaneously (change by [4,3,2-cd] -7- azaindole -2- carboxylic acid, ethyl esters Compound 11)
With iodo- 1H- pyrrolo-es [2, the 3-c] pyridines of 4- for raw material, title is prepared by the method similar to embodiment 1 and 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.33 (s, 1H), 8.86 (s, 1H), 8.36 (s, 1H), 6.37 (s, 1H), 4.43 (s,1H),4.26(m,2H),4.01(m,1H),1.42(d,J=6.5Hz,3H),1.30(m,3H)。MS(ESI+)m/z:246.10 [M]+。
Embodiment 22：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,7- diazas indoles -2- formyls Ethamine (compound 12)
With iodo- 1H- pyrrolo-es [3, the 2-d] pyridazines of 4- for raw material, title is prepared by the method similar to embodiment 1 and 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.43 (s, 1H), 8.32 (s, 1H), 7.83 (s, 1H), 6.37 (s, 1H), 4.43 (s,1H),4.26(m,2H),4.01(m,1H),1.42(d,J=6.5Hz,3H),1.30(m,3H)。MS(ESI+)m/z:262.09 [M]+。
Embodiment 23：The fluoro- 3,5- dihydros -2H- sulphur pyrans of 3- methyl -7- simultaneously [4,3,2-cd] the indole-2-carboxylic acid tert-butyl ester (compound 13)
Using the fluoro- 1H- indoles of the iodo- 6- of 4- as raw material, title compound is prepared by the method similar to embodiment 1 and 12, It is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.36 (s, 1H), 8.95 (s, 1H), 7.36 (s, 1H), 6.37 (s, 1H), 3.56 (s,1H),3.48(m,1H),1.40(s,9H),1.34(d,J=6.5Hz,3H)。MS(ESI+)m/z:307.10[M]+。
Embodiment 24：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- formyl tert-butylamine (chemical combination Thing 14)
Using the iodo- 1H- indoles of 4- as raw material, title compound is prepared by the method similar to embodiment 1 and 12, it is outer Racemic mixture or (2R, 3S) isomers, related data are as follows：
1H NMR (500MHz, chloroform) δ 11.66 (s, 1H), 9.79 (s, 1H), 8.00 (s, 1H), 7.02 (s, 1H), 6.90 (s,1H),6.85(s,1H),4.00(s,1H),3.81(m,1H),1.50(s,9H),1.34(d,J=6.5Hz,3H)。MS(ESI+)m/z:288.13[M]+。
Embodiment 25：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diazas indoles -2- formyls Methylamine (compound 15)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- for raw material, title is prepared by the method similar to embodiment 1 and 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.75 (s, 1H), 9.80 (s, 1H), 8.21 (s, 1H), 7.02 (s, 1H), 4.11 (s,1H),3.48(m,1H),1.53(s,3H),1.29(d,J=6.5Hz,3H)。MS(ESI+)m/z:248.07[M]+。
Embodiment 26：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6- azaindoles -2- formyl ethamine (compound 16)
With iodo- 1H- pyrrolo-es [3, the 2-c] pyridines of 4- for raw material, title is prepared by the method similar to embodiment 1 and 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.66 (s, 1H), 9.05 (s, 1H), 8.03 (s, 1H), 7.43 (s, 1H), 6.37 (s,1H),4.11(s,1H),3.48(m,1H),2.92(m,2H),1.34(d, J=6.5Hz,3H),1.20(s,3H)。MS(ESI+)m/z:261.09[M]+。
Embodiment 27：Simultaneously [4,3,2-cd] -6,7- diazas indoles -2- formyls are different for 3- methyl -3,5- dihydro -2H- pyrans Propylamine (compound 17)
With iodo- 1H- pyrrolo-es [3, the 2-d] pyridazines of 4- for raw material, title is prepared by the method similar to embodiment 1 and 12 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.88 (s, 1H), 8.92 (s, 1H), 8.02 (s, 1H), 6.01 (s, 1H), 6.37 (s,1H),4.11(s,1H),3.84(m,1H),1.31(d,J=6.5Hz,3H),1.07(s,6H)。MS(ESI+)m/z:260.13 [M]+。
Embodiment 30：3- (1- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridin-3-yl) butyric acid (compound 21)
With iodo- 1H- pyrrolo-es [2, the 3-c] pyridines of 1- methyl -4- for raw material, pass through the method system similar to embodiment 1 and 3 Standby title compound, it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.78 (s, 1H), 8.45 (s, 1H), 8.28 (d, J=6.5Hz, 1H), 7.22 (d,J=6.5Hz,1H),6.45(s,1H),3.36(s,1H),3.20(m,1H),2.51(m,2H),1.39(d,J=6.5Hz, 3H)。MS(ESI+)m/z:218.11[M]+。
Embodiment 32：3- (7- methoxyl groups -1- methyl isophthalic acid H- pyrrolo-es [3,2-c] pyridin-3-yl) butyric acid (compound 22)
With iodo- 7- methoxyl groups -1- methyl isophthalic acids H- pyrrolo-es [3, the 2-c] pyridines of 4- for raw material, by similar to the He of embodiment 1 3 method prepares title compound, and it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.06 (s, 1H), 7.98 (s, 1H), 7.85 (s, 1H), 6.14 (s, 1H), 3.91 (s,3H),3.66(s,1H),3.20(m,1H),2.50(m,2H),1.39(d,J=6.5Hz,3H)。MS(ESI+)m/z:248.12 [M]+。
Embodiment 33：3- (fluoro- 1H- pyrrolo-es [2,3-c] pyridin-3-yls of 7-) butyric acid (compound 23)
With fluoro- 1H- pyrrolo-es [2, the 3-c] pyridines of the iodo- 7- of 4- for raw material, prepared by the method similar to embodiment 1 and 3 Title compound, it is racemic mixture or (S) isomers, and related data is as follows
1H NMR (500MHz, chloroform) δ 11.36 (s, 1H), 10.55 (s, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 6.83(s,1H),3.20(m,1H),2.51(m,2H),1.40(d,J=6.5Hz, 3H)。MS(ESI+)m/z:222.08[M]+。
Embodiment 34：3- (fluoro- 1- methyl isophthalic acids H- pyrrolo-es [2,3-c] pyridin-3-yls of 7-) butyric acid ethyl ester (compound 24)
With fluoro- 1H- pyrrolo-es [2, the 3-c] pyridines of the iodo- 7- of 1- methyl -4- for raw material, by similar to embodiment 1,3 and 12 Method prepare title compound, it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 7.96 (s, 1H), 7.50 (s, 1H), 6.27 (s, 1H), 4.01 (m, 2H), 3.84 (s,3H),3.51(m,1H),2.54(m,2H),1.39(d,J=6.5Hz,3H),1.15(m,3H)。MS(ESI+)m/z:264.13 [M]+。
Embodiment 35：N- ethyls -3- (5- methyl isophthalic acid H- pyrrolo-es [2,3-c] pyridin-3-yl) butyryl ethamine (compound 25)
With iodo- 5- methyl isophthalic acids H- pyrrolo-es [2, the 3-c] pyridines of 4- for raw material, pass through the side similar to embodiment 1,3 and 12 Method prepares title compound, and it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.39 (s, 1H), 8.29 (s, 1H), 7.32 (s, 1H), 6.84 (s, 1H), 3.26 (m,2H),3.18(m,1H),2.66(m,2H),2.57(s,3H),2.49(s,1H),1.39(d,J=6.5Hz,3H),1.08(m, 3H)。MS(ESI+)m/z:245.15[M]+。
Embodiment 36：3- (7H- pyrrolo-es [2,3-c] pyridazine -5- bases) butyric acid tertiary butyl ester (compound 26)
With iodo- 7H- pyrrolo-es [2, the 3-c] pyridazines of 4- for raw material, prepared by the method similar to embodiment 12 titled Compound, it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 9.08 (s, 1H), 7.57 (s, 2H), 6.38 (s, 1H), 3.51 (m, 1H), 2.54 (m,2H),1.40(d,J=6.5Hz,3H),1.36(s,9H)。MS(ESI+)m/z:261.15[M]+。
Embodiment 37：3- (7- methyl -7H- pyrrolo-es [2,3-d] pyrimidine -5- bases) butyric acid tertiary butyl ester (compound 27)
With iodo- 7- methyl -7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- for raw material, pass through the side similar to embodiment 1,3 and 12 Method prepares title compound, and it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 9.25 (s, 1H), 8.52 (s, 1H), 6.15 (s, 1H), 3.78 (s, 3H), 3.51 (m,1H),2.53(m,2H),1.38(d,J=6.0Hz,3H),1.33(s,9H)。MS(ESI+)m/z:275.16[M]+。
Embodiment 38：N- ethyls -3- (5- (methylamino) -1H- indol-3-yls) butyramide (compound 28)
Using 4- iodo- 5- (methylamino) -1H- indoles as raw material, prepared and marked by the method similar to embodiment 1,3 and 12 Compound is inscribed, it is racemic mixture or (S) isomers, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.30 (s, 1H), 9.52 (s, 1H), 8.03 (s, 1H), 7.26 (s, 1H), 7.17 (s,1H),6.50(s,1H),6.37(s,1H),3.27(m,2H),3.18(m,1H),2.80(s,3H),2.55(m,2H),1.39 (d,J=6.0Hz,3H),1.05(m,3H)。MS(ESI+)m/z:259.17[M]+。
Embodiment 39：3- (1- acetyl group -6- Methyl-1H-indole -3- bases) butyric acid isopropyl esters (compound 29)
Using the iodo- 6- Methyl-1H-indoles of 1- acetyl group -4- as raw material, pass through the method system similar to embodiment 1,3 and 12 Standby title compound, it is racemic mixture or (S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 7.68 (s, 1H), 7.37 (s, 1H), 7.00 (s, 1H), 6.98 (s, 1H), 4.92 (m,1H),3.51(m,1H),2.70(s,3H),2.50(m,1H),2.27(m,2H),2.20(s,3H),1.42(d,J=6.0Hz, 3H),1.15(s,6H)。MS(ESI+)m/z:301.17[M]+。
Embodiment 40：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-methyl cyclohexane Alkyl carbonyl epoxide) methyl ester (compound 30)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 9.65 (s, 1H), 7.11 (d, J=7.0Hz, 3H), 6.04 (d, J=6.5Hz, 1H), 5.91(t,J=6.5Hz,1H),4.00(s,1H),3.81(m,1H),2.28(m,1H),1.66(m,3H),1.56(m,3H), 1.38(d,J=6.0Hz,3H),1.26(m,4H),1.01(m,3H)。MS(ESI+)m/z:387.15[M]+。
Embodiment 41：(the fluoro- 3,5- dihydros -2H- sulphur pyrans of 3- methyl -7- simultaneously [4,3,2-cd] indole-2-carboxylic acid 4- methoxies Butylcyclohexane carbonyl epoxide) methyl ester (compound 31)
Using the fluoro- 1H- indoles of the iodo- 6- of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2, its For racemic mixture or (2R, 3S) isomers, related data is as follows：
1H NMR (500MHz, chloroform) δ 9.79 (s, 1H), 7.02 (s, 1H), 6.89 (s, 2H), 6.52 (d, J=6.5Hz, 1H),6.05(d,J=6.5Hz,1H),4.00(s,1H),3.81(m,1H),3.45(s,3H),2.97(m,1H),2.02(m, 4H),1.50(m,2H),1.40(m,3H),1.38(d,J=6.0Hz,3H)。MS(ESI+)m/z:421.14[M]+。
Embodiment 42：3- methyl -7- methoxyl group -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (ring Propane carbonyl epoxide) methyl ester (compound 32)
Using the iodo- 6- methoxyl groups -1H- indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 9.64 (s, 1H), 7.02 (s, 1H), 6.78 (s, 2H), 6.05 (d, J=6.5Hz, 1H),5.93(d,J=6.5Hz,1H),4.10(s,1H),3.83(m,1H),3.73(s,3H),1.43(m,1H),1.38(d,J= 6.0Hz,3H),1.11(m,2H),0.83(m,2H)。MS(ESI+)m/z:361.10[M]+。
Embodiment 43：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -6,8- diaza indole-2-carboxylic acid (rings Pentane formyloxy) methyl ester (compound 33)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.98 (s, 1H), 9.05 (s, 1H), 7.36 (s, 1H), 6.37 (d, J=6.5Hz, 1H),5.73(d,J=6.5Hz,1H),4.00(s,1H),3.81(m,1H),2.57(m,1H),2.10(m,2H),1.84(m, 2H),1.75(m,2H),1.69(m,2H),1.46(d,J=6.0Hz,3H)。MS(ESI+)m/z:361.11[M]+。
Embodiment 44：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -8- azaindoles -2- carboxylic acid (cyclobutane Formyloxy) methyl ester (compound 34)
With iodo- 1H- pyrrolo-es [2, the 3-b] pyridines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 8.45 (s, 1H), 7.63 (s, 1H), 6.57 (d, J=6.5Hz, 1H), 6.49 (s, 1H),5.92(d,J=6.5Hz,1H),3.82(s,2H),3.74(m,1H),2.91(m,1H),2.50(m,2H),2.35(m, 2H),2.16(m,2H),1.38(d,J=6.0Hz, 3H)。MS(ESI+)m/z:346.10[M]+。
Embodiment 45：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -8- azaindoles -2- carboxylic acid (4 '-hydroxyls Butylcyclohexane formyloxy) methyl ester (compound 35)
With iodo- 1H- pyrrolo-es [2, the 3-b] pyridines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 8.23 (s, 1H), 7.40 (s, 1H), 6.67 (d, J=6.0Hz, 1H), 6.37 (s, 1H),5.82(d,J=6.0Hz,1H),4.00(s,1H),3.81(m,1H),3.25(m,1H),2.90(s,1H),2.76(m, 2H),2.27(s,2H),1.95(m,2H),1.63(m,2H),1.42(m,2H),1.38(d,J=6.5Hz,3H)。MS(ESI+)m/ z:390.12[M]+。
Embodiment 46：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (1 '-methyl cyclohexane Alkyl carbonyl epoxide) methyl ester (compound 36)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows
1H NMR (500MHz, chloroform) δ 9.80 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.67 (d, J=6.0Hz, 1H),5.82(d,J=6.0Hz,1H),4.00(s,1H),3.83(m,1H),2.07(m,2H),1.66(m,4H),1.56(m, 3H),1.44(d,J=6.5Hz,3H),1.35(m,1H),1.09(s,3H)。MS(ESI+)m/z:387.15[M]+。
Embodiment 47：3- methyl -7- (methylamino) -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- carboxylics Sour (4 '-methoxycyclohexyl alkyl carbonyl epoxide) methyl ester (compound 37)
Using the iodo- N- Methyl-1H-indoles -6- amine of 4- as raw material, prepared by the method similar to Examples 1 and 2 titled Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 7.02 (s, 1H), 6.75 (d, J=6.0Hz, 1H), 6.45 (s, 1H), 6.24 (s, 1H),5.83(d,J=6.0Hz,1H),4.02(s,1H),3.84(m,1H),3.47(s,3H),2.84(s,3H),2.79(m, 1H),2.57(m,1H),2.21(m,3H),1.82(m,3H),1.50(m,4H),1.38(d,J=6.5Hz,3H)。MS(ESI+)m/ z:432.17[M]+。
Embodiment 48：3,6- dimethyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-methyl Cyclohexane carbo epoxide) methyl ester (compound 38)
Using the iodo- 7- Methyl-1H-indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 8.80 (s, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 6.75 (d, J=6.0Hz, 1H),5.83(d,J=6.0Hz,1H),4.02(s,1H),3.83(m,1H),2.84(s,3H),2.57(m,1H),1.85(m, 2H),1.73(m,4H),1.53(m,1H),1.52(m,4H),1.38(d,J=6.5Hz,3H),1.02(m,3H)。MS(ESI+)m/ z:401.17[M]+。
Embodiment 49：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diaza indole-2-carboxylic acids (4 '-methoxycyclohexyl alkyl carbonyl epoxide) methyl ester (compound 39)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 9.05 (s, 1H), 6.76 (d, J=6.0Hz, 1H), 6.37 (s, 1H), 5.88 (d, J =6.0Hz,1H),4.00(s,1H),3.81(m,1H),3.47(s,3H),2.84(m,1H),2.37(m,1H),2.36(m,3H), 2.25(m,2H),2.07(m,2H),1.65(m,2H),1.56(m,2H),1.47(d,J=6.5Hz,3H)。MS(ESI+)m/z: 405.14[M]+。
Embodiment 50：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -8- azaindoles -2- carboxylic acid (4 '-hydroxyls Butylcyclohexane carbonyl epoxide) methyl ester (compound 40)
With iodo- 1H- pyrrolo-es [2, the 3-b] pyridines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 8.16 (s, 1H), 6.96 (s, 1H), 6.86 (d, J=6.0Hz, 1H), 6.64 (s, 1H),5.78(d,J=6.0Hz,1H),4.81(s,1H),4.01(s,1H),3.68(m,1H),3.42(m,2H),2.66(m, 2H),1.95(m,2H),1.71(m,2H),1.52(m,3H),1.43(d,J=6.5Hz,3H)。MS(ESI+)m/z:374.15[M ]+。
Embodiment 51：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diaza indole-2-carboxylic acids (4 '-cyclohexanecarbonyl epoxide) methyl ester (compound 41)
With iodo- 1H- pyrrolo-es [2, the 3-b] pyrimidines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.20 (s, 1H), 8.23 (s, 1H), 7.26 (s, 1H), 6.86 (d, J=6.0Hz, 1H),5.78(d,J=6.0Hz,1H),4.05(s,1H),3.81(m,1H),3.75(s,1H),2.90(m,1H),2.76(m, 2H),2.06(m,2H),1.75(m,2H),1.55(m,3H),1.39(d,J=6.5Hz,3H)。MS(ESI+)m/z:390.12[M ]+。
Embodiment 52：3- methyl -8- methoxyl group -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 ' - Methylcyclohexanecarbonyl epoxide) methyl ester (compound 42)
Using the iodo- 5- methoxyl groups -1H- indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2 Thing, it is racemic mixture or (2R, 3S) isomers, and data are as follows：
1H NMR (500MHz, chloroform) δ 11.23 (s, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 6.80 (s, 1H), 6.56 (d,J=6.0Hz,1H),5.68(d,J=6.0Hz,1H),4.81(s,1H),4.01(m,1H),3.91(s,3H),2.52(m, 2H),1.67(m,2H),1.53(t,J=5.5Hz,3H),1.40(m,2H),1.34(d,J=6.5Hz,3H),1.03(m,2H)。MS (ESI+)m/z:401.18[M]+。
Embodiment 53：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4- fluorine hexamethylene carbonyls Base epoxide) methyl ester (compound 43)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.31 (s, 1H), 7.14 (s, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 6.82 (s,1H),6.66(d,J=6.0Hz,1H),5.73(d,J=6.0Hz,1H),4.81(s,1H),4.49(m,1H),2.69(m, 2H),1.51(m,3H),1.49(m,4H),1.34(d,J=6.5Hz,3H)。MS(ESI+)m/z:375.15[M]+。
Embodiment 54：3,7- dimethyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-chlorine hexamethylene Alkyl carbonyl epoxide) methyl ester (compound 44)
Using the iodo- 6- Methyl-1H-indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2, It is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.28 (s, 1H), 6.82 (s, 1H), 6.38 (s, 1H), 6.14 (s, 1H), 6.06 (d,J=6.0Hz,1H),5.83(d,J=6.0Hz,1H),4.33(s,1H),3.88(m,1H),3.11(m,1H),2.38(s, 3H),2.23(m,4H),1.75(m,3H),1.35(m,2H),1.26(d,J=6.5Hz,3H)。MS(ESI+)m/z:405.13[M ]+。
Embodiment 55：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -6,8- diaza indole-2-carboxylic acids (4 '-methylamino cyclohexane carbo epoxide) methyl ester (compound 45)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.19 (s, 1H), 9.12 (s, 1H), 6.37 (s, 1H), 6.26 (d, J=6.0Hz, 1H),5.83(d,J=6.0Hz,1H),4.03(s,1H),3.98(m,1H),2.48(s,3H),2.12(m,1H),1.82(m, 3H),1.56(m,3H),1.43(m,3H),1.26(d,J=6.5Hz,3H)。MS(ESI+)m/z:386.20[M]+。
Embodiment 56：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (isobutyryl oxygen Base) methyl ester (compound 46)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.21 (s, 1H), 8.66 (s, 1H), 7.17 (s, 1H), 7.05 (s, 1H), 7.02 (s,1H),6.86(d,J=6.0Hz,1H),5.63(d,J=6.0Hz,1H),4.00(s,1H),3.81(m,1H),2.66(m, 1H),1.41(d,J=6.5Hz,3H),1.15(s,6H)。MS(ESI+)m/z:333.10[M]+。
Embodiment 57：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (pivaloyl group oxygen Base) methyl ester (compound 47)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.80 (s, 1H), 8.60 (s, 1H), 7.56 (m, 1H), 7.16 (m, 1H), 7.02 (s,1H),6.36(d,J=6.0Hz,1H),5.23(d,J=6.0Hz,1H),4.06(s,1H),3.83(m,1H),1.46(d,J= 6.5Hz,3H),1.27(s,9H)。MS(ESI+)m/z:347.12[M]+。
Embodiment 58：3,7- dimethyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (pivaloyl Base epoxide) methyl ester (compound 48)
Using the iodo- 6- Methyl-1H-indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2, It is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.77 (s, 1H), 7.65 (s, 1H), 7.01 (s, 1H), 6.37 (s, 1H), 6.29 (d,J=6.0Hz,1H),5.73(d,J=6.0Hz,1H),3.85(s,1H),3.71(m,1H),2.47(s,3H),1.40(d,J= 6.5Hz,3H),1.26(s,9H)。MS(ESI+)m/z:361.13[M]+。
Embodiment 59：The fluoro- 3,5- dihydros -2H- sulphur pyrans of 3- methyl -6- simultaneously [4,3,2-cd] indole-2-carboxylic acid (1 '-it is (special Valeryl epoxide)) ethyl ester (compound 49)
Using the fluoro- 1H- indoles of the iodo- 7- of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2, its For racemic mixture or (2R, 3S) isomers, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.69 (s, 1H), 7.94 (s, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 6.87 (m,1H),4.08(s,1H),3.80(m,1H),1.74(m,3H),1.46(d,J=6.5Hz,3H),1.27(s,9H)。MS(ESI+)m/z:379.13[M]+。
Embodiment 60：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diaza indole-2-carboxylic acids (1 '-(pivaloyl group epoxide)) ethyl ester (compound 50)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.51 (s, 1H), 9.05 (s, 1H), 7.34 (s, 1H), 6.37 (m, 1H), 3.89 (s,1H),3.71(m,1H),1.75(s,3H),1.47(d,J=6.5Hz,3H),1.26(s,9H)。MS(ESI+)m/z:363.13 [M]+。
Embodiment 61：3- methyl -6- methoxyl group -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (1 '-(propiono epoxide)) ethyl ester (compound 51)
It is raw material with compound 4, title compound is prepared by the method similar to embodiment 2, it is mixed for racemic Thing or (2R, 3S) isomers, related data are as follows：
1H NMR (500MHz, chloroform) δ 11.28 (s, 1H), 7.94 (s, 1H), 7.13 (s, 1H), 7.02 (s, 1H), 6.67 (s,1H),4.10(s,3H),4.01(s,1H),3.81(s,1H),2.54(m,2H),1.75(m,3H),1.41(d,J=6.5Hz, 3H),1.28(m,3H)。MS(ESI+)m/z:363.11[M]+。
Embodiment 62：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] -6,8- diaza indole-2-carboxylic acids (1 '-(pivaloyl group epoxide)) ethyl ester (compound 52)
Title compound is prepared by the method similar to embodiment 43, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.30 (s, 1H), 9.02 (s, 1H), 6.57 (s, 1H), 6.39 (d, J=6.0Hz, 1H),5.63(d,J=6.0Hz,1H),4.43(s,1H),4.01(m,1H),1.54(d,J=6.5Hz,3H),1.28(s,9H)。MS (ESI+)m/z:333.13[M]+。
Embodiment 65：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid benzoyloxymethyl Ester (compound 55)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.39 (s, 1H), 7.89 (m, 2H), 7.71 (m, 2H), 7.28 (s, 1H), 7.10 (m,2H),6.80(m,2H),6.12(d,J=6.0Hz,1H),5.82(d,J=6.0Hz,1H),4.40(s,1H),3.81(m, 1H),1.26(d,J=7.0Hz,3H)。MS(ESI+)m/z:351.35[M]+。
Embodiment 66：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-methoxybenzene Formoxyl epoxide) methyl ester (compound 56)
Using compound C as raw material, it is racemic mixture or (2R, 3S) isomers, passes through the side similar to embodiment 2 Method prepares title compound, and it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.33 (s, 1H), 9.80 (s, 1H), 7.14 (m, 2H), 7.04 (m, 2H), 6.93 (m,4H),6.89(d,J=6.0Hz,1H),5.83(d,J=6.0Hz,1H),3.89(s,3H),3.77(s,1H),3.64(m, 1H),1.22(d,J=7.0Hz,3H)。MS(ESI+)m/z:397.10[M]+。
Embodiment 67：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-methylbenzene first Acyloxy) methyl ester (compound 57)
Using compound C as raw material, it is racemic mixture or (2R, 3S) isomers, passes through the side similar to embodiment 2 Method prepares title compound, and it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 7.98 (m, 2H), 7.75 (m, 2H), 7.13 (m, 2H), 7.13 (m, 3H), 6.81 (d,J=6.0Hz,1H),5.76(d,J=6.0Hz,1H),3.96(s,1H), 3.81(m,1H),2.47(s,3H),1.28(d,J= 7.0Hz,3H)。MS(ESI+)m/z:381.10[M]+。
Embodiment 68：The fluoro- 3,5- dihydros -2H- sulphur pyrans of 3- methyl -7- simultaneously [4,3,2-cd] indole-2-carboxylic acid (3 '-fluorine Benzoyl epoxide) methyl ester (compound 58)
Title compound is prepared by the method similar to embodiment 41, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.71 (s, 1H), 7.77 (m, 3H), 7.37 (m, 1H), 6.92 (m, 3H), 7.09 (d,J=6.0Hz,1H),5.80(d,J=6.0Hz,1H),3.86(s,1H),3.81(m,1H),1.26(d,J=7.0Hz,3H)。MS (ESI+)m/z:403.07[M]+。
Embodiment 69：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-methylamino Benzoyl epoxide) methyl ester (compound 59)
Using compound C as raw material, it is racemic mixture or (2R, 3S) isomers, passes through the side similar to embodiment 2 Method prepares title compound, and it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.82 (s, 1H), 8.36 (m, 1H), 7.78 (m, 2H), 7.12 (m, 2H), 7.09 (m,2H),6.68(m,2H),6.79(d,J=6.0Hz,1H),5.63(d,J=6.0Hz,1H),4.21(s,1H),4.00(m, 1H),2.90(s,3H),1.31(d,J=7.0Hz,3H)。MS(ESI+)m/z:396.11[M]+。
Embodiment 70：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-hydroxy benzenes first Acyloxy) methyl ester (compound 60)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.61 (s, 1H), 7.87 (s, 2H), 7.14 (m, 2H), 6.93 (m, 4H), 6.64 (d,J=6.0Hz,1H),5.57(d,J=6.0Hz,1H),4.13(s,1H),3.84(s,1H),3.81(m,1H),1.42(d,J= 7.0Hz,3H)。MS(ESI+)m/z:383.42[M]+。
Embodiment 71：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-toluyl Base epoxide) methyl ester (compound 61)
Using compound C as raw material, it is racemic mixture or (2R, 3S) isomers, by similar to embodiment 2 Method prepares title compound, and it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.83 (s, 1H), 7.89 (m, 2H), 7.21 (m, 2H), 7.13 (m, 2H), 6.80 (m,2H),6.72(d,J=6.0Hz,1H),5.62(d,J=6.0Hz,1H),4.01(s,1H),3.81(m,1H),2.47(s, 3H),1.28(d,J=7.0Hz,3H)。MS(ESI+)m/z:365.38[M]+。
Embodiment 72：3- methyl -7- methoxyl group -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (1 '-(4 ' '-methyl benzoyl epoxide)) ethyl ester (compound 62)
Using the iodo- 6- methoxyl groups -1H- indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.81 (s, 1H), 7.89 (m, 2H), 7.20 (m, 2H), 6.80 (s, 1H), 6.68 (m,2H),6.58(m,1H),4.00(s,1H),3.88(s,3H),3.81(m,1H),2.46(s,3H),1.81(m,3H),1.52 (d,J=7.0Hz,3H)。MS(ESI+)m/z:425.13[M]+。
Embodiment 73：3- methyl -7- methoxyl group -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diazas Yin Diindyl -2- carboxylic acids (1 '-(4 ' '-ethylamino benzonitrile acyl group epoxide)) ethyl ester (compound 63)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 2- methoxyl groups -4- for raw material, pass through the method similar to Examples 1 and 2 Title compound is prepared, it is racemic mixture or (2R, 3S) isomers, related data is as follows：
1H NMR (500MHz, chloroform) δ 7.94 (m, 2H), 7.53 (m, 2H), 6.61 (m, 1H), 6.28 (s, 1H), 4.38 (s,1H),3.87(m,1H),3.74(s,3H),2.71(s,3H),1.82(m,3H),1.26(d,J=7.0Hz,3H),1.19(m, 3H)。MS(ESI+)m/z:441.14[M]+。
Embodiment 74：3,7- dimethyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -8- azaindole -2- carboxylic acids (1 '-(4 ' '-methoxybenzoyl base epoxide)) ethyl ester (compound 64)
With iodo- 6- methyl isophthalic acids H- pyrrolo-es [2, the 3-b] pyridines of 4- for raw material, pass through the method system similar to Examples 1 and 2 Standby title compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.77 (s, 1H), 7.94 (m, 2H), 7.19 (s, 1H), 6.92 (m, 2H), 6.61 (m,1H),6.28(s,1H),4.13(s,1H),3.84(m,1H),3.81(s, 3H),1.78(m,3H),1.54(d,J= 7.0Hz,3H)。MS(ESI+)m/z:426.12[M]+。
Embodiment 75：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -7,8- diaza indole-2-carboxylic acids (1 '-benzoyl epoxide) ethyl ester (compound 65)
With iodo- 7H- pyrrolo-es [2, the 3-c] pyridazines of 4- for raw material, title is prepared by the method similar to Examples 1 and 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.77 (s, 1H), 9.16 (m, 1H), 8.01 (m, 2H), 7.60 (m, 3H), 6.65 (m,1H),6.22(s,1H),4.38(s,1H),3.79(m,1H),1.80(m,3H),1.34(d,J=7.0Hz,3H)。MS(ESI+)m/z:383.09[M]+。
Embodiment 76：3,7- dimethyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] -6,8- diaza indoles -2- Carboxylic acid (1 '-benzoyl epoxide) ethyl ester (compound 66)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 2- methyl -4- for raw material, pass through the method system similar to Examples 1 and 2 Standby title compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.81 (s, 1H), 8.01 (m, 2H), 7.72 (m, 2H), 7.57 (s, 2H), 6.54 (m,1H),6.37(m,1H),4.86(s,1H),3.81(m,1H),2.48(s,3H),1.81(m,3H),1.29(d,J=7.0Hz, 3H)。MS(ESI+)m/z:397.11[M]+。
Embodiment 77：The fluoro- 3,5- dihydros -2H- pyrans of 3- methyl -7- simultaneously [4,3,2-cd] indole-2-carboxylic acid (3 '-fluorobenzene Formoxyl epoxide) methyl ester (compound 67)
Title compound is prepared by the method similar to embodiment 41, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 7.71 (m, 2H), 7.38 (m, 2H), 6.80 (s, 1H), 6.64 (d, J=6.0Hz, 1H),6.59(s,1H),6.51(s,2H),5.57(d,J=6.0Hz,1H),4.81(s,1H),4.01(m,1H),1.24(d,J= 7.0Hz,3H)。MS(ESI+)m/z:387.09[M]+。
Embodiment 78：3- methyl -3,5- dihydro -2H- pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-methoxybenzene first Acyloxy) methyl ester (compound 68)
Using the iodo- 1H- indoles of 4- as raw material, title compound is prepared by the method similar to Examples 1 and 2, it is outer Racemic mixture or (2R, 3S) isomers, related data are as follows：
1H NMR (500MHz, chloroform) δ 11.75 (s, 1H), 7.98 (m, 2H), 7.13 (m, 1H), 6.98 (m, 3H), 6.75 (m,2H),6.72(d,J=6.0Hz,1H),5.65(d,J=6.0Hz, 1H),4.43(s,1H),4.01(m,1H),3.87(s, 3H),1.55(d,J=7.0Hz,3H)。MS(ESI+)m/z:381.12[M]+。
Embodiment 79：Benzoic acid (3- (1H- indol-3-yls) bytyry epoxide) methyl ester (compound 69)
Title compound is prepared by the method similar to embodiment 4, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.68 (s, 1H), 8.04 (m, 2H), 7.59 (m, 4H), 7.29 (m, 2H), 6.97 (m,1H),6.80(s,1H),6.62(d,J=6.0Hz,1H),5.83(d,J=6.0Hz,1H),3.51(m,1H),2.64(m, 2H),1.38(d,J=7.0Hz,3H)。MS(ESI+)m/z:337.13[M]+。
Embodiment 80：4- methyl benzoic acids (3- (1H- indol-3-yls) bytyry epoxide) methyl ester (compound 70)
Title compound is prepared by the method similar to embodiment 4, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.81 (s, 1H), 7.89 (m, 2H), 7.49 (m, 2H), 7.25 (m, 3H), 6.97 (m,1H),6.80(s,1H),6.72(d,J=6.5Hz,1H),5.63(d,J=6.5Hz,1H),3.58(m,1H),2.43(m, 2H),1.30(d,J=7.0Hz,3H)。MS(ESI+)m/z:351.15[M]+。
Embodiment 81：4- methoxy benzoic acids (3- (1H- indol-3-yls) bytyry epoxide) methyl ester (compound 71)
Title compound is prepared by the method similar to embodiment 4, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
H NMR (500MHz, chloroform) δ 11.90 (s, 1H), 7.98 (m, 2H), 7.44 (m, 2H), 7.20 (m, 2H), 6.90 (m,2H),6.80(s,1H),6.68(d,J=6.5Hz,1H),5.59(d,J=6.5Hz,1H),3.56(m,1H),2.37(m, 2H),2.11(m,3H),1.32(d,J=7.0Hz,3H)。MS(ESI+)m/z:367.14[M]+。
Embodiment 82：4- methoxycyclohexyl alkane carboxylic acid (3- (6- Methyl-1H-indole -3- bases) bytyry epoxide) methyl ester (compound 72)
Using the iodo- 6- Methyl-1H-indoles of 2- as raw material, title compound is prepared by the method similar to embodiment 1,3 and 4 Thing, it is racemic mixture or (2R, 3S) isomers, and related data is as follows：
1H NMR (500MHz, chloroform) δ 11.69 (s, 1H), 7.72 (s, 1H), 6.98 (m, 2H), 6.80 (m, 1H), 6.74(d,J=6.5Hz,1H),5.62(d,J=6.5Hz,1H),3.51(m,1H),3.45(s,3H),2.83(m,2H),2.35 (m,3H),1.93(m,2H),1.88(m,3H),1.66(m,4H),1.45(m,2H),1.39(d,J=7.0Hz,3H)。MS(ESI+)m/z:387.20[M]+。
Embodiment 83：Cyclohexane-carboxylic acid (3- (7H- pyrrolo-es [2,3-d] pyrimidine -5- bases) bytyry epoxide) methyl ester (is changed Compound 73)
With iodo- 7H- pyrrolo-es [2, the 3-d] pyrimidines of 6- for raw material, prepared and marked by the method similar to embodiment 1,3 and 4 Compound is inscribed, it is racemic mixture or (2R, 3S) isomers, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.39 (s, 1H), 9.25 (s, 1H), 8.74 (s, 1H), 6.73 (s, 1H), 6.34 (d,J=6.5Hz,1H),5.53(d,J=6.5Hz,1H),3.51(m,1H),2.48(m,3H),1.92(m,2H),1.72(m, 2H),1.48(m,6H),1.35(d,J=7.0Hz,3H)。MS(ESI+)m/z:345.17[M]+。
Embodiment 84：3- (7H- pyrrolo-es [2,3-d] pyrimidine -5- bases) butyric acid (pivaloyl group epoxide) methyl ester (compound 74)
Title compound is prepared by the method similar to embodiment 83, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.53 (s, 1H), 9.25 (s, 1H), 8.71 (s, 1H), 6.79 (s, 1H), 6.29 (d,J=6.5Hz,1H),5.33(d,J=6.5Hz,1H),3.51(m,1H),2.52(m,2H),1.39(d,J=7.0Hz,3H), 1.11(s,9H)。MS(ESI+)m/z:319.15[M]+。
Embodiment 85：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (pyridine -2- Ji Jia Acyloxy) methyl ester (compound 81)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.91 (s, 1H), 9.65 (s, 1H), 8.27 (m, 2H), 8.04 (s, 1H), 7.14 (m,2H),7.92(m,2H),6.29(d,J=6.5Hz,1H),5.33(d,J=6.5Hz,1H),4.00(s,1H),3.81(m, 1H),1.18(d,J=7.0Hz,3H)。MS(ESI+)m/z:368.08[M]+。
Embodiment 86：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (benzofuran -2- Base formoxyl epoxide) methyl ester (compound 82)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.09 (s, 1H), 7.49 (m, 4H), 7.12 (m, 3H), 7.04 (m, 2H), 6.65 (d,J=6.5Hz,1H),5.53(d,J=6.5Hz,1H),4.86(s,1H),3.81(m,1H),1.46(d,J=7.0Hz,3H)。MS (ESI+)m/z:407.08[M]+。
Embodiment 87：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (indol-3-yl first Acyloxy) methyl ester (compound 83)
Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomery Body, related data is as follows：
1H NMR (500MHz, chloroform) δ 11.81 (s, 1H), 9.90 (m, 1H), 8.84 (s, 1H), 7.92 (s, 1H), 7.44 (m,2H),7.11(m,3H),7.02(m,2H),6.72(d,J=6.5Hz,1H),5.65(d,J=6.5Hz,1H),4.00(s, 1H),3.81(m,1H),1.18(d,J=7.0Hz,3H)。MS(ESI+)m/z:406.10[M]+。
Embodiment 88：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- formyls（2 '-morpholino second Base）Amine（Compound 84）
Using compound 2- morpholinoes-ethamine and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, Method according to similar embodiment 12 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, related data It is as follows：
1H NMR(400MHz,DMSO)δ10.88(s,1H),7.87(s,1H),7.15(d,J=2.0Hz,1H),7.09(d, J=8.0Hz,1H),6.99(t,J=7.6Hz,1H),6.76(d,J=7.2Hz,1H),4.10(d,J=3.6Hz,1H),3.59(m, 1H),3.54(t,J=4.4Hz,4H),3.29(m,1H),3.11(m,1H),2.32(t,J=2.4Hz,6H),1.26(d,J= 6.4Hz,3H)。MS(ESI+)m/z:346.2[M+H]+。
Embodiment 89：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid（2 '-morpholino） Ethyl ester（Compound 85）
Using compound 2- morpholinoes-ethanol and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, Method according to similar embodiment 12 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, dependency number According to as follows：
1H NMR(400MHz,DMSO)δ10.91(s,1H),7.17(d,J=2.0Hz,1H),7.11(d,J=8.4Hz, 1H),7.00(t,J=7.6Hz,1H),6.78(d,J=7.2Hz,1H),4.29(d,J=3.6Hz,1H),4.12(m,2H),3.55 (m,1H),3.52(m,4H),2.39(m,2H),2.31(m,4H),1.27(d,J=6.8Hz,3H)。MS(ESI+)m/z:347.2 [M+H]+。
Embodiment 90:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- formyls（3 '-dimethylamino Propyl group）Amine（Compound 86）
With N, N- dimethyl -1,3 propane diamine and compound C are raw material, and it is racemic mixture or (2R, 3S) isomery Body, title compound is prepared according to the method for similar embodiment 12, and it is racemic mixture or (2R, 3S) isomers, correlation Data are as follows：
1H NMR(400MHz,DMSO)δ10.87(s,1H),8.07(t,J=3.6Hz,1H),7.14(d,J=2.0Hz, 1H),7.09(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.11(d,J=3.6Hz, 1H),3.59(m,1H),3.16(m,1H),3.04(m,1H),2.19(t,J=7.2Hz,2H),2.11(s,6H),1.53(m, 2H),1.19(d,J=6.8Hz,3H)。MS(ESI+)m/z:318.2[M+H]+。
Embodiment 91:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- formyls（2 '-dimethylamino Ethyl）Amine（Compound 87）
With N, N- dimethyl-ethylenediamines and compound C are raw material, and it is racemic mixture or (2R, 3S) isomers, is pressed Method according to similar embodiment 12 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, and related data is such as Under：
1H NMR(400MHz,DMSO)δ10.87(s,1H),7.95(s,1H),7.14(d,J=2.0Hz,1H),7.09(d, J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.11(d,J=3.2Hz,1H),3.58(m, 1H),3.22(m,1H),3.09(m,1H),2.26(t,J=6.8Hz,2H),2.10(d,J=3.6Hz,6H),1.19(d,J= 6.8Hz,3H)。MS(ESI+)m/z:304.1[M+H]+。
Embodiment 92：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (4 '-fluorobenzoyl Base epoxide) methyl ester（Compound 88）
Using 4- fluobenzoic acid chloromethane base esters and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, Method according to similar embodiment 2 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, related data It is as follows：
1H NMR(400MHz,DMSO)δ10.92(s,1H),7.99(d,J=8.0Hz,2H),7.38(d,J=8.0Hz, 2H),7.16(s,1H),7.12(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),6.00 (d,J=6.0Hz,1H),5.92(d,J=6.0Hz,1H),4.42(d,J=3.6Hz,1H),3.62(m,1H),1.24(d,J= 6.8Hz,3H)。MS(ESI+)m/z:408.1[M+Na]+,424.0[M+Ka]+。
Embodiment 93：3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (adamantane -1- first Acyloxy) methyl ester（Compound 89）
Using amantadine -1- bases formic acid chloromethane base ester and compound C as raw material, it is racemic mixture or (2R, 3S) Isomers, title compound is prepared according to the method for similar embodiment 2, and it is racemic mixture or (2R, 3S) isomers, phase Close data as follows：
1H NMR(400MHz,DMSO)δ10.93(s,1H),7.18(d,J=1.2Hz,1H),7.13(d,J=8.0Hz, 1H),7.00(t,J=7.6Hz,1H),6.77(d,J=7.2Hz,1H),5.73(d,J=5.6Hz,1H),5.67(d,J=5.6Hz, 1H),4.34(d,J=4.0Hz,1H),3.58(m,1H),1.97(s,3H),1.77(d,J=2.4Hz,6H),1.66(m,6H), 1.27(d,J=6.8Hz,3H)。MS(ESI+)m/z:448.2[M+Na]+,464.1[M+Ka]+。
Embodiment 94:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid cyclohexane carbo oxygen Ylmethyl ester（Compound 90）
Using naphthenic acid chloromethane base ester and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, Title compound is prepared by the method similar to embodiment 2, it is racemic mixture or (2R, 3S) isomers, dependency number According to as follows：
1H NMR(400MHz,DMSO)δ10.93(s,1H),7.18(s,1H),7.13(d,J=8.4Hz,1H),7.00(t, J=7.6Hz,1H),6.78(d,J=7.2Hz,1H),5.73(d,J=6.0Hz,1H),5.67(d,J=6.0Hz,1H),4.35(d,J =3.6Hz,1H),3.59(m,1H),2.31(m,1H),1.79(m,2H),1.67(m,2H),1.57(d,J=10.4Hz,1H), 1.26(m,8H)。MS(ESI+)m/z:396.1[M+Na]+,412.1[M+Ka]+。
Embodiment 95:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (1 '-benzoyl Epoxide) ethyl ester（Compound 91）
Using 1- benzoic acid chloro-ethyl ester and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, is led to The method crossed similar to embodiment 2 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, related data It is as follows：
1H NMR(400MHz,DMSO)δ10.85(s,1H),8.01(d,J=8.0Hz,2H),7.66(t,J=7.2Hz, 1H),7.55(d,J=8.0Hz,2H),7.16(s,1H),7.12(d,J=8.0Hz,1H),7.00(t,J=7.6Hz,1H),6.77 (d, J=7.2Hz, 1H), 6.76 (m, 1H), 4.34 (d, J=4.0Hz, 1H), 3.58 (m, 1H), 1.40 (m, 3H), 1.24 (d, J= 6.8Hz,3H)。MS(ESI+)m/z:404.1[M+Na]+,420.1[M+Ka]+。
Embodiment 96:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid (1 '-hexamethylene carbonyl Base epoxide) ethyl ester（Compound 92）
Using 1- naphthenic acids chloro-ethyl ester and compound C as raw material, it is racemic mixture or (2R, 3S) isomery Body, title compound is prepared by the method similar to embodiment 2, and it is racemic mixture or (2R, 3S) isomers, correlation Data are as follows：
H NMR(400MHz,DMSO)δ10.92(s,1H),7.18(s,1H),7.13(d,J=8.4Hz,1H),7.00(t,J =7.6Hz,1H),6.78(d,J=7.2Hz,1H),6.76(m,1H),2.31(m,3H),1.40(m,14H)。MS(ESI+)m/z: 410.1[M+Na]+,426.1[M+Ka]+。
Embodiment 97:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- formyls（3 '-imidazoles -1- Base propyl group）Amine（Compound 93）
Using compound 3- imidazoles -1- bases propylamine and compound C as raw material, it is racemic mixture or (2R, 3S) isomery Body, title compound is prepared according to the method for similar embodiment 12, and it is racemic mixture or (2R, 3S) isomers, correlation Data are as follows：
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.19(t,J=3.2Hz,1H),7.60(s,1H),7.15(t, J=3.6Hz,2H),7.09(d,J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.89(s,1H),6.76(d,J=7.2Hz, 1H),4.14(d,J=3.6Hz,1H),3.96(t,J=7.6Hz,2H),3.63(m,1H),3.09(m,1H),3.01(m,1H), 1.84(m,2H),1.19(d,J=6.8Hz,3H)。MS(ESI+)m/z:341.1[M+H]+,363.1[M+Na]+。
Embodiment 98:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indoles -2- formyls（3 '-Ding Nei acyls Amine -1- base propyl group）Amine（Compound 94）
Using compound 3- butyrolactams -1- bases propylamine and compound C as raw material, it is racemic mixture or (2R, 3S) Isomers, title compound is prepared according to the method for similar embodiment 12, and it is racemic mixture or (2R, 3S) isomers, Related data is as follows：
1H NMR(400MHz,DMSO)δ10.87(s,1H),8.13(t,J=4.8Hz,1H),7.14(s,1H),7.08(d, J=8.0Hz,1H),6.98(t,J=7.6Hz,1H),6.75(d,J=7.2Hz,1H),4.12(d,J=3.2Hz,1H),3.61(m, 1H),3.23(m,3H),3.06(m,1H),2.20(t,J=8.0Hz,2H),1.92(m,2H),1.57(t,J=6.8Hz,2H), 1.18(d,J=6.8Hz,3H)。MS(ESI+)m/z:358.2[M+H]+,380.2[M+Na]+。
Embodiment 99:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid（2- benzoxies Base）Ethyl ester（Compound 95）
Using 2- benzoic acid chloro-ethyl ester and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, is led to The method crossed similar to embodiment 2 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, related data It is as follows：
1H NMR(400MHz,DMSO)δ10.90(s,1H),7.97(d,J=7.2Hz,1H),7.68(t,J=7.6Hz, 1H),7.54(t,J=7.7Hz,2H),7.12(m,2H),6.96(t,J=7.2Hz,1H),6.76(d,J=7.2Hz,1H),4.45 (m,2H),4.36(d,J=3.6Hz,1H),3.63(m,1H),1.22(d,J=6.8Hz,3H).MS(ESI+)m/z:404.2[M+ Na]+,420.0[M+Ka]+。
Embodiment 100:3- methyl -3,5- dihydro -2H- sulphur pyrans simultaneously [4,3,2-cd] indole-2-carboxylic acid（3- benzoxies Base）Propyl diester（Compound 96）
Using 3- benzoic acid chloropropyl esters and compound C as raw material, it is racemic mixture or (2R, 3S) isomers, is led to The method crossed similar to embodiment 2 prepares title compound, and it is racemic mixture or (2R, 3S) isomers, related data It is as follows：
1H NMR(400MHz,DMSO)δ10.92(s,1H),7.97(m,2H),7.65(d,J=7.4Hz,1H),7.53(t, J=7.7Hz,2H),7.13(dd,J=9.5,4.9Hz,2H),6.96(m,1H),6.78(d,J=7.1Hz,1H),4.32(d,J= 3.7Hz,1H),4.24(dd,J=13.7,7.5Hz,4H),3.63(m,1H),2.00(t,J=6.2Hz,2H),1.23(d,J= 6.8Hz,3H)。MS(ESI+)m/z:418.0[M+Na]+,434.0[M+Ka]+
Embodiment 101:The bromo- 3,5- dihydros-2H- sulphur pyrans of 3- methyl-4,7,8-three simultaneously [4,3,2-cd] indole-2-carboxylic acid Benzoyloxymethyl esters（Compound 97）
With compounds benzoic acid chloromethane base ester and the bromo- 3,5- dihydros -2H- sulphur pyrans of 2- carboxylic acid -3- methyl -4,7,8- three simultaneously [4,3,2-cd] indoles is raw material, and it is racemic mixture or (2R, 3S) isomers, according to the method system of similar embodiment 2 Standby title compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows
1H NMR(400MHz,DMSO)δ12.34(s,1H),8.01(d,J=8.0Hz,1H),7.74(m,2H),7.53(m, 3H),5.85(q,J=5.9Hz,2H),4.49(d,J=4.0Hz,1H),3.57(m,1H),1.23(d,J=8.0Hz,3H)。MS (ESI+)m/z:,622.9[M+Na]+。
Embodiment 102:The bromo- 3,5- dihydros -2H- sulphur pyrans of 3- methyl -4- simultaneously [4,3,2-cd] indole-2-carboxylic acid benzoyl Epoxide methyl ester（Compound 98）
With compounds benzoic acid chloromethane base ester and 2- carboxylic acid-3- methyl-4-bromo- 3,5- dihydros-2H- sulphur pyrans simultaneously [4,3, 2-cd] indoles be raw material, its be racemic mixture or (2R, 3S) isomers, prepare title according to the method for similar embodiment 2 Compound, it is racemic mixture or (2R, 3S) isomers, and related data is as follows
1H NMR(400MHz,DMSO)δ11.68(s,1H),7.80(dd,J=8.3,1.2Hz,2H),7.69(d,J= 7.5Hz,1H),7.53(t,J=7.8Hz,2H),7.04(dd,J=8.1,0.7Hz,1H),6.98(m,1H),6.78(dd,J= 7.1,0.7Hz,1H),5.84(s,2H),4.28(d,J=2.2Hz,1H),3.55(m,1H),1.26(d,J=6.9Hz,3H)。MS (ESI+)m/z:,523.9[M+H]+。
The active testing of the compounds of this invention
The antibacterial activity of the compounds of this invention be by determine its to reference culture, the bacterial strain being clinically separated and to some The MIC (MlC, mg/L) of the antibody-resistant bacterium of antiseptic is come what is determined：In this experiment, the sweet ammonia of nearest new listing The plain class antibiotic tigecycline (Tige) of sour ring compares medicine.Minimal inhibitory concentration is determined as follows：In in sterilized petri dishes 1ml decoctions are added, 50 DEG C of MH culture medium 14ml of thawing are added, mixed, contained drug final concentration in its every ware is followed successively by 128、64、32、16、8、4、2、1、0.5、0.25、0.125、0.06、0.03mg/L；After cooling instrument is inoculated with multiple spot（Denley A400, England）Gram- bacteria, preferably Gram-negative bacteria or gram-positive bacteria are inoculated with, quantity of microorganism inoculated is about 105CFU/ Ml, covers ware lid.Above-mentioned bacterial strains are placed in culture 18-20h, observed and recorded result in 35-37 DEG C of incubator；The plate of asepsis growth The minimum concentration of middle contained drug is minimum inhibitory concentration（MIC).
Table 3 lists antibacterial activity in vitro of the representation compound in formula (I) compound of the application to gram bacterial strain, And be compared with the plain class antibiotic tigecycline of glycine ring of nearest new listing.From table 3, formula (I) chemical combination of the present invention The plain antibiotic tigecycline of glycine ring that thing is better than nearest new listing to the external activity of these gram- bacterias, or phase therewith When formula (I) compound of the invention is to clinically increasing MRSA（Mrsa In Rabbits）And MRSE（Methoxy west Linne medicine form staph）Also good activity is shown.For mushroom, especially gram- bacteria, preferably Gram-negative bacteria or leather Lan Shi positive bacterias.
The preferred compound of the present invention of table 3 is to being clinically separated the antibacterial activity in vitro of gram- bacteria（MICμg/ml）
Applicant also uses the above method, with creatmycin (CD) and desulfurization creatmycin (DSC, corresponding in the present invention The compound of numbering 20) contrast test has been carried out for positive control, acquired results are as shown in table 4-8.
Table 4
Table 5
Table 6
Table 7
As described above, the compounds of this invention is to including the various pathogenic microorganisms of Gram-negative bacteria and gram-positive bacteria There are stronger antibacterial activity and wide antimicrobial spectrum.The compounds of this invention is to gram bacterial strain, especially to including MRSA, MRSE The antibacterial activity of staphylococcus be better than or equivalent in the plain class antibiotic tigecycline of the glycine ring that lists recently.This hair Bright compound is to gram bacterial strain, especially to including S. aureus L-forms MRSA12-1, ATCC25923, MSSE12-8, Klebsiella Pneumoniae Antibacterial activity including E-12-1, pseudomonas aeruginosa 12-20, streptococcus pneumonia 10-11 better than positive control creatmycin and Desulfurization creatmycin.
The antibacterial activity of the anti-bacillus of the compounds of this invention, preferably anti-mycobacterium tuberculosis is by determining it to reference culture H37Rv MIC (MlC, mg/L) is come what is determined：In this experiment medicine is compared with rifampin (RFP).Minimum suppression Bacteria concentration is determined as follows：200 μ l aqua sterilisas are added in each hole of 96 orifice plates, to prevent each experimental port in incubation Composition evaporates, and precision weighs each compound 1mg, plus sterile purified water 1ml respectively, and 1000 μ g/ml storing solution is made；RFP Dissolved with dimethylformamide；0.22 μm of filtering with microporous membrane.Needed for being diluted to respectively with 7H9 culture mediums (not tween 80) Each two times of concentration, adds the μ l of 96 orifice plate 100, the final concentration of investigational agent (the compounds of this invention, especially table 1 or the compound of table 2) For：128.0、64.0、32.0、16.0、8.0、4.0、2.0、1.0、0.5、0.25、0.125、0.0625μg/ml.Comparison medicine RFP It is final concentration of：32.0、16.0、8.0、4.0、2.0、1.0、0.5、0.25、0.125、0.0625、0.032μg/ml.From improvement Eugonic each strain culture, is made bacteria suspension on Russell medium, is inoculated into 7H9 fluid nutrient mediums, 37 DEG C It is incubated 10-14 hours, it is grown to turbidity for McFarland1 (equivalent to 107CUF/ml), be inoculated with 100 μ after dilution per hole L, bacterium solution final concentrationIf 2 growth control holes for being free of antimicrobial, are placed in 37 DEG C of incubations.5th day The μ l of growth control hole 20 are added afterwardsBlue (Setotec Products) and the μ l of 5% Tween 80 50 mixing Liquid, 37 DEG C of incubation 24h, if color is changed into pink colour from blueness, adds the Alamar of above-mentioned amount in the hole of each Experimental agents Blue and Tween 80 mixed liquor, 37 DEG C of incubation 24h record the color in each hole, and MIC is defined as preventing color change (from blueness change For pink colour) lowest concentration of drug.As a result show that the compounds of this invention has in terms of anti-bacillus, preferably Mycobacterium tuberculosis bright Effective fruit.
Table 8 lists the body of representation compound CV2 in formula (I) compound of the application to bacillus, preferred tubercle bacillus Outer antibacterial activity, and be compared with rifampin.From table 4, formula (I) compound of the present invention is to bacillus, preferably tubercle bacillus External activity it is suitable with rifampin.Formula (I) compound of the present invention, the especially compound of table 1 are to bacillus, preferably tubercle bacillus External activity MIC is 0.25-8 μ g/ml, and vertical with the compound of table 1 of specific spatial configuration shown in formula (II) or Formula X V Body isomers, the especially compound of table 2 are 0.125-4 μ g/ml to the external activity MIC of bacillus, preferably tubercle bacillus.With innovation Mycin (CD) and desulfurization creatmycin (DSC, corresponding to the compound of numbering in the present invention 20) are compared, and the compounds of this invention has More preferable antibacterial activity.
Antibacterial activity in vitro (MIC μ g/ml) of the compound of table 8 to tubercle bacillus
Compound number Activity Compound number Activity Compound number Activity Compound number Activity
RFP 0.108 57 0.90 12' 2.62 70' 1.26
CD 6.00 58 0.72 13' 2.90 71' 1.20
CV2 0.78 59 0.70 14' 2.86 72' 1.34
1 3.62 60 0.71 15' 2.17 73' 1.38
2 3.54 61 2.48 16' 2.43 74' 1.52
3 4.21 62 1.01 17' 2.95 75' 1.84
4 3.84 63 1.32 20' 4.00 76' 1.80
5 4.38 64 1.42 21' 3.51 77' 3.39
7 4.86 65 1.58 22' 2.62 78' 1.95
8 5.23 66 1.60 23' 2.69 79' 2.11
9 5.06 67 3.07 24' 4.18 80' 1.64
10 4.82 68 2.40 25' 4.14 81' 0.48
11 3.82 69 2.38 26' 4.19 82' 0.64
12 5.23 70 2.52 27' 4.26 83' 0.58
13 5.80 71 2.40 28' 3.83 84' 1.88
14 5.72 72 2.68 29' 3.83 85' 1.86
15 4.33 73 2.76 30' 0.42 86' 2.01
16 4.85 74 3.04 31' 0.39 87' 1.93
17 5.90 75 3.68 32' 1.13 88' 0.39
20 8.00 76 3.60 33' 0.63 89' 0.58
21 7.02 77 6.77 34' 0.99 90' 0.40
22 5.23 78 3.89 35' 0.40 91' 0.54
23 5.37 79 4.22 36' 0.54 92' 0.56
24 8.35 80 3.28 37' 0.38 93' 1.94
25 8.28 81 0.96 38' 0.61 94' 1.91
26 8.37 82 1.28 39' 0.37 95' 0.46
27 8.52 83 1.16 40' 1.19 96' 0.52
28 7.66 84 3.76 41' 0.45 97' 1.17
29 7.66 85 3.72 42' 1.27 98' 0.84
30 0.83 86 4.01 43' 1.19
31 0.78 87 3.85 44' 1.71
32 2.25 88 0.78 45' 1.28
33 1.26 89 1.16 46' 0.63
34 1.98 90 0.80 47' 0.69
35 0.80 91 1.08 48' 0.84
36 1.08 92 1.12 49' 0.65
37 0.76 93 3.87 50' 0.68
38 1.22 94 3.82 51' 0.94
39 0.74 95 0.92 52' 0.73
40 2.38 96 1.03 55' 1.18
41 0.90 97 2.33 56' 0.36
42 2.54 98 1.68 57' 0.45
43 2.38 58' 0.36
44 3.42 CV2’ 0.39 59' 0.35
45 2.55 1' 1.81 60' 0.36
46 1.26 2' 1.77 61' 1.24
47 1.38 3' 2.11 62' 0.51
48 1.67 4' 1.92 63' 0.66
49 1.29 5' 2.19 64' 0.71
50 1.35 7' 2.43 65' 0.79
51 1.88 8' 2.62 66' 0.80
52 1.46 9' 2.53 67' 1.54
55 2.36 10' 2.41 68' 1.20
56 0.72 11' 1.91 69' 1.19
Test on toxic side effect
Acute toxic test：Using ICR mouse, body weight:The compounds of this invention, preferably table is administered in 18-22g, male and female half and half 1 and 2 compound.Totally 20 animals.According to dosage distinguish compound described in gavage, record the abnormal response that animal occurs in 14 days And dead animal number.Result of the test shows that gavage of compound CV2 gives mouse 2g/kg, has no animal dead, ICR mouse Gastric infusion CV2 LD50 is more than 2.0g/kg.In addition to compound CV2, the chemical combination of the compounds of this invention, preferably table 1 and 2 Thing is suitable with compound CV2 LD50.

Claims (45)

1. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein,
R1For H, C1-6Alkyl or C1-6Alkanoyl；
R2For H；
R3For H, C1-6Alkyl, or C1-6Alkoxy；
R4For C1-6Alkyl；
B and D is carbon atom, and A is nitrogen-atoms；
D is carbon atom, and A and B are nitrogen-atoms；
A and D is carbon atom, and B is nitrogen-atoms；
A and B is carbon atom, and D is nitrogen-atoms；
A is carbon atom, and B and D are nitrogen-atoms；Or
B is carbon atom, and A and D are nitrogen-atoms；
X is O, or S；
Y is OR8；
R8For H or C1-6Alkyl, the R8Can be independently by 1-3 R9Substitution, each R9For phosphate；
Or
R8For
Wave represented at bonding,
R11Represent H or C1-6Alkyl；
R12Represent
II) it is unsubstituted or by C1-6Alkyl amino, hydroxyl or C1-6The C of alkoxy substitution3-8Cycloalkyl, the cycloalkyl is ring Propyl group, cyclobutyl, cyclopenta or cyclohexyl；
III) it is unsubstituted or by 1-3 R106 yuan of aryl of substitution；
R10Selected from C1-6Alkyl and C1-6Alkoxy；The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y define,
Condition is that formula (I) compound does not include following compound：
1) compound of following formula 4
R1It is methyl and R2It is hydroxyl.
2. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein,
R1For H,
R2For H,
R3For H,
R4For C1-6Alkyl；
B and D is carbon atom, and A is nitrogen-atoms；
D is carbon atom, and A and B are nitrogen-atoms；
A and D is carbon atom, and B is nitrogen-atoms；
A and B is carbon atom, and D is nitrogen-atoms；
A is carbon atom, and B and D are nitrogen-atoms；Or
B is carbon atom, and A and D are nitrogen-atoms；
X is O, or S；
Y is N (R8)2,
The R8For H and C1-6Alkyl, the C1-6Alkyl is unsubstituted or by 1-3 R9Substitution,
Each R9For C1-6Alkyl amino；
The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y defines.
3. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein,
R1For H,
R2For H, or halogen,
R3For H, C1-6Alkyl, C1-6Alkoxy, halogen or N (R5)2,
R4For C1-6Alkyl,
Each R5It independently is H or C1-6Alkyl,
A, B and D are carbon atom；
X is O, or S；
Y is OR8,
Each R8Independently selected from
(1)C1-6Alkyl, it is by 1 R9Substitution, each R9It is described non-aromatic miscellaneous for the non-aromatic heterocycle containing 6 annular atoms Ring group is morpholinyl；
(2)
Wave represented at bonding,
R11Represent H or C1-6Alkyl；
R12Represent
I) it is unsubstituted or by 1-3 R9’Substituted C1-6Alkyl；
II) it is unsubstituted or by C1-6Alkyl, halogen or C1-6The C of alkoxy substitution3-8Cycloalkyl, the cycloalkyl be cyclopropyl, Or cyclohexyl；
III) it is unsubstituted or by 1 R10The 6 yuan of aryl or 5 to 14 unit's heteroaryls of substitution, the heteroaryl are pyridine, benzo furan Mutter base, indyl or isoindolyl；
Iv) adamantyl；
Each R9’For 6 yuan of aryl-carbonyl oxygens,
R10Selected from halogen, hydroxyl, C1-6Alkyl, C1-6Alkoxy and C1-6Alkyl amino；
The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y defines.
4. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein,
R1For H,
R2For H,
R3For C1-6Alkoxy,
R4For C1-6Alkyl,
A, B and D are carbon atom；
X is O, or S；
Y is OR8,
R8For C1-6Alkyl, it is by 1 R9Substitution, each R9For two (C1-6Alkyl) amino.
5. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein,
R1For H,
R2For H,
R3For H,
R4For C1-6Alkyl,
A, B and D are carbon atom；
X is O, or S；
Y is N (R8)2,
The R8For H and C1-6Alkyl, the C1-6Alkyl is by 1-3 R9Substitution,
Each R9Independently selected from C1-6Alkyl amino, morpholinyl, imidazoles and butyrolactam -1- bases,
The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y defines.
6. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein
R1For H,
R2For H, or C1-6Alkyl
R3For C1-6Alkoxy, CF3Or N (R5)2,
R4For C1-6Alkyl,
Each R5It independently is H or C1-6Alkyl,
A, B and D are carbon atom；
X is O, or S；
Y is OR8；
Each R8For H；
The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y defines.
7. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein
R1For H,
R2For H,
R3For halogen,
R4For C1-6Alkyl,
A, B and D are carbon atom；
X is O, or S；
Y is OR8；
Each R8For C1-6Alkyl；
The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y defines.
8. a kind of indole derivatives or its stereoisomer or their officinal salt as shown in formula (I)：
Wherein
R1For H,
R2For H,
R3For H,
R4For C1-6Alkyl,
A, B and D are carbon atom；
X is O, or S；
Y is N (R8)2；
The R8For H and C1-6Alkyl；
The stereoisomer has below general formula (II)
R1、R2、R3、R4, such as logical formula (I) of A, B, D, X, Y defines.
9. compound or its stereoisomer or their officinal salt as described in any one of claim 1 to 2,6 and 8：
Wherein,
The C1-6Alkyl is C1-4Alkyl.
10. compound as claimed in claim 3 or its stereoisomer or their officinal salt：
Wherein,
The C1-6Alkyl is C1-4Alkyl.
11. compound as claimed in claim 5 or its stereoisomer or their officinal salt：
Wherein,
The C1-6Alkyl is C1-4Alkyl.
12. compound or its stereoisomer or their officinal salt as described in any one of claim 4 and 7：
Wherein,
The C1-6Alkyl is C1-4Alkyl.
13. compound as claimed in claim 1 or its stereoisomer or their officinal salt：
Wherein, the C1-6Alkanoyl is C1-4Alkanoyl.
14. compound or its stereoisomer or their officinal salt as described in any one of claim 1 and 6：
Wherein, the C1-6Alkoxy is C1-4Alkoxy.
15. compound as claimed in claim 4 or its stereoisomer or their officinal salt：
Wherein, the C1-6Alkoxy is C1-4Alkoxy.
16. compound as claimed in claim 3 or its stereoisomer or their officinal salt：
Wherein, the C1-6Alkoxy is C1-4Alkoxy.
17. compound as claimed in claim 3 or its stereoisomer or their officinal salt：
Wherein, the halogen is selected from F, Cl or Br.
18. compound as claimed in claim 7 or its stereoisomer or their officinal salt：
Wherein, the halogen is selected from F, Cl or Br.
19. compound or its stereoisomer or their officinal salt as described in any one of claim 1 to 2,6 and 8：
Wherein,
The alkyl is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, just Amyl group, isopentyl, n-hexyl and isohesyl.
20. compound as claimed in claim 3 or its stereoisomer or their officinal salt：
Wherein,
The alkyl is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, just Amyl group, isopentyl, n-hexyl and isohesyl.
21. compound as claimed in claim 5 or its stereoisomer or their officinal salt：
Wherein,
The alkyl is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, just Amyl group, isopentyl, n-hexyl and isohesyl.
22. compound or its stereoisomer or their officinal salt as any one of claim 4 and 7：
Wherein,
The alkyl is selected from methyl, ethyl, isopropyl, n-propyl, cyclopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, just Amyl group, isopentyl, n-hexyl and isohesyl.
23. compound or its stereoisomer as any one of claim 10,16 and 20 or theirs is pharmaceutically acceptable Salt：
Wherein, the halogen is selected from F, Cl or Br.
24. compound as claimed in claim 12 or its stereoisomer or their officinal salt：
Wherein, the halogen is selected from F, Cl or Br.
25. compound as claimed in claim 22 or its stereoisomer or their officinal salt：
Wherein, the halogen is selected from F, Cl or Br.
26. compound or its stereoisomer as any one of claim 10,16,17 and 20 or they can medicine Use salt：
Wherein,
The heterocyclic radical is selected from morpholino.
27. compound, it is the compound selected from following table
28. a kind of method of compound and its pharmaceutical salts prepared described in any one of claim 1 to 27 or its isomers, its It is characterised by that methods described comprises the following steps：
Step 1) make formula III compound
Reacted with the compound of formula 1,
(R’1)2O formulas 1
So as to production IV compounds,
Wherein each R '1It independently is-COR4, R1、R2、R3、R4, the formula (I) of A, B, D as described in 1 to 19 any one define, R13 For halogen；
Step 2) make formula IV compound and HXCH2COY ' reacts, and obtains Formula V compound,
Wherein Y ' is C1-6Alkoxy, R1、R2、R3、R4, the formula (I) of A, B, D as described in 1 to 19 any one define, X be O or S；
Step 3) by Formula V compound and acid and its reactant salt, obtain Formula IV compound
Wherein Y ' such as Formula V is defined, R1、R2、R3、R4, the formula (I) of A, B, D as described in 1 to 19 any one define, X be O or S；
Step 4) by Formula IV hydrogenation of compounds, obtain Formula VII compound
Wherein Y ' such as Formula V is defined, R1、R2、R3、R4, the formula (I) of A, B, D as described in 1 to 19 any one define, X be O or S； With
Step 5) Formula VII compound and alkali are reacted, formula (I) compound is obtained, it has the structure of Formula VIII
Wherein R1、R2、R3、R4, the formula (I) of A, B, D as described in 1 to 19 any one define, X be O or S.
29. the method described in claim 28, can also comprise the following steps：
Step 7) in the presence of DIC and DMAP, by Formula VIII compound
With R8ZH reacts, and obtains Formula X compound
Wherein, Z is O or N, and R8To be unsubstituted or by 1-3 R9Substituted C1-6Alkyl, R1、R2、R3、R4、R9, A, B, D such as 1 Defined to the formula (I) described in 19 any one, X is O or S.
30. the method described in claim 28, can also comprise the following steps：
Step 9) by Formula VIII compound
WithReaction, obtains Formula X III compounds
Wherein, R1、R2、R3、R4、R11、R12, the formula (I) of A, B, D and X as described in 1 to 19 any one defines.
31. the method for any one of claim 28 to 30, wherein, step 1) it is carried out as follows, in the presence of an inert gas, having In machine solvent, in the presence of a catalyst, formula III compound is reacted with the compound of formula 1, so that production IV compounds.
32. the method for claim 31, wherein, step 1) it is carried out as follows, in the presence of nitrogen, in dichloromethane, in tetrachloro Change in the presence of tin, and/or nitromethane, at room temperature, formula III compound is reacted with the compound of formula 1, so that production IV chemical combination Thing.
33. the method for any one of claim 28 to 30, wherein, step 2) it is carried out as follows, in the presence of an inert gas, by formula IV compounds, HXCH2COY ' and anhydrous pyridine, in absolute methanol, react 48h at 90 DEG C, obtain Formula V compound.
34. the method for claim 33, wherein, step 2) be carried out as follows, in the presence of nitrogen, by formula IV compound, HXCH2COY ' and anhydrous pyridine, in absolute methanol, react 48h at 90 DEG C, obtain Formula V compound.
35. the method for any one of claim 28 to 30, wherein, step 3) it is carried out as follows, in the presence of an inert gas, by formula V compounds and acid and its reactant salt, obtain Formula IV compound.
36. the method for claim 28, wherein, step 3) it is carried out as follows, in the presence of nitrogen, by Formula V compound and ammonium acetate With glacial acetic acid reaction, Formula IV compound is obtained.
37. the method for any one of claim 28 to 30, wherein, step 4) it is carried out as follows, in the presence of a catalyst, organic In solvent, in 45 atmospheric pressure, by Formula IV hydrogenation of compounds, Formula VII compound is obtained.
38. the method for claim 37, wherein, step 4) it is carried out as follows, in the presence of 10% Pd-C, in ethyl acetate, In 45 atmospheric pressure, by Formula IV hydrogenation of compounds, Formula VII compound is obtained.
39. the method for any one of claim 28 to 30, wherein, step 5) it is carried out as follows, by Formula VII compound and hydroxide Sodium, in ethanol, water and/or tetrahydrofuran, in room temperature reaction 5h, obtains formula (I) compound, it has the structure of Formula VIII.
40. the method for claim 30, wherein,
Described method and step 9) it is carried out as follows：In the presence of an inert gas, it is anti-in room temperature in DMF in the presence of triethylamine Answer 5min, by Formula VIII compound withReaction, obtains Formula X III compounds.
41. the method for claim 40, wherein,
Described method and step 9) it is carried out as follows：In the presence of nitrogen, in the presence of triethylamine, in DMF, in room temperature reaction 5min, by Formula VIII compound withReaction, obtains Formula X III compounds.
42. a kind of pharmaceutical composition, wherein any one of claim 1 to 27 containing therapeutically effective amount indole derivatives, Its stereoisomer or their officinal salt, and one or more pharmaceutically acceptable carriers.
43. indole derivatives, its stereoisomer or their officinal salt are in system as described in any one of claim 1 to 27 Application in standby antibacterials.
44. application as claimed in claim 43, wherein the antibacterials are anti-bacillus or gram- bacteria medicine.
45. application as claimed in claim 43, wherein the antibacterials are anti-mycobacterium tuberculosis or Gram-negative bacteria or leather Lan Shi positive bacteria medicines.
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